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

Phase 1

Terminated

Conditions: Hematologic Malignancies
Solid Tumor

Interventions: Drug: PF-07901800 (TTI-621) plus Nivolumab
Drug: PF-0791800 (TTI-621)
Drug: PF-07901800 (TTI-621) plus Rituximab

Registration Number: NCT02663518

Lead Sponsor: Pfizer

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.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 249

Inclusion Criteria

Not provided

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Nivolumab Combination	PF-07901800 (TTI-621) plus Nivolumab	Combination therapy expansion cohort with PF-07901800 (TTI-621) plus Nivolumab for Hodgkin Lymphoma
Hodgkin Lymphoma	PF-0791800 (TTI-621)	Monotherapy expansion cohort with PF-07901800 (TTI-621)
Aggressive B-Cell Lymphoma	PF-0791800 (TTI-621)	Monotherapy expansion cohort with PF-07901800 (TTI-621)
Multiple Myeloma	PF-0791800 (TTI-621)	Monotherapy expansion cohort with PF-07901800 (TTI-621)
Rituximab Combination	PF-07901800 (TTI-621) plus Rituximab	Combination therapy expansion cohort with PF-07901800 (TTI-621) plus Rituximab for CD20 positive malignancies
PF-07901800 (TTI-621) Escalation Phase - R/R Lymphoma	PF-0791800 (TTI-621)	The Escalation Phase will include multiple doses of PF-07901800 (TTI-621)
T-Cell Lymphoma	PF-0791800 (TTI-621)	Monotherapy expansion cohort with PF-07901800 (TTI-621)
Chronic Lymphocytic Leukemia	PF-0791800 (TTI-621)	Monotherapy expansion cohort with PF-07901800 (TTI-621)
Myeloproliferative Neoplasms	PF-0791800 (TTI-621)	Monotherapy expansion cohort with PF-07901800 (TTI-621)
Peripheral T-Cell Lymphoma (PTCL)	PF-0791800 (TTI-621)	Monotherapy expansion cohort with PF-07901800 (TTI-621)
Small Cell Lung Cancer	PF-0791800 (TTI-621)	Monotherapy expansion cohort with PF-07901800 (TTI-621)
Indolent B-Cell Lymphoma	PF-0791800 (TTI-621)	Monotherapy expansion cohort with PF-07901800 (TTI-621)
Acute Myeloid Leukemia	PF-0791800 (TTI-621)	Monotherapy expansion cohort with PF-07901800 (TTI-621)
Myelodysplastic Syndrome	PF-0791800 (TTI-621)	Monotherapy expansion cohort with PF-07901800 (TTI-621)
Cutaneous T-Cell Lymphoma (CTCL)	PF-0791800 (TTI-621)	Monotherapy expansion cohort with PF-07901800 (TTI-621)
Part 4: Cutaneous T-Cell Lymphoma (CTCL)	PF-0791800 (TTI-621)	Monotherapy expansion Part 4 (Dose Optimization) cohort with PF-07901800 (TTI-621)

Primary Outcome Measures

Name	Time	Method
Part 4: Number of Participants With TEAEs and TESAEs	Part 4: Day 1 of dosing up to 1 year of safety follow-up visit after the last dose (maximum treatment exposure for Part 4 was 667 days)	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 event 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.
Part 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs)	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)	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.
Part 1: Number of Participants With Dose Limiting Toxicities (DLTs)	Part 1: Day 1 of dosing up to Pre-dose on Day 22	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.
Part 2 and 3: Number of Participants With TEAEs and TESAEs	Day 1 of dosing up to 30 days of safety follow-up visit after the last dose (maximum treatment exposure for Part 2 was 1793 days and for Part 3 was 938 days)	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.
Part 4: Number of Participants With Dose Limiting Toxicities (DLTs)	Part 4: Day 1 of dosing up to Pre-dose on Day 22	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 (ANC \< 1.0 x 109/L, fever \> 38.5°C); Grade 3 or higher non-hematologic toxicity except for alopecia and nausea controlled by medical management; Grade 3 or 4 hemorrhage.

