Advances in the Treatment of Hematologic Malignancies A Review of Newly Approved Drugs

Katherine Shah, PharmD, BCOP Clinical Pharmacy Specialist, Hematology/Oncology Emory University Hospital / Winship Cancer Institute

Disclosures • I do not (nor does any immediate family member have) a vested interest in or affiliation with any corporate organization offering financial support or grant monies for this continuing education activity or any affiliation with an organization whose philosophy could potentially bias my presentation • There was no financial support obtained for this CPE activity

1 Objectives • Discuss the pharmacologic principles of several new agents approved for use in hematologic malignancies – Drug class – Mechanism of action – highlights • Review approved dosing and recommend appropriate clinical monitoring and management of toxicities of new agents covered – Dosing recommendations for new agents – Side effect profile – Clinical management

Approvals 1980‐2014

http://innovation.org/images/dmImage/SourceImage/lg_FDA_Approval.jpg

2 2014 Novel Drug Approvals

Nature Reviews Drug Discovery 14, 77–81(2015) doi:10.1038/nrd4545

Select 2014 Novel Oncology Drugs

Drug Indication Approval Date Siltuximab (Sylvant) Multicentric Castleman’s April 2014 Disease Belinostat (Beleodaq) Peripheral T‐cell Lymphoma July 2014 Idelalisib (Zydelig) CLL, Follicular NHL, SLL July 2014 Netupitant and Nausea/vomiting October 2014 palonosetron (Akynzeo) Acute Lymphoblastic December 2014 (Blincyto) Leukemia, Ph‐

Ph-= Philadelphia Chromosome-negative

http://www.fda.gov/downloads/drugs/developmentapprovalprocess/druginnovation/ucm430299.pdf

3 Siltuximab (Sylvant™)

•FDA Approval: April 23, 2014 •First in class, accelerated approval for treatment of Multicentric Castleman’s Disease •Chimeric against IL‐6

Castleman’s Disease

• 1954: First case report by Dr. Benjamin Castleman

• Rare, non-clonal lymphoproliferative disorder

• Enlarged hyperplastic lymphadenopathy involving either: • Single lymph node = Unicentric (UCD) • Multiple lymph nodes = Multicentric (MCD)

•MCD • Risk Factors: HIV and Human Herpes Virus 8 (HHV-8) • Pathogenesis: HIV, HHV-8, -6 (IL-6)

4 Classifications

Castleman’s Disease

Unicentric Multicentric (UCD) (MCD)

HHV8 + HHV8 _

HIV + HIV _

Clinical Presentation: MCD • Clinical spectrum range – Waxing and waning lymphadenopathy with mild symptoms to a more aggressive systemic disease • Systemic inflammatory manifestations – Fevers, night sweats, weight loss, fatigue • Physical examination – Generalized lymphadenopathy, hepatosplenomegaly, edema • Common lab abnormalities – Anemia, thrombocytopenia, thrombocytosis, hypergammaglobulinemia, hypoalbuminemia, elevated inflammatory markers

Cancer Control. 2014 Oct;21(4):266-78, Expert Rev. Hematol. 7(5), 545–557 (2014).

5 Role of IL‐6

Trends Immunol. 2012 Nov;33(11):571-7

Siltuximab Mechanism

Chimeric IL-6 monoclonal antibody

6 Siltuximab in MCD Study design

• Randomized, double-blind, placebo-controlled study in HIV- and HHV8- patients with symptomatic MCD • Newly diagnosed or previously treated (except those who had received IL-6 targeted treatment) • Primary endpoint: durable tumor and symptomatic response Treatment groups

2:1

Siltuximab + BSC Placebo + BSC 11 mg/kg IV q3 weeks q3 weeks n=26 n=53 BSC= Best Supportive Care

Lancet Oncol. 2014 Aug;15(9):966-74

Results Days to Treatment Failure Disease Related Overall Symptom Score HR 2.774 37% difference (1.068 to 7.206) p= 0.0018

