A Multicenter, Randomized, Open-label, Phase 2 Study of Carfilzomib With or Without ARRY-520 in Patients With Advanced Multiple Myeloma

Summary

This multicenter, randomized, open-label, Phase 2 study is designed to assess the efficacy, safety and PK of carfilzomib (+-) aRRY-520 in approximately 75 patients with multiple myeloma who have received at least 2 prior treatment regimens (including bortezomib and an immunomodulatory agent [iMiD]) and have disease refractory to their last myeloma therapy. eligible patients will be stratified by bortezomib-refractory disease status and randomized in a 2:1 ratio to receive carfilzomib + aRRY-520 (~50 patients) or single-agent carfilzomib (~25 patients). The primary endpoint is PFS. no formal comparisons will be made between treatment arms. Crossover from single-agent carfilzomib to carfilzomib + aRRY-520 will be allowed upon confirmation of disease progression per the international Myeloma Working Group (iMWG) criteria.

Patients randomized to treatment with carfilzomib + aRRY-520 will receive the following per
28-day cycle:
* aRRY-520: 1.5 1.25 mg/m2/day administered iV over 1 hour (+-) 10 minutes on Days 1, 2,
15 and 16 of each cycle.
* Carfilzomib: administered as described above. Carfilzomib administration will be initiated
within 1 hour after the end of the aRRY-520 infusion.
* Filgrastim prophylaxis: administered subcutaneously (SC) per the product prescribing
information and institutional guidelines, starting on Day 3 and Day 17 of each cycle (each
for a total of 5 days).
note: Patients randomized to carfilzomib + aRRY-520 who initiated study treatment under
Version 2 or Version 3 of the protocol (aRRY-520 dose 1.5 mg/m2/day) are permitted to continue
to receive aRRY-520 at that dose unless they meet the protocol-specified criteria for dose
reduction.

endpoints
Primary:
[?] PFS

Secondary:
[?] PFS rate at 6 months
[?] oRR
[?] Duration of response (DoR)
[?] Time to best response
[?] Clinical benefit rate (CBR)
[?] Disease control rate (DCR)
[?] Safety
[?] PK parameters of aRRY-520, carfilzomib and carfilzomib-M14 in
patients treated with carfilzomib + aRRY-520

exploratory:
[?] CYP2C19 genotype
[?] Baseline and postdose levels of aaG
[?] Free concentration of aRRY-520 in plasma

Treatment with carfizomib alone is standard of care for patients being recruited for this study.

Participant Eligibility

(1) Provide a personally signed and dated informed consent form prior to initiation of any
study-related procedures that are not considered standard of care.

(2) Male or female >= 18 years of age at time of informed consent.

(3) Patients with confirmed multiple myeloma whose treatment history must include all of
the following:
a. Received at least 2 prior treatment regimens, including bortezomib and an IMiD (e.g., lenalidomide, thalidomide, pomalidomide). Induction therapy and stem cell transplant (+ or -) maintenance are to be considered as a single regimen.
b. Refractory disease, defined as documented disease progression during or within 60 days of completing the last myeloma therapy.

(4) Measurable multiple myeloma disease, defined as meeting at least 1 of the following
criteria within 14 days prior to randomization:
a. A monoclonal Ig (M-protein) concentration on serum protein electrophoresis (SPEP) of >= 0.5 g/dL.
b. Measurable urinary light chain secretion by quantitative analysis using urine protein electrophoresis (UPEP) of >= 200 mg/24 hours.
c. Involved serum free light chain (FLC) level >= 10 mg/dL, provided the serum FLC ratio is abnormal.

(5) Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2 within
14 days prior to randomization.

(6) Adequate hematology laboratory values within 14 days prior to randomization:
a. Neutrophils >= 1.5 x 109/L without growth factor support (defined as no growth factor administration for at least 14 days prior to observation). If the bone marrow contains >= 50% plasma cells, a neutrophil count of >= 1.0 x 109/L is allowed.
b. Platelets >= 75 x 109/L. If the bone marrow contains >= 50% plasma cells, a platelet count of >= 50 x 109/L is allowed.

(7) Adequate hepatic and renal function laboratory values within 14 days prior to randomization:
a. Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) <= 2.5 x the upper limit of normal (ULN).
b. Total bilirubin <= 1.5 mg/dL.
c. Calculated (Cockcroft and Gault formula) or measured creatinine clearance >= 25 mL/min.

(8) Left ventricular ejection fraction (LVEF) >= 40% within 28 days prior to randomization, evaluated by 2-D transthoracic echocardiogram (ECHO) or, if ECHO is not available, by multi-gated acquisition (MUGA) scan.

(9) If patient is female and of childbearing potential, she must have a negative serum beta human chorionic gonadotropin ([BETA]-HCG) test within 14 days prior to randomization and consent to ongoing pregnancy testing during the course of the study.

(10) Male patients must agree to use an effective method of contraception per institutional standard through 90 days after the last administration of study drug and female patients of childbearing potential must agree to use an effective method of contraception per institutional standard through 30 days after the last administration of study drug.

(11) Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests and other study procedures.


Inclusion Criteria for Treatment Crossover
Patients must meet all of the following criteria to be eligible for crossover treatment.
(1) Discontinued single-agent carfilzomib treatment in Clinical Study ARRAY-520-216 solely due to confirmed progressive disease per IMWG criteria.

(2) ECOG performance status of 0, 1 or 2.

(3) LVEF >= 40%, evaluated by ECHO or, if ECHO is not available, by MUGA scan.