Secondary Outcome Measures

Name	Time	Method
Part 2 and 3: Number of Participants With Positive Anti-Drug Antibody (ADA) and Neutralizing Antibodies (NAb)	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)	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).
Part 1: Maximum Plasma Concentration (Cmax) of TTI-621	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	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	Part 1: Week 1 end of infusion (EOI)	CD47 is a cell-surface protein expressed on multiple normal cell types and often at high levels on many malignant tumour cells .
Part 1: Number of Participants With Positive Anti-Drug Antibody (ADA) and Neutralizing Antibodies (NAb)	Part 1: From pre-infusion on day 1 up to end of study treatment (maximum treatment exposure for Part 1 was 414 days)	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).
Part 2 and 3 Combined: Area Under the Plasma Concentration Time Curve From Time Zero to 168 (AUC[0-168]) of TTI-621	Part 2 and 3: Pre-dose, end of infusion (EOI), 2, 4, 24, 72, 168 hours post dose on Week 1	Results for this outcome measure was reported for Part 2 and Part 3 combined.
Part 2 and 3 Combined: Percentage of CD47 Receptor Occupancy on Peripheral Blood CD3+ Cells	Part 2 and 3: Week 1 end of infusion (EOI)	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.
Part 4: Maximum Plasma Concentration (Cmax) of TTI-621	Part 4: Pre-dose, end of infusion (EOI), 2, 4, 24, 72, 168 hours post dose on Week 1
Part 4: Area Under the Plasma Concentration Time Curve From Time Zero to 168 (AUC[0-168]) of TTI-621	Part 4: Pre-dose, end of infusion (EOI), 2, 4, 24, 72, 168 hours post dose on Week 1
Part 2 and 3 Combined: Maximum Plasma Concentration (Cmax) of TTI-621	Part 2 and 3: Pre-dose, end of infusion (EOI), 2, 4, 24, 72, 168 hours post dose on Week 1	Results for this outcome measure was reported for Part 2 and Part 3 combined.
Part 2: Overall Response Rate (ORR)-Savona 2015- Disease Indication	From first dose of study till the progressive disease/ death or withdrawal (maximum observation 6 years 10 months)	ORR is presented in this outcome measure as number of responders. Responders were those who had complete remission, partial remission and marrow response. International Consortium Proposal of Uniform Response Criteria for Myelodysplastic/Myeloproliferative Neoplasms (MDS/MPN) in adults (Savona et al., 2015) was used for assessment of tumors. Tumor types evaluated include Myelodysplastic/Myeloproliferative Neoplasms (MDS/MPN).
Part 4: Overall Response Rate (ORR) in Cutaneous T-Cell Lymphoma (CTCL) Both Fungoides and Sezary Syndrome	From first dose of study till the progressive disease/death or withdrawal (maximum observation 6 years 10 months)	ORR is presented in this outcome measure as number of responders.
Part 2 and 3: Overall Response Rate (ORR) - Lugano Classification (Cheson 2014) and Refinement (Cheson 2016) Disease Indications and Nivolumab/Rituximab Combinations	From first dose of study till the progressive disease/ death or withdrawal (maximum observation 6 years 10 months)	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).
Part 2: Overall Response Rate (ORR)- Durie 2006- Disease Indication	From first dose of study till the progressive disease/ death or withdrawal (maximum observation 6 years 10 months)	ORR is presented in this outcome measure as number of responders. Responders were those who had complete response, stringent complete response, very good partial response, partial response. International Uniform Response Criteria for Multiple Myeloma (Durie et al., 2006). was used for assessment of tumors.Tumor types evaluated include Multiple Myeloma (MM).
Parts 2 and 3: Overall Response Rate (ORR)-Olsen 2011-Disease Indication	From first dose of study till the progressive disease/ death or withdrawal (maximum observation 6 years 10 months)	ORR is presented in this outcome measure as number of responders. Responders were those who had complete response and partial response. Clinical endpoints and response criteria (Olsen et al., 2011) for in CTCL (mycosis fungoides and Sezary syndrome) and TCL were used for assessment. Tumor types evaluated included Cutaneous T-cell lymphoma (CTCL) and a part of T-cell lymphoma (TCL).
