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Disclosure

• I do not have a vested interest in or affiliaon New Targeted Drug Therapies for with any corporate organizaon offering Oncology financial support or grant monies for this connuing educaon acvity, or any affiliaon with an organizaon whose philosophy could Eliza W. Dollard, PharmD potenally bias my presentaon PGY-1 Pharmacy Pracce Resident Jackson Memorial Hospital, Miami FL

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Pharmacist’s Objecves Pharmacy Technician’s Objecves

• Upon compleon of this acvity, the • Understand mechanisms of acon for parcipant should be able to: idenfied therapies in oncology – Describe mechanisms of acon for idenfied • List vial size, compounding instrucons, and therapies in oncology storage parameters for new targeted therapies – Recognize indicaons, dosing, and monitoring for • Recognize dosing for new targeted therapies. new targeted therapies – Apply new clinical evidence for pertuzumab to clinical pracce

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Chronic Myeloid Leukemia (CML) CML Current Therapies

• Represents 10% of all adult leukemias First-line • CCyR = 65-82% st • BCR-ABL1 oncoprotein, aka Philadelphia Chromosome Treatment: 1 • PFS ≥ 94% at 24 Tyrosine Kinase months (Ph), is present in >90% of cases Inhibitor (TKI) • Within 5 years: 25% disconnuaon • Characterized by increased and unregulated growth of myeloid cells in bone marrow • CCyR ≤ 50% Second-line • PFS = 75–80% at 24 Treatment: 2nd TKI months

Third-line Treatment: Third TKI or Allogeneic Stem Cell Transplantaon

Janet Rowley. Digital image. National Institute of Health. N.p., n.d. Web. Khoury, H. Jean, et al. Leukemia & Lymphoma (2014): 1-24. Web. 5 Cortez, Jorge E. Cancer (2015): n. pag. Web. 1 Feb. 2015. 6 Philadelphia Chromosome. Digital image. CML Society. N.p., n.d. Web. Khoury, H. Jean, et al. Leukemia & Lymphoma (2014): 1-24. Web.

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FDA Approved TKIs TKI Resistance or Intolerance

• Gleevec ® (imanib) • Genec mutaons • Sprycel® (dasanib) – T315I: ponanib • Bosulif® (bosunib) • Overexpression of BCR-ABL • Tasigna® (nilonib) • Iclusig® (ponanib)

7 Cortez, Jorge E. Cancer (2015): n. pag. Web. 1 Feb. 2015. 8 Hematology/Oncology (Cancer) Approvals & Safety Noficaons. Food and Drug Administraon, 24 Feb. 2015. Web. Khoury, H. Jean, et al. Leukemia & Lymphoma (2014): 1-24. Web. 1 Feb. 2015.

Synribo® (omacetaxine mepesuccinate) Omacetaxine Study Abbreviaons

• Protein synthesis inhibitor, binding directly to • Progression-free Survival (PFS) the ribosome and blocking the inial step of • Chronic-Phase CML (CP-CML) protein translaon • Accelerated-Phase CML (AP-CML) – Induces apoptosis in leukemic cells by reducing • levels of BCR-ABL1 Complete cytogenic response (CCyR) – Direct binding of BCR-ABL is not required • Major cytogenec response (MCyR)

Cortez, Jorge E. Cancer (2015): n. pag. Web. 1 Feb. 2015. 9 Cortez, Jorge E. Cancer (2015): n. pag. Web. 1 Feb. 2015. 10 Khoury, H. Jean, et al. Leukemia & Lymphoma (2014): 1-24. Web. 1 Feb. 2015. Khoury, H. Jean, et al. Leukemia & Lymphoma (2014): 1-24. Web. 1 Feb. 2015.

