Phase 1 Study of the Novel Kinesin Spindle Protein Inhibitor Filanesib + in Patients with Relapsed and/or Refractory (RRMM)

Jatin J. Shah1, Lei Feng2, Sheeba K. Thomas1, Donna Weber1, Michael Wang1, Elisabet E. Manasanch1, Kathleen Mendoza1 and Robert Z. Orlowski1

1Department of Lymphoma/Myeloma and 2Department of Biostatistics The University of Texas MD Anderson Cancer Center Background

• Filanesib (ARRY‐520) ‐ a kinesin spindle protein (KSP) inhibitor targeting KSP which is a microtubule motor protein critical to the function of proliferating cells

• The ORR as a single agent was 16% and CBR of 19% in phase 2 single arm single study of filanesib in RRMM • Low AAG selected pt population (21/34): ORR was 24% and CBR of 29% • Preclinical data support thecombination between filanesib and PI KAS‐6 2000 vehicle BTZ • Carfilzomib (Car) ‐ an irreversible proteasome 3 1600 ARRY‐520 mm

ARRY‐520 + BTZ inhibitor (PI) with single agent activity in 1200

2 2 volume, RRMM at 27 mg/m as well as 56 mg/m 800

in combination with . tumor 400

ARRY‐520 20 40 60 80 days after initiation of treatment Background

• Preliminary results of phase 1 dose escalation study previously presented demonstrated that Carfilzomib 20/27 mg/m2 can be safely combined with Filanesib 1.5 mg/m2 with growth factor support

• Subsequently proceeded with enrollment in dose expansion to further characterize the clinical activity and side effect profile • Enrolled in 2 cohorts of patients: Car naïve and Car refractory pts

• Higher doses of carfilzomib in earlier course of disease was subsequently established to be both safe with increased activity and confirmed in ENDEAVOR study establishing Car 56 mg/m2/dex as a SOC option in RRMM

• No DLT were encountered in the initial dose escalation of carfilzomib + filanesib and MTD was not reached allowing for potentially increased dose of carfilzomib. • Proceeded with second dose escalation, with increasing dose of carfilzomib Study Objectives

Primary Objectives: • To determine the MTD and the safety/tolerability of Carfilzomib and filanesib in RRMM

Secondary Objectives: • To determine:  efficacy as measured by the overall response rate (ORR)  time to progression  progression free survival  time to next therapy Study Design

Part A Part B • 3+3 Dose Escalation Study with fixed dose of • 3+3 Dose Escalation Study with escalating doses carfilzomib, escalating doses of filanesib of Carfilzomib • Dexamethasone sparing (4 mg) • Dexamethasone sparing (4 mg)

Dose Filanesib Carfilzomib Level mg/m2/day IV mg/m2/day IV Dose Filanesib Carfilzomib −1 0.5 20/27 Level mg/m2/day IV mg/m2/day IV 1 0.75 20/27 1 1.5 20/36 2 1.00 20/27 2 1.5 20/45 3 1.25 20/27 3 1.5 20/56 4 1.5 20/27

Dose Expansion Dose Expansion Dose Expansion Dose Expansion Car Naïve Car Refractory Car Naïve Car Refractory N=14 N=14 N=14 N=14 Dosing Schema

Induction Therapy Cycle 1‐8: 28 day cycle Carfilzomib (30 min infusion) + Dexamethasone 4 mg (IV/PO)

1 2 8 9 15 16

ARRY‐520 (IV)

1 2 15 16

Neupogen: Days 3‐7 and 17‐21 Maintenance Therapy > 8 cycles

Carfilzomib: Days 1,2,15,16 ARRY‐520: Days 1,2,15,16

Patients treated until progressive disease Key Inclusion Criteria

• Patients with relapsed/refractory multiple myeloma

• Prior treatment must have included at least one full cycle of a and at least one full cycle of an IMiD

• Patients must be refractory or intolerant to therapy

• Patients who have had prior ARRY‐520 and carfilzomib will be allowed in the dose escalation phase, however prior ARRY‐520 and carfilzomib will be excluded in the dose expansion cohort 1 of Part A.

