Clinical trial NCT04996004: A Study to Learn About the Study Medicine (Called Ontorpacept or TTI-621) Given Alone and in Combination With Doxorubicin in People With Leiomyosarcoma
Official title: A Phase I/II Study of TTI-621 in Combination With Doxorubicin in Patients With Unresectable or Metastatic High-Grade Leiomyosarcoma
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Leiomyosarcoma
Keywords: Leiomyosarcoma
Pleomorphic sarcoma
Myxofibrosarcoma
Liposarcoma
Angiosarcoma
Epithelioid sarcoma
Lead sponsor: Pfizer
Sponsor class: INDUSTRY
First posted: 2021-08-09
Enrollment: 76
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to learn about the safety and effects of the study medicine (called Ontorpacept or TTI-621) when given alone and when given in combination with doxorubicin for people with leiomyosarcoma. Leiomyosarcoma is a tumor of the smooth muscles.

This study is seeking participants who have:

* leiomyosarcoma that is advanced or has spread to other parts of the body (metastatic)
* not received prior treatment with anthracyclines (a drug commonly used in patients with some kinds of cancer, including leiomyosarcoma)
* not received more than one prior treatment for their leiomyosarcoma During the first 18 weeks of this study, participants will receive doxorubicin by IV infusion (given directly into a vein) at the study clinic every 3 weeks for a total of 6 doses. Participants will also receive Ontorpacept (TTI-621) by IV infusion at the study clinic on the same day as doxorubicin and again one week later for the first 18 weeks.

After the first 18 weeks, participants will stop receiving doxorubicin but will continue receiving Ontorpacept (TTI-621) as IV infusion every 14 days at the study clinic. They will keep receiving Ontorpacept (TTI-621) until their cancer is no longer responding to treatment.

We will examine the experiences of participants receiving Ontorpacept (TTI-621) in combination with doxorubicin in the first 18 weeks and then Ontorpacept (TTI-621) by itself after the doxorubicin is stopped. This will help us determine if the study medicine Ontorpacept (TTI-621) given with doxorubicin and then by itself is safe and effective.

Participants will be involved in the study for approximately one year, depending on how their cancer responds to the study treatment. They will have study visits about 12 times in the first 18 weeks (when the study medicine Ontorpacept is given with doxorubicin) and then every two weeks after the doxorubicin is stopped and the study medicine Ontorpacept (TTI-621) is given by itself.

Detailed description: This trial will be conducted in 2 phases: Phase I (dose escalation of Ontorpacept in combination with fixed-dose doxorubicin) and Phase II (dose expansion of Ontorpacept in combination with fixed-dose doxorubicin).

Phase I will enroll patients with soft-tissue sarcomas including leiomyosarcoma, undifferentiated pleomorphic sarcoma, myxofibrosarcoma, dedifferentiated liposarcoma, angiosarcoma or epithelioid sarcoma to evaluate escalating doses of Ontorpacept (TTI-621) administered in combination with fixed-dose doxorubicin for up to six cycles followed by Ontorpacept (TTI-621) monotherapy.

Phase II will enroll patients with high-grade leiomyosarcoma and will evaluate two dose levels of Ontorpacept (TTI-621) in combination with fixed-dose doxorubicin for up to six cycles followed by Ontorpacept (TTI-621) monotherapy.

.

Eligibility criteria: Key Inclusion Criteria:

1. Eastern Co-operative Oncology Group Performance Status Performance Status (ECOG-PS) 0 or 1.
2. Histologically-confirmed high-grade soft tissue sarcoma that is metastatic or locally advanced and not amenable to curative treatment with surgery or radiation.

   1. In the Dose Escalation phase, indications will be limited to high-grade leiomyosarcoma, undifferentiated pleomorphic sarcoma, myxofibrosarcoma, dedifferentiated liposarcoma, angiosarcoma and epithelioid sarcoma
   2. In the Dose Expansion phase, indications will be limited to high-grade leiomyosarcoma.
3. Objective evidence of disease progression unless disease is newly-diagnosed.
4. Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 (expansion cohorts).
5. Adequate organ and hematologic function.
6. No more than 1 prior treatment regimen for advanced disease, which is limited to gemcitabine with docetaxel.
7. Anthracycline-naïve.
8. Patients who were treated with a prior chemotherapy regimen must have completed treatment at least three weeks before initiation of study treatment.
9. All adverse events from prior treatment must be NCI CTCAE (National Cancer Institute Common Terminology Criteria for Adverse Events) v5 Grade ≤ 1, except alopecia and stable neuropathy, which must have resolved to Grade ≤ 2 or baseline.
10. Radiotherapy, including palliative radiotherapy, completed at least two weeks prior to treatment; palliative radiation to non-target lesions while on study is allowed.

