Study of Magrolimab Combinations in Patients With Relapsed/Refractory Multiple Myeloma

Phase 2

Terminated

Conditions: Multiple Myeloma

Interventions: Drug: Magrolimab
Drug: Daratumumab
Drug: Pomalidomide
Drug: Dexamethasone
Drug: Carfilzomib
Drug: Bortezomib

Registration Number: NCT04892446

Lead Sponsor: Gilead Sciences

Brief Summary: The goal of this clinical study is to learn more about the safety and dosing of the study drug, magrolimab, in combination with other anticancer therapies in participants with relapsed/refractory multiple myeloma.

Detailed Description: Not available

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 36

Inclusion Criteria

All Individuals:

Have been previously diagnosed with MM based on the International Myeloma Working Group (IMWG) 2016 criteria and currently requires treatment.
Must have measurable disease as defined by 1 or more of the following:
- Serum monoclonal protein (M-protein) ≥ 0.5 grams per deciliter (g/dL) (greater than or equal to [≥] 5 grams per liter [g/L]).
- Urine M-protein ≥ 200 mg/24 hours (h).
- Serum free light chain (SFLC) assay: involved SFLC level ≥ 10 mg/dL (100 mg/L) with abnormal SFLC ratio.
Has provided informed consent.
Is willing and able to comply with clinic visits and procedure outlined in the study protocol.
Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.
Life expectancy ≥ 3 months.
Absolute neutrophil count (ANC) ≥ 1000 cells/uL (1.0 x 10^9/L); granulocyte colony-stimulating factor (G-CSF) is not permitted within 1 week of screening to meet eligibility criteria.
Platelet count ≥ 75,000 cells/uL (75 x 10^9/L); platelet transfusion is not permitted within 1 week of screening to meet eligibility criteria.
Hemoglobin ≥ 9 g/dL; prior to initial dose of study treatment. Note: Transfusions are allowed to meet hemoglobin eligibility
Adequate liver function as demonstrated by the following:
- Aspartate aminotransferase (AST) ≤ 3.0 x upper limit of normal (ULN).
- Alanine aminotransferase (ALT) ≤ 3.0 x ULN.
- Total bilirubin ≤ 1.5 x ULN (or ≤ 3.0 x ULN and primarily unconjugated if individual has a documented history of Gilbert's syndrome or genetic equivalent).
International normalized ratio (INR) ≤ 1.2; Individuals receiving anticoagulation treatment may be allowed to participate if INR is within the therapeutic range prior to alternate assignment.
Individuals must have adequate renal function as demonstrated by a creatinine clearance ≥ 30 mL/min calculated by the Cockcroft-Gault formula or measured by 24 hours urine collection.
Corrected serum calcium ≤ 2.9 millimoles per liter (mmol/L) (11.5 mg/dL); measures to reduce calcium to acceptable levels, such as a short course of steroids, bisphosphonates, hydration, or calcitonin are acceptable.
Pretreatment blood cross-match completed.
Males and females of childbearing potential who engage in heterosexual intercourse must agree to use protocol-specified method(s) of contraception.
Must be willing to consent to mandatory pretreatment and on-treatment bone marrow biopsies (trephines).
Magrolimab in Combination with Daratumumab: In addition to fulfilling the inclusion criteria for all individuals, individuals who are assigned to receive magrolimab in combination with daratumumab should fulfill the following:
- Must have received at least 3 previous lines of therapy for MM including an IMiD such as lenalidomide and a PI such as bortezomib.
- Individuals must have not had prior anti-cluster differentiation 38 (CD38) antibody therapy for at least 6 months prior to enrollment.
- No prior history of discontinuation of daratumumab due to toxicity.
Magrolimab in Combination with Pomalidomide and Dexamethasone: In addition to fulfilling the inclusion criteria for all Individuals, Individuals who are assigned to receive magrolimab in combination with pomalidomide and dexamethasone should fulfill the following:
- Must have received at least 3 previous lines of therapy for MM including an IMiD such as lenalidomide and a PI such as bortezomib.
- Prior treatment with pomalidomide is allowed if the Individual achieved at least a partial response (PR) to the most recent pomalidomide therapy and will have had at least a 6-month treatment-free interval from the last dose of pomalidomide until first study treatment.
- No prior history of discontinuation of pomalidomide due to toxicity.
- No contraindication to dexamethasone.
Magrolimab in Combination with Carfilzomib and Dexamethasone: In addition to fulfilling the inclusion criteria for all patients, patients who are assigned to receive magrolimab in combination with carfilzomib and dexamethasone should fulfill the following:
- Patient must have received at least 3 previous lines of therapy for MM including an IMiD such as lenalidomide and a PI such as bortezomib.
- Prior treatment with a PI, including carfilzomib, is allowed if the patient achieved at least a PR to the most recent prior PI therapy, and will have had at least a 6-month PI treatment-free interval from the last dose until first study treatment.
- No prior history of discontinuation of carfilzomib due to toxicity.
- No contraindication to dexamethasone
Magrolimab in Combination with Bortezomib and Dexamethasone: In addition to fulfilling the inclusion criteria for all individuals, individuals who are assigned to receive magrolimab in combination with bortezomib and dexamethasone should fulfill the following:
- Must have received at least 1 previous line of therapy for MM including an IMiD such as lenalidomide and a PI such as bortezomib.
- Prior treatment with a PI, including bortezomib, is allowed if the Individual achieved at least a PR to the most recent prior PI therapy, and will have had at least a 6-month PI treatment-free interval from the last dose until first study treatment.
- No prior history of discontinuation of bortezomib due to toxicity.
- No contraindication to dexamethasone.

Key

Exclusion Criteria

Individuals with known amyloidosis including myeloma complicated by amyloidosis.
Multiple myeloma of immunoglobulin M subtype.
Individuals with Waldenstrom's macroglobulinemia.
Individuals with myelodysplastic syndrome (MDS).
Plasma cell leukemia (defined as either 20% of peripheral blood white blood cell (WBC) count comprised of plasma/CD138-positive cells) or circulating plasma cells ≥ 2 x 10^9/L.
Individuals with solitary bone or extramedullary plasmacytoma as the only evidence of plasma cell dyscrasia.
Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal protein, Skin changes (POEMS) syndrome (plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes).
Glucocorticoid therapy (prednisone > 40 mg/day or equivalent) within 14 days prior to enrollment; corticosteroid therapy for hypercalcemia is allowed.
Chemotherapy with approved or investigational anticancer therapeutics within 28 days prior to enrollment.
Focal radiation therapy within 7 days prior to enrollment; radiation therapy to an extended field involving a significant volume of bone marrow within 21 days prior to enrollment (ie, prior radiation must have been to less than 30% of the bone marrow).
Immunotherapy within 28 days prior to enrollment.
Major surgery (excluding procedures to stabilize the vertebrae) within 28 days prior to enrollment.
Positive serum pregnancy test.
Breastfeeding female.
Known hypersensitivity to any of the study drugs, the metabolites, or formulation excipient.
Prior treatment with CD47 or signal regulatory protein alpha (SIRPα)-targeting agents.
Current participation in another interventional clinical trial.
Autologous stem cell transplant < 100 days prior to enrollment.
Considered eligible to receive autologous or allogeneic stem cell transplant (SCT) at the time of enrollment.
Allogeneic SCT for the treatment of MM within 6 months of enrollment or active graft-versus-host disease requiring immunosuppression.
Significant neuropathy (Grade 3 to 4, or Grade 2 with pain) within 14 days prior to enrollment.
Known inherited or acquired bleeding disorders.
Known cirrhosis.
Clinical suspicion or documentation of central nervous system (CNS) disease.
Significant disease or medical conditions, as assessed by the investigator and sponsor, that would substantially increase the risk-benefit ratio of participating in the study. This includes, but is not limited to, acute myocardial infarction within the last 6 months, unstable angina, uncontrolled diabetes mellitus, significant active infections, congestive heart failure, or New York Heart Association (NYHA) Class III or IV heart failure.
Acute active infection requiring systemic antibiotics, antiviral (except antiviral therapy directed against reactivation) or antifungal agents within 14 days prior to enrollment.
Second malignancy, except treated basal cell or localized squamous skin carcinomas, localized prostate cancer, or other malignancies for which patients are not on active anticancer therapies and have had no evidence of active malignancy for at least 1 year. Other exceptions may be considered with sponsor approval. Previous hormonal therapy with luteinizing hormone-releasing hormone agonists for prostate cancer and treatment with bisphosphonates and receptor activator of nuclear factor kappa-B ligand (RANKL) inhibitors are not criteria for exclusion.
Known active or chronic hepatitis B or C infection or human immunodeficiency virus (HIV) infection in medical history.
Active hepatitis B virus (HBV) and/or active hepatitis C virus (HCV), and/or HIV infection following testing at screening:
Individuals who test positive for hepatitis B surface antigen (HBsAg). Patients who test positive for hepatitis B core antibody (anti-HBc) will require HBV DNA by quantitative polymerase chain reaction (PCR) for confirmation of active disease.
Individuals who test positive for HCV antibody. Patients who test positive for HCV antibody will require HCV ribonucleic acid (RNA) by quantitative PCR for confirmation of active disease.
Individuals who test positive for HIV.

Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Magrolimab+Daratumumab	Magrolimab	Participants with relapsed/refractory multiple myeloma (MM) who have had 3 or more prior therapies including an immunomodulatory drug (IMiD) and a proteasome inhibitor (PI) will receive magrolimab as per protocol and daratumumab 1800 mg subcutaneously (SC) or 16 milligrams per kilogram (mg/kg) intravenously (IV) on Days 8, 15, 22, 29 of Cycle 1, Days 1, 8, 15, 22 of Cycle 2 and Days 1 and 15 (every 2 weeks) until Cycle 6 (total of 8 doses) followed by Day 1 (every 4 weeks) for subsequent cycles. (Cycle 1=35 days, All other Cycles=28 days).
Magrolimab+Daratumumab	Daratumumab	Participants with relapsed/refractory multiple myeloma (MM) who have had 3 or more prior therapies including an immunomodulatory drug (IMiD) and a proteasome inhibitor (PI) will receive magrolimab as per protocol and daratumumab 1800 mg subcutaneously (SC) or 16 milligrams per kilogram (mg/kg) intravenously (IV) on Days 8, 15, 22, 29 of Cycle 1, Days 1, 8, 15, 22 of Cycle 2 and Days 1 and 15 (every 2 weeks) until Cycle 6 (total of 8 doses) followed by Day 1 (every 4 weeks) for subsequent cycles. (Cycle 1=35 days, All other Cycles=28 days).
Magrolimab+Pomalidomide+Dexamethasone	Magrolimab	Participants with relapsed/refractory multiple myeloma who have had 3 or more prior therapies including an IMiD and a PI will receive magrolimab as per protocol and pomalidomide 4 mg on Days 1 to 21 (daily) of Cycle 1, Days 1 to 21 (daily) of Cycle 2 and onward and dexamethasone 40 mg on Days 1, 8, 15, 22, 29 of Cycle 1, Days 1, 8, 15, 22 of Cycle 2 and onward. (Cycle 1=35 days, All other Cycles=28 days).
Magrolimab+Pomalidomide+Dexamethasone	Pomalidomide	Participants with relapsed/refractory multiple myeloma who have had 3 or more prior therapies including an IMiD and a PI will receive magrolimab as per protocol and pomalidomide 4 mg on Days 1 to 21 (daily) of Cycle 1, Days 1 to 21 (daily) of Cycle 2 and onward and dexamethasone 40 mg on Days 1, 8, 15, 22, 29 of Cycle 1, Days 1, 8, 15, 22 of Cycle 2 and onward. (Cycle 1=35 days, All other Cycles=28 days).
Magrolimab+Pomalidomide+Dexamethasone	Dexamethasone	Participants with relapsed/refractory multiple myeloma who have had 3 or more prior therapies including an IMiD and a PI will receive magrolimab as per protocol and pomalidomide 4 mg on Days 1 to 21 (daily) of Cycle 1, Days 1 to 21 (daily) of Cycle 2 and onward and dexamethasone 40 mg on Days 1, 8, 15, 22, 29 of Cycle 1, Days 1, 8, 15, 22 of Cycle 2 and onward. (Cycle 1=35 days, All other Cycles=28 days).
Magrolimab+Carfilzomib+Dexamethasone	Magrolimab	Participants with relapsed/refractory multiple myeloma who have had 3 or more prior therapies including an IMiD and a PI will receive magrolimab as per protocol and carfilzomib 20 mg/m\^2 on Days 8, 15, 22 of Cycle 1, Days 1, 8, 15 of Cycle 2 and onward (if the carfilzomib starting dose of 20 mg/m\^2 is tolerated after Cycle 1, Day 8, the dose will be escalated to 70 mg/m\^2 on Cycle 1, Day 15 and thereafter) and dexamethasone 40 mg on Days 1, 8, 15, 22, 29 of Cycle 1, Days 1, 8, 15, 22 of Cycles 2 to 9 and then Days 1, 8, 15 from Cycle 10 and onward. (Cycle 1=35 days, All other Cycles=28 days).
Magrolimab+Carfilzomib+Dexamethasone	Dexamethasone	Participants with relapsed/refractory multiple myeloma who have had 3 or more prior therapies including an IMiD and a PI will receive magrolimab as per protocol and carfilzomib 20 mg/m\^2 on Days 8, 15, 22 of Cycle 1, Days 1, 8, 15 of Cycle 2 and onward (if the carfilzomib starting dose of 20 mg/m\^2 is tolerated after Cycle 1, Day 8, the dose will be escalated to 70 mg/m\^2 on Cycle 1, Day 15 and thereafter) and dexamethasone 40 mg on Days 1, 8, 15, 22, 29 of Cycle 1, Days 1, 8, 15, 22 of Cycles 2 to 9 and then Days 1, 8, 15 from Cycle 10 and onward. (Cycle 1=35 days, All other Cycles=28 days).
Magrolimab+Carfilzomib+Dexamethasone	Carfilzomib	Participants with relapsed/refractory multiple myeloma who have had 3 or more prior therapies including an IMiD and a PI will receive magrolimab as per protocol and carfilzomib 20 mg/m\^2 on Days 8, 15, 22 of Cycle 1, Days 1, 8, 15 of Cycle 2 and onward (if the carfilzomib starting dose of 20 mg/m\^2 is tolerated after Cycle 1, Day 8, the dose will be escalated to 70 mg/m\^2 on Cycle 1, Day 15 and thereafter) and dexamethasone 40 mg on Days 1, 8, 15, 22, 29 of Cycle 1, Days 1, 8, 15, 22 of Cycles 2 to 9 and then Days 1, 8, 15 from Cycle 10 and onward. (Cycle 1=35 days, All other Cycles=28 days).
Magrolimab+Bortezomib+Dexamethasone	Magrolimab	Bortezomib + Dexamethasone may be initiated based on the preliminary safety and efficacy of the Carfilzomib + Dexamethasone cohort. Participants with relapsed/refractory multiple myeloma who have had 1 or more prior therapies including an IMiD and a PI will receive magrolimab as per protocol and carfilzomib 1.3 mg/m\^2 on Days 8, 15, 22, 29 of Cycle 1, Days 1, 8, 15, 22 of Cycle 2 and onward (Maximum of 8 cycles in those who have previously received bortezomib) and dexamethasone 40 mg on Days 1, 8, 15, 22, 29 of Cycle 1, Days 1, 8, 15, 22 of Cycles 2 to 9 and then Days 1, 8, and 15 from Cycle 10 and onward. (Cycle 1=35 days, All other Cycles=28 days).
Magrolimab+Bortezomib+Dexamethasone	Dexamethasone	Bortezomib + Dexamethasone may be initiated based on the preliminary safety and efficacy of the Carfilzomib + Dexamethasone cohort. Participants with relapsed/refractory multiple myeloma who have had 1 or more prior therapies including an IMiD and a PI will receive magrolimab as per protocol and carfilzomib 1.3 mg/m\^2 on Days 8, 15, 22, 29 of Cycle 1, Days 1, 8, 15, 22 of Cycle 2 and onward (Maximum of 8 cycles in those who have previously received bortezomib) and dexamethasone 40 mg on Days 1, 8, 15, 22, 29 of Cycle 1, Days 1, 8, 15, 22 of Cycles 2 to 9 and then Days 1, 8, and 15 from Cycle 10 and onward. (Cycle 1=35 days, All other Cycles=28 days).
Magrolimab+Bortezomib+Dexamethasone	Bortezomib	Bortezomib + Dexamethasone may be initiated based on the preliminary safety and efficacy of the Carfilzomib + Dexamethasone cohort. Participants with relapsed/refractory multiple myeloma who have had 1 or more prior therapies including an IMiD and a PI will receive magrolimab as per protocol and carfilzomib 1.3 mg/m\^2 on Days 8, 15, 22, 29 of Cycle 1, Days 1, 8, 15, 22 of Cycle 2 and onward (Maximum of 8 cycles in those who have previously received bortezomib) and dexamethasone 40 mg on Days 1, 8, 15, 22, 29 of Cycle 1, Days 1, 8, 15, 22 of Cycles 2 to 9 and then Days 1, 8, and 15 from Cycle 10 and onward. (Cycle 1=35 days, All other Cycles=28 days).

Primary Outcome Measures

Name	Time	Method
Percentage of Participants Experiencing Dose-limiting Toxicities (DLTs) According to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0	Up to 35 days	A DLT was defined as any Grade 3 or higher hematologic toxicity or Grade 3 or higher nonhematologic toxicity, that had worsened in severity from pretreatment baseline during the DLT assessment period and, in the opinion of the investigator, the adverse event (AE) was at least possibly related to magrolimab. Percentages are rounded off.
Percentage of Participants Experiencing Treatment-emergent Adverse Events (TEAE's) According to the NCI CTCAE Version 5.0	Up to 1.3 years plus 70 days	An AE is any untoward medical occurrence in a clinical study participant administered a study drug that does not necessarily have a causal relationship with the treatment. An AE can therefore be any unfavorable and/or unintended sign, symptom, or disease temporally associated with the use of a study drug, whether or not the AE is considered related to the study drug. A treatment-emergent AE was defined as any AE that began on or after the date of first dose of any study drug up to the date of last dose of any study drug plus 70 days.
Percentage of Participants Experiencing Treatment-emergent Laboratory Abnormalities According to the NCI CTCAE Version 5.0	Up to 1.3 years plus 70 days	Treatment-emergent laboratory abnormalities were defined as values that increase at least 1 toxicity grade from baseline at any postbaseline time point, up to and included the date of last dose of study drug plus 70 days for participants who permanently discontinued study drug, or the day before initiation of new anticancer therapy including stem cell transplant (SCT) (whichever was earlier). If the relevant baseline laboratory value was missing, any abnormality of at least Grade 1 observed within the time frame specified above was considered treatment emergent. Percentages are rounded off.
Objective Response Rate (ORR)	Up to 1.5 years	Objective response rate is defined as the percentage of participants who achieve confirmed stringent complete response (sCR), complete response (CR), very good partial response (VGPR), or partial response (PR), as assessed by the investigator per the International Myeloma Working Group (IMWG) 2016 criteria. CR defined as negative immunofixation on serum and urine and disappearance of any soft tissue plasmacytomas and \< 5% plasma cells in bone marrow (BM) aspirates; sCR defined as CR as above plus normal serum free light-chain (FLC) assay ratio and absence of clonal cells in BM biopsy by immunohistochemistry; VGPR defined as serum and urine M-protein detectable by immunofixation but not on electrophoresis or ≥ 90% reduction in serum M-protein plus urine M-protein \<100 mg/24 h; PR defined as ≥50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥90% or to \<200 mg/24 h. Percentages are rounded off.

Secondary Outcome Measures

Name	Time	Method
Duration of Response (DoR)	Up to 1.5 years	DoR was measured from earliest date of sCR, CR, VGPR, or PR, whichever was first recorded, until earliest date of documented progression disease (PD) per IMWG 2016, documented relapse, or death from any cause, whichever occurred first. sCR, CR, VGPR, or PR are defined in outcome measure #4. PD is having any 1 or more of following criteria: increase of 25% from lowest confirmed response value; increase between involved and uninvolved FLC levels \>10 mg/dL; increase in BM plasma-cell ≥10%; appearance of new lesion, ≥ 50% increase in sum of products of 2 longest perpendicular diameters of \>1 lesion, or ≥ 50% increase in longest diameter of a previous lesion \>1 cm in short axis; ≥ 50% increase in circulating plasma cells. Relapse is new soft tissue plasmacytomas or bone lesions; increase in size of existing plasmacytomas or bone lesions; hypercalcemia (\> 11 mg/dL); decrease in hemoglobin of ≥ 2 g/dL; rise in serum creatinine by 2 mg/dL; hyperviscosity. Kaplan Meier estimates were used.
Serum Concentration of Magrolimab	Arm 1, 2, 3: Predose: Days 1 and 22 of Cycle 1, Day 1 of Cycles 2, 3, 4, 5, 7, and on last sample collection day (anytime; up to Day 358); Arm 1 and 3: Predose: Day 1 of Cycles 10 and 13	Arm 1: Magrolimab+Daratumumab; Arm 2: Magrolimab+Pomalidomide+Dexamethasone; Arm 3: Magrolimab+Carfilzomib+Dexamethasone.
Percentage of Participants With Positive Anti-magrolimab Antibodies	Up to Day 358	The percentage of participants who had treatment induced or treatment-boosted anti-drug antibody (ADA) based on participants who had non-missing baseline ADA sample and at least one post-treatment ADA result reported in Immunogenicity Analysis Set. Treatment-Induced ADA: participants who had negative baseline ADA sample and at least one positive post-treatment ADA sample based on participants who had both non-missing baseline and at least one post-treatment ADA result reported. Treatment-Boosted ADA: participants who had positive baseline ADA sample and at least one positive post-treatment ADA sample and the (max titer of the posttreatment ADA) / (titer of baseline ADA) \>= 4.

Trial Locations

Locations (22): US Oncology, Inc., IRB
🇺🇸
Fairfax, Virginia, United States
US San Diego Moores Cancer Center
🇺🇸
La Jolla, California, United States
Stanford Cancer Institute
🇺🇸
Palo Alto, California, United States
Roswell Park Cancer Institute
🇺🇸
Buffalo, New York, United States
Levine Cancer Institute
🇺🇸
Charlotte, North Carolina, United States
Cleveland Clinic - Taussig Cancer Institute
🇺🇸
Cleveland, Ohio, United States
US Oncology, Inc. IRB
🇺🇸
Dallas, Texas, United States
Cross Cancer Institute
🇨🇦
Edmonton, Canada
Fakultní nemocnice Brno
🇨🇿
Brno, Czechia
Fakultní Nemocnice Olomouc
🇨🇿
Olomouc, Czechia
Vseobecna fakultni nemocnice v Praze
🇨🇿
Prague, Czechia
Fakultní nemocnice Ostrava
🇨🇿
Severomoravsky KRAJ, Czechia
Arizona Oncology Associates , PC - HOPE
🇺🇸
Tucson, Arizona, United States
The Ohio State University
🇺🇸
Columbus, Ohio, United States
Karmanos Cancer Institute
🇺🇸
Detroit, Michigan, United States
Duke University
🇺🇸
Durham, North Carolina, United States
Hightower Clinical
🇺🇸
Oklahoma City, Oklahoma, United States
Oregon Health and Science University
🇺🇸
Portland, Oregon, United States
Huntsman Cancer Institute
🇺🇸
Salt Lake City, Utah, United States
Memorial Sloan Kettering Cancer Center - Main Campus
🇺🇸
New York, New York, United States
Bend Memorial Clinic, P.C. d/b/a Summit Health
🇺🇸
Bend, Oregon, United States
Princess Margaret Cancer Centre
🇨🇦
Toronto, Canada