• Pts had to be ineligible for autologous stem cell transplant (ASCT)

• Adequate cardiac, pulmonary and renal function • Adequate hematology laboratory values  Absolute neutrophil count (ANC) ≥1.5 × 109/L  Platelets ≥75 × 109/L Patient Demographics

Dosed Patients N = 58

Gender Male: 37 (64%) Age, median 63 (38 to 84) African American 15 (26%) Asian 2 (3%) Race Hispanic 8 (14%) White 32 (55%) Prior Lines of Therapy 5 (1 to 15) median I: 13 (22%) II: 9 (16%) ISS Stage III: 11 (19%) UNK: 25 (43%) FISH / Cytogenetics

Abnormality N=58

t(11;14) / amp CCND1 17 (29%) Del(13) / RB1 loss 18 (31%) CKS1B amplification 7 (12%) Del(17p) / p53 loss 5 (9%)

Prior Therapies

N = 58 Revlimid Bortezomib Carfilzomib Filanesib

Naïve 1 2% 36 62% 50 86%

Refractory 43 74% 41 70% 22 38% 8 14%

Intolerant 12 20% 15 27%

Unavailable 2 3% 2 3% Part A: Fixed Dosed Carfilzomib 20/27 mg/m2 (n=20 + 25,;45) Filanesib Dosing Patient DLT Cohort 1: 0.75 mg/m2 30 Non Neutropenic Cohort 2: 1.0 mg/m2 61 Fever Parainfluenza 3 Cohort 3: 1.25 mg/m2 5* 0 Non Neutropenic Cohort 4: 1.5 mg/m2 61 Fever PNA

Carfilzomib 27 mg/m2 + Filanesib 1.5 mg/m2 was safe and well tolerated

Dose Expansion Dose Expansion Car Naïve Car Refractory N=14/14 N=11/14

* 2 pts were not evaluable for DLT and replaced (LTFU and WC during C1) Part B: Fixed Dosed Filanesib 1.5 mg/m2 (n=13)

Carfilzomib dosing Patient DLT Cohort 1: 36 mg/m2 30

Cohort 2: 45 mg/m2 30 Cohort 3: 56 mg/m2 7* 0

Carfilzomib 56 mg/m2 + Filanesib 1.5 mg/m2 is safe and well tolerated

Dose Expansion Dose Expansion Car Naïve Car Refractory N=14 planned N=14 planned

* 1 pt was not evaluable for DLT and replaced (rapid PD after D2 of therapy) Clinical Activity Part A ( ITT)

Part A Carfilzomib 27 mg/m2 + Filanesib 1.5 mg/m2 (escalation + expansion: n=45)

Carfilzomb naïve Carfilzomib refractory (n=34) (n=11) nCR/CR 2 VGPR 1 PR 12 MR 3 SD 11 6 PD 3 5 Unknown/inevaluable 2

Carfilzomib naïve: ORR on an ITT was 44% (15/34) Response evaluable (n=32): 47% (no dexamethasone and carfilzomib 27 mg/m2 in BZ refractory/intorelant)

Carfilzomib Refractory; ORR was 0% Part A: PFS/OS Carfilzomib naïve (n=34)

Progression Free Survival for Carfilzomib Naive Overall Survival for Carfilzomib Naive

1.0 1.0

0.8 0.8

0.6 0.6 Probability Probability 0.4 0.4

0.2 0.2

0.0 0.0

0 6 12 18 24 30 36 42 0 6 12 18 24 30 36 42 Time (Months) Time (Months)

median overall survival time has not median progression free survival time was been reached median follow‐up time 12.9 months (95% CI: 6.44, NA) was 24 months Clinical Activity Part B (ITT)

