Phase Ib Study of SAR650984 in Combination With Carfilzomib for Treatment of Relapsed or Refractory Multiple Myeloma

NCT02332850 | Active Not Recruiting Phase 1 DMC FDA Drug

• 2 other identifiers: 139511NCI-2015-00712
• Study Type: interventional
• Target: 83
• Locations: 2 countries
• Sites: 6

Brief Summary

This phase Ib trial studies the side effects and best dose of isatuximab when given together with carfilzomib with or without dexamethasone and lenalidomide in treating patients with multiple myeloma that has returned after a period of improvement (relapsed) or has not respond to previous treatment (refractory). Immunotherapy with monoclonal antibodies, such as isatuximab, may induce changes in the body's immune system and may interfere with the ability of tumor cells to grow and spread. Carfilzomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as dexamethasone and lenalidomide, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving isatuximab and carfilzomib with or without dexamethasone and lenalidomide may be a better treatment for patients with multiple myeloma.

Conditions

Multiple Myeloma

Keywords

Relapsed; Refractory

Outcome Measures

Primary Outcomes (3)

• ARM I: Incidence of Dose-Limiting Toxicities (DLT)

  Treatment-related Adverse events resulting in a DLT will be summarized by maximum toxicity grade for each dose level of isatuximab.

  Up to 60 days of the last dose of study drug

• ARM I: Maximum tolerated dose (MTD) of isatuximab

  The MTD is defined as the dose level below the lowest dose that induces dose- limiting toxicity in at least one-third of patients Adverse events will be summarized by maximum toxicity grade and by dose level for each ARM of the trial using NCI CTCAE v4.03

  At the end of Cycle 1 (each cycle is 28 days)

• ARM II: Overall Response Rate (ORR)

  Overall response rate (ORR) as define by the International Myeloma Working Group (IMWG) uniform response criteria of patients obtaining Stringent Complete Remission (sCR), Complete Remission (CR), Very Good Partial Remission (VGPR), Partial Remission (PR), or Minimal Remission (MR)

  Up to 60 days of the last dose of study drug

Secondary Outcomes (10)

• ARM I: Pharmacokinetic (PK) profile of isatuximab

  Baseline, 2 hours mid-infusion, 4, 7, and 11 hours after end of infusion on day 1, days 2, 3, 8, and 15 of course 1, and 0 and 4 hours after end of infusion on day 1 of courses 2-8 (and 0 hours on day 15 of course 2 only)

• ARM I: Overall Response Rate (ORR)

  Up to 60 days of the last dose of study drug

• ARM I: Clinical benefit response (CBR)

  Up to 60 days of the last dose of study drug

• ARM I: Incidence of isatuximab-specific antidrug antibodies (ADA)

  Up to 1 year

• ARM I: Percentage of bone marrow cells expressing cell surface determinant, CD38 and receptor density

  Up to 30 days of the last dose of study drug

Study Arms (2)

Arm I (20 mg dexamethasone, isatuximab, carfilzomib)

EXPERIMENTAL

20 mg dexamethasone IV given on days 1, 8, 15, 22 (pre- SAR650984 and carfilzomib), then dexamethasone 4 IV or PO mg Day 2, 9, 16. All patients will receive a fixed dose of Isatuximab (SAR650984) according to their assigned dose cohort. Patients receive isatuximab IV over 4-6 hours on days 1 and 15 of every cycle for the starting cohort, and days 1, 8, 15, and 22 of cycle 1 and days 1 and 15 of subsequent cycles. Carfilzomib IV will be administered over 10 minutes on days 1, 2, 8, 9, 15, and 16 . Treatment repeats every 28 days for 8 courses in the absence of disease progression or unacceptable toxicity. Patients may continue treatment after 8 courses if clinical benefit is present at the investigator's discretion (carfilzomib may be switched to days 1, 2, 15, and 16 after 8 cycles per investigator discretion).

