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Home , Obinutuzumab, Siltuximab

8/7/2014

Faculty Disclosures NEW DRUG UPDATE

I have no relevant financial interests, Maurice D. Alexander, PharmD, BCOP, CPP arrangements or affiliations with companies or Clinical Specialist, Hematology/Oncology/HSCT other organizations whose products or services University of North Carolina Medical Center/ are discussed in this session. North Carolina Cancer Hospital

August 9, 2014

Objectives New Drug Approvals 2013-2014 Brand Approval Generic Name Company Indication Name Date Gastric or  Identify new drug approvals in hematology/oncology Eli Lilly & gastroesophageal Cyramza 4/21/2014 in the past year Company junction adenocarcinoma  Discuss mechanisms of action, dosing, and major Boehringer Gilotrif 7/12/2013 EGFR-mutated NSCLC toxicities of these agents Ingelheim, Inc. Zykadia 4/29/2014 Novartis ALK+ NSCLC  Review relevant data for newly approved Mantle Cell Lymphoma 11/13/2013 Pharmacyclics, Imbruvica Chronic Lymphocytic agents 2/12/2014 Inc. Leukemia  Understand the role in therapy of newly approved Chronic Lymphocytic Gazyva 11/1/2013 , Inc. agents Leukemia Spectrum Peripheral T-cell Belinostat Beleodaq 7/3/2013 Pharmaceuticals Lymphoma , Multicentric Castleman’s Sylvant 4/23/2014 Inc. Disease www.fda.gov/drugs

Ramucirumab

Medical Oncology  FDA Approval: April 21, 2014  Single agent for advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma NEW DRUG UPDATE  Disease progression on or after prior treatment with fluoropyrimidine- or platinum-containing .

 Human IgG1 Antiangiogenic Monoclonal

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Ramucirumab Mechanism of Action Ramucirumab Dosing and

 Dosing: 8 mg/kg IV over 60 minutes every 2 weeks until disease progression or unacceptable toxicity

 Preparation and Administration:  Preparation: Do not dilute with dextrose containing solutions  Premedication: diphenhydramine ± acetaminophen and dexamethasone (if previous Grade 1 or 2 infusion reaction)

 Pharmacokinetics  Receptor-mediated clearance  Half-life: 123-318 hours

Clarke et al. J Gastrointest Oncol 2013;4(3):253-263. Cyramza™ (Ramucirumab) infusion. Indianapolis (IN): Eli Lilly and Company; 2014 June. Package Insert.

Ramucirumab: REGARD Trial Ramucirumab: REGARD Trial

Ramucirumab monotherapy for previously treated R N = 238 advanced gastric or GEJ adenocarcinoma N = 355 A Ramucirumab 8 mg/kg IV q2 Fuchs CS et al. Lancet 2014;383:31-39 - Advanced gastric N or GEJ wks + Best S D adenocarcinoma supportive care U O - Progression after R M  Design: International, randomized, multicenter, 1st line platinum- V I 2:1 placebo-controlled, phase III trial or I Z fluor0pyrimidine V –containing A N = 117 A regimen T Placebo + Best  Objective: To assess whether ramucirumab supportive care L - ECOG 0-1 I prolonged survival in patients with advanced gastric O cancer N

Fuchs CS et al. Lancet 2014;383:31-39. .

REGARD Trial Results: Overall Survival REGARD Trial Results: Adverse Events

Median OS: Ramucirumab (%) Placebo (%) - Ramucirumab: 5.2 months - Placebo: 3.8 months All Grade ≥3 All Grade ≥3 Hypertension 16 8 8 3

Bleeding/hemorrhage 13 3 11 3

Arterial thromboembolism 2 1 0 0

Venous thromboembolism 4 1 7 4

Proteinuria 3 <1 3 0

Gastrointestinal perforation <1 <1 <1 <1

Fistula formation <1 <1 <1 <1

Infusion-related reaction <1 0 2 0

Fuchs CS et al. Lancet 2014;383:31-39. Fuchs CS et al. Lancet 2014;383:31-39. . .

