A Trial of PF-07901800 (TTI-621) for Patients With Hematologic Malignancies and Selected Solid Tumors

Study Overview
=================
Brief Summary
-----------------
Multicenter, open-label, phase 1a/1b trial of PF-07901800 (TTI-621) in subjects with relapsed or refractory hematologic malignancies and selected solid tumors.

Detailed Description
-----------------
This is a trial of PF-07901800 (TTI-621) in subjects with relapsed or refractory hematologic malignancies and selected solid tumors. TTI-621 (SIRPαFc) is a soluble recombinant fusion protein created by directly linking the sequences encoding the N-terminal CD47 binding domain of human SIRPα with the Fc domain of human immunoglobulin (IgG1). TTI-621 acts by binding human CD47 and preventing it from delivering an inhibitory do not eat (anti phagocytic) signal to macrophages. This trial will be conducted in 2 phases and 4 parts: Phase 1a Part 1 (escalation phase) and Phase 1b Parts 2-4 (expansion phase). In the dose Escalation Phase (phase 1a Part 1), subjects with lymphoma will be enrolled in sequential dose cohorts to receive TTI-621 to characterize safety, tolerability, pharmacokinetics, and the maximum-tolerated dose (MTD). In the Expansion Phase (phase 1b Parts 2-4), TTI-621 will be given to subjects with a variety of hematologic malignancies and selected solid tumors to further define safety and to characterize efficacy. In the Expansion Phase Part 2, the safety and efficacy of TTI-621 will also be assessed when it is given in combination with other anti-cancer drugs. The dose of TTI-621 to be delivered in the Expansion Phase Parts 2-3 of the study may be increased or decreased based on the subject's tolerability and on the subject's response to treatment. In the phase 1b dose optimization of the study (Part 4), further dose escalation of TTI-621, beyond the dose determined during phase 1a dose escalation, will be pursued in patients with relapsed and/or refractory CTCL following a 3+3 escalation design and using a revised DLT criteria to further evaluate the safety and tolerability of TTI-621 at dose levels higher than the initially recommended phase 1b Parts 2-3. Secondary objectives include further characterization of the pharmacokinetics, pharmacodynamics, and development of ADA; and to gain preliminary evidence of the anti-tumor activity of TTI-621 in subjects with a variety of hematologic malignancies and selected solid tumors. In addition, the safety of TTI-621 will be evaluated in combination with other anti-cancer agents. Pfizer decided terminating this study for administrative reasons on 22Mar2022 (stopping enrollment as of 15Apr2022). The decision wasn't due to safety concerns or requests from regulatory authorities.

Official Title
-----------------
A Phase 1a/1b Dose Escalation and Expansion Trial of PF-0791800 (TTI-621), a Novel Biologic Targeting CD47, in Subjects With Relapsed or Refractory Hematologic Malignancies and Selected Solid Tumors

Conditions
-----------------
Hematologic Malignancies, Solid Tumor

Intervention / Treatment
-----------------
* Drug: PF-0791800 (TTI-621)
* Drug: PF-07901800 (TTI-621) plus Rituximab
* Drug: PF-07901800 (TTI-621) plus Nivolumab


Participation Criteria
=================
Eligibility Criteria
-----------------
