New Drug Updates in Hematologic Malignancies: CAR T Cells, Targeted Therapeutics, and Other Agents

R. Donald Harvey, PharmD, BCOP, FCCP, FHOPA Associate Professor, Hematology/Medical Oncology and Pharmacology Director, Phase I Clinical Trials Section Emory University and Winship Cancer Institute Learning Objectives

1. Discuss the pharmacology and indications of medications approved from late 2016 to 2017 for the management of patients with hematologic cancers 2. Recall the pivotal clinical trial data considered by the FDA when approving new oncologic agents 3. Identify the signs and symptoms of serious or life-threatening adverse effects of newly approved oncology drugs 4. Describe the impact of these agents in advanced practice Financial Disclosure

Dr. Harvey has received research funding from BMS, and is a consultant to Amgen, BMS, and Takeda. New Agents/Approvals in Hematologic Cancers • (April 2017) • SC with hyaluronidase (June 2017) • (August 2017) • (August 2017) • Liposomal daunorubicin and cytarabine (August 2017) • (August 2017) • Tisagenlecleucel (August 2017) • (September 2017) • Copanlisib (September 2017)

US Food and Drug Administration, Hematology/Oncology (Cancer) approvals & Safety Notifications, http://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm279174.htm. Additional Approvals

• Lenalidomide (February 2017) • Myeloma: maintenance post-autologous transplant beginning after day +90 • Dose 10 mg PO daily, may be increased to 15 mg after 3 cycles as tolerated • (March 2017) • Classical Hodgkin after 3 or more lines, adult (200 mg) and pediatrics (2 mg/kg) • JAK2 testing (March 2017) • Approved PCR testing for mutations associated with polycythemia vera

PCR = polymerase chain reaction; PO = by mouth.

US Food and Drug Administration, Hematology/Oncology (Cancer) approvals & Safety Notifications, http://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm279174.htm. Additional Approvals

• Betrixaban (June 2017) • VTE prophylaxis in medically ill patients • Dosing: 160 mg PO day 1, then 80 mg PO daily for 35-42 days with food • L-glutamine oral powder (March 2017) • Reduction of acute complications in sickle cell disease in adult and pediatric patients • 10-30 grams PO (weight based) twice daily mixed with liquid in patients receiving hydroxyurea • (July 2017) • Expansion to include Philadelphia+ ALL

ALL = acute lymphoblastic ; VTE = venous thromboembolism.

US Food and Drug Administration, Hematology/Oncology (Cancer) approvals & Safety Notifications, http://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm279174.htm. Additional Approvals

• Ibrutinib (August 2017) • First agent approved for chronic graft-versus-host disease following allogeneic stem cell transplant • Dose: 420 mg PO daily • Trial in 42 patients who failed corticosteroids • Overall response rate 67% • Median time to response 12.3 weeks (range, 4.1-42.1 weeks) • Activity seen in all involved organs

US Food and Drug Administration, Hematology/Oncology (Cancer) approvals & Safety Notifications, http://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm279174.htm. Midostaurin: FLT3-Positive AML April 28, 2017 FLT3 and AML

• Type III transmembrane • Same family as KIT, PDGFR-�/β • Highly expressed on hematopoietic progenitors and required for myeloid differentiation • Mutations in the FLT3 gene cause constitutive activation of the receptor • Most common mutation is the ITD

AML = acute myeloid leukemia; FLT3 = FMS-like tyrosine kinase 3; ITD = internal tandem duplication; PDGFR = platelet-derived growth factor receptor.

Fathi AT, et al. Eur J Haematol 2017;98:330-6. Midostaurin

• Mechanism: small molecule that inhibits wild-type FLT3, FLT3 mutant kinases (ITD and TKD), KIT (wild-type and D816V-mutant), PDGFRα/β, VEGFR2, as well as members of the serine/threonine kinase PKC family • Indication: Newly diagnosed AML that is FLT3 mutation-positive as detected by an FDA-approved test, in combination with standard cytarabine and daunorubicin induction and cytarabine consolidation

FDA = US Food and Drug Administration; PKC = protein kinase C; TKD = tyrosine kinase domain; VEGFR2 = vascular endothelial growth factor receptor 2.

Novartis 2017. Rydapt (midostaurin) product information. https://www.pharma.us.novartis.com/sites/www.pharma.us.novartis.com/files/rydapt.pdf. Midostaurin

• Dose: 50 mg PO BID with food (for nausea prevention) on days 8-21 of induction and consolidation ; for maintenance, continuous post-consolidation dosing • Prophylactic antiemetics needed (e.g., ondansetron) • No change for mild or moderate renal or hepatic function, no data in severe dysfunction • Hold for • Pneumonitis without infectious etiology

Midostaurin product information. 2017. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/207997s000lbl.pdf Midostaurin

• Warnings and precautions • Embryo-fetal toxicity: may cause fetal harm when administered to a pregnant woman; advise of the potential risk to a fetus • Pulmonary toxicity: monitor for symptoms of interstitial lung disease or pneumonitis; discontinue in patients with signs or symptoms of pulmonary toxicity • Try to avoid strong CYP3A inhibitors (e.g., posaconazole, voriconazole) and inducers • Most pronounced effects early in therapy • Common adverse events (> 20%): febrile , nausea, mucositis, vomiting, headache, petechiae, musculoskeletal pain, epistaxis, device-related infection, hyperglycemia, and upper respiratory tract infections • Grade 3/4 adverse reactions (> 10%): febrile neutropenia, device-related infection, and mucositis

Midostaurin product information. 2017. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/207997s000lbl.pdf Midostaurin Phase III Clinical Trial

Midostaurin product information. 2017. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/207997s000lbl.pdf Midostaurin Phase III Clinical Trial

Midostaurin product information. 2017. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/207997s000lbl.pdf Rituximab SC With Hyaluronidase

June 22, 2017 Hyaluronidase and Subcutaneous Tissue • Hyaluronan (hyaluronic acid) • Carbohydrate polymer that forms an extracellular matrix in subcutaneous tissue • Forms tight junctions and barriers to interstitial fluid flow • Hyaluronidase • Cleaves hyaluronan through depolymerization • Allows for large volume injections and systemic absorption

SC = subcutaneously. www.halozyme.com. Rituximab SC with Hyaluronidase

• Mechanism: hyaluronidase (an endoglycosidase) cleaves hyaluronan; anti-CD20 monoclonal antibody • Indications: newly diagnosed diffuse large B-cell lymphoma with CHOP, chronic lymphocytic leukemia with FC, single agent or with chemotherapy • Key points • Patients must have had at least one prior rituximab IV infusion • Not indicated for non-malignant disorders

CHOP = cyclophosphamide, doxorubicin, vincristine, prednisone; FC = fludarabine, cyclophosphamide.

Rituximab and hyaluronidase product information. 2017. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/761064s000lbl.pdf. Rituximab SC with Hyaluronidase

• Dosing: premedicate with acetaminophen and antihistamine (and corticosteroid) • Inject into abdomen • FL/DLBCL: 1,400 mg/23,400 Units (1,400 mg rituximab and 23,400 Units hyaluronidase) – 11.7 mL over approx. 5 minutes • CLL: 1,600 mg/26,800 Units (1,600 mg rituximab and 26,800 Units hyaluronidase) – 13.4 mL over approx. 7 minutes • Observe 15 minutes following administration

CLL = chronic lymphocytic leukemia; DLBCL = diffuse large B-cell lymphoma; FC = follicular lymphoma.