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Ramucirumab Role in Therapy Afatinib

Trial Patients Treatment Overall Survival  FDA Approval: July 12, 2013 Kang et al. Docetaxel or Irinotecan + 5.3 mo vs. 3.8 mo  First-line treatment of patients with metastatic non-small cell N = 202 JCO 2012 BSC vs. Placebo + BSC HR: 0.657; p = 0.007 lung cancer (NSCLC) whose tumors have epidermal growth factor Ford et al. receptor (EGFR) exon 19 deletions or exon 21 substitution Lancet Oncol Docetaxel + ASC vs. 5.2 mo vs. 3.6 mo mutations N = 168 2014 Placebo + ASC HR: 0.67; p = 0.01  EGFR PCR kit approved for detection of these mutations (COUGAR-02)

Fuchs et al. Ramucirumab + BSC vs. 5.2 mo vs. 3.8 mo Lancet 2014 N = 355  Placebo + BSC HR: 0.776; p = 0.047 Tyrosine kinase inhibitor of EGFR (REGARD) Wilke et al. Ramucirumab + 9.63 mo vs. 7.36 mo ASCO GI 2014 N = 655 Paclitaxel vs. Paclitaxel HR: 0.807; p = 0.0169 (RAINBOW) BSC = Best Supportive Care; ASC = Active Symptom Control

Afatinib Mechanism of Action Afatinib Dosing and Pharmacokinetics

 Dosing: 40 mg PO daily until disease progression or intolerance

 Absorption  Steady state achieved within 8 days  High-fat meal: decreased Cmax by 50% and AUC by 39%

 Metabolism  Minimal enzymatic metabolism  Pgp inhibitors: increased exposure by 48%  Pgp inducers: decreased exposure by 34%

 Elimination  Half-life: 37 hours  85% excreted via feces; 4% in urine  88% recovered dose was parent compound

www.onclive.com Gilotrif™ (Afatinib). Ridgefield (CT): Boehringer Ingelheim Pharmaceuticals, Inc; 2014 April. Package Insert.

Afatinib: LUX-Lung 3 Trial Afatinib: LUX-Lung 3 Trial

Afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations R A N = 230 N Afatinib 40 mg N = 345 D PO daily Sequist LV et al. J Clin Oncol. 2013;31(27):3327-34. - Activating EGFR O mutation M P - Treatment-naïve I 2:1 F  Design: Multinational, randomized, open-label advanced NSCLC N = 115 (adenocarcinoma) Z Cisplatin 75 S phase III trial - ECOG 0-1 A mg/m2 + T Pemetrexed I 500 mg/m2  Objective: To assess if afatinib improved PFS over O once every 21 chemotherapy in EGFR-mutated NSCLC N days x 6 cycles

Sequist LV et al. J Clin Oncol. 2013;31(27):3327-34.

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LUX-Lung 3 Trial: Progression-Free Survival LUX-Lung 3 Trial: Adverse Events

All Grades (%) ≥ Grade 3 (%) Diarrhea 95.2 14.4 Rash/acne 89.1 16.2 Stomatitis/mucositis 72.1 8.7 Paronychia 56.8 11.4 Dry Skin 29.3 0.4 Decreased appetite 20.5 3.1

Other Warnings and Precautions Bullous and exfoliative skin disorders: <1% Interstitial Lung Disease: 1.5% Hepatic toxicity: 10.1% Keratitis: <1% Sequist LV et al. J Clin Oncol. 2013;31(27):3327-34. Sequist LV et al. J Clin Oncol. 2013;31(27):3327-34. Gilotrif™ (Afatinib). Ridgefield (CT): Boehringer Ingelheim Pharmaceuticals, Inc; 2014 April. Package Insert.

