Clinical trial NCT02663518: A Trial of PF-07901800 (TTI-621) for Patients With Hematologic Malignancies and Selected Solid Tumors
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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Hematologic Malignancies
Solid Tumor
Keywords: 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
Lead sponsor: Pfizer
Sponsor class: INDUSTRY
First posted: 2016-01-26
Enrollment: 249
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Intervention 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.
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Part 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs)
timeFrame: 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)
measure: Part 1: Number of Participants With Dose Limiting Toxicities (DLTs)
timeFrame: Part 1: Day 1 of dosing up to Pre-dose on Day 22
measure: Part 2 and 3: Number of Participants With TEAEs and TESAEs
timeFrame: 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)
measure: Part 4: Number of Participants With TEAEs and TESAEs
timeFrame: 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)
measure: Part 4: Number of Participants With Dose Limiting Toxicities (DLTs)
timeFrame: Part 4: Day 1 of dosing up to Pre-dose on Day 22
Secondary outcomes:
measure: Part 1: Maximum Plasma Concentration (Cmax) of TTI-621
timeFrame: Part 1: Pre-dose, end of infusion (EOI), 2, 4, 24, 72, 168 hours post dose on Week 1
measure: Part 1: Area Under the Plasma Concentration Time Curve From Time Zero to 168 (AUC[0-168]) of TTI-621
timeFrame: Part 1: Pre-dose, end of infusion (EOI), 2, 4, 24, 72, 168 hours post dose on Week 1
measure: Part 1: Percentage of CD47 Receptor Occupancy on Peripheral Blood CD3+ Cells
timeFrame: Part 1: Week 1 end of infusion (EOI)
measure: Part 1: Number of Participants With Positive Anti-Drug Antibody (ADA) and Neutralizing Antibodies (NAb)
timeFrame: Part 1: From pre-infusion on day 1 up to end of study treatment (maximum treatment exposure for Part 1 was 414 days)
measure: Part 2 and 3 Combined: Maximum Plasma Concentration (Cmax) of TTI-621
timeFrame: Part 2 and 3: Pre-dose, end of infusion (EOI), 2, 4, 24, 72, 168 hours post dose on Week 1
measure: Part 2 and 3 Combined: Area Under the Plasma Concentration Time Curve From Time Zero to 168 (AUC[0-168]) of TTI-621
timeFrame: Part 2 and 3: Pre-dose, end of infusion (EOI), 2, 4, 24, 72, 168 hours post dose on Week 1
measure: Part 2 and 3 Combined: Percentage of CD47 Receptor Occupancy on Peripheral Blood CD3+ Cells
timeFrame: Part 2 and 3: Week 1 end of infusion (EOI)
measure: Part 2 and 3: Number of Participants With Positive Anti-Drug Antibody (ADA) and Neutralizing Antibodies (NAb)
timeFrame: 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)
measure: Part 2 and 3: Overall Response Rate (ORR) - Lugano Classification (Cheson 2014) and Refinement (Cheson 2016) Disease Indications and Nivolumab/Rituximab Combinations
timeFrame: From first dose of study till the progressive disease/ death or withdrawal (maximum observation 6 years 10 months)
measure: Parts 2 and 3: Overall Response Rate (ORR)-Olsen 2011-Disease Indication
timeFrame: From first dose of study till the progressive disease/ death or withdrawal (maximum observation 6 years 10 months)
measure: Part 2: Overall Response Rate (ORR)-Savona 2015- Disease Indication
timeFrame: From first dose of study till the progressive disease/ death or withdrawal (maximum observation 6 years 10 months)
measure: Part 2: Overall Response Rate (ORR)- Hallek 2008- Disease Indication
timeFrame: From first dose of study till the progressive disease/ death or withdrawal (maximum observation 6 years 10 months)
measure: Part 2: Overall Response Rate (ORR)- Durie 2006- Disease Indication
timeFrame: From first dose of study till the progressive disease/ death or withdrawal (maximum observation 6 years 10 months)
measure: Part 2: Overall Response Rate (ORR)- Cheson 2003- Disease Indication
timeFrame: From first dose of study till the progressive disease/ death or withdrawal (maximum observation 6 years 10 months)
measure: Part 2: Overall Response Rate (ORR)- Bohnsack 2014- Disease Indication
timeFrame: From first dose of study till the progressive disease/ death or withdrawal (maximum observation 6 years 10 months)
measure: Parts 2 and 3: Duration of Response (DoR)- Disease Indication and Nivolumab/Rituximab Combinations
timeFrame: From first dose of study till the progressive disease/ death or withdrawal (maximum observation 6 years 10 months)
measure: Parts 2 and 3: Progression Free Survival (PFS)
timeFrame: From first dose of study till the progressive disease/ death or withdrawal (maximum observation 6 years 10 months)
measure: Part 4: Maximum Plasma Concentration (Cmax) of TTI-621
timeFrame: Part 4: Pre-dose, end of infusion (EOI), 2, 4, 24, 72, 168 hours post dose on Week 1
measure: Part 4: Area Under the Plasma Concentration Time Curve From Time Zero to 168 (AUC[0-168]) of TTI-621
timeFrame: Part 4: Pre-dose, end of infusion (EOI), 2, 4, 24, 72, 168 hours post dose on Week 1
measure: Part 4: Percentage of CD47 Receptor Occupancy on Peripheral Blood CD3+ Cells
timeFrame: Part 4: Week 1 end of infusion (EOI)
measure: Part 4: Number of Participants With Positive Anti-Drug Antibody (ADA) and Neutralizing Antibodies (NAb)
timeFrame: Part 4: From pre-infusion on day 1 up to end of study treatment (maximum treatment exposure for Part 4 was 667 days)
measure: Part 4: Overall Response Rate (ORR)
timeFrame: From first dose of study till the progressive disease/death or withdrawal (maximum observation 6 years 10 months)