Siltuximab Placebo p value Durable tumor and 34% 0 0.0012 symptomatic response CR 2% 0 ‐‐‐ PR 32% 0 ‐‐‐

Lancet Oncol. 2014 Aug;15(9):966-74

7 Toxicity

Adverse Effect (all grades) Siltuximab Placebo Pruritis 42% 12% Upper respiratory tract infection 36% 15% Fatigue 34% 38% Maculopapular rash 34% 12% Peripheral edema 32% 23% Peripheral neuropathy 25% 19% Diarrhea 23% 19% Weight gain 21% 0 • Discontinued due to adverse events in only 1 patient due to anaphylactic reaction

Lancet Oncol. 2014 Aug;15(9):966-74

Dosing and Administration

First drug approved in MCD (HHV8‐ & HIV‐)

Dose: – 11 mg/kg IV infusion over 1 hour every 3 weeks until treatment failure – No renal or hepatic dose adjustments – Treatment should be delayed if: • First dose: ANC <1000; Plt <75,000; Hgb >17 g/dL • Subsequent: ANC <1000; Plt < 50,000; Hgb>17g/dL Sylvant® [package insert] Horsham, PA: ; 2014

8 Dosing and Administration • Do not administer with severe infections • Infusion reaction rate in 249 patients treated: <5%

• T1/2: 20.6 days • Cost: ~ $5,000 for 70 kg patient every 3 weeks

Sylvant® [package insert] Horsham, PA: Janssen Biotech; 2014

Belinostat (Beleodaq®)

•FDA Approval: July 3, 2014 •Accelerated approval for treatment of relapsed or refractory peripheral T‐cell lymphoma (PTCL) •Histone deacetylase (HDAC) inhibitor

9 Belinostat Mechanism

Marks P et al. Nature Reviews Cancer 2001;1:194-202.

Belinostat Mechanism • Small molecule

10 Inhibition of HDAC

http://medind.nic.in/jat/t14/i3/JCanResTher_2014_10_3_469_137937_f2.jpg

11 Results

Response Rate n= 120 ORR 26% Complete Response (CR) 11% Partial Response (PR) 15% Stable disease 15% Progressive disease 40% Not evaluable* 19%

*Prior to first radiologic assessment due to death (n=7); clinical progression (n=10); patient withdrawal (n=5); lost to follow-up (n=1)

O’Connor OA et al. Proc ASCO 2013; Abstract 8507.

Select Grade ≥ 3 Adverse Events

O’Connor OA et al. Proc ASCO 2013; Abstract 8507.

12 Dosing and Administration • Indication: Relapsed or refractory PTCL • Dosing: 1000 mg/m2 IV daily on Days 1‐5 of a 21‐day cycle – Continue until disease progression or unacceptable toxicity

Idelasilib (Zydelig™)

•FDA Approval: July 23, 2014 •First in class, accelerated approval for treatment of relapsed CLL, follicular B‐ cell NHL and SLL. •PI3K inhibitor

13 Idelalisib Mechanism • Inhibits PI3K delta kinase – Expressed on normal & malignant B‐cells • Induces apoptosis, inhibits proliferation & cell signaling pathways – Involved in trafficking and homing of B‐cells to lymph nodes and bone marrow • Inhibits chemotaxis and Fruman DA, Cantly LC. N Engl J Med 2014; 370:1061-1062 adhesion

Idelalisib Indications

Relapsed CLL in combination 1 with

Relapsed Follicular B‐cell 2 Non‐Hodgkin Lymphoma after at least 2 systemic therapies

Relapsed SLL after at least 2 3 systemic therapies

14 Idelasilib in CLL

15 Outcomes

Coutre et al ASCO 2014

Toxicities

Coutre et al ASCO 2014

16 Toxicities

Warnings and Precautions

Grade 5

Hepatotoxicity 1/1192 = 0.1%

Diarrhea 1/1192 = <0.1%

Pneumonitis 3/760 = 0.5%

Perforation 2/1192 = 0.2%

Zydelig [package insert]. Foster City, CA; Gilead Sciences Inc.; 2014.