Omacetaxine Approval in CML Methods

• Evaluate omacetaxine mepesuccinate in • Data pooled from 2 phase II trials of subcutaneous previously treated paents with CML who had (SQ) omacetaxine resistance or intolerance to 2 or more TKIs • Treatment: – Inducon Therapy: 1.25 mg/m2 SQ BID for 14 consecuve • Inclusion criteria: days every 28 days unl response – Age ≥ 18 with Ph+ CML – Maintenance Therapy: 1.25 mg/m2 SQ BID for 7 – Previously treated with imanib and consecuve days every 28 days unl no longer responding documentaon of resistance or intolerance to or experiencing benefit dasanib and/or nilonib – Treatment Delay: • Maintain ANC >0.5 x 109/L and PTL >50 x 109/L • Grade 2 or higher events that were unresponsive to supporve care Cortez, Jorge E. Cancer (2015): n. pag. Web. 1 Feb. 2015. 11 Cortez, Jorge E. Cancer (2015): n. pag. Web. 1 Feb. 2015. 12 Khoury, H. Jean, et al. Leukemia & Lymphoma (2014): 1-24. Web. 1 Feb. 2015. Khoury, H. Jean, et al. Leukemia & Lymphoma (2014): 1-24. Web. 1 Feb. 2015.

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Results: Efficacy Populaon Results: Safety Populaon

• Primary Endpoints: • Grade 3-4 Adverse Events (AEs): • CP-CML: MCyR (CCyR or a paral cytogenec response) – Hematologic AEs were most common – All paents: 18%, median response duraon 12.5 months – Infecons were most common non-hematologic AEs – >3 cycles of omacetaxine: MCyR rate 22%, with 6% maintaining • CP-CML: 13% response for ≥12 months • AP-CML: 41% • AP-AML: MaHR (Complete hematologic response [CHR] • Almost all paents required treatment delay in at maintained for ≥4 weeks or no evidence of leukemia [NEL] least 1 maintenance cycle and/or MCyR) – 14%, median response duraon, 4.7 months • 6 deaths reported within 30 days of last dose – >3 cycles of omacetaxine: 29% achieved MHR – Progressive disease: 3 • T315I Mutaon: – Cerebral Hemorrhage: 2 • CP-CML: MCyR in 3/16 (19%; 1-sided 95% LCL, 5%) – Mul-organ Failure: 1 Cortez, Jorge E. Cancer (2015): n. pag. Web. 1 Feb. 2015. 13 Cortez, Jorge E. Cancer (2015): n. pag. Web. 1 Feb. 2015. 14 Khoury, H. Jean, et al. Leukemia & Lymphoma (2014): 1-24. Web. 1 Feb. 2015. Khoury, H. Jean, et al. Leukemia & Lymphoma (2014): 1-24. Web. 1 Feb. 2015.

Addional Prescribing Informaon Preparaon, Storage, and Administraon

• Warnings and Precauons: • Single-use vial containing 3.5mg omacetaxine – Myelosuppression mepesuccinate as a lyophilized powder – Bleeding – Reconstute with 1mL of 0.9% NaCl – Hyperglycemia • Storage: – Embryo-fetal Toxicity – Room Temperature: 12 hours • Dose Adjustment: None – Refrigerated: 6 days • Drug Interacons: • Home Administraon: provide training on proper – Not a CYP450 substrate, inhibitor, or inducer in vitro handling, storage condions, administraon, – PGP Substrate in vitro, no inhibion seen disposal, and clean-up of accidental spillage

Cortez, Jorge E. Cancer (2015): n. pag. Web. 1 Feb. 2015. Cortez, Jorge E. Cancer (2015): n. pag. Web. 1 Feb. 2015. Khoury, H. Jean, et al. Leukemia & Lymphoma (2014): 1-24. Web. 1 Feb. 2015. 15 Khoury, H. Jean, et al. Leukemia & Lymphoma (2014): 1-24. Web. 1 Feb. 2015. 16 Synribo(R) [package insert]. North Wales, PA: Teva Pharmaceucals USA, Inc; 2014. Synribo(R) [package insert]. North Wales, PA: Teva Pharmaceucals USA, Inc; 2014.

