Study of Maplirpacept (PF-07901801) in Combination With PLD in Patients With Platinum-Resistant Ovarian Cancer

Study Overview
=================
Brief Summary
-----------------
Pegylated liposomal doxorubicin (PLD), a type of chemotherapy, is a standard treatment option for patients with platinum-resistant ovarian cancer. However, despite being consider a standard treatment option, the clinical benefit of chemotherapy alone for these patients is small. Historically, response rates for PLD monotherapy have only ranged from 12 to 35% with a high likelihood of recurrence within months after treatment initiation. Although bevacizumab (BEV), an anti-new-vascular growth monoclonal antibody has been approved by FDA to combine with standard chemotherapy (e.g., PLD) for platinum-resistant recurrent ovarian cancer, there are still many restrictions or contraindications preventing certain women from receiving bevacizumab's combination treatment. The goal of this study is to improve upon the activity of PLD in a safe manner to provide a more effective therapeutic option for this group of patients. The purpose of this study is to assess maplirpacept (PF-07901801) administered in combination with PLD in patients with platinum-resistant ovarian cancer and for whom PLD is a reasonable treatment option. The first portion of the study will evaluate the safety of increasing dose levels of maplirpacept (PF-07901801) in combination with PLD at 40 mg/m2 in patients with platinum-resistant EOC (epithelial ovarian cancer). This is a group of cancer, including ovarian, peritoneal, and fallopian tube malignancy. The aim of the first portion of the study is to establish a combination regimen for further assessment in a dose expansion cohort. The study will consist of a 28-day screening period to ensure participants are qualified for the study treatment plan. During the treatment period, patients will receive maplirpacept (PF-07901801) in combination with PLD in 28-day cycles until their disease progresses or unacceptable toxicity develops. There will be a long-term follow-up period in this study to assess overall survival (length of time since start of treatment patients are alive).

Detailed Description
-----------------
Pegylated liposomal doxorubicin (PLD) is a standard treatment option for patients with platinum-resistant ovarian cancer who are not candidates for chemotherapy in combination with bevacizumab. However, despite being consider a standard treatment option, the clinical benefit of chemotherapy for this patient population is small. The goal of this clinical trial is to improve upon the activity of PLD in a safe manner to provide a more effective therapeutic option for this group of patients. C4971002 (TTI-622-02) is a multi-center, open-label study designed to evaluate maplirpacept (PF-07901801) administered in combination with PLD in patients with platinum-resistant ovarian cancer and for whom PLD is a reasonable treatment option. The first portion of the study will evaluate the safety of increasing dose levels of maplirpacept (PF-07901801) in combination with PLD at 40 mg/m2 in patients with platinum-resistant EOC, including ovarian, peritoneal and fallopian tube malignancy, and establish a combination regimen for further evaluation in a dose expansion cohort. The study will consist of a 28-day screening period, a treatment period in which patients will receive maplirpacept (PF-07901801) in combination with PLD in 28-day cycles until documentation of objective disease progression or development of unacceptable toxicity, and a long-term follow-up period to assess overall survival.

Official Title
-----------------
A Phase Ⅰ/Ⅱ Study of TTI-622 in Combination With Pegylated Liposomal Doxorubicin in Patients With Platinum-Resistant Ovarian Cancer

Conditions
-----------------
Epithelial Ovarian Cancer, Ovarian Cancer, Ovarian Neoplasms, Ovarian Carcinoma, Fallopian Tube Cancer, Primary Peritoneal Carcinoma

Intervention / Treatment
-----------------
* Drug: maplirpacept (PF-07901801)
* Drug: Pegylated Liposomal Doxorubicin (PLD)