Afatinib Dose Modifications Afatinib Role in Therapy

 Interrupt therapy: Trial Patients Treatment Results  Any Grade 3+ adverse reaction Miller et al. OS: 10.8 mo vs. 12.0 mo Lancet Oncol Afatinib + BSC vs. HR: 1.08; p = 0.74  Diarrhea: Grade 2+ persisting for 2+ days while on treatment N = 585 2012 Placebo + BSC PFS: 3.3 mo vs. 1.1 mo  Cutaneous reactions: Grade 2+ lasting > 7 days or intolerable (LUX-Lung 1) HR 0.38; p < 0.0001  Renal dysfunction: Grade 2+ Katakami et al. ORR: 8.2% (all PRs) J Clin Oncol N = 62 Afatinib (single-arm) Stable Disease: 57.4% 2013 (Asian)  Resume with 10 mg/day dose reduction: (LUX-Lung 4) PFS 4.4 mo  Resolution of adverse reaction Sequist et al. J PFS: 11.1 mo vs. 6.9 mo Afatinib vs. cisplatin + Clin Oncol 2013 N = 345 HR: 0.58;  Return to baseline pemetrexed (LUX-Lung 3) p < 0.001  Improvement of adverse reaction to Grade 1 Wu et al. Lancet PFS: 11.0 mo vs. 5.6 mo N = 364 Afatinib vs. cisplatin + Oncol 2014 HR: 0.28; (Asian) gemcitabine (LUX-Lung 6) p < 0.0001

Ceritinib Ceritinib Mechanism of Action

 FDA Approval: April 29, 2014  Accelerated approval for treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic NSCLC who have progressed on or are intolerant to

 Anaplastic Lymphoma Kinase (ALK) Inhibitor

Shaw et al Clin Cancer Res 2011;17(8):2081-6.

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Ceritinib Dosing and Pharmacokinetics Ceritinib Pharmacokinetics

 Dosing: 750 mg PO daily  Metabolism: extensively hepatic via CYP3A

 Time to Css: 15 days  Strong inhibitor: 3-fold increase in AUC; 22% increase in Cmax  Food-effect  Strong inducer: 70% decrease in AUC; 44% decrease in Cmax  Substrate of P-gp; no inhibitory activity AUC (% increase) Cmax (% increase)

High-fat meal 73% 41% Low-fat meal 58% 43%  Elimination:  600 mg + food > 750 mg fasting  Half-life: 41 hours  Take on EMPTY STOMACH!  92% recovered in feces (68% as parent compound)  pH-dependent solubility  1.3% recovered in urine  Caution gastric acid reducing agents

Zykadia™ (Ceritinib). East Hanover (NJ): Novartis Pharmaceutical Corp; 2014 April. Package Insert. Zykadia™ (Ceritinib). East Hanover (NJ): Novartis Pharmaceutical Corp; 2014 April. Package Insert.

Ceritinib: ASCEND-1 Trial ASCEND-1 Trial Results: Response

Ceritinib in advanced ALK-rearranged NSCLC  MTD = 750 mg PO daily Kim D et al. J Clin Oncol. 2014;32:5s (suppl; abst 8003)  N = 255 patients treated at 750 mg PO daily  163 (64%) pts with previous ALK-inhibitor therapy  Design: Multinational, single-arm, open-label dose-  Median follow-up: 4.5 months escalation study with expansion phase ALK inhbitior ALK inhibitior All pretreated naïve N = 180 N = 121 N = 59  Objective: to determine maximum tolerated dose ORR (%) 55.4 69.5 60.0 (MTD) and antitumor activity of ceritinib DOR (months) 7.4 NR 9.7 Time to 1st response 6.1 6.1 6.1 (weeks) PFS (months) 6.9 NR 7.0

NR = Not Reached Kim D et al. J Clin Oncol. 2014;32:5s (suppl; abst 8003).

ASCEND-1 Trial Results: Adverse Events Ceritinib Dosing Adjustments Adverse Event Dosing Recommendation Hepatic All Grade Hold until back to baseline or ≤3x ULN; Adverse Event Grades ALT/AST >5x ULN + T. bili ≤ 2x ULN 3-4 (%)  Other Warnings and resume with 150-mg reduction (%) Precautions: ALT/AST >3x ULN + T. bili >2x ULN Permanently discontinue Diarrhea 86 6  QTc prolongation: 4% Cardiovascular Nausea 80 4  Bradycardia: 3% Hold until QTc back to baseline or <481 QTc interval >500 msec x 2 Vomiting 60 4 msec; resume with 150-mg reduction  Vision disorders: 9% Abdominal pain 54 2 Hold until asymptomatic or to HR of ≥60  Interstitial Lung Symptomatic Bradycardia bpm; adjust concomitant medications ALT increased 80 27 Disease/Pneumonitis: 4% Gastrointestinal AST increased 75 13  Rash: 16% Hold until improved; resume with 150- T. Bili increased 15 1 Severe/Intolerable N/V/D  Neuropathy: 17% mg reduction Hyperglycemia 49 13 Endocrine Hold until controlled; resume with 150- Hypophosphatemia 36 7 Hyperglycemia >250 mg/dL mg reduction Kim D et al. J Clin Oncol. 2014;32:5s (suppl; abst 8003). ™ Zykadia™ (Ceritinib). East Hanover (NJ): Novartis Pharmaceutical Corp; 2014 April. Package Insert. Zykadia (Ceritinib). East Hanover (NJ): Novartis Pharmaceutical Corp; 2014 April. Package Insert.

