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

Solid Tumor Clinical Trial

Official title:

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT02663518
• Other study ID #: TTI-621-01
• Secondary ID: C4961001
• Status: Terminated
• Phase: Phase 1
• Start date: January 28, 2016
• Est. completion date: November 23, 2022

Study information

• Verified date: November 2023
• Source: Pfizer
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Terminated
• Enrollment: 249
• Est. completion date: November 23, 2022
• Est. primary completion date: November 23, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Hematologic Malignancies
• Hematologic Neoplasms
• Neoplasms
• Solid Tumor

Intervention

Drug:
• PF-0791800 (TTI-621)
Monotherapy
• PF-07901800 (TTI-621) plus Rituximab
Combination therapy
• PF-07901800 (TTI-621) plus Nivolumab
Combination therapy

Locations

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

Sponsors (1)

Lead Sponsor	Collaborator
Pfizer

Countries where clinical trial is conducted

United States,  Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	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)
Primary	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.	Part 1: Day 1 of dosing up to Pre-dose on Day 22
Primary	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.	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)
Primary	Part 4: 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 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 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)
Primary	Part 4: 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 (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.	Part 4: Day 1 of dosing up to Pre-dose on Day 22
Secondary	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
Secondary	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
Secondary	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 .	Part 1: Week 1 end of infusion (EOI)
Secondary	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).	Part 1: From pre-infusion on day 1 up to end of study treatment (maximum treatment exposure for Part 1 was 414 days)
Secondary	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.	Part 2 and 3: Pre-dose, end of infusion (EOI), 2, 4, 24, 72, 168 hours post dose on Week 1
Secondary	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.	Part 2 and 3: Pre-dose, end of infusion (EOI), 2, 4, 24, 72, 168 hours post dose on Week 1
Secondary	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.	Part 2 and 3: Week 1 end of infusion (EOI)
Secondary	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).	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)
Secondary	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).	From first dose of study till the progressive disease/ death or withdrawal (maximum observation 6 years 10 months)
Secondary	Parts 2 and 3: Overall Response Rate (ORR)-Olsen 2011-Disease Indication	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).	From first dose of study till the progressive disease/ death or withdrawal (maximum observation 6 years 10 months)
Secondary	Part 2: Overall Response Rate (ORR)-Savona 2015- Disease Indication	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).	From first dose of study till the progressive disease/ death or withdrawal (maximum observation 6 years 10 months)
Secondary	Part 2: Overall Response Rate (ORR)- Hallek 2008- Disease Indication	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).	From first dose of study till the progressive disease/ death or withdrawal (maximum observation 6 years 10 months)
Secondary	Part 2: Overall Response Rate (ORR)- Durie 2006- Disease Indication	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).	From first dose of study till the progressive disease/ death or withdrawal (maximum observation 6 years 10 months)
Secondary	Part 2: Overall Response Rate (ORR)- Cheson 2003- Disease Indication	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).	From first dose of study till the progressive disease/ death or withdrawal (maximum observation 6 years 10 months)
Secondary	Part 2: Overall Response Rate (ORR)- Bohnsack 2014- Disease Indication	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).	From first dose of study till the progressive disease/ death or withdrawal (maximum observation 6 years 10 months)
Secondary	Parts 2 and 3: Duration of Response (DoR)- Disease Indication and Nivolumab/Rituximab Combinations	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.	From first dose of study till the progressive disease/ death or withdrawal (maximum observation 6 years 10 months)
Secondary	Parts 2 and 3: Progression Free Survival (PFS)	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.	From first dose of study till the progressive disease/ death or withdrawal (maximum observation 6 years 10 months)
Secondary	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
Secondary	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
Secondary	Part 4: 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 tumor cells.	Part 4: Week 1 end of infusion (EOI)
Secondary	Part 4: Number of Participants With Positive Anti-Drug Antibody (ADA) and Neutralizing Antibodies (NAb)	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: From pre-infusion on day 1 up to end of study treatment (maximum treatment exposure for Part 4 was 667 days)
Secondary	Part 4: Overall Response Rate (ORR)	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).	From first dose of study till the progressive disease/death or withdrawal (maximum observation 6 years 10 months)
Secondary	Part 4: Duration of Response (DoR)	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.	From first dose of study till the progressive disease/death or withdrawal (maximum observation 6 years 10 months)
Secondary	Part 4: Overall Response Rate (ORR) in Cutaneous T-Cell Lymphoma (CTCL) Both Fungoides and Sezary Syndrome	ORR is presented in this outcome measure as number of responders.	From first dose of study till the progressive disease/death or withdrawal (maximum observation 6 years 10 months)

External Links

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