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

Phase 1TerminatedNCT02663518

Pfizer249 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

249

Conditions

Hematologic Malignancies Solid Tumor

Interventions

PF-0791800 (TTI-621)DRUG

Monotherapy

PF-07901800 (TTI-621) plus RituximabDRUG

Combination therapy

PF-07901800 (TTI-621) plus NivolumabDRUG

Combination therapy

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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

Locations (51)

Outcomes

Primary Outcomes

Part 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs)

An adverse event (AE) was any untoward medical occurrence in administered medicinal product, event need not necessarily have a causal relationship with product treatment or usage. A serious adverse event (SAE) was any untoward medical occurrence in a participant administered a medicinal or nutritional product (including pediatric formulas) at any dose that: resulted in death; was life-threatening; required inpatient hospitalization or prolongation of hospitalization; resulted in persistent or significant disability/incapacity (substantial disruption of the ability to conduct normal life functions); resulted in congenital anomaly/birth defect. Treatment emergent AEs were events emerged during treatment period and were absent before treatment or that worsened relative to pretreatment state.

Time frame: Part 1: Day 1 of dosing up to 30 days of safety follow-up visit after the last dose (maximum treatment exposure for Part 1 was 414 days)

Part 1: Number of Participants With Dose Limiting Toxicities (DLTs)

DLT was defined as any of the protocol specified TEAEs that occurred during the 21-day. DLT treatment/observation period (including the pre-dose tests on Day 22/Week 4 Day 1) and that were considered at least possibly related to study treatment by the investigator. Protocol specified DLT TEAE criteria: Grade 4 thrombocytopenia; Grade 3 thrombocytopenia with bleeding (with the exception of brief, easily-controlled epistaxis, mild gum bleeding or normal menses) or with any requirement for platelet transfusions; Grade 4 anemia, unexplained by underlying disease; Grade 4 neutropenia lasting more than 5 days; Febrile neutropenia of any duration ( Absolute Neutrophil Count (ANC) less than (\<) 1.0 \* 10\^9/L. fever greater than (\>) 38.5° Degree Celsius (C); Grade 3 or higher non-hematologic toxicity except for alopecia and nausea controlled by medical management; Grade 3 or 4 hemorrhage.

Time frame: Part 1: Day 1 of dosing up to Pre-dose on Day 22

Part 2 and 3: Number of Participants With TEAEs and TESAEs

An AE was any untoward medical occurrence in administered medicinal product, event need not necessarily have a causal relationship with product treatment or usage. A SAE was any untoward medical occurrence in a participant administered a medicinal or nutritional product (including pediatric formulas) at any dose that: resulted in death; was life-threatening; required inpatient hospitalization or prolongation of hospitalization; resulted in persistent or significant disability/incapacity (substantial disruption of the ability to conduct normal life functions); resulted in congenital anomaly/birth defect. Treatment emergent AEs were events emerged during treatment period and were absent before treatment or that worsened relative to pretreatment state.

Data from ClinicalTrials.gov

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Secondary Outcomes

Part 1: Maximum Plasma Concentration (Cmax) of TTI-621

Time frame: Part 1: Pre-dose, end of infusion (EOI), 2, 4, 24, 72, 168 hours post dose on Week 1

Part 1: Area Under the Plasma Concentration Time Curve From Time Zero to 168 (AUC[0-168]) of TTI-621

Time frame: Part 1: Pre-dose, end of infusion (EOI), 2, 4, 24, 72, 168 hours post dose on Week 1

Part 1: Percentage of CD47 Receptor Occupancy on Peripheral Blood CD3+ Cells

CD47 is a cell-surface protein expressed on multiple normal cell types and often at high levels on many malignant tumour cells .

Time frame: Part 1: Week 1 end of infusion (EOI)

Part 1: Number of Participants With Positive Anti-Drug Antibody (ADA) and Neutralizing Antibodies (NAb)

A participant was ADA (or NAb) positive if: (1) baseline titer was missing or negative and participants had \>1 post-treatment positive titer (treatment-induced), or (2) positive titer at baseline and had a \> \[4-fold dilution increase\] in titer from baseline in \>1 post-treatment sample (treatment-boosted).

Time frame: Part 1: From pre-infusion on day 1 up to end of study treatment (maximum treatment exposure for Part 1 was 414 days)

Part 2 and 3 Combined: Maximum Plasma Concentration (Cmax) of TTI-621

Results for this outcome measure was reported for Part 2 and Part 3 combined.

Time frame: Part 2 and 3: Pre-dose, end of infusion (EOI), 2, 4, 24, 72, 168 hours post dose on Week 1

Part 2 and 3 Combined: Area Under the Plasma Concentration Time Curve From Time Zero to 168 (AUC[0-168]) of TTI-621

Results for this outcome measure was reported for Part 2 and Part 3 combined.

Time frame: Part 2 and 3: Pre-dose, end of infusion (EOI), 2, 4, 24, 72, 168 hours post dose on Week 1

Part 2 and 3 Combined: Percentage of CD47 Receptor Occupancy on Peripheral Blood CD3+ Cells

CD47 is a cell-surface protein expressed on multiple normal cell types and often at high levels on many malignant tumour cells. Results are reported for combined Part 2 and 3.

Time frame: Part 2 and 3: Week 1 end of infusion (EOI)

Part 2 and 3: Number of Participants With Positive Anti-Drug Antibody (ADA) and Neutralizing Antibodies (NAb)

A participant was ADA (or NAb) positive if: (1) baseline titer was missing or negative and participants had \>1 post-treatment positive titer (treatment-induced), or (2) positive titer at baseline and had a \> 4-fold dilution increase in titer from baseline in \> 1 post-treatment sample (treatment-boosted).

Time frame: Part 2 and 3: From pre-infusion on day 1 up to end of study treatment (maximum treatment exposure for Part 2 was 1793 days and for Part 3 was 938 days)

Part 2 and 3: Overall Response Rate (ORR) - Lugano Classification (Cheson 2014) and Refinement (Cheson 2016) Disease Indications and Nivolumab/Rituximab Combinations

ORR is presented in this outcome measure as number of responders. Responders were those who had complete remission and partial remission. Lugano classification (Cheson et al., 2014) and refinement (Cheson et al., 2016) were used for tumor response assessment for lymphomas by computed tomography (CT)-based criteria and complete metabolic response (CMR) or partial metabolic response (PMR) by positron emission tomography (PET-CT) based criteria were used for evaluation. Lymphomas evaluated by Lugano Classification include aggressive B-cell lymphoma (ABCL), Hodgkin's lymphoma (HL), Non-Hodgkin's lymphoma, indolent B-cell lymphoma (IBCL), peripheral T-cell lymphoma (PTCL), and part of T-cell lymphoma (TCL).