Trial of Magrolimab (Hu5F9-G4) in Combination With Rituximab or Rituximab + Chemotherapy in Participants With Relapsed/Refractory B-cell Non-Hodgkin's Lymphoma

Study Overview
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Brief Summary
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The primary objectives of this study are: To investigate the safety and tolerability, and to define the recommended Phase 2 dose and schedule (RP2DS) for magrolimab in combination with rituximab and for magrolimab in combination with rituximab, gemcitabine, and oxaliplatin (R-GemOx). To evaluate the efficacy of magrolimab in combination with rituximab in participants with indolent lymphoma and diffuse large B-cell lymphoma (DLBCL) and to evaluate the efficacy of magrolimab in combination with R-GemOx in autologous stem cell transplant (ASCT) ineligible DLBCL participants.

Official Title
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A Phase 1b/2 Trial of Hu5F9-G4 in Combination With Rituximab or Rituximab + Chemotherapy in Patients With Relapsed/Refractory B-cell Non-Hodgkin's Lymphoma

Conditions
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Non Hodgkin Lymphoma

Intervention / Treatment
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* Drug: Magrolimab
* Drug: Rituximab
* Drug: Gemcitabine
* Drug: Oxaliplatin


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Phase 1b only: B-cell non-Hodgkin's lymphoma (NHL), relapsed or refractory to standard approved therapies DLBCL Phase 2 cohort: De novo or transformed diffuse large B-cell lymphoma (DLBCL) expressing CD 20, relapsed or refractory to at least 2 prior lines treatment containing anti-CD20 therapy Indolent lymphoma Phase 2 cohort: Marginal zone or follicular lymphoma, relapsed or refractory to standard approved therapies DLBCL chemotherapy combination cohort: De novo or transformed diffuse large B-cell lymphoma (DLBCL), relapsed or refractory to 1-3 prior lines of treatment Adequate performance status and hematological, liver and kidney functions Willing to consent to 1 mandatory pre-treatment and 1 on-treatment tumor biopsy Key Exclusion Criteria: Active brain metastases Prior allogeneic hematopoietic cell transplantation Prior treatment with CD47 or signal regulatory protein alpha (SIRPα) targeting agents Second malignancy within the last 3 years Known active or chronic hepatitis B or C infection or HIV Pregnancy or active breastfeeding Prior chimeric antigen receptor (CAR-T) therapy Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Magrolimab + Rituximab, Phase 1b Dose Escalation<br>Participants with B-cell non-Hodgkin's lymphoma will receive 1 mg/kg magrolimab priming dose on Day 1 of Cycle 1 followed by weekly maintenance doses of 10, 20, 30, or 45 mg/kg on Days 8, 15, 22 for Cycle 1 and Days 1, 8, 15, and 22 for each cycle to determine the maximum tolerated dose (MTD) and recommended Phase 2 dose and schedule (RP2DS) in combination with rituxumab 375 mg/m^2. Cycle length is 28 days. | Drug: Magrolimab<br>* Administered intravenously<br>* Other names: Hu5F9-G4;Drug: Rituximab<br>* Administered intravenously on Days 8, 15, and 22 during Cycle 1, followed by 1 dose on Day 1 for Cycles 2 through 6, and Day 1 for every other cycle until Cycle 13<br>* Other names: MabThera;|
| Experimental: Magrolimab + Rituximab, Phase 2 Indolent Lymphoma<br>Participants with indolent lymphoma will receive magrolimab based on RP2DS from Phase 1b portion of the study in combination with rituxumab 375 mg/m^2. | Drug: Magrolimab<br>* Administered intravenously<br>* Other names: Hu5F9-G4;Drug: Rituximab<br>* Administered intravenously on Days 8, 15, and 22 during Cycle 1, followed by 1 dose on Day 1 for Cycles 2 through 6, and Day 1 for every other cycle until Cycle 13<br>* Other names: MabThera;|
| Experimental: Magrolimab + Rituximab, Phase 2 Diffuse Large B-Cell lymphoma<br>Participants with diffuse large B-cell lymphoma (DLBCL) will receive magrolimab based on RP2DS from Phase 1b portion of the study in combination with rituxumab 375 mg/m^2. | Drug: Magrolimab<br>* Administered intravenously<br>* Other names: Hu5F9-G4;Drug: Rituximab<br>* Administered intravenously on Days 8, 15, and 22 during Cycle 1, followed by 1 dose on Day 1 for Cycles 2 through 6, and Day 1 for every other cycle until Cycle 13<br>* Other names: MabThera;|
| Experimental: Magrolimab + R-GemOx, Phase 1b Safety Dose Escalation Phase<br>Autologous stem cell transplant (or transplantation) ineligible DLBCL participants will receive 1 mg/kg magrolimab priming dose on Day 1 for Cyle 1 followed by maintenance doses of 30 or 45 mg/kg on Days 8, 11, 15, 22, and 29 for Cycle 1, every week for Cycle 2, and every 2 weeks for each cycle to determine maximum tolerated dose (MTD) + rituxumab 375 mg/m^2 + gemcitabine 1000 mg/m^2 + oxaliplatin 100 mg/m^2. Cycle length is 28 days. | Drug: Magrolimab<br>* Administered intravenously<br>* Other names: Hu5F9-G4;Drug: Rituximab<br>* Administered intravenously on Days 8, 15, and 22 during Cycle 1, followed by 1 dose on Day 1 for Cycles 2 through 6, and Day 1 for every other cycle until Cycle 13<br>* Other names: MabThera;Drug: Gemcitabine<br>* Administered intravenously on Days 11, 23 for Cycle 1 and Days 2 and 15 for Cycles 2 to 4<br>* Other names: Gemzar®;Drug: Oxaliplatin<br>* Administered intravenously on Days 11, 23 for Cycle 1 and Days 2 and 15 for Cycles 2 to 4<br>* Other names: Eloxatin®;|
