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

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

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

Pfizer decided terminating study for administrative reasons on 22Mar2022 (stopping enrollment as of 15Apr2022). The decision wasn't due to safety concerns or requests from regulatory authorities.

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

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.

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

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.

Combination therapy expansion cohort with PF-07901800 (TTI-621) plus Rituximab for CD20 positive malignancies

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.

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)

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

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

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

In patients with R/R Lymphoma: pharmacodynamics: CD47 receptor occupancy on peripheral blood CD3+ cells Measurement unit: %

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.

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

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

In patients with various hematological malignancies and selected solid tumors: pharmacodynamics: CD47 receptor occupancy on peripheral blood CD3+ cells Measurement unit: %

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.

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)

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)

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)

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)

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

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

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: %

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.

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)

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)

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)

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

Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.

Ansell SM, Maris MB, Lesokhin AM, Chen RW, Flinn IW, Sawas A, Minden MD, Villa D, Percival MM, Advani AS, Foran JM, Horwitz SM, Mei MG, Zain J, Savage KJ, Querfeld C, Akilov OE, Johnson LDS, Catalano T, Petrova PS, Uger RA, Sievers EL, Milea A, Roberge K, Shou Y, O'Connor OA. Phase I Study of the CD47 Blocker TTI-621 in Patients with Relapsed or Refractory Hematologic Malignancies. Clin Cancer Res. 2021 Apr 15;27(8):2190-2199. doi: 10.1158/1078-0432.CCR-20-3706. Epub 2021 Jan 15.

Johnson LDS, Banerjee S, Kruglov O, Viller NN, Horwitz SM, Lesokhin A, Zain J, Querfeld C, Chen R, Okada C, Sawas A, O'Connor OA, Sievers EL, Shou Y, Uger RA, Wong M, Akilov OE. Targeting CD47 in Sezary syndrome with SIRPalphaFc. Blood Adv. 2019 Apr 9;3(7):1145-1153. doi: 10.1182/bloodadvances.2018030577.