Key Exclusion Criteria:

1. History of acute coronary syndromes.
2. History of or current Class II, III, or IV heart failure.
3. History or evidence of known CNS (central nervous system) metastases or carcinomatous meningitis.
4. Significant bleeding disorders, vasculitis or a significant bleeding episode from the GI (gastrointestinal) tract.
5. History of severe hypersensitivity reactions to antibodies.
6. Systemic steroid therapy.
7. History or autoimmune disease that has required systemic treatment with disease-modifying agents, corticosteroids, or immunosuppressive drugs.
8. Prior organ transplantation including allogenic or autologous stem cell transplantation
9. Prior treatment with anti-CD47 (Cluster of Differentiation 47) or anti-signal regulatory protein alpha (SIRPα) therapy.

Primary outcomes:
measure: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs: Phase I
timeFrame: From first dose of study treatment (Day 1) up to 30 Days post last dose of study treatment or start of new anti-cancer therapy whichever occurred soonest (maximum treatment exposure for Phase I was 74.1 weeks; maximum follow up to approx. 78.1 weeks)
measure: Mean Change From Baseline in Blood Pressure at 30 Minutes Post Dose on Cycle 1 Day 1 (C1D1): Phase I
timeFrame: Baseline, 30 minutes post dose on Day 1 of Cycle 1
measure: Mean Change From Baseline in Blood Pressure at 60 Minutes Post Dose on C1D1: Phase I
timeFrame: Baseline, 60 minutes post dose on Day 1 of Cycle 1
measure: Mean Change From Baseline in Blood Pressure at 30 Minutes Post Dose on Cycle 1 Day 8 (C1D8): Phase I
timeFrame: Baseline, 30 minutes post dose on Day 8 of Cycle 1
measure: Mean Change From Baseline in Blood Pressure at 60 Minutes Post Dose on C1D8: Phase I
timeFrame: Baseline, 60 minutes post dose on Day 8 of Cycle 1
measure: Mean Change From Baseline in Blood Pressure at 30 Minutes Post Dose on Cycle 2 Day 1 (C2D1): Phase I
timeFrame: Baseline, 30 minutes post dose on Day 1 of Cycle 2
measure: Mean Change From Baseline in Blood Pressure at 60 Minutes Post Dose on C2D1: Phase I
timeFrame: Baseline, 60 minutes post dose on Day 1 of Cycle 2
measure: Mean Change From Baseline in Blood Pressure at 30 Minutes Post Dose on Cycle 3 Day 1 (C3D1): Phase I
timeFrame: Baseline, 30 minutes post dose on Day 1 of Cycle 3
measure: Mean Change From Baseline in Blood Pressure at 60 Minutes Post Dose on C3D1: Phase I
timeFrame: Baseline, 60 minutes post dose on Day 1 of Cycle 3
measure: Mean Change From Baseline in Blood Pressure at Safety Follow up: Phase I
timeFrame: Baseline, Safety follow up (up to 30 Days post last dose of study treatment or start of new anti-cancer therapy whichever occurred soonest (maximum treatment exposure for Phase I was 74.1 weeks; maximum follow up to approx. 78.1 weeks)
measure: Mean Change From Baseline in Body Weight at C3D1: Phase I
timeFrame: Baseline, Day 1 of Cycle 3
measure: Mean Change From Baseline in Body Weight at Cycle 5 Day 1 (C5D1): Phase I
timeFrame: Baseline, Day 1 of Cycle 5
measure: Mean Change From Baseline in Body Weight at Cycle 7 Day 1 (C7D1): Phase I
timeFrame: Baseline, Day 1 of Cycle 7
measure: Mean Change From Baseline in Body Weight at Safety Follow up: Phase I
timeFrame: Baseline, Safety follow up (up to 30 Days post last dose of study treatment or start of new anti-cancer therapy whichever occurred soonest (maximum treatment exposure for Phase I was 74.1 weeks; maximum follow up to approx. 78.1 weeks)
measure: Number of Participants With Overall Electrocardiogram (ECG) Abnormalities: Phase I
timeFrame: From first dose of study treatment (Day 1) up to 30 Days post last dose of study treatment or start of new anti-cancer therapy whichever occurred soonest (maximum treatment exposure for Phase I was 74.1 weeks; maximum follow up to approx. 78.1 weeks)
measure: Number of Participants With Shift in National Cancer Institute, Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version (v)5.0 Grade <=2 at Baseline to >=3 Post-baseline in Hematology Parameters: Phase I
timeFrame: Baseline up to 30 Days post last dose of study treatment or start of new anti-cancer therapy whichever occurred soonest (maximum treatment exposure for Phase I was 74.1 weeks; maximum follow up to approx. 78.1 weeks)