MAJOR ELIGIBILITY CRITERIA: Phase 1a Escalation • Histologically documented, measurable, advanced lymphomas, transfusion-independence Phase 1b Expansion (Part 2 and 3) • Advanced malignancy: IBCL, ABCL, cHL, AML, ALL, MDS, MPN, SCLC, PTCL and CTCL; measurable disease who have relapsed or are refractory following at least 2 prior systemic therapeutic attempts (1 prior systemic attempt for PTCL). For CTCL, extracorporeal photochemotherapy (ECP) considered a systemic therapy. Local radiation and topical agents are not systemic therapies. Phase 1b dose optimization (Part 4) • Histologically confirmed diagnosis of CTCL (both Mycosis Fungoides and Sezary Syndrome): Failed at least 2 prior systemic therapies for CTCL (Systemic therapy does not include local radiation therapy or topical agents); History of histologically documented diagnosis of CTCL stage IB to IVB Inclusion Criteria (all subjects): Advanced measurable malignancy with previously progressed on, or currently progressing on standard anticancer therapy or for whom no other approved conventional therapy exists Eastern Cooperative Oncology Group (ECOG) 0-2 Adequate hematologic, hepatic, renal, and coagulation function; fresh or archived tumor tissue available for immunohistochemistry Recovery from prior treatments and/or surgeries; no history of hemolytic anemia or bleeding diathesis. AML M3 (French American British, FAB, classification) (i.e., acute promyelocytic leukemia [APL]) excluded Exclusion Criteria: Known current central nervous system disease involvement or untreated brain metastases Allogeneic transplant within 30 days prior to the planned start of treatment or subjects with active graft-vs-host disease with the exception of Grade 1 skin involvement History of hemolytic anemia or bleeding diathesis

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: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Phase 1a/1b trial of PF-07901800 (TTI-621) for relapsed or refractory hematologic malignancies and selected solid tumors were conducted in 4 parts. In the dose escalation phase (Part 1), advanced lymphomas were enrolled in sequential dose cohorts for safety, tolerability, PK, and MTD. In the expansion phase (Part 2), subjects with various hematologic malignancies and selected solid tumors were treated at recommended dose determined in phase 1a (Part 1) for safety and efficacy. In the expansion phase (Part 3), 2 cohorts (cutaneous T-cell lymphoma and peripheral T-cell lymphoma) were evaluated for potentially further studied using Simon 2-stage design. In the phase 1b dose optimization (Part 4), further dose escalation was investigated in patients with relapsed and/or refractory CTCL following a 3+3 escalation and revised DLT criteria.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PF-07901800 (TTI-621) Escalation Phase - R/R Lymphoma<br>The Escalation Phase will include multiple doses of PF-07901800 (TTI-621) | Drug: PF-0791800 (TTI-621)<br>* Monotherapy<br>* Other names: TTI-621 (SIRPα-IgG1 Fc);|
| Experimental: Indolent B-Cell Lymphoma<br>Monotherapy expansion cohort with PF-07901800 (TTI-621) | Drug: PF-0791800 (TTI-621)<br>* Monotherapy<br>* Other names: TTI-621 (SIRPα-IgG1 Fc);|
| Experimental: Aggressive B-Cell Lymphoma<br>Monotherapy expansion cohort with PF-07901800 (TTI-621) | Drug: PF-0791800 (TTI-621)<br>* Monotherapy<br>* Other names: TTI-621 (SIRPα-IgG1 Fc);|
| Experimental: T-Cell Lymphoma<br>Monotherapy expansion cohort with PF-07901800 (TTI-621) | Drug: PF-0791800 (TTI-621)<br>* Monotherapy<br>* Other names: TTI-621 (SIRPα-IgG1 Fc);|
| Experimental: Hodgkin Lymphoma<br>Monotherapy expansion cohort with PF-07901800 (TTI-621) | Drug: PF-0791800 (TTI-621)<br>* Monotherapy<br>* Other names: TTI-621 (SIRPα-IgG1 Fc);|
| Experimental: Chronic Lymphocytic Leukemia<br>Monotherapy expansion cohort with PF-07901800 (TTI-621) | Drug: PF-0791800 (TTI-621)<br>* Monotherapy<br>* Other names: TTI-621 (SIRPα-IgG1 Fc);|
| Experimental: Multiple Myeloma<br>Monotherapy expansion cohort with PF-07901800 (TTI-621) | Drug: PF-0791800 (TTI-621)<br>* Monotherapy<br>* Other names: TTI-621 (SIRPα-IgG1 Fc);|
| Experimental: Acute Myeloid Leukemia<br>Monotherapy expansion cohort with PF-07901800 (TTI-621) | Drug: PF-0791800 (TTI-621)<br>* Monotherapy<br>* Other names: TTI-621 (SIRPα-IgG1 Fc);|
