A Study to Learn About the Effects of Two Study Medicines (Maplirpacept [PF-07901801] And Glofitamab) When Given Together In People With Relapsed Or Refractory Diffuse Large B Cell Lymphoma.

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to learn about the effects of two study medicines (maplirpacept [PF-07901801] and glofitamab) when given together for the treatment of diffuse large B-cell lymphoma (DLBCL) that is relapsed or is refractory. Relapsed means has returned after last treatment. Refractory means that it has not responded to last treatment. The two study medicines are given after a single dose of obinutuzumab which is the third study medicine. DLBCL is a type of non-Hodgkin lymphoma (NHL). NHL is a cancer of the lymphatic system. It develops when the body makes abnormal B lymphocytes. These lymphocytes are a type of white blood cell that normally help to fight infections. This study is seeking adult participants who: Have histologically confirmed diagnosis of DLBCL Have received at least one first line of treatment for NHL. Are unable or unwilling to undergo a stem cell transplant or CAR-T cell therapy. Stem cell transplant is a procedure in which a patient receives healthy blood-forming cells to replace their own stem cells that have been destroyed by treatment. A CAR-T therapy is a type of treatment in which a patient's T cells are changed in the laboratory so they will attack cancer cells. Everyone in this study will receive all three medicines at the study site by intravenous (IV) infusion which is given directly into a vein. The two study medicines (maplirpacept [PF-07901801] and glofitamab) will be given in 21-day cycles. At Cycle 0, participants will receive a single dose of obinutuzumab pre-treatment followed by two step-up doses of glofitamab. The combination of maplirpacept (PF-07901801) with glofitamab full dose will be administered for the first time at Cycle 1 Day 1. Maplirpacept (PF-07901801) will be given weekly for the first three cycles and then every three weeks. Glofitamab will be given every 3 weeks for approximately 9 months. Thereafter participants will continue to receive maplirpacept alone. Maplirpacept (PF-07901801) will be given at different doses to different participants. Everyone taking part will receive the same fixed doses of glofitamab and obinutuzumab studied in patients with DLBCL. The study will compare the experiences of people receiving different doses of maplirpacept (PF-07901801). This will help to determine what dose is safe and effective when given with the other 2 study medicines.

Detailed Description
-----------------
This is a multicenter, open-label, Phase 1b/2 study to evaluate the safety, tolerability and potential clinical benefits of maplirpacept PF-07901801, an anti-CD47 molecule, in combination with fixed doses of glofitamab after a single dose of obinutuzumab in participants with relapsed/refractory (R/R) DLBCL not eligible for or unwilling to undergo high dose chemotherapy and subsequent autologous stem cell transplantation (ASCT) or unable to receive approved chimeric antigen receptor T-cell (CAR-T) therapy (for example, due to logistical limitations). For Phase 1b, participants must have previously received at least 1 prior systemic treatment regimen. For Phase 2, participants must have received at least 1 but no more than 2 prior systemic treatment regimens. All participants must have previously received an anti-CD20 containing regimen. Phase 1b will assess dose-limiting toxicities of PF-07901801 when administered in combination with glofitamab, to select up to 2 doses for the Phase 2 part of the study. Phase 2 will evaluate safety and efficacy to determine the recommended Phase 3 dose of PF-07901801 to be administered in combination with glofitamab.

Official Title
-----------------
A PHASE 1b/2, OPEN-LABEL STUDY OF PF-07901801 IN COMBINATION WITH GLOFITAMAB AFTER A FIXED, SINGLE DOSE OF OBINUTUZUMAB IN PARTICIPANTS WITH RELAPSED/REFRACTORY DIFFUSE LARGE B CELL LYMPHOMA NOT ELIGIBLE FOR STEM CELL TRANSPLANTATION

Conditions
-----------------
Diffuse Large B-Cell Lymphoma

Intervention / Treatment
-----------------
* Drug: maplirpacept (PF-07901801)
* Drug: Glofitamab
* Drug: Obinutuzumab