Rituximab and hyaluronidase product information. 2017. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/761064s000lbl.pdf. Rituximab SC with Hyaluronidase

• Warnings and precautions • Hypersensitivity and local administration reactions • • Infections • Hepatitis B reactivation • Common adverse events (> 20%): infections, neutropenia, nausea, injection site erythema • Grade 3/4 adverse reactions (≥ 10%): neutropenia

Rituximab and hyaluronidase product information. 2017. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/761064s000lbl.pdf. Rituximab SC with Hyaluronidase: DLBCL

Rituximab and hyaluronidase product information. 2017. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/761064s000lbl.pdf. Enasidenib

August 1, 2017 IDH Mutations in AML

• Occur in 20% of cases • IDH2 – 8-18% of all patients • Increased prevalence as age increases • Present at diagnosis, not progression • Impacts cellular metabolism • Also important in gliomas and cholangiocarcinomas

IDH = isocitrate dehydrogenase.

Chou WC, et al. Leukemia 2011;25:246-53; Patel JP, et al. N Engl J Med 2012;366:1079-89. Enasidenib

• Mechanism: IDH2 inhibitor • Indications: adult patients with relapsed or refractory AML with an IDH2 mutation as detected by an FDA-approved test • Abbott RealTime™ IDH2 PCR assay • Dosing: 100 mg PO once daily continuously • No significant interactions (food, antacids, other agents)

Enasidenib product information. 2017. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/209606s000lbl.pdf. Enasidenib

• Warnings and precautions • Tumor lysis syndrome • Differentiation syndrome • Similar to that seen with arsenic trioxide, all-trans-retinoic acid in promyelocytic leukemia • Treat with hemodynamic monitoring and support, corticosteroids • Leukocytosis • May initiate hydroxyurea until WBC < 30,000/mm3 • Bilirubin elevation > 3 x ULN • Reduce dose to 50 mg; may resume 100 mg if resolution to 2 x ULN or lower • Common adverse events (> 20%): nausea, vomiting, diarrhea, elevated bilirubin, decreased appetite • Grade 3/4 adverse reactions (> 5 %): nausea, diarrhea, tumor lysis syndrome, differentiation syndrome, leukocytosis

ULN = upper limit of normal; WBC = white blood cell.

Enasidenib product information. 2017. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/209606s000lbl.pdf. Enasidenib

Enasidenib product information. 2017. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/209606s000lbl.pdf. Liposomal Daunorubicin and Cytarabine August 3, 2017 Liposomal Daunorubicin and Cytarabine

• Indications: adults with newly diagnosed therapy-related acute myeloid leukemia (t-AML) or AML with myelodysplasia-related changes (AML-MRC) • This is not your grandmother’s 7 + 3 • Liposomal cholesterol membrane of cytarabine and daunorubicin in a 5:1 molar ratio • Dosing: induction: daunorubicin 44 mg/m2 and cytarabine 100 mg/m2; liposome over 90 minutes on days 1, 3, and 5 and on days 1 and 3 for subsequent cycles of induction, if needed • Consolidation: daunorubicin 29 mg/m2 and cytarabine 65 mg/m2 liposome over 90 minutes on days 1 and 3

AML-MRC = AML with myelodysplasia-related changes; t-AML = therapy-related AML.

Daunorubicin and cytarabine liposomal product information. 2017. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/209401s000lbl.pdf. Liposomal Daunorubicin and Cytarabine

• Warnings and precautions • Same as those with 7 + 3 • Cardiotoxicity, cytopenias, extravasation (daunorubicin) • Common adverse events (> 25%): hemorrhage, febrile neutropenia, rash, , nausea, mucositis, diarrhea, constipation, musculoskeletal pain, fatigue, abdominal pain, dyspnea, headache, cough, decreased appetite, arrhythmia, , bacteremia, chills, sleep disorders, and vomiting • Grade 3/4 adverse reactions (≥ 10 %): febrile neutropenia, dyspnea, pneumonia, bacteremia, hypoxia

Daunorubicin and cytarabine liposomal product information. 2017. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/209401s000lbl.pdf. Liposomal Daunorubicin and Cytarabine

Daunorubicin and cytarabine liposomal product information. 2017. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/209401s000lbl.pdf. Inotuzumab Ozogamicin August 17, 2017 Inotuzumab Ozogamicin Tumor cell

• Antibody-chemotherapy complex internalized into tumor cells upon Nucleus binding to CD22 on cell surface • Cytotoxin calicheamicin is released from the complex inside the tumor cell Internalization Calicheamicin binds to • More potent than other cytotoxic DNA chemotherapeutic agents • Calicheamicin binds to DNA, inducing double-stranded DNA breaks CD22 • DNA break development followed by of the tumor cell Inotuzumab ozogamicin

Jabbour E, et al. ASH 2014. Abstract 794. Inotuzumab Ozogamicin

• Mechanism: anti-CD22 monoclonal antibody-drug conjugate with calicheamicin • Indications: adults with relapsed or refractory B-cell precursor ALL • Dosing • Premedicate with corticosteroid, acetaminophen, diphenhydramine

Inotuzumab ozogamicin product information. 2017. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/761040s000lbl.pdf. Inotuzumab Ozogamicin

• Warnings and precautions • Hepatotoxicity/VOD or sinusoidal obstruction syndrome and increased risk of post-stem cell transplant non-relapse mortality • Myelosuppression • Infusion reactions • QT prolongation • Common adverse events (> 20%): thrombocytopenia, neutropenia, infection, anemia, fatigue, hemorrhage, pyrexia, nausea, headache, febrile neutropenia, increased ALT, GGT, bilirubin, abdominal pain • Grade 3/4 adverse reactions (≥ 20 %): thrombocytopenia, neutropenia, infection, anemia, febrile neutropenia

ALT = alanine aminotransferase; GGT = gamma-glutamyl transferase; VOD = veno-occlusive disease.

Inotuzumab ozogamicin product information. 2017. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/761040s000lbl.pdf. Phase III Trial of Inotuzumab Ozogamicin in Relapsed/Refractory CD22+ ALL • Multicenter, randomized, open-label phase III study • Primary endpoints: CR and OS

Inotuzumab ozogamicin Starting dose 1.8 mg/m2/cycle (0.8 mg/m2 on Day 1; 0.5 Patients with relapsed or mg/m2 on Days 8, 15 of a 21-28 day cycle) for up to 6 cycles refractory CD22+ ALL due for Stratified by duration of first remission (≥ 12 vs. < 12 months), salvage (2 vs. 1), age (≥ 55 vs. < 55 years) salvage therapy (Ph- or Ph+) (N = 326) Standard of Care FLAG or Ara-C + mitoxantrone or HiDAC

Inotuzumab dose reduced to 1.5 mg/m2/cycle once patient achieves CR/Cri. CR = complete remission; CRi = complete remission with incomplete blood count recovery; OS = overall survival.

ClinicalTrials.gov. NCT01564784. Inotuzumab Ozogamicin

Inotuzumab ozogamicin product information. 2017. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/761040s000lbl.pdf. Tisagenlecleucel: CAR T-Cell Therapeutics August 30, 2017 CAR T-Cell Derivation

CAR = chimeric antigen receptor.