| Experimental: Magrolimab + R-GemOx, Phase 1b Dose Expansion Phase<br>Autologous stem cell transplant (or transplantation) ineligible DLBCL participants will receive magrolimab at a dose determined from Phase 1b Safety Dose-Escalation Phase in combination with rituxumab 375 mg/m^2 + gemcitabine 1000 mg/m^2 + oxaliplatin 100 mg/m^2. | Drug: Magrolimab<br>* Administered intravenously<br>* Other names: Hu5F9-G4;Drug: Rituximab<br>* Administered intravenously on Days 8, 15, and 22 during Cycle 1, followed by 1 dose on Day 1 for Cycles 2 through 6, and Day 1 for every other cycle until Cycle 13<br>* Other names: MabThera;Drug: Gemcitabine<br>* Administered intravenously on Days 11, 23 for Cycle 1 and Days 2 and 15 for Cycles 2 to 4<br>* Other names: Gemzar®;Drug: Oxaliplatin<br>* Administered intravenously on Days 11, 23 for Cycle 1 and Days 2 and 15 for Cycles 2 to 4<br>* Other names: Eloxatin®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1b: Percentage of Participants Experiencing Dose-limiting Toxicities (DLTs) | DLTs refer to toxicities experienced during the first 28 days of study treatment that have been judged to be clinically significant and related to study treatment in participant in Phase 1b. | Up to 28 days | 
| Percentage of Participants Experiencing Treatment Emergent Adverse Events |  | First dose date up to 5 years | 
| Objective Response Rate as Defined by the Investigator According to the Lugano Classification for Lymphomas | Objective response is defined as complete response (CR) + partial response (PR) determined by Lugano classification for lymphomas. | Up to 5 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PK Parameter of Magrolimab: AUClast | AUClast is defined as the concentration of drug from time zero to the last observable concentration. | Before magrolimab infusion (within 12 hours) on Day 1, 8, and 15 of Cycle 1, Day 1 and 15 of Cycle 2, Day 1 of Cycles 3, 4, 5, 9, and 13 and until safety follow-up visit (30 days ± 7 days after last dose of magrolimab); Cycle length is 28 days | 
| PK Parameter of Rituximab: AUClast | AUClast is defined as the concentration of drug from time zero to the last observable concentration. | Before rituximab infusion (within 12 hours) on Day 8 and 15 of Cycle 1, Day 1 of Cycle 2, Day 1 of Cycles 3 - 6; Cycle length is 28 days | 
| PK Parameter of Magrolimab: AUCtau | AUCtau is defined as concentration of drug over time (the area under the concentration verses time curve over the dosing interval). | Before magrolimab infusion (within 12 hours) on Day 1, 8, and 15 of Cycle 1, Day 1 and 15 of Cycle 2, Day 1 of Cycles 3, 4, 5, 9, and 13 and until safety follow-up visit (30 days ± 7 days after last dose of magrolimab); Cycle length is 28 days | 
| PK Parameter of Rituximab: AUCtau | AUCtau is defined as concentration of drug over time (the area under the concentration verses time curve over the dosing interval). | Before rituximab infusion (within 12 hours) on Day 8 and 15 of Cycle 1, Day 1 of Cycle 2, Day 1 of Cycles 3 - 6; Cycle length is 28 days | 
| PK Parameter of Magrolimab: Cmax | Cmax is defined as the maximum observed concentration of drug. | Before magrolimab infusion (within 12 hours) on Day 1, 8, and 15 of Cycle 1, Day 1 and 15 of Cycle 2, Day 1 of Cycles 3, 4, 5, 9, and 13 and until safety follow-up visit (30 days ± 7 days after last dose of magrolimab); Cycle length is 28 days | 
| PK Parameter of Rituximab: Cmax | Cmax is defined as the maximum observed concentration of drug. | Before rituximab infusion (within 12 hours) on Day 8 and 15 of Cycle 1, Day 1 of Cycle 2, Day 1 of Cycles 3 - 6; Cycle length is 28 days | 
| Percentage of Participants who Developed Anti-Magrolimab Antibodies |  | Day 1 of Cycle 1 to 5, Day 1 Cycle 9, 13, and until safety follow-up visit (30 days ± 7 days after last dose of magrolimab); Cycle length is 28 days | 
| Duration of Response | The duration of response is measured from when the first (objective) response is met (i.e., complete response or partial response) until the first date of objectively documented progressive disease. | Up to 5 years | 
| Progression Free Survival | Progression free survival is measured from dose initiation until the first date of objectively documented disease progression or death. | Up to 5 years | 
| Overall Survival | Overall Survival is measured from dose initiation until death. | Up to 5 years | 
| Time to Progression | Time to Progression is measured from dose initiation until the first date of objectively documented progressive disease criteria. | First dose date up to 5 years | 
| Objective Rate of Response Defined by the Investigator According to the LYRIC Criteria for Lymphomas | Objective response is defined as complete response + partial response determined by Lymphoma Response to Immunomodulatory Therapy Criteria (LYRIC) criteria. | Up to 5 months |