Acute Lymphoblasc Leukemia (ALL) Relapsed or Refractory ALL

• Too many stem cells become • Clofarabine in combinaon with convenonal therapy (cyclophosphamide, or a more intensive regimen with dexamethasone, mitoxantrone, lymphoblasts etoposide, and asparaginase) • Approximately 25% of adult – CR: 44% – paents with ALL are Ph+ OS: 6.5 months • Ifosfamide, etoposide, mitoxantrone • 20% of all leukemias among – CR: 73% adults – OS: 7.7 months • Hyper-CVAD: • Adults have the poorest 5-year – CR: 47% overall survival (OS) rates – OS: 10.2 months – Age 40-59: 24.1% • High-dose cytarabine and idarubicin – CR: 38% – Age 60-69: 17.7% – OS: 8 months

17 18 Clinical Pracce Guidelines. Naonal Comprehensive Cancer Network, 22 Dec. 2014. Web. 1 Feb. 2015. Clinical Pracce Guidelines. Naonal Comprehensive Cancer Network, 22 Dec. 2014. Web. 1 Feb. 2015.

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ALL Therapies: Second or Greater Relapse Blincyto® (blinatumomab) • Vincrisne sulfate liposome injecon (VSLI) • Bispecific an-CD3/CD19 monoclonal – N=65 anbody: BiTE® – 50% of paents received ≥ 3 prior therapies – CD19 expressed in more than 95% of B-precursor – 48% of paents had undergone HSCT acute lymphoblasc leukemia blasts – All had been previously treated with standard – CD3 located on cytotoxic T cells vincrisne – CR: 20% – Median duraon of CR: 20 weeks – OS: 7.7 months

19 Blincyto(R) [package insert]. Thousand Oaks, CA: Amgen, Inc; 2014. 20 Clinical Pracce Guidelines. Naonal Comprehensive Cancer Network, 22 Dec. 2014. Web. 1 Feb. 2015. Topp, Max S., et al. The Lancet Oncology 16.1 (2015): 57-66. Web. 1 Feb. 2015.

Blincyto® (blinatumomab) Blinatumomab Approval in ALL

• Confirm the acvity and safety profile of blinatumomab for acute lymphoblasc leukemia • Mulcenter, single-arm, phase 2 study • Inclusion criteria: – Adults ≥ 18 years – Ph- ALL – ≥ 10% bone-marrow blasts – Primary refractory aer inducon or who had relapsed within 12 months of first remission, relapsed within 12 months of allogeneic HSCT, or not responded to or relapsed aer first salvage therapy or beyond 21 Blincyto(R) [package insert]. Thousand Oaks, CA: Amgen, Inc; 2014. 22 BiTE. Digital image. American Society of Clinical Oncology, n.d. Web. 10 Feb. 2015. Topp, Max S., et al. The Lancet Oncology 16.1 (2015): 57-66. Web. 1 Feb. 2015.

Treatment Methods

• Dexamethasone pre-treatment for paents with bone- • Paents who achieved complete remission marrow blasts >50%, elevated LDH, or peripheral blasts ≥15,000 cells/µL (CR) or CR with paral recovery (CRh) within • Blinatumomab connuous IV infusion with portable pump the first two cycles could receive up to 3 – Stepwise dosing in cycle 1 to reduce risk of cytokine addional cycles release syndrome • Treatment interrupted: – 28 µg/day in 4 week cycles, followed by two treatment- free weeks – Grade 3 CNS-related AEs – Dexamethasone 20mg premedicaon within 1 h before – Other clinically relevant grade 3 or 4 AE treatment iniaon in each cycle

Blincyto(R) [package insert]. Thousand Oaks, CA: Amgen, Inc; 2014. 23 Blincyto(R) [package insert]. Thousand Oaks, CA: Amgen, Inc; 2014. 24 Topp, Max S., et al. The Lancet Oncology 16.1 (2015): 57-66. Web. 1 Feb. 2015. Topp, Max S., et al. The Lancet Oncology 16.1 (2015): 57-66. Web. 1 Feb. 2015.

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Results: Study Populaon Results: Efficacy

• 34% had failure of previous allogeneic HSCT • Primary Endpoint: CR or CRh • 51% without previous allogeneic HSCT – 81/189 (43%, 95% CI 36-50) within first 2 treatment cycles – 43/59 (73%, 95% CI 60-84) of paents with <50% bone- received blinatumomab as second or later marrow blasts salvage – 38/130 (29%, 95% CI 22-38) of paents with ≥ 50% bone- marrow blasts • Median relapse-free survival was 6.9 months for paents in CR • 32 (40%) paents who achieved CR proceeded to receive allogeneic HSCT while sll in remission

Blincyto(R) [package insert]. Thousand Oaks, CA: Amgen, Inc; 2014. 25 Blincyto(R) [package insert]. Thousand Oaks, CA: Amgen, Inc; 2014. 26 Topp, Max S., et al. The Lancet Oncology 16.1 (2015): 57-66. Web. 1 Feb. 2015. Topp, Max S., et al. The Lancet Oncology 16.1 (2015): 57-66. Web. 1 Feb. 2015.