Barrett DM, et al. Annu Rev Med 2014;65:333-47. CAR T Cells After Infusion

1. T cells traffic to site of disease 2. T cells accumulate at the site of disease by a combination of trafficking and proliferation 3. T cells recognize their cognate target and are activated 4. Leads to induction of effector functions 5. T cells must avoid inhibitor and suppressive signals from the target cells, regulatory immune cells, and the tumor microenvironment 6. T cells must persist until elimination of the tumor

Gill S, et al. Transl Res 2013;161:365-79. CAR T Cells for B-Cell Malignancies

• First investigated at City of Hope and Fred Hutchinson in 2008 • July 1, 2014, FDA granted breakthrough therapy to CTL019 • Anti-CD19 CAR T developed at U Penn for patients with high-risk B-cell malignancies • On August 30, 2017, FDA granted regular approval to tisagenlecleucel for the treatment of patients up to age 25 years with B-cell precursor ALL that is refractory or in second or later relapse • Approval based on single-arm trial of 63 patients with relapsed or refractory pediatric precursor B-cell ALL, including 35 patients who had a prior hematopoietic stem cell transplantation • Overall remission rate was 82.5%, consisting of 63% of patients with CR and 19% with CRi

US Food and Drug Administration, FDA approval brings first gene therapy to the United States, August 30, 2017. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm574058.htm. Tisagenlecleucel • Mechanism: CD19-directed genetically modified autologous T-cell immunotherapy • Indications: patients up to 25 years of age with B-cell precursor ALL that is refractory or in second or later relapse • Dosing • One treatment course consists of fludarabine and cyclophosphamide lymphodepleting chemotherapy followed by infusion of CAR-positive T cells in the product • Lymphodepleting chemotherapy: fludarabine (30 mg/m2daily for 4 days) and cyclophosphamide (500 mg/m2 daily for 2 days starting with the first dose of fludarabine) • Infuse tisagenlecleucel 2 to 14 days after completion of the lymphodepleting chemotherapy • Verify the patient’s identity prior to infusion • Premedicate with acetaminophen and diphenhydramine • Confirm availability of tocilizumab prior to infusion • Dosing is based on the number of CAR-positive viable T cells • For patients 50 kg or less, administer 0.2 to 5.0 x 106 CAR-positive viable T cells • For patients above 50 kg, administer 0.1 to 2.5 x 108 total CAR-positive viable T cells (non-weight based)

Tisagenlecleucel product information. 2017. https://www.fda.gov/downloads/BiologicsBloodVaccines/CellularGeneTherapyProducts/ApprovedProducts/UCM573941.pdf. Tisagenlecleucel • Warnings and precautions • Hypersensitivity reactions • Serious infections • Prolonged cytopenias: patients may exhibit cytopenias for several weeks • Hypogammaglobulinemia: monitor and provide replacement therapy until resolution • Secondary malignancies • Effects on ability to drive and use machines • Common adverse events (> 20%): cytokine release syndrome, hypogammaglobulinemia, infections-pathogen unspecified, pyrexia, decreased appetite, headache, encephalopathy, hypotension, bleeding episodes, tachycardia, nausea, diarrhea, vomiting, viral infectious disorders, hypoxia, fatigue, acute kidney injury, and delirium • Grade 3/4 adverse reactions (≥ 10 %): pyrexia, cytokine release syndrome, infections (viral, bacterial), anorexia, encephalopathy, acute kidney injury, hypoxia, pulmonary edema, hypotension, increased AST/ALT/bilirubin, hypokalemia, hypophosphatemia

AST = aspartate transaminase.

Tisagenlecleucel product information. 2017. https://www.fda.gov/downloads/BiologicsBloodVaccines/CellularGeneTherapyProducts/ApprovedProducts/UCM573941.pdf. Tisagenlecleucel

• N = 107 patients screened, 88 enrolled, 68 treated, 63 evaluable for efficacy • Of n = 63 • 35 males • Median age 12 years (3-23) • 53 received bridging chemotherapy • 30 had one prior allogeneic BMT, 2 had two

BMT = bone marrow transplantation.

Tisagenlecleucel product information. 2017. https://www.fda.gov/downloads/BiologicsBloodVaccines/CellularGeneTherapyProducts/ApprovedProducts/UCM573941.pdf; US Food and Drug Administration, https://www.fda.gov/biologicsbloodvaccines/cellulargenetherapyproducts/approvedproducts/ucm573706.htm. Gemtuzumab Ozogamicin September 1, 2017 Gemtuzumab Ozogamicin • Mechanism: anti-CD33 monoclonal antibody-drug conjugate with calicheamicin • Indications: treatment of newly diagnosed CD33-positive AML in adults and treatment of relapsed or refractory CD33-positive AML in adults and in pediatric patients 2 years and older • Dosing • Premedicate with corticosteroid, acetaminophen, diphenhydramine • Newly diagnosed, de novo AML (combination regimen) • Induction: 3 mg/m2 (up to one 4.5-mg vial) on days 1, 4, and 7 in combination with daunorubicin and cytarabine • Consolidation: 3 mg/m2 on day 1 (up to one 4.5-mg vial) in combination with daunorubicin and cytarabine • Newly diagnosed AML (single-agent regimen) • Induction: 6 mg/m2 on day 1 and 3 mg/m2 on day 8 • Continuation: For patients without evidence of disease progression following induction, up to 8 continuation courses of 2 mg/m2 day 1 every 4 weeks • Relapsed or refractory AML (single-agent regimen) • 3 mg/m2 on days 1, 4, 7

Gemtuzumab ozogamicin product information. 2017. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/761060lbl.pdf. Gemtuzumab Ozogamicin

• Warnings and precautions • Hepatotoxicity, including severe or fatal hepatic VOD, aka SOS • Infusion-related reactions (including anaphylaxis); monitor patients during and for at least 1 hour after the end of the infusion; interrupt the infusion, administer steroids or antihistamines, or permanently discontinue treatment as necessary • Hemorrhage: severe, including fatal, hemorrhage may occur at recommended doses; monitor platelet counts frequently • Common adverse events (> 15%): hemorrhage, infection, fever, nausea, vomiting, constipation, headache, increased AST, increased ALT, rash, and mucositis • Grade 3/4 adverse reactions (≥ 20%): fatigue, thrombocytopenia, neutropenia, infection, anemia, febrile neutropenia

SOS = sinusoidal obstruction syndrome.

Gemtuzumab ozogamicin product information. 2017. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/761060lbl.pdf. Gemtuzumab Ozogamicin

Gemtuzumab ozogamicin product information. 2017. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/761060lbl.pdf. Copanlisib September 14, 2017 PI3K in Lymphoma • PI3K regulates • Proliferation • Differentiation • Trafficking • Four isoforms: α, β, γ, δ • Copanlisib • Inhibits PI3K-α and PI3K-δ isoforms • Induces apoptosis and inhibits proliferation of primary malignant B cells • Inhibits several key cell-signaling pathways, including BCR signaling, CXCR12 mediated chemotaxis of malignant B cells, and NFκB signaling in lymphoma cell lines

BCR = B-cell receptor; PI3K = phosphotidylinositol-3-kinase.

