| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Relapsed/Refractory Multiple Myeloma |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10028228 |
| E.1.2 | Term | Multiple myeloma |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Objectives for the Safety Run-in Cohorts:
To evaluate the safety and tolerability of magrolimab in combination with other anticancer therapies and to determine the recommended Phase 2 dose (RP2D) of magrolimab for the following combinations in patients with relapsed/refractory MM:
- Magrolimab in combination with daratumumab
- Magrolimab in combination with pomalidomide and dexamethasone
- Magrolimab in combination with carfilzomib and dexamethasone
- Magrolimab in combination with bortezomib and dexamethasone
Objectives for the Dose Expansion Cohorts:
To evaluate the efficacy of magrolimab in combination with other anticancer therapies in patients with relapsed/refractory multiple myeloma as determined by objective response rate (ORR) |
|
| E.2.2 | Secondary objectives of the trial |
Secondary Objectives for the Safety Run-in Cohorts:
None
Secondary Objectives for the Dose Expansion Cohorts:
- To evaluate the safety and tolerability of magrolimab in combination with other anti-cancer therapies
- To investigate other parameters of efficacy including the depth and duration of response and survival
- To evaluate the pharmacokinetics (PK) and immunogenicity of magrolimab in combination with other anticancer therapies in patients with relapsed/refractory multiple myeloma |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1) Patient has been previously diagnosed with MM based on the International Myeloma Working Group (IMWG) 2016 criteria and currently requires treatment.
2) Patients must have measurable disease as defined by 1 or more of the following:
a) Serum monoclonal protein (M-protein) ≥ 0.5 g/dL (≥ 5 g/L)
b) Urine M-protein ≥ 200 mg/24 h
c) Serum free light chain (SFLC) assay: involved SFLC level ≥ 10 mg/dL (100 mg/L) with abnormal SFLC ratio
3) Patient has provided informed consent.
4) Patient is willing and able to comply with clinic visits and procedure outlined in the study protocol.
5) Male or female ≥ 18 years of age
6) Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
7) Life expectancy ≥ 3 months
8) Absolute neutrophil count (ANC) ≥ 1000 cells/dL (1.0 x 109/L); granulocyte colony-stimulating factor (G-CSF) is not permitted within 1 week of screening to meet eligibility criteria.
9) Platelet count ≥ 75,000 cells/dL (75 x 109/L); platelet transfusion is not permitted within 1 week of screening to meet eligibility criteria.
10) Hemoglobin ≥ 9.0 g/dL; no more than 4 units of packed RBCs are allowed in the 30 days prior to screening
11) For patients with prior cardiac history such as ischemic heart disease, left ventricular ejection fraction ≤ 45%, symptomatic congestive heart failure, New York Heart Association (NYHA) Class III or IV heart failure, or other conditions that may be sensitive to demand ischemia, the hemoglobin must be ≥ 9.5 g/dL prior to initial dose of study treatment. Transfusions are allowed to meet hemoglobin eligibility criterion.
12) Adequate liver function as demonstrated by the following:
a) AST ≤ 3.0 x upper limit of normal (ULN)
b) ALT ≤ 3.0 x ULN
c) Total bilirubin ≤ 1.5 x ULN (or ≤ 3.0 x ULN and primarily unconjugated if patient has a documented history of Gilbert’s syndrome or genetic equivalent).
13) Prothrombin time (PT)/international normalized ratio (INR) and partial thromboplastin time ≤ 1.2; patients receiving anticoagulation treatment may be allowed to participate if INR is within the therapeutic range prior to alternate assignment.
14) Patients 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.
15) Corrected serum calcium ≤ 2.9 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.
16) Pretreatment blood cross-match completed (Section 7.8.1)
17) Male and female patients of childbearing potential who engage in heterosexual intercourse must agree to use protocol-specified method(s) of contraception
18) Patients must be willing to consent to mandatory pretreatment and on-treatment bone marrow biopsies (trephines).
Magrolimab in Combination Wwith Daratumumab
19) 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.
20) Patients must have CD38-positive myeloma and have not had prior anti-CD38 antibody therapy for at least 6 months prior to enrollment.
21) No prior history of discontinuation of daratumumab due to toxicity Magrolimab in Combination With Pomalidomide and Dexamethasone
22) 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.
23) Prior treatment with pomalidomide is allowed if the patient achieved at least a 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.
24) No prior history of discontinuation of pomalidomide due to toxicity
25) No contraindication to dexamethasone Magrolimab in Combination With Carfilzomib and Dexamethasone
26) 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.
27) 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.
28) No prior history of discontinuation of carfilzomib due to toxicity.
29) No contraindication to dexamethasone
Magrolimab in Combination With Bortezomib and Dexamethasone:
30) Patient must have received at least 1 previous line of therapy.
31) Prior treatment with a PI, including bortezomib, 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.
32) No prior history of discontinuation of bortezomib due to toxicity.
33) No contraindication to dexamethasone. |
|
| E.4 | Principal exclusion criteria |
1) Patients with known amyloidosis including myeloma complicated by amyloidosis
2) Multiple myeloma of immunoglobulin M subtype
3) Patients with Waldenstrom’s macroglobulinemia
4) Patients with MDS
5) 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 × 109/L
6) Patients with solitary bone or extramedullary plasmacytoma as the only evidence of plasma cell dyscrasia
7) POEMS syndrome (plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes)
8) Glucocorticoid therapy (prednisone > 40 mg/day or equivalent) within 14 days prior to enrollment; corticosteroid therapy for hypercalcemia is allowed
9) Chemotherapy with approved or investigational anticancer therapeutics within 28 days prior to enrollment
10) 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)
11) Immunotherapy within 28 days prior to enrollment
12) Major surgery (excluding procedures to stabilize the vertebrae) within 28 days prior to enrollment
13) Positive serum pregnancy test
14) Breastfeeding female
15) Known hypersensitivity to any of the study drugs, the metabolites, or formulation excipient
16) Prior treatment with CD47 or SIRPα-targeting agents.
17) Current participation in another interventional clinical trial
18) Autologous stem cell transplant < 100 days prior to enrollment
19) Considered eligible to receive autologous or allogeneic SCT at the time of enrollment
20) Allogeneic SCT for the treatment of MM within 6 months of enrollment or active graft-versus-host disease requiring immunosuppression
21) Significant neuropathy (Grade 3 to 4, or Grade 2 with pain) within 14 days prior to enrollment
22) Known inherited or acquired bleeding disorders
23) Known cirrhosis
24) Clinical suspicion or documentation of CNS disease
25) 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 NYHA Class III or IV heart failure.
26) Acute active infection requiring systemic antibiotics, antiviral (except antiviral therapy directed against reactivation) or antifungal agents within 14 days prior to enrollment
27) 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.
28) Known active or chronic hepatitis B or C infection or HIV infection in medical history
29) Active hepatitis B virus (HBV) and/or active hepatitis C virus (HCV), and/or HIV infection following testing at screening:
a) Patients 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.
b) Patients who test positive for HCV antibody. Patients who test positive for HCV antibody will require HCV RNA by quantitative PCR for confirmation of active disease.
c) Patients who test positive for HIV |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Endpoints for the Safety Run-in Cohorts:
The incidence of dose-limiting toxicities (DLTs), adverse events (AEs) and laboratory abnormalities according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0
Endpoints for the Dose Expansion Cohorts:
Objective response rate, defined as the percentage of patients who achieve stringent complete response (sCR), complete response (CR), very good partial response (VGPR), or partial response (PR) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
The DLT assessment period will be the first cycle (35 days). Efficacy assessments will be done in conjunction with bone marrow assessments, according to the schedule of assessments on Day 1 of Cycle 2 onward. Disease assessments will be based on central laboratory data obtained every 28 ± 7 days until
confirmed PD irrespective of cycle duration, including dose delays and treatment discontinuation. |
|
| E.5.2 | Secondary end point(s) |
Objectives and Endpoints for the Safety Run-in Cohorts:
N/A
Objectives and Endpoints for the Dose Expansion Cohorts:
- The incidence of AEs and laboratory abnormalities according to the NCI CTCAE Version 5.0
- Duration of response (DOR)a
- Progression-free survival (PFS)
- Overall survival (OS)
- Magrolimab concentration versus time
- Measurements of antidrug antibody (ADA) against magrolimab |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Serum protein electrophoresis, UPEP, SFLC, SIFE, and UIFE will be conducted at the central laboratory during screening and subsequently every 28 ± 7 days (starting from Cycle 1 Day 1) irrespective of cycle duration including dose delays and treatment discontinuation. Antidrug antibodies will be assessed on Day 1 of each cycle. Efficacy assessments will be done in conjunction with bone marrow assessments, according to the schedule of assessments on Day 1 of Cycle 2 onward. Disease assessments will be based on central laboratory data obtained every 28 ± 7 days until confirmed PD irrespective of cycle duration, including dose delays and treatment discontinuation. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Canada |
| United States |
| Czechia |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
All Patients: The end of the entire study for all patients is defined as the date on which the last patient remaining on study completes the last study visit/call or when the sponsor decides to end the study. The sponsor reserves the right to terminate the study at any time for any reason (including safety).
Individual Patients: Patients are considered to have completed study participation altogether when they are no longer followed for either disease progression or survival. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
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