17 Warnings and Precautions • Severe cutaneous reactions • Neutropenia – 30% ≥ Grade 3 – CBC at least every 2 weeks for first 3 months • Anaphylaxis

Zydelig [package insert]. Foster City, CA; Gilead Sciences Inc.; 2014.

Adverse Reactions

• Diarrhea • Chills • Pyrexia • Rash • Fatigue • Neutropenia • Nausea • Hypertriglyceremia • Cough • Hyperglycemia • Pneumonia • AST/ALT increases • Abdominal pain

18 Dosing and Administration • Starting dose: 150 mg PO BID • Take without regard to food, swallow whole • Continue until progression or http://images2.ddccdn.com/images/pills/fio/GIL17010.JPG unacceptable toxicity 100 mg, 150 mg tablets Renal Dose No dose adjustment if CrCL ≥ 15 ml/min Adjustment Patients with AST/ALT > 2.5 x ULN and Hepatic Dose T.Bili > 1.5 x ULN excluded from studies. Adjustment If hepatic impairment at baseline, monitor for toxicity.

Blinatumomab (Blincyto™)

•FDA Approval: July 23, 2014 •First in class, accelerated approval for treatment of relapsed/refractory Ph‐ ALL •Bispecific CD19‐directed CD3 T‐cell engager

19 Blinatumomab Mechanism Bispecific CD19‐directed CD3 T‐cell engager

Kapoor A, et al. Clinical Cancer Investigation Journal. 2014: 3 (6) 577-578

Blinatumomab in Relapsed/Refractory B‐Precursor ALL

Study Design •Multicenter, single‐arm, open label phase 2 study •Patients ≥ 18 y.o. with Philadelphia chromosome negative, primary refractory or relapsed ALL •Primary endpoint: CR or CRh within the first two cycles Treatment • Blinatumomab (9 mcg/day for the first 7 days and 28 mcg/day thereafter) by continuous intravenous infusion over 4 weeks every 6 weeks CR = complete remission CRh = CR with partial haematological recovery of peripheral blood counts

Topp MS et al Lancet Oncol 2015; 16: 57–66.

20 Results Patients (%) CR or CRh during the first two cycles 81/189 (43) Best response during the first two cycles CR 63/189 (33) CRh 18/189 (10) No response to therapy 90/189 (48) Not evaluable 18/189 (10) Allogeneic HSCT after CR or CRh 32/81 (40) Allogeneic HSCT after CR 28/63 (44) Allogeneic HSCT after CRh 4/18 (22)

Topp MS et al Lancet Oncol 2015; 16: 57–66

Safety Adverse Event Any Grade (%) Patients with adverse events 188 (99%) Febrile neutropenia 53 (28%) Neutropenia 33 (17%) Anemia 38 (20%) Hyperglycemia 24 (13%) ALT increased 24 (13%) Hypokalemia 45 (24%) Pyrexia 113 (60%) Tremor 33 (17%) Dizziness 26 (14%) Cytokine release syndrome 20 (11%)

Topp MS et al Lancet Oncol 2015; 16: 57–66

21 Dosing One cycle = 4 weeks of continuous intravenous infusion followed by a 2 week treatment free interval 2 induction cycles + 3 consolidation cycles

Cycle 1 (patients ≥ 45 kg)

9 mcg/day on Days 1‐7 28 mcg/day on Days 9‐28

Hospitalized: first 9 days Cycle 1 first 2 days Cycle 2 Subsequent cycles 28 mcg/day on Days 1‐28

Blincyto [package insert]. Thousand Oaks, CA; Amgen Inc.; 2014.