Cheah CY, et al. Blood 2016;128:331-6. Copanlisib

• Mechanism: PI3Kα and δ inhibitor • Indications: adult patients with relapsed FL who have received at least two prior systemic therapies (accelerated approval) • Dosing: 60 mg administered as a 1-hour IV infusion on days 1, 8, and 15 of a 28- day treatment cycle (3 weeks on, 1 week off) • Drug Interactions • Avoid concomitant use with strong CYP3A inducers • Strong CYP3A inhibitors: reduce dose to 45 mg

Copanlisib product information.2017. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/209936s000lbl.pdf. Copanlisib • Warnings and precautions • Infections: withhold treatment for grade 3 and higher infections until resolution • Hyperglycemia: start each infusion once optimal blood glucose control is achieved; withhold treatment, reduce dose, or discontinue treatment depending on the severity and persistence of hyperglycemia • : withhold treatment in patients until both the systolic less than 150 mmHg and the diastolic less than 90 mmHg; consider reducing dose if anti-hypertensive treatment is required; discontinue in patients with BP that is uncontrolled or with life-threatening consequences • NIP: treat NIP and reduce dose; discontinue treatment if grade 2 NIP recurs or in patients experiencing grade 3 or higher NIP • Neutropenia: monitor blood counts at least weekly while under treatment; withhold treatment until ANC ≥ 500 • Severe cutaneous reactions: withhold treatment, reduce dose, or discontinue treatment depending on the severity and persistence of severe cutaneous reactions • Common adverse events (> 20%): hyperglycemia, diarrhea, decreased general strength and energy, hypertension, , neutropenia, nausea, lower respiratory tract infections, thrombocytopenia ANC = absolute neutrophil count; BP = blood pressure; NIP = non-infectious pneumonitis.

Copanlisib product information.2017. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/209936s000lbl.pdf. Copanlisib

Copanlisib product information.2017. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/209936s000lbl.pdf. Conclusions

• A number of novel, first-in-class agents have been approved for the treatment and supportive care of patients with hematologic malignancies • Each agent has unique profiles and use criteria that should be reviewed prior to prescribing • Evolving safety and efficacy data, alone and in combinations, are expected over the coming months

New Drug Updates in Hematologic Malignancies: CAR T Cells, Targeted Therapeutics, and Other Agents R. Donald Harvey, PharmD, BCOP, FCCP, FHOPA Associate Professor, Hematology/Medical Oncology and Pharmacology Director, Phase I Clinical Trials Section, Emory University and Winship Cancer Institute, Atlanta, GA

INTRODUCER Welcome back, everyone. I hope you were able to enjoy the break and got to visit with some of the exhibitors. As a gentle reminder, please be sure to silence your cell phones for our next session. This next session is the presentation of the “New Drug Updates in Hematologic Malignancies: CAR

T, Targeted Therapeutics, and Other Agents.” Please welcome back Dr. Donald

Harvey of the Winship Cancer Institute of Emory University.

DR. HARVEY Thanks, everybody. I want to thank the organizers for having me back. I think this is continuing to be a great meeting. I want to send a shout out to the organizers for the attendance. This is growing every year, and certainly I jokingly say with my work wife, Colleen, who is probably somewhere here, she and I are better together than any oncologist in our building because we know the drugs that we deal with and I think what we actually do a better job than they do, but since there are no oncologists in the room, I can get away with that.

It has been a pretty banner year for hematologic cancers in terms of approvals, and it’s not just the things that we commonly think about. I like to think of drug development and cancer in general as having two main drivers and one is personalized molecular small molecule therapies that we have that are there to really hone in on a population of patients, and then the other side is let’s go

1 www.transcriptionexperts.com immunotherapy and really try to teach the immune system in one way, shape or another to attack what should be foreign to the body and that’s cancer. The drugs that have been approved from last year to this year are absolutely indicative of those two major paradigms, and that’s what we’ll go through here.

We’ll talk about some pharmacology, how these drugs work, we’ll certainly talk about adverse events and clinical trial data, and in the end, I’ll try to contextualize a little bit about where these drugs may fit into therapy overall and then what populations will be best served to receive these agents. These are my disclosures. When you look at agents and approvals, you can see that there’s a list of drugs that are here and you have to put both of them in because those of you who remember the world of gemtuzumab ozogamicin know that it’s been actually around for a while. It was on the market and then pulled and then came back, so it’s certainly not a new agent. Similarly ibrutinib is not a new agent because it’s already out there, but it represents the first drug that’s been approved in a relatively difficult to treat population, those patients with steroid- refractory chronic graft-versus-host disease, and certainly rituximab we all know and love and there’s a new formulation that we’ll go through.

When you look at this list of drugs, again, you have sort of what I consider three main buckets. You have drugs that are very targeted for a population. As an example midostaurin for the FLT3-mutated AML population. You have the immunotherapy approaches, and so tisagenlecleucel—and there will be a quiz at the end to make sure you can say that word over and over in your sleep. And then finally a new formulation of drugs or a new way to deliver drugs, whether it

2 www.transcriptionexperts.com be with a targeted antibody targeted with a Trojan horse like ozogamicin, whether its inotuzumab or gemtuzumab ozogamicin or a new way to think about delivering conventional agents, and that’s liposomal daunorubicin and cytarabine.

There are additional approvals, and lenalidomide got the final approval for something that’s probably been happening in many of your centers for a while already and that’s maintenance treatment post-autologous stem cell transplant for patients with myeloma. I liken this approval to getting married after you’ve lived with somebody for a while; it was just going to happen eventually, it just took some time. Pembrolizumab is also in approval following on the heels of . Pembro got approval in Hodgkin’s lymphoma after nivolumab did as a flat dose, interestingly here compared to nivolumab, but it is also approved. Then

JAK2 testing for patients who are at potential risk for who you consider clinically who have polycythemia vera, so the FDA does approve tests as well.

Other agents that are in the heme space, but I’m not going to go into too much depth today on, one is another oral anticoagulant that directly targets factor

II, betrixaban, so VTE prophylaxis in medically ill patients is its approval and indication. There’s the dosing; you can see a fixed period of time post-discharge for patients who are medically ill. It’s other thing that patients may come in on. L- glutamine oral powder in sickle cell disease, and so we’ve had hydroxyurea for a while. In sickle cell, L-glutamine at doses of 10 to 30 gm that are weight-based twice daily with liquid for adult and pediatric patients has shown to reduce the complications of acute crises. Then finally blinatumomab originally was approved for –negative ALL and they’ve just tacked on with data

3 www.transcriptionexperts.com for the positive population. I did want to cover ibrutinib a little bit. Again, the first drug approved in a space that has been studied for decades in an incredibly difficult population of chronic graft-versus-host disease. This is approved in patients who have failed corticosteroids, which those of you who are in allogeneic transplant settings, you’ll know that after that steroid failure, there’s about a 30- drug different menu you can pick from, and it kind of depends on where you practice what your next go-to drug is—420 mg daily, the same dose as it’s other indications. The trial was done in 42 subjects who failed steroids and two-thirds of patients responded.

Chronic graft-versus-host disease does have a very well-defined response criteria across all organs, liver, skin, GI tract, etc., are all part of the categorization of responses. Median time can be a little bit long, and so it can take 12 weeks for patients to respond. That’s median; some are early or some are much later. The bottom line is don’t give up early on ibrutinib in patients who are getting it with chronic graft-versus-host disease. Let’s move into the approvals. Midostaurin has been around for a little while and we’ll talk about

FLT3-positive acute leukemia and where midostaurin fits in. So FLT3 and AML.

FLT3 is a transmembrane receptor, so it’s kind of akin to a few other receptors that are out there. It’s in the same tyrosine kinase family as the KIT receptor and

PDGFR. So you might remember that was originally developed as a

PDGFR antagonist and was found to have much more activity in the BCR-ABL activated structures, but this is the same type of tyrosine kinases as that. It’s high expressed on early progenitors and hematopoietic cells and so you can imagine

4 www.transcriptionexperts.com then that if it’s highly expressed, the FLT3 is highly expressed and you’re going to have potentially additional cytopenias that would be seen with inhibition of an activated mutation.