Part B: Carfilzomib 36‐56 mg/m2 + Filanesib 1.5 mg/m2

Response n=13 nCR/CR VGPR 1 (car ref) PR 3 (car ref: n=1) MR SD 6 (all car ref) PD 3 (all car ref) Unknown/inevaluable

Carfilzomib naïve: 2/2 pt with PR

Carfilzomib Refractory: 2/11 had ≥PR Cycles Administered N = 377; Median 3.5 (0.5 – 31)

12 * * Active Patient 10 * * 8 *

6 * * 4 * Frequency *

2 * * * *

0 0.5123456789111213141617262731 Number of cycles per patient Hematologic Adverse Events

Grade 1Grade 2Grade 3Grade 4 Anemia 13 22 17 1

Thrombocytopenia 17 8 14 13

Neutropenia 8 12 6 18

Cytopenias are transient, and limited dose reductions or delays in therapy

Recover by D1 on next cycle

Growth factor support used in all patients Non‐hematologic Adverse Events Reported in >30% of patients

Adverse Event G1 G2 G3 G4 Fatigue 17 24 6 0 Myalgia 18 15 4 0 Diarrhea 15 18 1 0 Hypomagnesemia 33 0 0 0 Hyperuricemia 29 0 2 1 Creatinine Increased 18 9 1 1 Hypoalbuminemia 15 13 0 0 Alkaline Phosphatase Increased 27 0 0 0 Dyspnea 11 13 3 0 Peripheral Sensory Neuropathy 18 7 1 0 Nausea 11 11 3 0 Aspartate Aminotransferase Increased 17 4 1 0 Memory Impairment 19 3 0 0 Constipation 17 4 0 0 Blurred Vision 12 8 0 0 Dizziness 15 4 1 0 Edema Limbs 14 4 1 0 Dry Eye 15 3 0 0 Non‐hematologic Adverse Events Additional G3/G4/G5 events

Adverse Event G1 G2 G3 G4 G5 Lung Infection 0 1 9 0 0 Serum Lipase Increased 5 3 4 0 0 Febrile Neutropenia 0 0 1 0 1 Hyponatremia 6 0 2 0 0 Sinusitis 0 1 2 0 0 Acute Renal Failure 0 0 0 0 1 Alanine Aminotransferase Increased 13 3 1 0 0 Back Pain 5 3 100 Bacteremia 0 0 1 0 0 Fever 114 100 Fluid Overload 0 0 100 Mucositis Oral 124 100 Sepsis/Pneumonia 0 0 1 0 0 Unintended Pregnancy 0 0 1 0 0 Conclusions

• Enrolled in 2 dose expansion cohorts of part A with filanesib + cafilzomib 27 mg/m2 In patients with RRMM, bortezomib refractory/intolerant: – Carfilzomib naïve: ORR on an ITT was 44% (15/34) – Response evaluable patient population (n=32) the ORR was 47% – PFS was 12.7 months and OS not reached in 24 months

– Carfilzomib refractory: ORR was 0% – No new additional toxicities were seen in dose expansion

– Data from our Phase I trial lead to a randomized phase II study of carfilzomib vs carfilzomib/filanesib

• Subsequently show in Part B, that full dose filanesib, 1.5 mg/m2,can be safely combined with full dose carfilzomib 56 mg/m2, in a steroid sparing regimen (dex 4 mg) with no DLT. • Further explore the activity in a dose expansion in 1‐3 lines of prior therapy similar to patient population on the ENDEAVOR study Acknowledgment

• Robert Z. Orlowski, Donna Weber, Sheeba Thomas, Elisabet Manasanch, Michal Wang and colleagues at M D Anderson Myeloma Section

• Patients/Caregivers/Families

• Research staff

MD Anderson Lymphoma/Myeloma Fellowship information:

http://bit.ly/LymphomaMyelomaFellowship

[email protected]