| Experimental: Myelodysplastic Syndrome<br>Monotherapy expansion cohort with PF-07901800 (TTI-621) | Drug: PF-0791800 (TTI-621)<br>* Monotherapy<br>* Other names: TTI-621 (SIRPα-IgG1 Fc);|
| Experimental: Myeloproliferative Neoplasms<br>Monotherapy expansion cohort with PF-07901800 (TTI-621) | Drug: PF-0791800 (TTI-621)<br>* Monotherapy<br>* Other names: TTI-621 (SIRPα-IgG1 Fc);|
| Experimental: Small Cell Lung Cancer<br>Monotherapy expansion cohort with PF-07901800 (TTI-621) | Drug: PF-0791800 (TTI-621)<br>* Monotherapy<br>* Other names: TTI-621 (SIRPα-IgG1 Fc);|
| Experimental: Rituximab Combination<br>Combination therapy expansion cohort with PF-07901800 (TTI-621) plus Rituximab for CD20 positive malignancies | Drug: PF-07901800 (TTI-621) plus Rituximab<br>* Combination therapy<br>* Other names: TTI-621 plus Rituxan;|
| Experimental: Nivolumab Combination<br>Combination therapy expansion cohort with PF-07901800 (TTI-621) plus Nivolumab for Hodgkin Lymphoma | Drug: PF-07901800 (TTI-621) plus Nivolumab<br>* Combination therapy<br>* Other names: TTI-621 plus Opdivo;|
| Experimental: Cutaneous T-Cell Lymphoma (CTCL)<br>Monotherapy expansion cohort with PF-07901800 (TTI-621) | Drug: PF-0791800 (TTI-621)<br>* Monotherapy<br>* Other names: TTI-621 (SIRPα-IgG1 Fc);|
| Experimental: Peripheral T-Cell Lymphoma (PTCL)<br>Monotherapy expansion cohort with PF-07901800 (TTI-621) | Drug: PF-0791800 (TTI-621)<br>* Monotherapy<br>* Other names: TTI-621 (SIRPα-IgG1 Fc);|
| Experimental: Part 4: Cutaneous T-Cell Lymphoma (CTCL)<br>Monotherapy expansion Part 4 (Dose Optimization) cohort with PF-07901800 (TTI-621) | Drug: PF-0791800 (TTI-621)<br>* Monotherapy<br>* Other names: TTI-621 (SIRPα-IgG1 Fc);|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1a Dose Escalation (Part 1) - Dose Limiting Toxicity (DLT) (incidence and severity of AEs) | To characterize the safety profile and DLT per predefined set of AEs related to PF-07901800 (TTI-621) in order to identify the MTD and/or the optimal dose in adult subjects with advanced relapsed or refractory lymphomas. | During the first 3 weeks of treatment/21-day DLT observation period | 
| Phase 1b Expansion (Part 2 and 3) - incidence and severity of AEs | To further characterize the safety of PF-07901800 (TTI-621) in an expanded number of primary hematologic malignancies and selected solid tumors, and to evaluate the safety of individual subject TTI-621 dose intensification. Type and severity (severity according to the National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE], version 4.03). | Time from the date of first dose of study intervention through 30 days after last dose of study intervention (assessed up to approximately 12 months, and Entire cohort for 35 months) | 
| Phase 1b Dose Optimization (Part 4) - Dose Limiting Toxicity (DLT) | Dose optimization phase in subjects with R/R CTCL, to further evaluate the safety and tolerability of PF-07901800 (TTI-621) at dose levels higher than the initially recommended phase 1b dose (as determined during phase 1a dose escalation) and the MTD and/or recommended phase 2 dose per revised DLT criteria following a 3+3 dose escalation schema starting from the highest dose during phase 1b dose expansion following dose intensification regimens permissible per Part 2 and Part 3 | During the first 3 weeks of treatment/21-day DLT observation period | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1a Escalation (Part 1) - Pharmacokinetics (PK): Maximum Serum Concentration [Cmax] of PF-07901800 | In subjects with R/R lymphoma: Pharmacokinetics: Cmax: serum concentration at the end of study drug infusion | Pre-dose, end of infusion (EOI), 2, 4, 24, 72, 168 hours post dose on Week 1 and/or Week 6/8 | 