Participation Criteria
=================
Eligibility Criteria
-----------------
Key Inclusion Criteria: Histologically confirmed diagnosis of DLBCL Relapsed or refractory disease Participant is not be a candidate for or is unwilling to undergo high dose chemotherapy and subsequent stem cell transplant and/or is unable to receive chimeric antigen receptor (CAR) T-cell therapy Previous treatment with at least one prior line of systemic therapy (for phase 2, at least 1 and no more than 2 prior lines of systemic therapy). Prior therapy must include an anti-CD20 antibody. Adequate bone marrow, hepatic and renal function Eastern Cooperative Oncology Group (ECOG) ≤2 Key Exclusion Criteria: Prior treatment with anti-CD47 and/or prior glofitamab or anti-CD20 x CD3 containing regimen. Refractoriness to an obinutuzumab monotherapy containing regimen. Prior allogeneic stem cell transplantation or autologous stem cell transplantation within 12 weeks prior to enrolment High Grade B-Cell Lymphoma Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Open label/randomized
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1b<br>Participants will be allocated to sequential dose levels of PF-07901801, administered in combination with fixed doses of glofitamab after a dose of obinutuzumab, to select two doses of PF-07901801 for further evaluation in Phase 2. Approximately 20 participants will be enrolled. | Drug: maplirpacept (PF-07901801)<br>* Intravenous infusion<br>Drug: Glofitamab<br>* Intravenous infusion<br>Drug: Obinutuzumab<br>* Intravenous infusion<br>|
| Experimental: Phase 2<br>Participants will be randomized to 1 of 2 different dose levels of PF-07901801 which will be administered in combination with fixed doses of glofitamab after a dose of obinutuzumab. Approximately 50 participants will be enrolled (25 per dose). | Drug: maplirpacept (PF-07901801)<br>* Intravenous infusion<br>Drug: Glofitamab<br>* Intravenous infusion<br>Drug: Obinutuzumab<br>* Intravenous infusion<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1b: Number of participants with Dose limiting toxicities (DLT) | DLTs are a predefined set of adverse events that are at least possibly related to any or all of the investigational agents. | 21 days following first PF-07901801 dose | 
| Phase 2: Objective Response (OR) | OR defined as proportion of participants with objective response based assessment of complete response (CR) or partial response (PR) according to Lugano Response Classification Criteria 2014. | Time from the date of first dose of study intervention until the first documentation of disease progression, death, or start of new anticancer therapy (assessed up to approximately 24 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1b and Phase 2: Frequency of adverse events (AE) | Type and severity (severity according to the National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE], version 5.0). Severity of Cytokine Release Syndrome (CRS) and Immune effector cell-associated neurotoxicity syndrome (ICANS) assessed according to ASTCT criteria. | Time from the date of first dose of study intervention through 28 days after last dose of PF-07901801 or 90 days after last dose of glofitamab or obinutuzumab (assessed up to approximately 24 months) | 
| Phase 1b and Phase 2: Frequency of clinical laboratory abnormalities | Type and severity (severity according to the National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE], version 5.0). | Time from the date of first dose of study intervention through 28 days after last dose of PF-07901801 or 90 days after last dose of glofitamab or obinutuzumab (assessed up to approximately 24 months) | 
| Phase 1b: Objective Response (OR) | OR defined as proportion of participants with objective response based assessment of complete response (CR) or partial response (PR) according to Lugano Response Classification Criteria 2014. | Time from the date of first dose of study intervention until the first documentation of disease progression, death, or start of new anticancer therapy (assessed up to approximately 24 months) | 
| Phase 1b and Phase 2: Duration of Response (DoR) | DoR defined as the time from the first documentation of OR until progressive disease (PD), or death due to any cause, whichever occurs first. | Time from the date of first dose of study intervention until the first documentation of disease progression, death, or start of new anticancer therapy (assessed up to approximately 24 months) | 
| Phase 1b and Phase 2: Complete Response (CR) | CR defined per Lugano Response Classification Criteria 2014 | Time from the date of first dose of study intervention until the first documentation of disease progression, death, or start of new anticancer therapy (assessed up to approximately 24 months) | 
| Phase 1b and Phase 2: Duration of Complete Response (DoCR) | DoCR defined as the time from the first documentation of a CR until PD, or death due to any cause, whichever occurs first. | Time from the date of first dose of study intervention until PD, or death due to any cause, whichever occurs first (assessed up to approximately 24 months) | 
| Phase 1b and Phase 2: Progression Free Survival (PFS) | PFS is defined as the time from the date of first dose until PD per Lugano Response Classification Criteria 2014, or death due to any cause, whichever occurs first. | Time from the date of first dose of study intervention until PD, or death due to any cause, whichever occurs first (assessed up to approximately 24 months) | 
| Phase 1b and Phase 2: Serum Concentration Versus Time Summary of PF-07901801 | Pre- and post-dose concentrations of PF-07901801 | Pre and post-infusion on Day 1 of Cycle 1 and 2 (each cycle is 21 days), Pre-infusion on Day 8 of Cycle 1, Pre-infusion on Day 1 of Cycles 3, 4, 5, 7, 10, 13 and every 6 cycle thereafter until end of treatment (approximately 24 months) | 
| Phase 1b and Phase 2: Serum Concentration Versus Time Summary of glofitamab | pre- and post-dose concentrations of glofitamab | Pre-infusion on Days 8 and 15 of Cycle 0 (cycle duration is 21 days), Pre-infusion, post-Infusion on Day 1 of Cycle 1 and 2, Pre-infusion on Day 1 of Cycle 3, 4, 7, 10 and 12. | 
| Phase 1b and Phase 2: Number of participants with Anti-Drug Antibody (ADA) against PF-07901801 | To evaluate immunogenicity of PF-07901801 | On the first day of every 21-day cycle through 5 cycles, then every third cycle from cycle 7 through cycle 13 and then every sixth cycle thereafter until end of PF-07901801 treatment (assessed up to approximately 24 months) | 
| Phase 1b and Phase 2: Number of participants with Anti-Drug Antibody (ADA) against glofitamab | To evaluate immunogenicity of glofitamab | On the 8th day of cycle 0 (cycle duration is 21 days), then the first day of every 21-day cycle through cycle 4, then the first day of cycle 7, 10 and 12 (last assessment). | 
| Phase 1b and Phase 2: Number of participants with Neutralizing antibody (NAb) for PF-07901801 | To evaluate immunogenicity of PF-07901801 | On the first day of every 21-day cycle through 5 cycles, then every third cycle from cycle 7 through cycle 13 and then every sixth cycle thereafter until end of PF-07901801 treatment (assessed up to approximately 24 months) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
DLBCL, Lymphoma, Relapsed, Refractory, CD20, CD3, CD47, Glofitamab, Obinutuzumab, Maplirpacept