Blinatumomab No dose adjustment; no information in Renal Dose severe renal impairment Adjustment (CrCl < 30 mL/min, or HD) No formal studies; drug is degraded into Hepatic Dose small peptides and amino acids via Adjustment catabolic pathways, unlikely to need adjustment 35 mcg of lyophilized powder in a single‐ How Supplied use vial for reconstitution, stabilizer Half‐Life 2.11 hours NSAIDS ↓ efficacy, Transient elevaon of Drug Interactions cytokines may suppress CYP450 enzyme activities

Blincyto [package insert]. Thousand Oaks, CA; Amgen Inc.; 2014. Kapoor A, et al. Clinical Cancer Investigation Journal. 2014: 3 (6) 577-578

22 Warnings & Precautions Black Box Warnings: • Cytokine Release Syndrome – 11% overall, 1% ≥ Grade 3 – Pyrexia, HA, nausea, asthenia, hypotension, ↑LFTs • Neurological Toxicities – 50% overall, 15% ≥ Grade 3 – Confusion/disorientation, disturbances in consciousness, speech disorders, coordination/balance disorders, convulsions, encephalopathy – Must have driver for outpatient therapy

Warnings & Precautions High Potential Admixture/Administration Errors! • Outpatient pumps can be 24 hr or 48 hr – Treated via infusion center or home health • Do NOT flush infusion line at any time during infusion – Only flush with NS when hanging a new bag (remove 10 mL active drug/waste before) • When infusion complete, bag will have drug left in it (30‐40 mL) – Must discard Blincyto [package insert]. Thousand Oaks, CA; Amgen Inc.; 2014.

23 Cost

Cycle #1 Induction‐ $79,450 • Inpatient (first 9 days with 9 mcg/day on days 1‐7, and 28 mcg/day thereafter) ‐ $19,068 • Outpatient (days 10‐28 with 28 mcg/day) ‐ $60,382

Cycle #2 Induction‐ $88,984 • Inpatient (first 2 days with 28 mcg/day) ‐ $6,356 • Outpatient (days 3‐28) ‐ $82,628

Cycle #3, 4, 5 Consolidation • Outpatient ‐ $88,984/cycle

Netupitant + palonosetron (Akynzeo®)

Netupitant Palonosetron (300 mg) (0.5 mg) •Acute • Delayed •1st 24 hours •25‐120 hours

• Dosing [highly emetogenic (HEC) or anthracycline and cyclophosphamide based]: – 1 capsule PO 1 hour prior to chemotherapy (Day 1) – Co‐administer with dexamethasone • HEC: 12 mg PO on Day 1, 8 mg PO on Days 2‐4 • Others: 12 mg PO on Day 1 • AEs: HA, asthenia, fatigue, indigestion, constipation

24 Expanded Indications & New Formulations

Ibrutinib (Imbruvica™) • Accelerated approval for the treatment of CLL who have received at least one prior therapy. • Dosing: 420 mg PO once daily

25 (Arzerra®) • Approved in combination with chlorambucil, for the treatment of previously untreated CLL – Where fludarabine‐based therapy is considered inappropriate • Dosing: – Cycle 1: 300 mg on Day 1 followed 1 week later by 1000 mg on Day 8 – Cycles 2+: 1000 mg on Day 1 (1 cycle= 28 days) • minimum of 3 cycles until best response • max of 12 cycles

Ruxolitinib (Jakafi™) • Approved for treatment of patients with polycythemia vera who have had an inadequate response to or are intolerant of hydroxyurea • Dose: 10 mg PO BID – 5 mg PO BID if on CYP3A4 inhibitors, moderate‐ severe renal impairment or hepatic impairment

26 Mercaptopurine (Purixan™) • Approved an oral suspension (20 mg/ml) • Indicated for the treatment ALL as part of a combination regimen. • Suspension advantage: more accurately delivers desired dose to children – Weights vary greatly using a consistent administration schedule – Tablets available in 50 mg

Questions? • Thank you for your attention!

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