measure: Part 4: Duration of Response (DoR)
timeFrame: From first dose of study till the progressive disease/death or withdrawal (maximum observation 6 years 10 months)
measure: Part 4: Overall Response Rate (ORR) in Cutaneous T-Cell Lymphoma (CTCL) Both Fungoides and Sezary Syndrome
timeFrame: From first dose of study till the progressive disease/death or withdrawal (maximum observation 6 years 10 months)
Other outcomes:
Locations:
city: Duarte
country: United States
facility: City of Hope National Medical Center
state: California
city: Duarte
country: United States
facility: City of Hope
state: California
city: Palo Alto
country: United States
facility: Freidenrich Center for Translational Research (CTRU)
state: California
city: Palo Alto
country: United States
facility: Stanford Cancer Institute
state: California
city: Denver
country: United States
facility: Colorado Blood Cancer Institute
state: Colorado
city: Denver
country: United States
facility: Presbyterian/St.Luke's Medical Center
state: Colorado
city: Jacksonville
country: United States
facility: Mayo Clinic Jacksonville
state: Florida
city: Jacksonville
country: United States
facility: Mayo Clinic
state: Florida
city: Tampa
country: United States
facility: Moffitt Cancer Center Richard M Schulze Family Foundation Outpatient Center at McKinley Campus
state: Florida
city: Tampa
country: United States
facility: Moffitt Cancer Center
state: Florida
city: Greenfield
country: United States
facility: Covance Biorepository
state: Indiana
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Hackensack
country: United States
facility: Hackensack Meridian Health John Theurer Cancer Center
state: New Jersey
city: Hackensack
country: United States
facility: Hackensack UMC
state: New Jersey
city: Hackensack
country: United States
facility: The John Theurer Cancer Center at Hackensack UMC
state: New Jersey
city: Middletown
country: United States
facility: Memorial Sloan Kettering Cancer Center- Monmouth
state: New Jersey
city: Harrison
country: United States
facility: Memorial Sloan Kettering Cancer Center Westchester
state: New York
city: New York
country: United States
facility: Laura and Isaac Perlmutter Cancer Center at NYU Langone Health
state: New York
city: New York
country: United States
facility: Laura and Isaac Perlmutter Cancer Center at NYU Langone
state: New York
city: New York
country: United States
facility: NYU Investigational Pharmacy
state: New York
city: New York
country: United States
facility: NYU Langone Health (Tisch Hospital)
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center-Clinical Trails Office
state: New York
city: New York
country: United States
facility: Columbia Univeristy
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center - David H. Koch Center for Cancer Care
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center Rockefeller Outpatient Pavillion
state: New York
city: New York
country: United States
facility: Columbia University Medical Center.
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Cleveland
country: United States
facility: Cleveland Clinic Taussig Cancer Center
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Portland
country: United States
facility: Oregon Health & Science University-Research Pharmacy Services
state: Oregon
city: Portland
country: United States
facility: Oregon Health & Science University
state: Oregon
city: Portland
country: United States
facility: Oregon Health and Sciences University
state: Oregon
city: Pittsburgh
country: United States
facility: University of Pittsburgh Medical Center Presbyterian Shadyside
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh Medical Center
state: Pennsylvania
city: Nashville
country: United States
facility: Centennial Medical Center
state: Tennessee
city: Nashville
country: United States
facility: Sarah Cannon Research Institute (Pharmacy)
state: Tennessee
city: Nashville
country: United States
facility: Tennessee Oncology PLLC
state: Tennessee
city: Nashville
country: United States
facility: Tennessee Oncology, PLLC
state: Tennessee
city: Nashville
country: United States
facility: Tennessee Oncology
state: Tennessee
city: Austin
country: United States
facility: Myriad RMB Inc
state: Texas
city: Houston
country: United States
facility: The University of Texas MD Anderson Cancer Center
state: Texas
city: Houston
country: United States
facility: University of Texas MD Anderson Cancer Center, Cancer Prevention Center
state: Texas
city: Houston
country: United States
facility: University of Texas MD Anderson Cancer Center, Melanoma and Skin Clinic
state: Texas
city: Houston
country: United States
facility: University of Texas MD Anderson Cancer Center
state: Texas
city: Seattle
country: United States
facility: Seattle Cancer Care Alliance
state: Washington
city: Seattle
country: United States
facility: University of Washington - Seattle Cancer Care Alliance
state: Washington
city: Seattle
country: United States
facility: University of Washington Medical Center
state: Washington
city: Vancouver
country: Canada
facility: Fairmont Medical Building, Suite 810
state: B.C.
city: Vancouver
country: Canada
facility: British Columbia Cancer Agency
state: British Columbia
city: Toronto
country: Canada
facility: Princess Margaret Cancer Center
state: Ontario
city: Toronto
country: Canada
facility: University Health Network - Princess Margaret Cancer Centre
state: Ontario
Study officials:
affiliation: Pfizer
name: Pfizer CT.gov Call Center
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.