Advances in the Treatment of Hematologic Malignancies. Disclosures

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1 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

2 Objectives Discuss the pharmacologic principles of several new agents approved for use in hematologic malignancies Drug class Mechanism of action Clinical trial 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

3 2014 Novel Drug Approvals Nature Reviews Drug Discovery 14, 77 81(2015) doi: /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 palonosetron (Akynzeo) Nausea/vomiting October 2014 Blinatumomab (Blincyto) Acute Lymphoblastic Leukemia, Ph December 2014 Ph-= Philadelphia Chromosome-negative 3

4 Siltuximab (Sylvant ) FDA Approval: April 23, 2014 First in class, accelerated approval for treatment of Multicentric Castleman s Disease Chimeric monoclonal antibody 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, Interleukin-6 (IL-6) 4

5 Classifications Castleman s Disease Unicentric (UCD) Multicentric (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 Oct;21(4):266-78, Expert Rev. Hematol. 7(5), (2014). 5

6 Role of IL 6 Trends Immunol Nov;33(11):571-7 Siltuximab Mechanism Chimeric IL-6 monoclonal antibody 6

7 Study design Siltuximab in MCD 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 11 mg/kg IV q3 weeks n=53 Placebo + BSC q3 weeks n=26 BSC= Best Supportive Care Lancet Oncol Aug;15(9): Days to Treatment Failure HR (1.068 to 7.206) Results Disease Related Overall Symptom Score 37% difference p= Siltuximab Placebo p value Durable tumor and 34% symptomatic response CR 2% 0 PR 32% 0 Lancet Oncol Aug;15(9):

8 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 Aug;15(9): Dosing and Administration Dose: First drug approved in MCD (HHV8 & HIV ) 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: Janssen Biotech;

9 Dosing and Administration Do not administer with severe infections Infusion reaction rate in 249 patients treated: <5% T 1/2 : 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

10 Belinostat Mechanism Marks P et al. Nature Reviews Cancer 2001;1: Small molecule Belinostat Mechanism 10

11 Inhibition of HDAC 11

12 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 Select Grade 3 Adverse Events O Connor OA et al. Proc ASCO 2013; Abstract

13 Dosing and Administration Indication: Relapsed or refractory PTCL Dosing: 1000 mg/m 2 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

14 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: adhesion Idelalisib Indications 1 Relapsed CLL in combination with rituximab 2 Relapsed Follicular B cell Non Hodgkin Lymphoma after at least 2 systemic therapies 3 Relapsed SLL after at least 2 systemic therapies 14

15 Idelasilib in CLL 15

16 Outcomes Coutre et al ASCO 2014 Toxicities Coutre et al ASCO

17 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.;

18 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.; Adverse Reactions Diarrhea Pyrexia Fatigue Nausea Cough Pneumonia Abdominal pain Chills Rash Neutropenia Hypertriglyceremia Hyperglycemia AST/ALT increases 18

19 Dosing and Administration Starting dose: 150 mg PO BID Take without regard to food, swallow whole Continue until progression or unacceptable toxicity mg, 150 mg tablets Renal Dose Adjustment Hepatic Dose Adjustment No dose adjustment if CrCL 15 ml/min Patients with AST/ALT > 2.5 x ULN and T.Bili > 1.5 x ULN excluded from studies. 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

20 Blinatumomab Mechanism Bispecific CD19 directed CD3 T cell engager Kapoor A, et al. Clinical Cancer Investigation Journal. 2014: 3 (6) 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:

21 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: 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:

22 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 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.; Renal Dose Adjustment Hepatic Dose Adjustment How Supplied Half Life Drug Interactions Blinatumomab No dose adjustment; no information in severe renal impairment (CrCl < 30 ml/min, or HD) No formal studies; drug is degraded into small peptides and amino acids via catabolic pathways, unlikely to need adjustment 35 mcg of lyophilized powder in a singleuse vial for reconstitution, stabilizer 2.11 hours NSAIDS efficacy, Transient eleva on of cytokines may suppress CYP450 enzyme activities Blincyto [package insert]. Thousand Oaks, CA; Amgen Inc.; Kapoor A, et al. Clinical Cancer Investigation Journal. 2014: 3 (6)

23 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.;

24 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 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 (300 mg) Acute 1 st 24 hours Palonosetron (0.5 mg) Delayed 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

25 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

26 Ofatumumab (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, moderatesevere renal impairment or hepatic impairment 26

27 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! 27