Results: Safety Blinatumomab REMS Program

• 23 (12%) paents had fatal AEs, mainly infecon • Cytokine Release Syndrome: First 2 days – No paents in remission died during blinatumomab treatment – Includes pyrexia, headache, nausea, asthenia, • 3 (2%) had grade 3 cytokine release syndrome hypotension, increased AST/ALT, increased total bilirubin – 2/3 achieved CR or CRh • Neurological Toxicies: First 7 days • 24 (13%) had grade 3-4 neurologic events – Includes encephalopathy, convulsions, speech disorders, – No fatal neurologic events were reported, but 29 paents required treatment interrupon disturbances in consciousness, confusion and disorientaon, and coordinaon and balance disorders • Most common grade 3-4 AE: – Febrile neutropenia • Preparaon and Administraon Error – Neutropenia – Hospitalizaon recommended for first 9 days of first cycle – Anemia and first 2 days of second cycle

Blincyto(R) [package insert]. Thousand Oaks, CA: Amgen, Inc; 2014. 27 Blincyto(R) [package insert]. Thousand Oaks, CA: Amgen, Inc; 2014. 28 Topp, Max S., et al. The Lancet Oncology 16.1 (2015): 57-66. Web. 1 Feb. 2015. Topp, Max S., et al. The Lancet Oncology 16.1 (2015): 57-66. Web. 1 Feb. 2015.

Addional Prescribing Informaon Preparaon, Storage, and Administraon

• Dose Adjustment: None • Preparaon: Single-use vial containing 35mcg of lyophilized powder – Reconstute with 3mL of sterile water – No informaon available in CrCl < 30 or – Use IV Soluon stabilizer hemodialysis – Add to 250mL 0.9% NaCl – Use only polyolefin, PVC non-di-ethylhexylphthalate (non-DEHP), or ethyl vinyl • Drug Interacons: acetate (EVA) infusion bags/pump cassees – Remove air – No formal studies have been conducted • Storage: – Possible transient suppression of CYP450 – Room temperature: 48 hours – Refrigerated: 8 days • Administraon: connuous infusion pump – 5 or 10 ml/hour – Do not flush line

Blincyto(R) [package insert]. Thousand Oaks, CA: Amgen, Inc; 2014. 29 Blincyto(R) [package insert]. Thousand Oaks, CA: Amgen, Inc; 2014. 30 Topp, Max S., et al. The Lancet Oncology 16.1 (2015): 57-66. Web. 1 Feb. 2015. Topp, Max S., et al. The Lancet Oncology 16.1 (2015): 57-66. Web. 1 Feb. 2015.

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HER2-Posive Breast Cancer Perjeta® (pertuzumab)

• 20-25% of breast cancers over-express HER2 • Humanised monoclonal anbody directed at the dimerisaon domain of HER2

31 32 HER2-Posive Cancer Cell. Digital image. Perjeta. Genentech, n.d. Web. 10 Feb. 2015. Pertuzumab and Trastuzumab. Digital image. Cancer Network. Oncology, n.d. Web. 10 Feb. 2015.

NeoSphere Trial NeoSphere Methods

• Invesgaon of the combinaon of pertuzumab or • Randomized 1:1:1:1 to receive neoadjuvant trastuzumab, or both, with docetaxel and the combinaon of pertuzumab and trastuzumab without chemotherapy in the therapy with: neoadjuvant seng – Trastuzumab + docetaxel • Randomized, mulcenter, internaonal, open-label phase 2 – Pertuzumab + docetaxel study – Pertuzumab + trastuzumab + docetaxel • Inclusion criteria: – Confirmed HER2 –posive, operable (T2-3, N0-1, M0), locally advanced – Pertuzumab + trastuzumab (T2-3, N2-3, M0 or T4a-c, any N, M0), or inflammatory (T4d, any N, M0) breast cancer – Primary tumors larger than 2 cm in diameter – No previous cancer therapy

33 34 Gianni, Luca, et al. The Lancet Oncology 13.1 (2012): 25-32. Web. Gianni, Luca, et al. The Lancet Oncology 13.1 (2012): 25-32. Web.