Participation Criteria
=================
Eligibility Criteria
-----------------
Key Inclusion Criteria: Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1 Histologically-confirmed epithelial ovarian cancer (EOC), fallopian tube carcinoma (FTC) or primary peritoneal carcinomas (PPC). Platinum-resistant recurrent (disease progression ≤6 months after the most recent platinum-based treatment regimen (date calculated from the last administered dose of platinum) or the participant is no longer able to receive. or declined treatment with platinum-based chemotherapy. Progression with standard of care therapies, including platinum-based therapies, poly ADP ribose polymerase (PARP) inhibitors or bevacizumab in the platinum-sensitive setting or intolerability to such therapies or patient refusal Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 Adequate organ and hematologic function No more than four prior treatment regimens for platinum-resistant disease All adverse events from prior treatment must be the Common Terminology Criteria for Adverse Events (NCI CTCAE) v5 Grade ≤ 1, except alopecia and stable neuropathy, which must have resolved to Grade ≤ 2 or baseline. Key Exclusion Criteria: Platinum-refractory disease (defined as progression on or within 3 months of completing primary first-line platinum-based treatment) Non-epithelial histology, including malignant mixed Mullerian tumors Ovarian tumors with low malignant potential (i.e., borderline tumors), low grade serous ovarian cancer or carcinosarcoma History of acute coronary syndromes. History of or current Class II, III, or IV heart failure. History or evidence of known central nervous system (CNS) metastases or carcinomatous meningitis. Significant bleeding disorders, vasculitis or a significant bleeding episode from the Gastrointestinal (GI) tract. History of severe hypersensitivity reactions to antibodies. Systemic steroid therapy. History or autoimmune disease that has required systemic treatment with disease-modifying agents, corticosteroids, or immunosuppressive drugs. Prior organ transplantation including allogenic or autologous stem cell transplantation Prior treatment with anti-cluster of differentiation 47 (CD47) or anti-SIRPα therapy.