| Phase 1a Escalation (Part 1) - Pharmacokinetics (PK): Area Under the Curve [AUC] from time 0 to 168 hours of PF-07901800 | In subjects with R/R lymphoma: Pharmacokinetics: AUC 0-168h: Area Under the Curve from time 0 to 168 hours post study drug administration | Pre-dose, end of infusion (EOI), 2, 4, 24, 72, 168 hours post dose on Week 1 and/or Week 6/8 | 
| Phase 1a Escalation (Part-1) - Pharmacodynamics (PD): Peripheral CD47 Receptor Occupancy | In patients with R/R Lymphoma: pharmacodynamics: CD47 receptor occupancy on peripheral blood CD3+ cells Measurement unit: % | Week 1 end of infusion (EOI) and/or additional post dose time point(s) | 
| Phase 1a Escalation (Part 1) - Incidence of Anti-Drug Antibody (ADA) against PF-07901800 | In patients with R/R Lymphoma: To evaluate the development of immunogenicity (immune response) against of PF-07901800 (TTI-621) - The percentage of participants with positive ADA and neutralizing antibodies. | Week 1, 8, Day 1 and EOT (assessed up to approximately 36 months) | 
| Phase 1b Escalation (Parts 2 and 3) - Pharmacokinetics (PK): Maximum Serum Concentration [Cmax] of PF-07901800 | In subjects with various hematological malignancies and selected solid tumors: Pharmacokinetics: Cmax: serum concentration at the end of study drug infusion | Pre-dose, end of infusion (EOI), 2, 4, 24, 72, 168 hours post dose on Week 1 and/or Week 6/8 | 
| Phase 1b Escalation (Parts 2 and 3) - Pharmacokinetics (PK): Area Under the Curve [AUC] from time 0 to 168 hours of PF-07901800 | In subjects with various hematological malignancies and selected solid tumors: Pharmacokinetics: AUC 0-168h: Area Under the Curve from time 0 to 168 hours post study drug administration | Pre-dose, end of infusion (EOI), 2, 4, 24, 72, 168 hours post dose on Week 1 and/or Week 6/8 | 
| Phase 1b Escalation (Parts 2 and 3) - Pharmacodynamics (PD): Peripheral CD47 Receptor Occupancy | In patients with various hematological malignancies and selected solid tumors: pharmacodynamics: CD47 receptor occupancy on peripheral blood CD3+ cells Measurement unit: % | Week 1 end of infusion (EOI) and/or additional post dose time point(s) | 
| Phase 1b Escalation (Parts 2 and 3) - Incidence of Anti-Drug Antibody (ADA) against PF-07901800 | In patients with various hematological malignancies and selected solid tumors: To evaluate the development of immunogenicity (immune response) against of PF-07901800 (TTI-621) - The percentage of participants with positive ADA and neutralizing antibodies. | Week 1, 8, Day 1 and EOT (assessed up to approximately 36 months) | 
| Phase 1b Expansion (Part 2 and 3) - Overall Response Rate (ORR) | In the subjects with various hematological malignancies and selected solid tumors, assess the Organ System Overall Response Rate per respective criteria by each tumor type. OR defined as complete response or partial response | Response assessments performed at the end of indicated weeks 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 12 months) | 
| Phase 1b Expansion (Part 2 and 3) - Duration of Response (DOR) | Various hematological malignancies and selected solid tumors response assessment per respective criteria by each tumor type. OR defined as complete response or partial response | Time from the first documentation of response until disease progression or death due to any cause, whichever occurs first (assessed up to approximately 12 months) | 
| Phase 1b Expansion (Part 2 and 3) - Progression-free Survival (PFS) | In the subjects with various hematological malignancies and selected solid tumors, the PFS assessment by respective criteria of each tumor | 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 12 months) | 