NeoSphere Results TRYPHAENA Trial

Primary Endpoint: pathological complete • Evaluate the safety and tolerability of trastuzumab response (pCR) and pertuzumab in combinaon with anthracycline-, or carboplan-based neoadjuvant chemotherapy – Pertuzumab + trastuzumab + docetaxel (n=107): 45.8% (95% CI, 36.1-55.7) • Randomized, mulcenter, open-label, phase 2 study – Trastuzumab + docetaxel (n=107): 29% (95% CI, • Inclusion criteria: 20.6-38.5) – Female paents age ≥ 18 – – Pertuzumab + trastuzumab (n=107): 16.8% (95% Confirmed HER2 –posive, operable (T2-3, N0-1, M0), locally advanced (T2-3, N2-3, M0 or T4a-c, any N, M0), or CI, 10.3-25.3) inflammatory (T4d, any N, M0) breast cancer – Pertuzumab + docetaxel (n=96): 24% (95% CI, – LVEF ≥ 55% at baseline 15.8-33.7) 35 36 Gianni, Luca, et al. The Lancet Oncology 13.1 (2012): 25-32. Web. Schneeweiss, A., et al. Annals of Oncology 24.9 (2013): 2278-284. Web.

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TRYPHAENA Methods TRYPHAENA Results

• Randomized 1:1:1 to receive 6 cycles of • Symptomac le ventricular systolic neoadjuvant therapy with: dysfuncon (LVSD): 1/223 paents (0.4%) in – A: FEC plus trastuzumab and pertuzumab followed treatment group B during neoadjuvant period by docetaxel, trastuzumab and pertuzumab • LVEF declines ≥ 10% points from baseline to – B: FEC followed by docetaxel, trastuzumab, and <50% pertuzumab – Neoadjuvant period: 11 paents – C: Docetaxel, carboplan, trastuzumab and – follow-up period: 9 paents pertuzumab – Measurements had improved to ≥ 50% in all paents at data cutoff

37 38 Schneeweiss, A., et al. Annals of Oncology 24.9 (2013): 2278-284. Web. Schneeweiss, A., et al. Annals of Oncology 24.9 (2013): 2278-284. Web.

Preparaon, Storage, and Addional Prescribing Informaon Administraon • Always Administer with trastuzumab • Single-use vial containing 420mg/14mL • Black Box Warnings: – Dilute into 250 mL 0.9% NaCl – Cardiomyopathy • Administraon: – Embryo-fetal toxicity – IV infusion over 30-60 minutes • Warnings and Precauons: – Infusion-Related Reacons • Storage: – Hypersensivity Reacons/Anaphylaxis – Refrigerator: 24 hours • Dose Adjustments: None – No informaon available in CrCl < 30 or hemodialysis • Drug Interacons: None

39 40 Perjeta(R) [package insert]. San Francisco, CA: Genentech, Inc; 2013. Perjeta(R) [package insert]. San Francisco, CA: Genentech, Inc; 2013.

Chronic Lymphocyc Leukemia (CLL) Relapsed or Refractory CLL

• Non-Hodgkin’s • FCR regimen (fludarabine/cyclophosphamide/ lymphoma (NHL) rituximab) • 7% of NHL • Pentostan + cyclophosphamide +/- rituximab • Most common adult • OFAR regimen (oxaliplan/fludarabine/ leukemia cytarabine/rituximab) • Abnormal lymphocytes • High-dose Methylprednisolone + rituximab found in bone marrow • Alemtuzumab and blood

41 42 Clinical Pracce Guidelines. Naonal Comprehensive Cancer Network, 6 Jan. 2015. Web. 1 Feb. 2015. Clinical Pracce Guidelines. Naonal Comprehensive Cancer Network, 6 Jan. 2015. Web. 1 Feb. 2015