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Ceritinib Role in Therapy Audience Response Question

 Ceritinib vs. standard chemotherapy (pemetrexed or docetaxel) Which of the following is true about ceritinib? in ALK-positive advanced NSCLC who have been treated

previously with chemotherapy (platinum doublet) and crizotinib (NCT01828112) A. Ceritinib has less potent inhibition of ALK than crizotinib  Ceritinib vs. standard chemotherapy in previously untreated B. Ceritinib should be taken on an empty stomach patients with ALK-rearranged, Stage IIIB or IV NSCLC (NCT01828099) C. Ceritinib exhibits no response in patients previously treated with an ALK-inhibitor

D. Ceritinib should be taken with a high-fat meal

www.clinicaltrials.gov

Ibrutinib

Malignant Hematology  FDA Approval:  November 13, 2013: Granted accelerated approval for mantle cell lymphoma (MCL) patients who have received at least one prior NEW DRUG UPDATE therapy  February 12, 2014: Granted accelerated approval for chronic lymphocytic leukemia (CLL) patients who have received at least one prior therapy

 Bruton’s Tyrosine Kinase (BTK) Inhibitor

Ibrutinib Mechanism of Action Ibrutinib Dosing and Pharmacokinetics

 Dosing  Mantle Cell Lymphoma: 560 mg PO daily  Chronic Lymphocytic Leukemia: 420 mg PO daily

 Food Effect: Increase AUC 2-fold

 Metabolism: Extensively hepatic via CYP3A, CYP2D6  Strong CYP3A inhibitor: increases AUC 24-fold; Cmax 29-fold  Moderate CYP3A inhibitor: increases AUC 6 to 9-fold  Strong CYP3A inducer: 10-fold decrease in concentrations  Active metabolite: 15x less inhibitory activity than ibrutinib

 Elimination  Half-life: 4-6 hours  80% excreted in feces; <10% in urine

www.organic-reaction.com/medicinal-chemistry-lectures/btk Imbruvica® (Ibrutinib). Sunnyvale (CA): Pharmacyclics, Inc; 2014 Feb. Package Insert.

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Ibrutinib in Mantle Cell Lymphoma Ibrutinib in MCL: Response

Targeting BTK with ibrutinib in relapsed or refractory N = 111 mantle-cell lymphoma At least one prior therapy (no more than 5); ECOG 0-2 Ibrutinib 560 mg PO daily Median follow-up = 15.3 months Wang ML et al. N Engl J Med 2013;369(6):507-16 No Prior All Bortezomib Bortezomib (N = 111) (N = 63) (N = 48)  Design: International, open-label, phase 2, single ORR (%) 68 67 68 arm study CR (%) 19 23 21 PR (%) 49 44 47  Objective: To determine the ORR of ibrutinib in DOR (months) 15.8 NR 17.5 relapse/refractory MCL. PFS (months) 7.4 16.6 13.9 OS NR NR NR

NR = not reached Wang ML et al. N Engl J Med 2013;369(6):507-16.