Part 2: Overall Response Rate (ORR)- Hallek 2008- Disease Indication	From first dose of study till the progressive disease/ death or withdrawal (maximum observation 6 years 10 months)	ORR is presented in this outcome measure as number of responders. Responders were those who had complete response or complete remission, complete response or complete remission with incomplete marrow recovery, partial response. International Workshop on CLL update of the NCI 1996 Guidelines (Hallek et al., 2008) was used for assessment of tumors. Tumor types evaluated include chronic lymphocytic leukemia (CLL).
Part 2: Overall Response Rate (ORR)- Cheson 2003- Disease Indication	From first dose of study till the progressive disease/ death or withdrawal (maximum observation 6 years 10 months)	ORR is presented in this outcome measure as number of responders. Responders were those who had morphologic leukemia-free state, morphologic complete remission, morphologic complete remission with incomplete blood count recovery, partial remission. International Working Group for trials in AML (Cheson et al., 2003) was used for assessment of tumor. Tumor types evaluated include Acute Myeloid Leukemia (AML).
Part 2: Overall Response Rate (ORR)- Bohnsack 2014- Disease Indication	From first dose of study till the progressive disease/ death or withdrawal (maximum observation 6 years 10 months)	ORR is presented in this outcome measure as number of responders. Responders were those who had irComplete Response, IrPartial Response. Immune-Related Response Criteria: RECIST (Bohnsack et al., 2014) was used for assessment of tumor. Tumor types evaluated included Small Cell Lung Cancer (SCLC).
Parts 2 and 3: Progression Free Survival (PFS)	From first dose of study till the progressive disease/ death or withdrawal (maximum observation 6 years 10 months)	PFS was defined as the number of weeks from the date of the first dose of study drug to the earliest of documented recurrent or progressive disease or death due to any cause without prior progression. The progression or censoring date was determined based on described conventions (Food and Drug Administration, 2007). Kaplan-Meier method was used.
Part 4: Duration of Response (DoR)	From first dose of study till the progressive disease/death or withdrawal (maximum observation 6 years 10 months)	DoR was defined, in participants who achieved a response as time from the first date of response to the first date of recurrent or progression disease. Participants without recurrent or progression disease were censored on date of the last adequate disease assessment, date of initiation of anticancer treatment or death of death, whichever was the earliest.
Parts 2 and 3: Duration of Response (DoR)- Disease Indication and Nivolumab/Rituximab Combinations	From first dose of study till the progressive disease/ death or withdrawal (maximum observation 6 years 10 months)	DoR was defined, in participants who achieved a response as time from the first date of response to the first date of recurrent or progression disease. Participants without recurrent or progression disease were censored on date of the last adequate disease assessment, date of initiation of anticancer treatment or death of death, whichever was the earliest.
Part 4: Percentage of CD47 Receptor Occupancy on Peripheral Blood CD3+ Cells	Part 4: Week 1 end of infusion (EOI)	CD47 is a cell-surface protein expressed on multiple normal cell types and often at high levels on many malignant tumor cells.
Part 4: Number of Participants With Positive Anti-Drug Antibody (ADA) and Neutralizing Antibodies (NAb)	Part 4: From pre-infusion on day 1 up to end of study treatment (maximum treatment exposure for Part 4 was 667 days)	A participant was ADA (or NAb) positive if: (1) baseline titer is 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).
Part 4: Overall Response Rate (ORR)	From first dose of study till the progressive disease/death or withdrawal (maximum observation 6 years 10 months)	ORR is presented in this outcome measure as number of responders. Responders were those who had complete response, partial response. Lymphomas evaluated include Non-Hodgkin's Lymphoma. Clinical endpoints and response criteria in mycosis fungoides and Sezary syndrome (Olsen et al., 2011).