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17p Deleon Imbruvica® (ibrunib)

• 17p or TP53 gene mutaon have poor • Inhibitor of Bruton’s tyrosine kinase (BTK) outcomes with convenonal treatment enzymac acvity – Lack wild-type p53 funcon, an important • BTK acvates pathways necessary for B-cell pathway for mediang the cytotoxicity of purine trafficking, chemotaxis, and adhesion analogs • Inhibits B-cell proliferaon and survival • FCR regimen: CR only achieved in 1/22 • paents with deleon 17p Previously FDA approved for treatment of Mantle Cell Lymphoma who had received at • Bendamusne + Rituximab: CR achieved in 0/8 least 1 prior therapy paents with deleon 17p

43 44 Clinical Pracce Guidelines. Naonal Comprehensive Cancer Network, 6 Jan. 2015. Web. 1 Feb. 2015 Byrd, John C., et al. New England Journal of Medicine 369.1 (2013): 32-42. Web.

Ibrunib Approval in CLL Methods

• Assess safety, efficacy, pharmacokinecs, and • Fixed dose of 420mg or 840mg daily pharmacodynamics of ibrunib • Administered connuously unl onset of • Single-arm, mulcenter, phase 1b-2 trial disease progression or unacceptable toxicity • Inclusion criteria: – Relapsed or refractory CLL – A need for treatment – Adequate renal and hepac funcon – Absence of acve infecon – At least 2 previous therapies, including a purine analogue, or lack of response to a chemoimmunotherapy regimen

45 46 Byrd, John C., et al. New England Journal of Medicine 369.1 (2013): 32-42. Web. Byrd, John C., et al. New England Journal of Medicine 369.1 (2013): 32-42. Web.

Results: Efficacy Results: Safety

• Received a median of 4 previous therapies • Modest AEs: • Overall response rate: 71% (including – Most AEs were grade 1-2, most commonly complete and paral responses) diarrhea, fague, upper respiratory tract infecon – • 17p deleon response rate: 68% Most common grade 3-4 AEs: neutropenia (15), pneumonia (10), hypertension (4) • Disease progression developed in 11 paents • Reasons for treatment disconnuaon: (13%) during follow-up – Disease progression: 11/85 – 10/11 had 17p or 11q deleons – Paent’s or invesgator’s decision: 13/85 – AEs: 6/85 • 2 from 420mg dose cohort, 4 from 840mg dose cohort 47 48 Byrd, John C., et al. New England Journal of Medicine 369.1 (2013): 32-42. Web. Byrd, John C., et al. New England Journal of Medicine 369.1 (2013): 32-42. Web.

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Addional Prescribing Informaon Assessment Quesons

• Warnings and Precauons: True or False: Pertuzumab has a new – Hemorrhage – Infecons indicaon for neoadjuvant therapy in HER2- – Cytopenias posive breast cancer. – Atrial Fibrillaon – Second Primary Malignancies – Tumor Lysis Syndrome (TLS) – Embryo-fetal toxicity • Dose Adjustments: – Child-Pugh Class A: 140mg daily – Child-Pugh Classes B and C: not recommended • Drug Interacons: – Strong CYP3A inhibitors or inducers – Reduce ibrunib dose with strong CYP3A inhibitors

49 50 Imbruvica(R) [package insert]. Sunnyvale, CA: Pharmacyclics, Inc; 2015.

Assessment Quesons Assessment Quesons

True or False: Perjeta (pertuzumab) has a True or False: Blincyto (blinatumomab) has new indicaon for neoadjuvant therapy in been approved for paents with Ph+ relapsed HER2-posive breast cancer. or refractory B-cell ALL.

Answer: True

51 52

Assessment Quesons Assessment Quesons

True or False: Blincyto (blinatumomab) has True or False: Synribo (omacetaxine) is been approved for paents with Ph+ relapsed intended to be used in paents whose cancer or refractory B-cell ALL. progressed aer treatment with at least two TKIs. Answer: False Approval was for Ph- relapsed or refractory B-cell ALL.

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Assessment Quesons

True or False: Synribo (omacetaxine) is intended to be used in paents whose cancer progressed aer treatment with at least two TKIs.

Answer: True

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10