Ibrutinib in CLL Ibrutinib in CLL

N = 85 previously treated CLL patients Targeting BTK with ibrutinib in relapsed chronic 420 mg (n = 51) vs. 840 mg (n = 35) lymphocytic leukemia

PK: Similar PK profile Byrd JC et al. N Engl J Med. 2013(1);369:32-42. PD: Full BTK occupancy at both doses Similar Response Rates (ORR: 71%)

420 mg  Design: Multicenter, single-arm, phase 1b-2 study N = 48 previously treated CLL patients ECOG 0-1 Median # prior treatments = 4  Objective: To assess safety, efficacy, pharmacokinetics ORR 58.3% and pharmacodynamics of ibrutinib in relapsed CLL DOR 5.6 – 24.2 months

Byrd JC et al. N Engl J Med. 2013(1);369:32-42.

Ibrutinib Adverse Events Ibrutinib Dose Adjustments

 Interrupt therapy for: All Adverse Events (≥ 20%) ≥ Grade 3 (≥5%)  ≥ Grade 3 non-hematological adverse event Pneumonia  ≥ Grade 3 or greater neutropenia with fever/infection Neutropenia Skin Infections  Grade 4 hematologic toxicity Anemia Atrial Fibrillation  Resume therapy once toxicity has resolved to Grade 1 or Fatigue Fatigue baseline Diarrhea Diarrhea Toxicity MCL CLL Abdominal Pain Abdominal Pain Occurrence 560 mg PO Qday 420 mg PO Qday Nausea/Vomiting Bleeding events Dose at reinitiation (mg) 1st 560 420 Peripheral Edema 2nd 420 280 URTI 3rd 280 140 Bruising 4th Discontinue Discontinue

Imbruvica® (Ibrutinib). Sunnyvale (CA): Pharmacyclics, Inc; 2014 Feb. Package Insert. Imbruvica® (Ibrutinib). Sunnyvale (CA): Pharmacyclics, Inc; 2014 Feb. Package Insert.

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Ibrutinib Role in Therapy Audience Response Question

 RESONATE: Ibrutinib vs. in Patients with Which of the following is NOT true about ibrutinib? Relapsed or Refractory CLL  PFS: HR 0.215, p <0.001; OS: HR 0.434; p = 0.0049 A. Ibrutinib inhibits Bruton’s tyrosine kinase  Ibrutinib Versus Ibrutinib + (i vs iR) in Patients B. CYP3A inhibitors should be cautioned with With Relapsed Chronic Lymphocytic Leukemia (CLL) ibrutinib

C. Ibrutinib is approved for both MCL and CLL in  Rituximab and Hydrochloride, Rituximab and patients who have received at least one prior Ibrutinib, or Ibrutinib Alone in Treating Older Patients With Previously Untreated Chronic Lymphocytic Leukemia therapy D. Ibrutinib is approved at a dose of 560 mg PO daily  RESONATE-2: Ibrutinib vs. in Patients 65 for MCL and CLL Years or Older with Treatment-naïve CLL or SLL

Byrd JC et al. N Engl J Med 2014; Epub May 31, 2014; www.clinicaltrials.gov.

Obinutuzumab Obinutuzumab Mechanism of Action

 FDA Approval: November 1, 2013  In combination with chlorambucil for the treatment of patients with previously untreated chronic lymphocytic leukemia

 Type II anti-CD20 humanized

Mossner E et al. Blood 2010.115:4393-4400; www.targetedonc.com/publications/targeted-therapies-cancer/2014.

Obinutuzumab Dosing and Administration Obinutuzumab for CLL

 Dosing Obinutuzumab plus chlorambucil in patients with CLL  28-day cycles x 6 cycles and coexisting conditions  Premedicate: glucocorticoid, acetaminophen, anti-histamine

Cycle 1 Goede V et al. N Engl J Med. 2014;370:1101-10

Day 1 Day 2 Day 8 Day 15

100 mg 900 mg 1000 mg  Design: Randomized, open-label, multicenter phase 25 mg/hr Initial: 50 mg/hr Initial: 100 mg/hr III trial Max: 400 mg/hr Max: 400 mg/hr

Cycles 2-6  Objective: To evaluate if obinutuzumab provides a Day 1 PFS benefit in previously untreated CLL 1000 mg

Gazyva™ (Obinutuzumab). South San Francisco (CA): Genentech, Inc; 2013 Nov. Package Insert.