You can also think about FLT3 a little bit like EGFR in lung cancer. It has to be activated to be constitutively important. It can be there, but it has to be turned on and it’s turned on through mutational structures. The most common mutations seen is called the internal tandem duplication; it’s basically a light switch that turns on the receptor to drive proliferation of the leukemic clone. This is the mechanism that inhibits lots of things, but most importantly it inhibits mutated FLT3 and that’s how it works. It’s approved for newly diagnosed acute . As we go through a number of these drugs today, you’ll see that there are a couple that are approved by the newly diagnosed and many others that are approved in the refractory and relapse setting following acute leukemia.

7+3 isn’t dead yet, hopefully it will be soon, but it’s still there and is still a backbone for many of our therapies in acute myeloid leukemia. It’s approved in combination with a test, an FDA-approved test, and generally lots of molecular panels will have FLT3 mutation detection and I don’t suspect that there will be a problem overall with, once you identify that mutation, getting a drug approved and paid for.

Standard cytarabine and daunorubicin, and you may ask what if we use idarubicin; it really doesn’t matter and so we’ll talk about that a little bit and I’ll tell you why it doesn’t matter. This is the dose, 50 mg twice a day with food. Take it with food not for concerns of absorption or , but rather for

5 www.transcriptionexperts.com nausea prevention. Midostaurin has its own set of emetic potential, so it’s important that patients take it with food as they can. You’ll see the start date as well, so 7+3, the 7 is the week of continuous infusion cytarabine and you want to start midostaurin the day after that completes, and that’s because of a potential interaction with daunorubicin, but also because you are trying to mop up the

FLT3-positive leukemic clones. You do need prophylactic antiemetics because of the rates of nausea and vomiting seen. You don’t need to change the dose in mild to moderate renal or hepatic dysfunction. If you have severe dysfunction, there’s no data, but if a patient has severe dysfunction you should probably be asking yourself do you need to treat them anyway.

You need to hold for pneumonitis, which can be seen. And you’ll find a common theme among a lot of small molecule tyrosine kinase inhibitors and some that are going to be presented today and that’s that there can be a noninfectious pneumonitis that occurs, and this is true of in lung cancer, it’s true of in many cancers as well. You can see in a certain proportion of patients a pneumonitis that is noninfectious, it’s generally pretty straightforward to see on radiograph, but the drug does need to be held should that pneumonitis occur. These are the warnings; I’m not going to go into them too much because we’ve already talked about it. One key clinical point is that midostaurin is a CYP3A4 substrate, and you can imagine that it becomes a bit challenging when you give drugs like the azoles like posa and vori specifically in acute leukemia antifungal prophylaxis. Because they are potent inhibitors at 3A4 and so optimally you want to try to avoid their use with midostaurin.

6 www.transcriptionexperts.com Now carry that a few steps forward. So what are you going to do? So the caspofungin world, the micafungin world are certainly safe to use, but they are intravenous and so there are still evolving data on how to think about azoles and midostaurin. Optimally avoiding those azoles is the best scenario if you can set up intravenous if patients need echinocandins, but it may be that you are going to take a little bit of a risk. At Emory we have begun to take a little bit of a risk, with that meaning we’ll put people on azoles, put them on midostaurin, and follow them closely because we’ll talk about some of the adverse events. Most of the adverse events you are going to see are adverse events that are common in patients getting induction and consolidation chemotherapy for leukemia, and so midostaurin doesn’t add a whole lot to this outside of that pneumonitis concern.

Most of this stuff, mucositis, neutropenia, and that’s leukemia, right, for those of you who work in it, you are going to see that’s garden variety kinds of stuff.

This was the trial that led to its approval, newly diagnosed AML with activating FLT3 mutations, and they were stratified by tyrosine kinase domain and internal tandem duplication ratios up front. So 717 patients, a large study,

28-day cycles, and they got this is where the world of acute leukemia is, but cytarabine 200, 100 is fine, there’s been no difference in 100 versus 200 for the development of this drug, though they elected to go with 200/m2 daily of cytarabine and, at the time, standard dose daunorubicin of 16. All of that is there and then you complete those agents and then move on to midostaurin and the induction or placebo on the other side. You can see midostaurin is carried through all the way for consolidation and post-consolidation. Now post-

7 www.transcriptionexperts.com consolidation is a bit of a tricky story because post-consolidation is truly that. You can elect to give high-dose ara-C in however many consolidation cycles that are standard for your institution.

In this trial, it was allowed to go up to four cycles of HiDAC, but once you complete your planned consolidation, then there’s this post=consolidation world, but it’s not maintenance but it kind of is maintenance, and so basically continue midostaurin as long as you can and don’t call it maintenance. That’s really confusing, I’m sure, but that’s the way the labeling and the regulatory language goes. What happened when they did this? Well, there was a survival advantage,

So it’s important to think about clinical trial endpoints overall. And oftentimes in solid tumor malignancies as well as some myeloma trials, you see progression- free survival as a clinical endpoint. What we are going to see today in a number of incidences is overall survival improvement, so this is an overall survival improvement with midostaurin in FLT3-mutated disease. That’s an important point. You might argue the significance of the overall survival difference, but it is an overall survival difference, thus it has become standard of care for FLT3- mutated patients to receive midostaurin in combination with conventional chemotherapy. So midostaurin, yes.

Now we are going to move on, and I went sequentially based on the approvals through the years. We are going to bounce around between lymphoma, leukemia, and others. Rituximab subcu with a hyaluronidase. As a reminder, there is a reason you can only give so much volume in a subcutaneous injection and that’s because of a protein in the subcutaneous tissue called

8 www.transcriptionexperts.com hyaluronan. Hyaluronan, think about it as a net, a fishing net, with a lot of tight junctions that are there. Hyaluronidase, back to you biochemistry, dases or enzymes, and they cleave stuff, so hyaluronidase is basically scissors for the net.

It opens up the subcutaneous tissue, and that allows for the injection of larger volumes of drugs. This is already approved in IVIG therapy, so it allows for injection of larger volumes of drugs into the subcutaneous space.

Why would you want to do that? Well, it’s actually more convenient. When you look at IVIG therapies, patients who get IVIG for immunodeficiencies actually can do this at home; it’s a little more straightforward than starting an IV. So hyaluronan is part of that; it’s cleaved by hyaluronidase, and hyaluronidase is manufactured by a company called Halozyme and it’s being added to a number of drugs including IVIG and now rituximab for allowing subcutaneous administration. So again, it’s both the hyaluronidase plus rituximab within the drug, and it’s got the same indications that rituximab has in cancer. Not for nonmalignant disorders, so your ITP patient is not a candidate for this therapy, at least not if you want to get it paid for or you want to give it away, the agents that are there. An important point clinically although this is a little bit unfortunate, but very understandable from a safety perspective, patients have to have had one intravenous infusion of rituximab before they can begin this subcutaneous approach.