| Phase 1b Expansion (Part 3) - Part 3: CTCL: organ system overall response rate | In the subjects with CTCL, assess the Organ System Overall Response Rate per Olsen 2011 criteria for CTCL. OR defined as complete response (CR) or partial response (PR). | Response assessments performed at the end of indicated weeks 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 12 months) | 
| Phase 1b Expansion (Part 3) - Part 3: PTCL: organ system overall response rate | In the subjects with PTCL, assess the Organ System Overall Response Rate per Lugano 2014 for PTCL. OR defined as complete response (CR) or partial response (PR). | Response assessments performed at the end of indicated weeks 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 12 months) | 
| Phase 1b Dose Expansion (Dosing Optimization, Part 4) - Pharmacokinetics (PK): Maximum Serum Concentration [Cmax] of PF-07901800 | In subjects with R/R CTCL: Pharmacokinetics: Cmax: serum concentration at the end of study drug infusion | Pre-dose, end of infusion (EOI), 2, 4, 24, 72, 168 hours post dose on Week 1 and/or Week 6/8 | 
| Phase 1b Dose Expansion (Dosing Optimization, Part 4) - Pharmacokinetics (PK): Area Under the Curve [AUC] from time 0 to 168 hours of PF-07901800 | In subjects with R/R CTCL: Pharmacokinetics: AUC 0-168h: Area Under the Curve from time 0 to 168 hours post study drug administration | Pre-dose, end of infusion (EOI), 2, 4, 24, 72, 168 hours post dose on Week 1 and/or Week 6/8 | 
| Phase 1b Dose Expansion (Dosing Optimization, Part 4) - Pharmacodynamics (PD): Peripheral CD47 Receptor Occupancy | In patients with R/R CTCL: pharmacodynamics: CD47 receptor occupancy on peripheral blood CD3+ cells Measurement unit: % | Week 1 end of infusion (EOI) and/or additional post dose time point(s) | 
| Phase 1b Dose Expansion (Dosing Optimization, Part 4) - Incidence of Anti-Drug Antibody (ADA) against PF-07901800 | In patients with R/R CTCL: To evaluate the development of immunogenicity (immune response) against of PF-07901800 (TTI-621) - The percentage of participants with positive ADA and neutralizing antibodies. | Week 1, 8, Day 1 and EOT (assessed up to approximately 36 months) | 
| Phase 1b Dose Expansion (Dosing Optimization, Part 4) - Overall Response Rate (ORR) | In subjects with R/R CTCL - Overall Response Rate per respective criteria by each tumor type. Objective response (OR) defined as complete response or partial response. | Response assessments performed at the end of indicated weeks 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 12 months) | 
| Phase 1b Dose Expansion (Dosing Optimization, Part 4) - Duration of Response (DOR) | In subjects with R/R CTCL, tumors response assessment per respective criteria by each tumor type. Objective Response defined as complete response or partial response. | Time from the first documentation of response until disease progression or death due to any cause, whichever occurs first (assessed up to approximately 12 months) | 
| Phase 1b Dose Expansion (Dosing Optimization, Part 4) - CTCL organ system overall response rate | In subjects with R/R CTCL - organ system overall response rate per Olsen 2011 for CTCL. OR includes CR/PR. | Response assessments performed at the end of indicated weeks 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 12 months) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
PF-07901800, ABCL, Aggressive B-cell lymphoma, CLL, Chronic lymphocytic leukemia, CTCL, Cutaneous T-Cell Lymphoma, HL, Hodgkin lymphoma, IBCL, Indolent B-cell lymphoma, MDS, Myelodysplastic syndromes, MPN, Myeloproliferative neoplasms, MM, Multiple Myeloma, PTCL, Peripheral T-cell lymphomas, SCLC, Small Cell Lung Cancer, T-cell lymphoma, Rituximab, Nivolumab, TTI-621, Solid Tumor, Hematologic Malignancies, Lymphoma, CD47, SIRPα-IgG1 Fc