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Obinutuzumab for CLL Obinutuzumab in CLL: PFS

N = 118 R Chlorambucil A 0.5 mg/kg PO 781 Patients N days 1 & 15 of - Previously D 28 day cycle untreated CLL O - Cumulative M N = 238 P Illness Rating I 1:2:2 Obinutuzumab F Scale (CIRS) Z + Chlorambucil Score >6 S A - CrCl 30-69 N = 233 T mL/min Rituximab 375 I mg/m2 C1D1; O 500 mg/m2 N C2-6D1 +

chlorambucil

Goede V et al. N Engl J Med. 2014;370:1101-10. Goede V et al. N Engl J Med. 2014;370:1101-10. . .

Obinutuzumab in CLL: PFS Obinutuzumab in CLL: Adverse Events

Obinutuzumab + Chlorambucil Chlorambucil All Grades Grades 3-4 All Grades Grades 3-4 (%) (%) (%) (%)

Infusion-related reactions 69 21 0 0

Neutropenia 40 35 18 16

Anemia 12 5 10 5

Thrombocytopenia 15 11 7 3

Leukopenia 7 5 0 0

Pyrexia 10 <1 7 0

Goede V et al. N Engl J Med. 2014;370:1101-10. Goede V et al. N Engl J Med. 2014;370:1101-10. . .

Obinutuzumab Infusion-Related Reactions Obinutuzumab Boxed Warnings

Premedication Recommendations  Virus (HBV) reactivation  Fulminant hepatitis, hepatic failure, death Patients Premedication Timing  Screen for HBV before initiation of therapy Dexamethasone 20 mg IV 1 hour prior Methylprednisolone 80 mg IV Cycle 1 All Day 1-2 APAP 650 – 1000 mg 30 mins prior  Progressive Multifocal Leukoencephalopathy (PML) Diphenhydramine 50 mg 30 mins prior  Potentially lethal All APAP 650 – 1000 mg 30 mins prior Cycle 1 Day 8, 15 ≥ Grade 1 IRR Diphenhydramine 50 mg 30 mins prior

Grade 3 IRR or Cycles 2-6 Dexamethasone 20 mg IV lymphocyte count 1 hour prior Day 1 Methylprednisolone 80 mg IV > 25 x 109/L

Gazyva™ (Obinutuzumab). South San Francisco (CA): Genentech, Inc; 2013 Nov. Package Insert. Gazyva™ (Obinutuzumab). South San Francisco (CA): Genentech, Inc; 2013 Nov. Package Insert.

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Obinutuzumab Role in Therapy Audience Response Question

 Phase IIIb study evaluating the safety of Which of the following is not recommended for obinutuzumab alone or in combination with obinutuzumab infusion-related reactions? chemotherapy in patients with previously untreated or relapsed/refractory CLL. A. Acetaminophen 650 mg PO

B. Diphenhydramine 50 mg PO  A study evaluating the efficacy and safety of C. Hydrocortisone 100 mg IV obinutuzumab and bendamustine treatment in patients with refractory or relapsed CLL. D. Dexamethasone 20 mg IV

www.clinical trial.gov

Belinostat Belinostat Mechanism of Action

 FDA Approval: July 3, 2014  Accelerated approval for treatment of patients with relapsed or refractory peripheral T-cell lymphoma (PTCL)

 Histone deacetylase (HDAC) inhibitor

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

Belinostat Dosing and Pharmacokinetics Belinostat: BELIEF Trial

 Dosing: 1,000 mg/m2 IV over 30 minutes on days 1-5 Belinostat in relapsed or refractory peripheral T-cell of 21-day cycle. lymphoma.

 Pharmacokinetics O’Connor et al. J Clin Oncol. 2013 (suppl; abstr 8507)  Primary metabolism: UGT1A1  Secondary metabolism: CYP2A6, CYP2C9, CYP3A4  Design: Multicenter phase II single-arm trial  Inhibitory activity: CYP2C8, CYP2C9  Urinary excretion of metabolites  Objective: To assess overall response rate of belinostat in relapsed/refractory PTCL

Beleodaq™ (belinostat). Irvine (CA): Spectrum Pharmaceuticals, Inc; 2014 July. Package Insert.