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

Sexes Eligible for Study
-----------------
Female

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

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

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Phase 1/2 (dose escalation and dose expansion)
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1: Dose Escalation<br>In the Phase 1 (dose escalation): Cycle 1 for dose levels 1 and 2, maplirpacept (PF-07901801) will be administered on Day 1, Day 8, Day 15 and Day 22 in combination with PLD on Day 1 of 28-day cycle. Beginning with Cycle 2 at dose levels 1 and 2, maplirpacept (PF-07901801) will be administered on Day 1 and Day 15 in combination with PLD on Day 1 of 28-day cycles. For Phase 1, dose level 3, maplirpacept (PF-07901801) will be administered on Day 1 and Day 15 in combination with PLD on Day 1 of 28-day cycles. Dose level 3 will be biweekly regimen from the start. | Drug: maplirpacept (PF-07901801)<br>* PF-07901801 Escalation (3-dose-level 12, 24, and 48 mg/kg), in combination with Pegylated Liposomal Doxorubicin (40mg/m2) will be administered by intravenous infusion.<br>* Other names: TTI-622;Drug: Pegylated Liposomal Doxorubicin (PLD)<br>* RP2D of maplirpacept (PF-07901801) biweekly of maplirpacept (PF-07901801) from Phase 1 escalation in combination with pegylated liposomal doxorubicin 40mg/m2<br>* Other names: PLD;|
| Experimental: Phase 2: Dose Expansion<br>In the Phase 2 (dose expansion): maplirpacept (PF-07901801) will be administered with selected dose from the escalation phase by intravenous infusion on Days 1, 8, 15 and 22 in Cycle 1, and then on Days 1 and 15 in subsequent cycles in combination with Pegylated Liposomal Doxorubicin 40 mg/m2 by intravenous infusion on Day 1 of each 28-day cycle. | Drug: maplirpacept (PF-07901801)<br>* PF-07901801 Escalation (3-dose-level 12, 24, and 48 mg/kg), in combination with Pegylated Liposomal Doxorubicin (40mg/m2) will be administered by intravenous infusion.<br>* Other names: TTI-622;Drug: Pegylated Liposomal Doxorubicin (PLD)<br>* RP2D of maplirpacept (PF-07901801) biweekly of maplirpacept (PF-07901801) from Phase 1 escalation in combination with pegylated liposomal doxorubicin 40mg/m2<br>* Other names: PLD;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluate DLTs (number) of each escalating dose level of cycle 1 of maplirpacept (PF-07901801) when administered in combination with 40 mg/m2 PLD in 28-day cycles in the Phase 1 escalation | DLTs assessments - defined TEAEs occur during Cycle 1, including specified treatment-related hematologic/non-hematologic toxicities, and other grade ≥2 treated-related non-hematologic toxicities that require a permanent dose reduction or discontinuation of maplirpacept (PF-07901801). | DLTs during the DLT observation period (28 days following C1D1) | 
| Identify the maximum tolerated dose (MTD) from the Phase 1 Escalation Phase | Determine MTD from Phase 1 Dose Escalation Phase | First dose up to 1 year | 
| Identify the Recommended Phase 2 Dose (RP2D) from the Phase 1 Escalation Phase | Determine the Recommended Phase 2 Dose (RP2D) for Phase 2 Dose Expansion Phase | First dose up to 1 year | 
| Assess preliminary evidence of anti-tumor activity of (RP2D) maplirpacept (PF-07901801) in combination with 40 mg/m2 PLD (Phase 2 portion of study) | Objective response (CR, PR) as defined by RECIST v1.1 criteria | First dose up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assess Duration of progression-free survival (PFS) of maplirpacept (PF-07901801) (RP2D) in combination with PLD 40mg/m2 in 28-day cycle in the Phase 2 expansion | Characterize progression-free survival (PFS) as defined by RECIST v1.1 criteria in the Phase 2 expansion | First Dose up to 3 years | 
| Assess Overall Survival (OS) of maplirpacept (PF-07901801) (RP2D) in combination with PLD 40mg/m2 in 28-day cycle in the Phase 2 expansion | The length of overall survival will be measured from the date of study treatment initiation until the date of death from any cause. | First Dose up to 3 years | 
| Assess Disease Control (DC) [CR+PR+SDS] of maplirpacept (PF-07901801) (RP2D) in combination with PLD 40mg/m2 in 28-day cycle in the Phase 2 expansion | Characterize Disease Control (DC) [CR+PR+SD] as defined by RECIST v1.1 criteria in the Phase 2 expansion | First Dose up to 3 years | 
| Assess Duration of response (DOR) of maplirpacept (PF-07901801) (RP2D) in combination with PLD 40mg/m2 in 28-day cycle in the Phase 2 expansion | Characterize duration of response (DOR) as defined by RECIST v1.1 criteria. | First Dose up to 3 years | 
| Further assess the overall safety profile of maplirpacept (PF-07901801) administered in combination with 40 mg/m2 PLD | Characterize by overall safety profiles of adverse events as assessed by: . type . frequency . severity . timing . causal relationship | First Dose up to 2 years | 
| Number and percentage of events with abnormalities in Electrocardiogram (ECG) findings. | Characterize the overall safety profile as assessed by the number/percentage, timing and relationship of events with abnormal Electrocardiogram (ECG) findings. | First dose up to 3 years | 
| Number/percentage, and severity, timing and relationship of hematology, serum chemistry or other laboratory assessments abnormalities (events) | Characterize the overall safety profile as assessed by number/percentage, the severity (CTCAE version 5), timing and relationship of abnormal hematology, serum chemistry or other laboratory assessments | First Dose up to 3 years | 
| Number/percentage, and severity, timing and relationship of abnormal changes in the vital signs events | Characterize the overall safety profile as assessed by number/percentage, the severity (CTCAE version 5), timing and relationship of abnormal changes in the vital signs' events. | First Dose up to 3 years | 
| Evaluate safety profile by number/percentage of treatment delays. | Characterize the overall safety profile as assessed by treatment delays. | First dose up to 3 years | 
| Evaluate safety profile by number/percentage of treatment discontinuation | Characterize the overall safety profile as assessed by treatment discontinuation | First dose up to 3 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Epithelial Ovarian Cancer (EOC), Ovarian Cancer, Platinum-Resistant Ovarian Cancer, Cluster of Differentiation 47 (CD47), maplirpacept (PF-07901801), TTI-622, Doxorubicin, Immune-oncology, chemotherapy, anti-SIRPα therapy