Biological: Isatuximab; Drug: Carfilzomib; Drug: Dexamethasone

Arm II (40 mg dexamethasone, isatuximab, carfilzomib)

EXPERIMENTAL

40 mg dexamethasone IV given on Days 1, 8, 15 and 22 (use as premed to isatuximab). All patients will receive a fixed dose of Isatuximab (SAR650984) according to the assigned dose. Patients receive isatuximab IV over 4-6 hours on day 1, 3-4 hours on Day 8, 15, and 22 of cycle 1 and then on days 1 and 15 of subsequent cycle (patients may be eligible for rapid siatuximab given over 75 minutes), and carfilzomib IV over 30 minutes on days 1, 8, and 15. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.

Biological: Isatuximab; Drug: Carfilzomib; Drug: Dexamethasone

Interventions

Isatuximab BIOLOGICAL

Given IV

Also known as: SAR 650984

Arm I (20 mg dexamethasone, isatuximab, carfilzomib); Arm II (40 mg dexamethasone, isatuximab, carfilzomib)

Carfilzomib DRUG

Given IV

Also known as: Kyprolis, PR-171

Arm I (20 mg dexamethasone, isatuximab, carfilzomib); Arm II (40 mg dexamethasone, isatuximab, carfilzomib)

Dexamethasone DRUG

Given IV or PO

Also known as: Orgadrone, Spersadex, Visumetazone

Arm I (20 mg dexamethasone, isatuximab, carfilzomib); Arm II (40 mg dexamethasone, isatuximab, carfilzomib)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Males or females, age 18 years or older
• Diagnosis of multiple myeloma (MM) and documentation of treatment
• ARM 1: Must have prior exposure to an immunomodulatory drug (IMiD) and proteasome inhibitor (PI) and have had 2 prior regimens/lines of therapy; but there is no maximum number of prior regimens, and prior autologous bone marrow transplant is acceptable if \> 12 weeks from transplantation; patients may have received prior carfilzomib (sensitive, relapsed and refractory \[having progressed while receiving carfilzomib or within 60 days of stopping carfilzomib\] are all eligible), but must be \> 4 weeks from last dosing of carfilzomib
• ARM 2: Must have had at least 1 but no more than 3 prior lines of anti-myeloma therapy; may be refractory to lenalidomide but sensitive to carfilzomib; prior exposure to carfilzomib is allowed but may not be refractory to carfilzomib; subjects must be \>= 8 weeks from last carfilzomib therapy
• A line of therapy is defined as a course of therapy that is not interrupted by progressive disease; for example, induction therapy, autologous stem cell transplantation, and maintenance therapy without intervening progressive disease is one line of therapy
• Confirmed evidence of relapse/disease progression from immediately prior MM therapy or relapsed and refractory to the immediately prior treatment; relapsed and refractory disease is defined as those who are non-responsive (\< minimal response) on salvage therapy or experience disease progression within 60 days of last therapy in patients who have achieved an MR or better to previous therapy; relapsed disease is defined as previously treated myeloma that progresses and requires the initiation of salvage therapy but does not meet IMWG criteria for relapsed and refractory
• Patients may have received prior carfilzomib (sensitive, relapsed and refractory all eligible); response and duration of prior carfilzomib therapy must be known
• Patients must have measurable disease defined as at least one of the following:
• Serum M-protein \>= 0.5 g/dl (\>= 5 g/l)
• Urine M-protein \>= 200 mg/24 hours (h)
• Serum free light chain (FLC) assay: involved FLC level \>= 10 mg/dl (\>= 100 mg/l) and an abnormal serum free light chain ratio (\< 0.26 or \> 1.65)
• Quantitative immunoglobulin \> 500mg/dL for Immunoglobulin A (IgA) or \> 500mg/L for Immunoglobulin D (IgD), only for IgA and IgD myeloma (by nephelometry) when the protein electrophoresis under-represents disease burden
• Biopsy proven plasmacytoma \> 1x1 cm (should be measured within 28 days prior to initial investigational agent dosing)
• Subject has an Eastern Cooperative Oncology Group (ECOG) =\< 2 performance status OR Karnofsky \>= 60% performance status
• Females of childbearing potential (FCBP)

You may not qualify if:

• Diagnosed or treated for another malignancy within 3 years of enrollment, with the exception of complete resection of basal cell carcinoma or squamous cell carcinoma of the skin, an in situ malignancy, low-risk prostate cancer after curative therapy or complete resection of other advanced malignancy with the expectation that the patient has received curative therapy
• Patient has received other investigational drugs with 21 days before enrollment (or must be \> than four half-lives of the experimental agent); no prior SAR650984 anti-CD38 antibody therapy allowed
• History of significant cardiovascular disease unless the disease is well-controlled or history of myocardial infarction in the past 6 months; significant cardiac diseases includes second/third degree heart block; significant conduction abnormalities, significant ischemic heart disease; poorly controlled hypertension; congestive heart failure of New York Heart Association (NYHA) class II or worse (slight limitation of physical activity; comfortable at rest, but ordinary physical activity results in fatigue, palpitation, or dyspnea) and inability to tolerate intravenous hydration necessary for study therapy administration
• Prior autologous or allogeneic peripheral stem cell transplant within 12 weeks of the first dose of study treatment
• Daily requirement for corticosteroids (\> 10 mg prednisone once daily (QD) or equivalent)
• Patients with evidence of significant mucosal or internal bleeding
• Prior radiation therapy or chemotherapy within 2 weeks or major surgical procedure within 4 weeks of the first dose of study treatment
• Known active infection requiring parenteral or oral anti-infective treatment, once a patient has completed antibiotics and symptoms of infection have resolved to \< grade 2, they are then considered eligible from an infection standpoint
• Serious psychiatric illness, active alcoholism, or drug addiction that may hinder or confuse follow-up evaluation
• Any medical conditions that, in the Investigator's opinion, would impose excessive risk to the patient; examples of such conditions include any pre-existing kidney disease (acute or chronic, unless renal insufficiency is felt to be secondary to MM), hypertension, active seizure disorder or pulmonary diseases that would impose excessive risk to the patient
• Patient has hypersensitivity to boron, mannitol sucrose, histidine (as base and hydrochloride salt) and polysorbate 80 or any of the components of study therapy including required prophylactic medications
• Known human immunodeficiency virus (HIV) seropositivity or active hepatitis B or C viral infection
• Neuropathy \>= grade 3 or painful neuropathy \>= grade 2 (National Cancer Institute Common Terminology Criteria for Adverse Events \[NCI CTCAE\] version \[v\]4.03)
• Gastro-intestinal abnormalities, including bowel obstruction, inability to take oral medication, requirement for intravenous (IV) alimentation, active peptic ulcer or prior surgical procedures or bowel resection affecting absorption

Sponsors & Collaborators

• Thomas Martin, MD: lead
• Amgen: collaborator
• Sanofi: collaborator

Study Sites (6)

University of California, San Francisco

San Francisco, California, 94143, United States

Location

Colorado Blood Cancer Institute

Denver, Colorado, 80218, United States

Location

Hackensack University Medical Center

Hackensack, New Jersey, 07601, United States

Location

Icahn School of Medicine at Mount Sinai

New York, New York, 10029, United States

Location

Sarah Cannon Cancer Center

Nashville, Tennessee, 37203, United States

Location

Princess Margaret Cancer Centre

Toronto, Ontario, M5G 2C1, Canada

Location

MeSH Terms

Conditions

Multiple Myeloma; Recurrence

Interventions

isatuximab; carfilzomib; Dexamethasone; Calcium Dobesilate; dexamethasone 21-phosphate

Condition Hierarchy (Ancestors)

Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Neoplasms; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemorrhagic Disorders; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Steroids, Fluorinated; Benzenesulfonates; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Arylsulfonates; Arylsulfonic Acids; Sulfonic Acids; Sulfur Acids; Sulfur Compounds

Study Officials

• Thomas Martin, MD

  University of California, San Francisco

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Clinical Professor of Medicine, Division of Hematology/Oncology and Director, Clinical Research, Hematologic Malignancies Program

Study Record Dates

• First Submitted: December 12, 2014
• First Posted: January 7, 2015
• Study Start: January 21, 2015
• Primary Completion: December 31, 2025
• Study Completion: December 31, 2025
• Last Updated: May 1, 2025

Record last verified: 2025-04

Data Sharing

• IPD Sharing: Will not share

Locations

CA (1); US (5)