measure: Number of Participants With Shift in NCI-CTCAE v5.0 Grade <=2 at Baseline to >=3 Post-baseline in Chemistry Parameters: Phase I
timeFrame: Baseline up to 30 Days post last dose of study treatment or start of new anti-cancer therapy whichever occurred soonest (maximum treatment exposure for Phase I was 74.1 weeks; maximum follow up to approx. 78.1 weeks)
measure: Number of Participants With Dose Modifications: Phase I
timeFrame: During study treatment (from first dose of study treatment [Day 1] to maximum treatment exposure of 74.1 weeks for ontorpacept and 20.1 weeks for doxorubicin)
measure: Number of Participants With Treatment Discontinuations: Phase I
timeFrame: During study treatment (from first dose of study treatment [Day 1] to maximum treatment exposure of 74.1 weeks for ontorpacept and 20.1 weeks for doxorubicin)
measure: Objective Response Rate (ORR): Phase I and Phase II
timeFrame: From the start of study treatment until disease progression (maximum exposure up to 74.1 weeks for Phase I and 88 weeks for Phase II)
Secondary outcomes:
measure: Number of Participants With TEAEs and Serious TEAEs: Phase II
timeFrame: From first dose of study treatment (Day 1) up to 30 Days post last dose of study treatment or start of new anti-cancer therapy whichever occurred soonest (maximum treatment exposure for Phase II was 88 weeks; maximum follow up to approx. 92 weeks)
measure: Mean Change From Baseline in Blood Pressure: Phase II
timeFrame: Baseline, 30 and 60min post dose of C1D1,C1D8,C2D1,C3D1 and safety follow up 30 Days post last dose of study treatment/start of new anti-cancer therapy whichever occurred soonest (maximum treatment exposure of Phase II:88 weeks;maximum follow up:92 weeks)
measure: Mean Change From Baseline in Body Weight: Phase II
timeFrame: Baseline, Day 1 of Cycle 3, 5, 7 and safety follow up (up to 30 Days post last dose of study treatment or start of new anti-cancer therapy whichever occurred soonest [maximum treatment exposure for Phase II was 88 weeks; maximum follow up to 92 weeks])
measure: Number of Participants With Overall ECG Abnormalities: Phase II
timeFrame: From first dose of study treatment (Day 1) up to 30 Days post last dose of study treatment or start of new anti-cancer therapy whichever occurred soonest (maximum treatment exposure for Phase II was 88 weeks; maximum follow up to approx. 92 weeks)
measure: Number of Participants With Shift in NCI-CTCAE v5.0 Grade <=2 at Baseline to >=3 Post-baseline in Hematology Parameters: Phase II
timeFrame: Baseline up to 30 Days post last dose of study treatment or start of new anti-cancer therapy whichever occurred soonest (maximum treatment exposure for Phase II was 88 weeks; maximum follow up to approx. 92 weeks)
measure: Number of Participants With Shift in NCI-CTCAE v5.0 Grade <=2 at Baseline to >=3 Post-baseline in Chemistry Parameters: Phase II
timeFrame: Baseline up to 30 Days post last dose of study treatment or start of new anti-cancer therapy whichever occurred soonest (maximum treatment exposure for Phase II was 88 weeks; maximum follow up to approx. 92 weeks)
measure: Number of Participants With Dose Modifications: Phase II
timeFrame: During study treatment (from first dose of study treatment [Day 1] to maximum treatment exposure of 88 weeks for ontorpacept and 25 weeks for doxorubicin)
measure: Number of Participants With Treatment Discontinuations: Phase II
timeFrame: During study treatment (from first dose of study treatment [Day 1] to maximum treatment exposure of 88 weeks for ontorpacept and 25 weeks for doxorubicin)
measure: Progression Free Survival (PFS): Phase I and Phase II
timeFrame: Time from the first ontorpacept infusion (Day 1 of Cycle 1) to PD or death of any cause or censoring, whichever occurred first (maximum exposure up to 74.1 weeks for Phase I and 88 weeks for Phase II)
measure: Overall Survival (OS): Phase I and Phase II
timeFrame: From the first ontorpacept infusion (Day 1 of Cycle 1) to death of any cause or censoring, whichever occurred first (maximum exposure up to 74.1 weeks for Phase I and 88 weeks for Phase II)
measure: Disease Control Rate (DCR): Phase I and Phase II
timeFrame: From the first dose of study treatment until PD or death, whichever occurred first (maximum exposure up to 74.1 weeks for Phase I and 88 weeks for Phase II)