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Belinostat: BELIEF Trial

 N = 129 Non-Malignant Hematology  Median number of prior therapies: 2  No prior HDAC Inhibitor therapy NEW DRUG UPDATE

Belinostat Adverse Events (≥Grade 3) (n = 120) Thrombocytopenia (7 %) ORR 26% Neutropenia (6 %) CR 10% Anemia (11 %) PR 16% Dyspnea (6 %) DOR (months) 8.3 Fatigue (5 %)

O’Connor O et al. J Clin Oncol. 2013 (suppl; abstr 8507).

Siltuximab Siltuximab Mechanism and Dosing

  FDA Approval: April 23, 2014 Multicentric Castleman’s Disease  Dysregulated IL-6 production  Treatment of patients with Multicentric Castleman’s Disease (MCD) who are HIV-negative and HHV-8-negative  Siltuximab  Binds with high affinity and specificity to IL-6 preventing  Chimeric monoclonal antibody inhibitor of interaction with IL-6 receptors -6  Does not bind to viral IL-6 produced by HHV-8

 Dosing  11 mg/kg IV over 1 hour every 3 weeks  Continue until treatment failure

El-Osta HE et al. The Oncologist 2011;16:497-511.

Siltuximab Drug Interactions Siltuximab for Multicentric Castleman’s Disease

 CYP450 Substrates Efficacy and safety of siltuximab in patients with  Infection and inflammatory stimuli can downregulate CYP450 multicentric castleman’s disease. enzymes in the liver  IL-6 inhibition  restoration of CYP450 activity  Increased metabolism of CYP450 substrates Van Rhee et al. Lancet Oncol 2014; 15:966-74

 Therapeutic drug monitoring  Design: Multicenter, randomized, double-blind,  After initiation of siltuximab placebo-controlled phase 2 study  After cessation of therapy  Objective: To evaluate safety and efficacy of siltuximab in MCD

Sylvant™ (Siltuximab). Horsham (PA): Janssen Biotech, Inc; 2014 June. Package Insert.

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Siltuximab for Multicentric Castleman’s Disease Siltuximab for MCD

R N = 53 Siltuximab Placebo + Endpoint + BSC BSC P-value A Patients N = 53 N = 26 N Siltuximab 11 D mg/kg IV q3 Durable tumor and symptomatic 79 Patients 34 0 0.0012 O wks + Best response (%) - HIV- and HHV-8 Durable M supportive care negative MCD tumor and CR (%) 2 0 -- I 2:1 symptomatic - Symptomatic PR (%) 32 0 -- - Newly diagnosed Z response Tumor response (%) 38 4 0.0022 or pretreated A N = 26 T Placebo + Best Symptom response (%) 57 19 0.0018 I supportive care Complete symptom resolution (%) 25 0 0.0037 O Duration of durable tumor and N 383 -- <0.05 symptomatic response (days)

Van Rhee et al. Lancet Oncol 2014; 15:966-74. Van Rhee et al. Lancet Oncol 2014; 15:966-74.

Siltuximab Adverse Events Siltuximab Role in Therapy

Siltuximab + BSC Placebo + BSC Pretreated Treatment Naïve (n = 53) (n = 26) Siltuximab Placebo Siltuximab Placebo (n = 29) (n = 17) (n = 24) (n = 9) All Grades Grades 3-4 All Grades Grades 3-4 Durable tumor (%) (%) (%) (%) and symptom 34.5% 0% 33.3% 0% response Pruritus 42 0 12 0 Maculopapular rash 34 0 12 0 Prior Therapies Upper Respiratory 36 2 15 4 Corticosteroids: 93.5% Tract Infections Cyclophosphamide: 50%

Weight gain 21 4 0 0 Vincristine: 26.1% Hyperuricemia 11 2 0 0 Rituximab: 17.4%

Van Rhee et al. Lancet Oncol 2014; 15:966-74. Van Rhee et al. Lancet Oncol 2014; 15:966-74.

NEW DRUG UPDATE

Maurice D. Alexander, PharmD, BCOP, CPP Clinical Specialist, Hematology/Oncology/HSCT University of North Carolina Medical Center/ North Carolina Cancer Hospital

August 9, 2014

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