The reason is if you think about it much like , CD20 expression and the number of CD20 cells in patients getting rituximab for the first time is up here. You give them rituximab with their chemotherapy backbone and

9 www.transcriptionexperts.com that CD20 population comes down, and that’s what mediates the infusion reactions is the presence and the bulk of CD20 that’s out there. So once you get that population down, you are then able to give the drug with much more safety involved. Premedications are the same, you inject it into the abdomen. The dosing that’s here is important, that’s different based on follicular lymphoma much like, again, the standard indications or CLL. It’s a flat dose of rituximab at

1,400 for and 1,600 for chronic lymphocytic leukemia, and it’s with ahead of time this 23,000 or 26,000 approximately units of hyaluronidase. So again, the hyaluronidase goes in, you inject it over approximately 5 minutes and it’s a dose-dependent injection and it’s about 12 mL or 13 mL based on indication, and then you give the rituximab. You are there to provide both of those in a way that you are opening up the space and then giving the drug following, and then you can watch them for 15 minutes, which is very different from our usual rituximab experience and say, “Bye,” and they go home.

These are the things to think about: the standard adverse events that are seen with rituximab are certainly there as well and the common adverse events are somewhat similar as well. Again, these are things that are not new based on the route of delivery. This is the data that’s supported its approval. This is a 2:1 randomization of standard rituximab with CHOP chemotherapy versus the subcutaneous formulation, again 2:1 randomization. Response rates were similar in that predefined criteria, and the difference in response rate was slightly numerically better with subcutaneous, but overall really not different than standard rituximab. This provides an option for patients and institutions that want

10 www.transcriptionexperts.com to give rituximab a little more quickly in subsequent treatment following the first

IV dose.

Moving on to enasidenib. This is like Hooked on Phonics day. So IDH mutations. IDH is isocyanine dehydrogenase; it’s an enzyme that’s present in a lot of different cancers. Most importantly from a drug perspective, it’s present in acute myeloid leukemia. It’s also important in cholangiocarcinomas as well as brain tumors and gliomas. The challenge there is you can’t get drugs to cross the blood-brain barrier. It’s present in about 20% of all AML cases, and it’s there at the beginning. We think about mutations often and think about T790M in different places and T315I in CML, and those are mutations that evolve after treatment.

IDH mutations are present at diagnosis, and so this drug is likely to move up in terms of where it is in its clinical use right now, but it certainly is more common in the elderly population and elderly AML certainly is a large proportion of the patients that are seen. IDH really regulates cellular metabolic fate, so it turns over a number of endogenous cellular products, and if you inhibit it, then the cell can’t get rid of those endogenous products and then is marked for apoptosis.

It’s an IDH2 inhibitor and it’s approved for patients with relapsed or refractory disease, so not an up-front therapy as of today. With the IDH2 mutation, that was identified by an FDA-approved test, the Abbott RealTime

IDH2 PCR assay was approved in conjunction with this drug. There are likely others, much like PD-L1 testing that you’ll find and other common molecular companion diagnostics that will evolve in this space as well. 100 mg once a day continuously, so that’s dosing that’s relatively straightforward for that and there

11 www.transcriptionexperts.com really aren’t significant interactions. Because this drug is a very in acute leukemia, you can see a number of adverse events that are akin to differentiation syndrome, tumor lysis, for example in acute promyelocytic leukemia, and it basically teaches these cells to grow up more quickly and become productive members of the cell society. And when that happens, they can then transform and traffic into different places in the body, the lungs for example, again those of you who treat patients with acute promyelocytic leukemia know that differentiation syndrome can be challenging and can be a problem in patients with those diseases.

If you start to monitor these patients early and often and their white counts start to skyrocket, they need to be placed on good dose hydroxyurea, not weenie dose hydroxyurea, so a gram three times a day or so at least 3 to 4 gm a day of hydroxyurea should be considered. It can cause hyperbilirubinemia as well, so doses do need to be adjusted secondary to that on-target drug effect of bilirubin elevation. These are some of the adverse events: nausea, vomiting, diarrhea, so again antiemetics may be important, on-demand loperamide or other antidiarrheals need to be there as well, and all those tumor lysis syndrome watching events need to happen too. Because this is such as small number of patients within the trial or at least this is more of an orphan kind of disease, the drug was developed and delivered based on some phase I trials of dose escalation that were done early on and then the drug was moved into an expansion phase, and so from these relatively small numbers of patients initially, it moved into a phase II trial with a dose defined as 100 mg daily in the relapsed

12 www.transcriptionexperts.com and refractory setting. And the testing was done centrally to confirm IDH2 within that space.

Again, these are patients with relapsed/refractory disease with this mutation, so the complete response rates are in about the 15 to 17% range overall, and the 95% confidence interval you can see here with a duration of response of about 6 months and so certainly it’s a challenging population, but

IDH2 tends to be in the elderly, so you may have patients that you don’t want to necessarily reinduce with a different regimen, for example, etoposide, mitoxantrone you might pick for a younger population; however, if an elderly patient is more likely to have IDH2 mutations and cannot tolerate another induction regimen, then you might want to consider this with careful monitoring for differentiation and tumor lysis syndrome. Liposomal daunorubicin and cytarabine.: this is a nice, new package, it’s a new way to deliver daunorubicin and cytarabine. I like to say that this is not your grandmother’s 7+3 because if you’ve been in acute leukemia 7+3 was used when our grandmothers were alive, it feels like. This is a drug and a combination of drugs that are sort of wrapped in micelles and cholesterol, so it is meant to try and deliver higher concentrations of the drug to the cells of interest, improve circulation time, and hopefully improve the therapeutic index of these drugs in difficult to treat patients. The approvals for this trial and the regulatory licensing trials were done in an incredibly difficult population and that’s therapy-related acute leukemia and those with MDS that have evolved into AML. So these are challenging patients to deal with, and this was a drug that was meant to come forward in that realm.

13 www.transcriptionexperts.com The dosing is different; talk to your local pharmacist about dosing with this drug. I want to thank whoever reviewed my slides for this because they told me that this drug is purple. I didn’t know that. I think that’s kind of cool. Daunorubicin is red certainly, but when you add them together in the same package it’s purple.

Who knew? The Barney induction. So it’s induction and consolidation dosing as options, and the indications for this are kind of—they are not all over the place, but there are lots of options for this compound to be used in various AML settings. And when you think about it, and there was a lot of thought, how will this toxicity be different? And how will it compare to 7+3? And we’ll go through that data, but in general it’s 7+3 in a different package. So the things that you need to worry about with 7+3 extravasation if it’s a peripheral IV, hopefully not, because it’s really not smart in acute leukemia, but extravasation is a concern, cardiotoxicity with anthracyclines, etc., and certainly cytopenias that we all know of and love in AML.

The common adverse events, again, are very much those that are seen in the acute leukemia population with a couple of important distinctions that we’ll go through. This is the data, this is a little bit of a busy slide, my apologies, but this data hasn’t been fully published, so this comes out of the product information.

You can see again here we have a difference in overall survival, an important endpoint for a difficult to treat population. Overall survival was improved with liposomal formulation compared to standard 7+3 with an improvement of about 3 and a half months comparatively. So it’s up to you and your institution and the

14 www.transcriptionexperts.com clinicians you work with to think about how you fit this in, but it is an approximately 3 and a half-month survival advantage with the new formulation.

The adverse events are quite similar, and you can see if you move to the grades 3 to 5, the ones that we think about as being most severe, they are really not different, but in the all grades category, there are a few that stand out. One is hemorrhage. Why people getting the liposomal formulation would hemorrhage more is a complete mystery to me. There might be come interactions with coagulation testing and coagulation parameters, but at least in terms of thrombocytopenia rates, they are really not that different between the two groups.

Similarly, there is a little more rash, which you might imagine with a new formulation of a drug, so about half of patients had some degree of a rash; generally it is self-limiting and not a problem overall, but it is more common. And similarly headache. Everything else in my eye is similar or better than 7+3, so at least in terms of adverse event profile, a couple stand out from the trials, but overall it’s pretty much similar to 7+3 overall.

We’ll move on to now what we call the Trojan horse category of drugs: inotuzumab ozogamicin. It was approved in August of 2017. This is the setup of inotuzumab: it’s a CD22 antibody linked to calicheamicin and similarly to gemtuzumab ozogamicin, it’s the same idea. The idea is that you bring the CD22

Trojan horse to the cell, it then releases its payload into the cell and then boom, the cell blows up or a few other things happen before that, but in general you are delivering a microtubule targeting agent to the cell and the cell dies. That’s how I explain it to my kids. So this drug is certainly labeled with calicheamicin, it’s ALL

15 www.transcriptionexperts.com and so there’s going to be—we have this drug in trial at Emory and we jokingly called it “lymphotarg,” which was not the real name by the way, and it looks very promising in a number of lymphomas, but ALL was where it came to market first, and adult ALL is certainly a challenging population of patients to treat, and so this came forward in the relapsed/refractory population. You might consider people who have failed hyper-CVAD or whatever cocktail of drugs you use in your shop for ALL treatment in the adult setting, and it does need premedication.

I won’t read the dosing here. Initially cycle 1 you want to try to get more drug in in a 21-day cycle; subsequent treatment is based on the presence or absence of a complete remission or a complete remission with incomplete hematologic recovery, that’s what CRi means. After that you can look at month cycles following that initial cycle. There are problems with these drugs. The ozogamicin side of these agents is hepatotoxic in certain instances; it’s hepatotoxic in people certainly who have had prior busulfan conditioning for autologous stem cell transplant and the reverse is true. If you get an ozogamicin- containing drug and then you get busulfan conditioning, your rate of VOD or SOS goes up. These are combined hepatotoxicity agents. There is some degree of QT prolongation, and it’s not that big of a deal to be honest, but it’s in the label. The adverse events that are here are things you would expect with a drug and a cytotoxic drug that’s mildly suppressive. Those are standard. LFTs need to be monitored carefully obviously for multiple reasons, but certainly the rest of these things are standard things we see in the population of interest.

16 www.transcriptionexperts.com This is the trial that got it onto market. CD22-positive ALL, Philadelphia positive or negative, 326 patients randomized to standard of care, which could have been dealer’s choice, one of three potential options, FLAG, fludarabine, cytarabine, and GCSF, ara-C, and mitoxantrone or just straight IDAC was compared, and these are the rates of CR within the two groups. Again, this is not an overall survival, but still an important rate of response, and complete remission was certainly improved in patients getting inotuzumab; MRD negativity was improved as well. You can see the duration of response was about 3 months longer across the population in the two groups. So a 1:1 randomization another option for patients with Philadelphia chromosome–positive or –negative ALL who are adults.

Let’s move into what I think is probably likely to be on the cover of Science at some point, and that’s CAR T-cell therapy. Tisagenlecleucel was the first CAR

T approved for therapy and there was one—I got these slides in really late and I still didn’t get to cover two drugs that were approved, by the way, after I got these slides in, so that’s how busy heme malignancies are. The other, the Kite CAR T- cell that’s also been approved for adults with diffuse large B-cell lymphoma, primary mediastinal lymphoma and high-grade B-cell lymphomas I’m not going to cover today, nor am I going to cover the approval, which also came out, but those are two drugs that have hit the market in the last literally two approaches in the last 2 to 3 weeks.

Let’s talk through a little bit of background on tisagenlecleucel and specifically chimeric antigen receptor T cells. If you go back to your Greek, you’ll

17 www.transcriptionexperts.com know that “chimera” is a fusion of two different things. In Greek mythology, a chimera was usually a human and an animal coming together, and so chimera really reflects the idea that you’re trying to do two things in a T-cell, and I’ll talk about what those two things are and how they can be used to target and hopefully provide a long-term disease remission or cure using this approach. This is a nice depiction of what happens in CAR T-cell therapies. In the first study, we can see the patient undergoes apheresis. A number of T cells are removed along with a bunch of other schmutz. That stuff is returned to the patient, the T cell is taken out by beads. What you’re looking for are CD4- and CD8-positive T cells, so you’ve heard a lot about immunotherapy; CD8-positive T cells are incredibly important, but you also want CD4-positive cells to come out of this apheresis product.

You then take those CD4-positive/CD8-positive populations and you try to expand them, and you expand them by adding in cytokines. So the beads on this depiction are artificial APCs are there to try to remove the cells, and then you want to grow these cells. You want to grow them like you grow anything else, and you do that from cytokines, and you do that through media and other ways to make these cells more viable. And then you want to teach them. So you’ve grown them up—think of them like children—you’ve grown them, now you want to teach them and you want to teach them in a way that will help them to go after the target of interest. That’s why CAR T cells are going to be applied at least investigationally across a number of different cancers. You can pick the antigen of interest. In myeloma, you can pick the B-cell maturation antigen or BCMA. In

18 www.transcriptionexperts.com solid tumors and small cell lung cancer, you can pick NY-ESO and target the cells to go after that, so it is an individualized immunotherapy based on the cancer and not on the patient.

You are teaching these cells in this instance to go after CD19-positive B cells. Those are lymphomatous B cells in ALL or leukemic cells in ALL whether lymphomatous cells and diffuse large . You transduce them and you teach them with a viral particle because viruses are very good at transfecting things.

You get the virus, you teach the virus what it’s going to transfect, and then you do it, and you expand that column, and then they now have antigen receptors on the T cell, so they have their warhead.

That warhead is then infused back into the patient, and that’s where the fun begins. After infusion, they go to the site of disease, so these T cells are very honing; they hone to what’s CD19 positive. The challenge, much like CD8- positive T cells after PD-1 antagonism, is they may not know what’s friend and what’s foe right away, and so they want to grow and go after the cell of interest and they want to get to the target and engage it, and so it really is like an army of soldiers going after it. Then after that engagement occurs, they bring more friends to the party—cytokines, complement, natural killer cells, cytotoxic T- lymphocytes that are innate—and so there’s an early phase of cellular kill that occurs after infusion of CAR T cells.

There are a couple of things that have to happen though for this to really work well. One thing is these are your cells as the patient, but they are also now a little bit foreign, so you want to try to accept these cells. It’s not full-on

19 www.transcriptionexperts.com transplant, but you want to create an environment where these CAR T cells are going to be welcomed, and you do that through lymphodepleting chemotherapy, which we’ll talk about in a second. That’s one thing you want to do is to let them come in and be welcomed, and then you want them to grow and stay there and move in, and that’s where the expansion of the CD8- and CD4-positive cell occurs in vivo in the patient, and that’s what leads to a long-term remission after the initial infusion of the cell. It’s a lot to ask of these CAR T cells, and it’s impressive that the group at Penn and others have been able to do this. It was first done in 2008, so it has been a while in development. Other cellular therapies are in development, natural killer cells are in development in Europe and in other places, but in this instance, they grant a breakthrough therapy to this product’s

CTL019.

In August of this year, FDA granted approval to the pediatric population up to 25 years of age, and so your institution may decide how they’re going to handle that, but it is in approval up to 25 and it was on a single-arm trial of 63 patients and about half of those, a little more than half, had a prior stem cell transplant. The overall remission rate was 83%, so you’ve got a young population who’s got bad ALL, you do this procedure, and 8 out of 10 of them go into remission. That’s unheard of in this place, and that’s why the excitement is around this. So if 63% got into a CR, out of those eight, six of those eight went into a complete remission and 19% had complete remission with incomplete hematologic recovery. Like many times when I’m giving these talks, this does come with a price, but the payoff in my opinion is certainly worth the price for the

20 www.transcriptionexperts.com right patient population. So it’s a CD19-directed genetically modified autologous

T-cell product. There’s the indication which we talked about. Patients need to get fludarabine and cyclophosphamide before they get this therapy. So if you’re a patient, you come in, you get your T cells collected, and then you hang out and you wait for the product to be made. Now in new trials and later on in the development of this product, patients were allowed to get chemotherapy in the interim between when the product was being made and when it was reinfused, but if you don’t have that or even if you do, you still have to get lymphodepleting chemotherapy and this is in the label: standard fludarabine, standard cyclophosphamide, and then you infuse the tisagenlecleucel 2 to 14 days after that lymphodepleting chemotherapy. I love that this is in the product label, “Verify the patient’s identity.” Because man, that would be a huge screw up, wouldn’t it?

“Oh, man, we gave Mr. Smith the T cells that we were supposed to…oh, that’s too bad.” So certainly verify the identity of the patient. I left this in because it is right in the product information. Premedicate with acetaminophen and diphenhydramine, which is a little bit like bringing a BB gun to a war, and then make sure you have tocilizumab. Tocilizumab is now FDA approved for complications associated with CAR T-cell therapy.

When you infuse CAR T cells, there is one cytokine, it’s my favorite cytokine that just cranks up, and that’s IL-6. You will get a ton of IL-6 release once you give CAR T-cell therapy. The dosing is based on the number of viable

CARs that are there, so it’s a weight-based dosing that you are going to infuse and it’s based on weight alone, but it’s a flat dose based on weight, not a per kilo

21 www.transcriptionexperts.com of cell infusion. These are the things that can happen; a couple of things to really point out: prolonged cytopenia. Cytopenias can be very long following these infusions. You can wipe out the marrow. Remember this is a CD19 cell. They hopefully will come back in many instances, but not necessarily all. You may have transfusion-dependent patients for an extended period of time. The other thing is hypogammaglobulinemia and you might think, “Oh, well that’s easy. We’ll just supplement them with IVIG like we do many other patients.” IVIG isn’t the only gammaglobulin, so IgA goes down, IgD goes down, IgE goes down, and those you can’t replace. So patients are at risk of infections from those types of hypogammaglobulinemia settings. So they do need—there are serious infections associated with this therapy that can be unusual in addition to your standard bacterial and fungal infections.

Common adverse events are listed here. Cytokine release syndrome I can’t talk about enough. It’s a CNS-based thing, you get a ton of cytokines released, again, IL-6 being the primary driver. You can have confusion, somnolence leading to encephalopathy, and so tocilizumab being there and being around is incredibly important. You can release bunches of cytokines, which can lead to capillary leak, which can then be a secondary acute renal failure, secondary acute hepatic insufficiency, usually though you have selected these patients well before coming on.

This is why people are excited, the swimmer’s plot here. I don’t have to tell you that these kinds of responses and these kinds of durations are what are exciting. Of the 107 screened, 88 were enrolled. This is an important point to this

22 www.transcriptionexperts.com trial and future products. 107 were screened, 88 were enrolled. That means you, off the bat, this is a 25 year and younger ALL population, you have a culling of the population right off the front of an otherwise healthy group, so not everyone is going to be a candidate. 68 of those 88 were treated. Why were only 68 treated?

Their disease got worse, their performance status declined, and the product wasn’t ready in time. Those are changing with this product and future products.

The turnaround time to get these back from manufacturers has very much gone down, and in general it’s usually about a 2- to 3-week process, but good communication is incredibly important. Of those 63 who were treated, 35 were men or boys, the median age was 12, 53 had gotten, did get bridging chemotherapy, and so that tells you right away the majority of patients in this trial are going to need some disease-based chemotherapy between collection of the cell and reinfusion, which is actually a good thing because you really don’t—if you’re going to invest in this, you want to make sure you can get the patient to the final product. 30 had a prior allogeneic stent transplant and two had two prior allogeneic transplants. So that’s CAR T cells; it’s an exciting area and certainly will continue to grow in terms of applications and investigations.

Let’s move on now to gemtuzumab ozogamicin approved in September of this year. Gemtuzumab has been around for a while. I’m really sorry that I’m going to be over, so I’m going to try to blaze through this, but my God, there was a lot of information. CD33 antibodies, calicheamicin, newly diagnosed CD33 positive AML and relapsed/refractory-positive AML in pediatric patients. You’ve got to premedicate. There’s a newly diagnosed regimen that can be used and

23 www.transcriptionexperts.com that’s generally in people who are not candidates for 7+3. There’s a single-agent regimen as well, so induction and consolidation. These are doses that are lower than the previous gemtuzumab label. And then finally relapsed and refractory both induction and consolidation regimens. These are the warnings, similar to inotuzumab ozogamicin; you can have hepatic insufficiency, again, the risks are the same as they were with inotuzumab. You can have infusion-related reactions, all the other stuff is stuff we see in acute leukemia patients generally and things to keep an eye on. This is the data, again, another overall survival improvement compared to daunorubicin and cytarabine in combination with gemtuzumab ozogamicin. This is a combination comparison to 7+3 alone versus gemtuzumab, and this I think the drug was evaluated correctly and I think provides a nice addition to what we have already in the armamentarium for AML. Copanlisib, a

PI3-kinase, you’ll know from other from idelalisib, it’s an important enzyme for the regulation of proliferation and differentiation of B cells. There are four subtypes to

PI3-kinase, alpha, beta, gamma, and delta. CAL-101 or idelalisib is a PI3-kinase delta primary inhibitor of that pathway, and PI3-kinase delta and alpha have slightly different activities; copanlisib inhibits both of them. It’s an IV drug and so it’s something that’s given weekly, and it certainly has a number of important biological effects. It’s approved for relapsed follicular disease who have gotten at least two prior systemic therapies, similarly to idelalisib. It’s in the same follicular space as idelalisib. The drug interactions are there. It is a 3A substrate, so you want to reduce the drug to 45 from 60 in patients who have concomitant siC3a inhibitor. It’s given weekly, days 1, 8, and 15 with a week off on a 28-day cycle.

24 www.transcriptionexperts.com These are the adverse events. A couple of key things with copanlisib: noninfectious pneumonitis, even though it’s an IV drug, it’s still a small molecule inhibitor, so it’s still at risk for pneumonitis, and patients need to be thought about in terms of pneumonitis. PI3-kinase inhibitors have downstream effects of glucose trafficking, and you can see hyperglycemia with these drugs and certainly something to think about. You can use insulin, you can do another of other manipulations to try to improve it, you can see hypertension, you can see neutropenia, and you can see in rare instances severe rashes and cutaneous reactions.

This is the data that led to its approval, again follicular lymphoma 0-1

ECOG performance status, three prior lines, thus the two or more prior lines in patients getting it, overall response rate 60% with 14% CRs in a relatively difficult to treat population. Median time to response was about 2 months, so if you are going to respond, it usually happens fairly early. These are the conclusions I’ll read and you can read on your own, and I’ll stop since I’m already over and I don’t know if we have time for questions. Thank you.

FEMALE Thank you very much, Dr. Harvey. Another exciting update on new medications.

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