measure: Duration of Response (DOR): Phase I and Phase II
timeFrame: Time from date of first documented response (CR or PR) to date of documented progression or death of any cause after achieving response or censoring, whichever occurred first (maximum exposure up to 74.1 weeks for Phase I and 88 weeks for Phase II)
measure: Duration of Disease Control (DDC): Phase I and Phase II
timeFrame: Time from first ontorpacept infusion (Day 1 of Cycle 1) to date of documented progression/death of any cause or censoring, whichever occurred first (maximum exposure up to 74.1 weeks for Phase I and 88 weeks for Phase II)
measure: Time to Progression (TTP): Phase I and Phase II
timeFrame: Time from the first ontorpacept infusion (Day 1 of Cycle 1) to PD or death of any cause or censoring, whichever is first (maximum exposure up to 74.1 weeks for Phase I and 88 weeks for Phase II)
measure: Time to New Metastases: Phase I and Phase II
timeFrame: Time from the first ontorpacept infusion (Day 1 of Cycle 1) until the appearance of new lesion or death or censoring date, whichever occurred first (maximum exposure up to 74.1 weeks for Phase I and 88 weeks for Phase II)
measure: Number of Participants With a Worsening of Eastern Cooperative Oncology Group (ECOG) Performance Status: Phase I and Phase II
timeFrame: From Baseline up to 30 Days post last dose of study treatment/start of new anti-cancer therapy whichever occurred first (maximum exposure upto 74.1 and 88 weeks; maximum follow up to approx. 78.1 and 92 weeks for Phase I and II respectively)
measure: Number of Participants With a Worsening of Global Health Status / Quality of Life (QoL) Status: Phase I and Phase II
timeFrame: From Baseline up to 30 Days post last dose of study treatment/start of new anti-cancer therapy whichever occurred first (maximum exposure upto 74.1 and 88 weeks; maximum follow up to approx. 78.1 and 92 weeks for Phase I and II respectively)
Other outcomes:
Locations:
city: Santa Monica
country: United States
facility: Sarcoma Oncology Research Center
state: California
city: Jacksonville
country: United States
facility: Mayo Clinic Florida
state: Florida
city: Tampa
country: United States
facility: Moffitt Cancer Center
state: Florida
city: Iowa City
country: United States
facility: University of Iowa Hospital and Clinics
state: Iowa
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Basking Ridge
country: United States
facility: MSK Basking Ridge.
state: New Jersey
city: Hackensack
country: United States
facility: Hackensack University Medical Center
state: New Jersey
city: Middletown
country: United States
facility: MSK Monmouth
state: New Jersey
city: Montvale
country: United States
facility: MSK Bergen
state: New Jersey
city: Commack
country: United States
facility: MSK Commack.
state: New York
city: Harrison
country: United States
facility: MSK Westchester
state: New York
city: Long Island City
country: United States
facility: Memorial Sloan Kettering Cancer Center - Investigational Drug Service Pharmacy
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center 53rd street.
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center - Main Campus
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center 53rd street.
state: New York
city: Uniondale
country: United States
facility: MSK Nassau
state: New York
city: Cleveland
country: United States
facility: University Hospitals Cleveland Medical Center
state: Ohio
city: Portland
country: United States
facility: Oregon Health & Science University (OHSU)
state: Oregon
city: Portland
country: United States
facility: Oregon Health and Science University - Center for Health and Healing 1 (CHH1)
state: Oregon
city: Portland
country: United States
facility: Oregon Health and Science University - Center for Health and Healing 2(CHH2)
state: Oregon
city: Pittsburgh
country: United States
facility: UPMC Hillman Cancer Center
state: Pennsylvania
city: Fairfax
country: United States
facility: Virginia Cancer Specialists
state: Virginia
city: Madison
country: United States
facility: University of Wisconsin Clinical Science Center
state: Wisconsin
Study officials:
affiliation: Pfizer
name: Pfizer CT.gov Call Center
role: STUDY_DIRECTOR
References: