Clinical trial NCT04892446: Study of Magrolimab Combinations in Patients With Relapsed/Refractory Multiple Myeloma
Official title: A Phase 2 Multi-Arm Study of Magrolimab Combinations in Patients With Relapsed/Refractory Multiple Myeloma
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Multiple Myeloma
Lead sponsor: Gilead Sciences
Sponsor class: INDUSTRY
First posted: 2021-05-19
Enrollment: 36
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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.


Eligibility criteria: Key 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.

Primary outcomes:
measure: 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
timeFrame: Up to 35 days
measure: Percentage of Participants Experiencing Treatment-emergent Adverse Events (TEAE's) According to the NCI CTCAE Version 5.0
timeFrame: Up to 1.3 years plus 70 days
measure: Percentage of Participants Experiencing Treatment-emergent Laboratory Abnormalities According to the NCI CTCAE Version 5.0
timeFrame: Up to 1.3 years plus 70 days
measure: Objective Response Rate (ORR)
timeFrame: Up to 1.5 years
Secondary outcomes:
measure: Duration of Response (DoR)
timeFrame: Up to 1.5 years
measure: Serum Concentration of Magrolimab
timeFrame: 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
measure: Percentage of Participants With Positive Anti-magrolimab Antibodies
timeFrame: Up to Day 358
Other outcomes:
Locations:
city: Tucson
country: United States
facility: Arizona Oncology Associates , PC - HOPE
state: Arizona
city: La Jolla
country: United States
facility: US San Diego Moores Cancer Center
state: California
city: Palo Alto
country: United States
facility: Stanford Cancer Institute
state: California
city: Detroit
country: United States
facility: Karmanos Cancer Institute
state: Michigan
city: Buffalo
country: United States
facility: Roswell Park Cancer Institute
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center - Main Campus
state: New York
city: Charlotte
country: United States
facility: Levine Cancer Institute
state: North Carolina
city: Durham
country: United States
facility: Duke University
state: North Carolina
city: Cleveland
country: United States
facility: Cleveland Clinic - Taussig Cancer Institute
state: Ohio
city: Columbus
country: United States
facility: The Ohio State University
state: Ohio
city: Oklahoma City
country: United States
facility: Hightower Clinical
state: Oklahoma
city: Bend
country: United States
facility: Bend Memorial Clinic, P.C. d/b/a Summit Health
state: Oregon
city: Portland
country: United States
facility: Oregon Health and Science University
state: Oregon
city: Dallas
country: United States
facility: US Oncology, Inc. IRB
state: Texas
city: Salt Lake City
country: United States
facility: Huntsman Cancer Institute
state: Utah
city: Fairfax
country: United States
facility: US Oncology, Inc., IRB
state: Virginia
city: Edmonton
country: Canada
facility: Cross Cancer Institute
city: Toronto
country: Canada
facility: Princess Margaret Cancer Centre
city: Brno
country: Czechia
facility: Fakultní nemocnice Brno
city: Olomouc
country: Czechia
facility: Fakultní Nemocnice Olomouc
city: Prague
country: Czechia
facility: Vseobecna fakultni nemocnice v Praze
city: Severomoravsky KRAJ
country: Czechia
facility: Fakultní nemocnice Ostrava
Study officials:
affiliation: Gilead Sciences
name: Gilead Study Director
role: STUDY_DIRECTOR
References:
citation: Paul B, Liedtke M, Khouri J, Rifkin R, Gandhi MD, Kin A, Levy MY, Silbermann R, Cottini F, Sborov DW, Sandhu I, Villarreal L, Murphy M, Gu L, Chen A, Rajakumaraswamy N, Usmani SZ. A phase II multi-arm study of magrolimab combinations in patients with relapsed/refractory multiple myeloma. Future Oncol. 2023 Jan;19(1):7-17. doi: 10.2217/fon-2022-0975. Epub 2023 Feb 13.
citation: Paul B, Minarik J, Cottini F, Gasparetto C, Khouri J, Gandhi M, et al. Safety and Tolerability of Magrolimab Combinations in Patients With Relapsed/Refractory Multiple Myeloma: Safety Run-in Results From a Phase 2 Study [Poster 3383]. 65th American Society of Hematology (ASH) Annual Meeting; 2023 December 9-12; San Diego, California.