Trial Locations

Locations (50): Cleveland Clinic
🇺🇸
Cleveland, Ohio, United States
The University of Texas MD Anderson Cancer Center
🇺🇸
Houston, Texas, United States
University of Texas MD Anderson Cancer Center, Melanoma and Skin Clinic
🇺🇸
Houston, Texas, United States
University of Texas MD Anderson Cancer Center
🇺🇸
Houston, Texas, United States
Seattle Cancer Care Alliance
🇺🇸
Seattle, Washington, United States
University of Washington - Seattle Cancer Care Alliance
🇺🇸
Seattle, Washington, United States
University of Washington Medical Center
🇺🇸
Seattle, Washington, United States
City of Hope
🇺🇸
Duarte, California, United States
Freidenrich Center for Translational Research (CTRU)
🇺🇸
Palo Alto, California, United States
Presbyterian/St.Luke's Medical Center
🇺🇸
Denver, Colorado, United States
Stanford Cancer Institute
🇺🇸
Palo Alto, California, United States
Colorado Blood Cancer Institute
🇺🇸
Denver, Colorado, United States
Moffitt Cancer Center Richard M Schulze Family Foundation Outpatient Center at McKinley Campus
🇺🇸
Tampa, Florida, United States
Moffitt Cancer Center
🇺🇸
Tampa, Florida, United States
Mayo Clinic Jacksonville
🇺🇸
Jacksonville, Florida, United States
Covance Biorepository
🇺🇸
Greenfield, Indiana, United States
Memorial Sloan Kettering Cancer Center Westchester
🇺🇸
Harrison, New York, United States
Laura and Isaac Perlmutter Cancer Center at NYU Langone Health
🇺🇸
New York, New York, United States
Laura and Isaac Perlmutter Cancer Center at NYU Langone
🇺🇸
New York, New York, United States
NYU Investigational Pharmacy
🇺🇸
New York, New York, United States
NYU Langone Health (Tisch Hospital)
🇺🇸
New York, New York, United States
Memorial Sloan Kettering Cancer Center-Clinical Trails Office
🇺🇸
New York, New York, United States
Columbia Univeristy
🇺🇸
New York, New York, United States
Memorial Sloan Kettering Cancer Center Rockefeller Outpatient Pavillion
🇺🇸
New York, New York, United States
Columbia University Medical Center.
🇺🇸
New York, New York, United States
Memorial Sloan Kettering Cancer Center - David H. Koch Center for Cancer Care
🇺🇸
New York, New York, United States
Cleveland Clinic Taussig Cancer Center
🇺🇸
Cleveland, Ohio, United States
Memorial Sloan Kettering Cancer Center
🇺🇸
New York, New York, United States
Oregon Health & Science University
🇺🇸
Portland, Oregon, United States
Oregon Health & Science University-Research Pharmacy Services
🇺🇸
Portland, Oregon, United States
University of Pittsburgh Medical Center Presbyterian Shadyside
🇺🇸
Pittsburgh, Pennsylvania, United States
University of Pittsburgh Medical Center
🇺🇸
Pittsburgh, Pennsylvania, United States
Oregon Health and Sciences University
🇺🇸
Portland, Oregon, United States
Myriad RMB Inc
🇺🇸
Austin, Texas, United States
University of Texas MD Anderson Cancer Center, Cancer Prevention Center
🇺🇸
Houston, Texas, United States
Fairmont Medical Building, Suite 810
🇨🇦
Vancouver, B.C., Canada
University Health Network - Princess Margaret Cancer Centre
🇨🇦
Toronto, Ontario, Canada
Princess Margaret Cancer Center
🇨🇦
Toronto, Ontario, Canada
The John Theurer Cancer Center at Hackensack UMC
🇺🇸
Hackensack, New Jersey, United States
Memorial Sloan Kettering Cancer Center- Monmouth
🇺🇸
Middletown, New Jersey, United States
Centennial Medical Center
🇺🇸
Nashville, Tennessee, United States
Sarah Cannon Research Institute (Pharmacy)
🇺🇸
Nashville, Tennessee, United States
Tennessee Oncology PLLC
🇺🇸
Nashville, Tennessee, United States
Tennessee Oncology, PLLC
🇺🇸
Nashville, Tennessee, United States
Tennessee Oncology
🇺🇸
Nashville, Tennessee, United States
City of Hope National Medical Center
🇺🇸
Duarte, California, United States
Hackensack Meridian Health John Theurer Cancer Center
🇺🇸
Hackensack, New Jersey, United States
Mayo Clinic
🇺🇸
Rochester, Minnesota, United States
Hackensack UMC
🇺🇸
Hackensack, New Jersey, United States
British Columbia Cancer Agency
🇨🇦
Vancouver, British Columbia, Canada