A Study to Learn About the Study Medicine (Called Ontorpacept or TTI-621) Given Alone and in Combination With Doxorubicin in People With Leiomyosarcoma

Study Overview
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Brief Summary
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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
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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. .

Official Title
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A Phase I/II Study of TTI-621 in Combination With Doxorubicin in Patients With Unresectable or Metastatic High-Grade Leiomyosarcoma

Conditions
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Leiomyosarcoma

Intervention / Treatment
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* Drug: Ontorpacept (TTI-621)
* Drug: Doxorubicin


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Eastern Co-operative Oncology Group Performance Status Performance Status (ECOG-PS) 0 or 1. Histologically-confirmed high-grade soft tissue sarcoma that is metastatic or locally advanced and not amenable to curative treatment with surgery or radiation. In the Dose Escalation phase, indications will be limited to high-grade leiomyosarcoma, undifferentiated pleomorphic sarcoma, myxofibrosarcoma, dedifferentiated liposarcoma, angiosarcoma and epithelioid sarcoma In the Dose Expansion phase, indications will be limited to high-grade leiomyosarcoma. Objective evidence of disease progression unless disease is newly-diagnosed. Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 (expansion cohorts). Adequate organ and hematologic function. No more than 1 prior treatment regimen for advanced disease, which is limited to gemcitabine with docetaxel. Anthracycline-naïve. Patients who were treated with a prior chemotherapy regimen must have completed treatment at least three weeks before initiation of study treatment. 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. 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: History of acute coronary syndromes. History of or current Class II, III, or IV heart failure. History or evidence of known CNS (central nervous system) metastases or carcinomatous meningitis. Significant bleeding disorders, vasculitis or a significant bleeding episode from the GI (gastrointestinal) tract. History of severe hypersensitivity reactions to antibodies. Systemic steroid therapy. History or autoimmune disease that has required systemic treatment with disease-modifying agents, corticosteroids, or immunosuppressive drugs. Prior organ transplantation including allogenic or autologous stem cell transplantation Prior treatment with anti-CD47 (Cluster of Differentiation 47) or anti-signal regulatory protein alpha (SIRPα) therapy.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Escalation (Ontorpacept+doxorubicin)<br>In the dose escalation portion of the study, participants with specific subsets of soft tissue sarcomas who have not received more than one prior line of therapy and have not received an anthracycline in any setting will be enrolled in three escalating dose cohorts to characterize the safety and tolerability of Ontorpacept (TTI-621) when administered in combination with doxorubicin for up to six cycles and followed by Ontorpacept (TTI-621) monotherapy | Drug: Ontorpacept (TTI-621)<br>* Ontorpacept (TTI-621) will be administered by intravenous infusion.<br>* Other names: Ontorpacept / SIRPα-IgG1 Fc;Drug: Doxorubicin<br>* 75 mg/m^2 by intravenous infusion in 21-day cycles for a maximum of six cycles.<br>* Other names: Adriamycin;|
| Experimental: Dose Expansion Dose Level A (Cohort A)<br>Participants with high-grade leiomyosarcoma will receive up to six cycles of Ontorpacept (TTI-621) at a pre-specified dose level (Dose Level A) in combination with fixed-dose doxorubicin followed by Ontorpacept (TTI-621) monotherapy to further characterize safety, tolerability, and clinical activity of the treatment regimen. | Drug: Ontorpacept (TTI-621)<br>* Ontorpacept (TTI-621) will be administered by intravenous infusion.<br>* Other names: Ontorpacept / SIRPα-IgG1 Fc;Drug: Doxorubicin<br>* 75 mg/m^2 by intravenous infusion in 21-day cycles for a maximum of six cycles.<br>* Other names: Adriamycin;|
| Experimental: Dose Expansion Dose Level B (Cohort B)<br>Participants with high-grade leiomyosarcoma will receive up to six cycles of Ontorpacept (TTI-621) at a pre-specified dose level (Dose Level B) in combination with fixed-dose doxorubicin followed by Ontorpacept (TTI-621) monotherapy to further characterize safety, tolerability, and clinical activity of the treatment regimen. | Drug: Ontorpacept (TTI-621)<br>* Ontorpacept (TTI-621) will be administered by intravenous infusion.<br>* Other names: Ontorpacept / SIRPα-IgG1 Fc;Drug: Doxorubicin<br>* 75 mg/m^2 by intravenous infusion in 21-day cycles for a maximum of six cycles.<br>* Other names: Adriamycin;|
| Experimental: Dose Expansion Dose Level C (Cohort C)<br>Participants with high-grade leiomyosarcoma will receive up to six cycles of Ontorpacept (TTI-621) at a pre-specified dose level (Dose Level C) in combination with fixed-dose doxorubicin followed by Ontorpacept (TTI-621) monotherapy to further characterize safety, tolerability, and clinical activity of the treatment regimen. | Drug: Ontorpacept (TTI-621)<br>* Ontorpacept (TTI-621) will be administered by intravenous infusion.<br>* Other names: Ontorpacept / SIRPα-IgG1 Fc;Drug: Doxorubicin<br>* 75 mg/m^2 by intravenous infusion in 21-day cycles for a maximum of six cycles.<br>* Other names: Adriamycin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants with Treatment Emergent Adverse Events (TEAE) and Serious Adverse Events (SAE) | An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship with the study treatment. TEAE was defined as an AE with onset date occurring during the on-treatment period. SAE was defined as one of the following: was fatal or life-threatening; resulted in persistent or significant disability/incapacity; constituted a congenital anomaly/birth defect; was medically significant; required inpatient hospitalization or prolongation of existing hospitalization. AEs included all SAEs and non-SAEs. Among patients in the dose escalation portion of the study. | From the first dose of study treatment through minimum (30 days + last dose of study treatment, start day of new anti-cancer drug therapy - 1 day) (Up to approximately 17 months) | 
| Mean and changes from baseline in blood pressure | Mean and changes from baseline in blood pressure will be summarized with continuous descriptive statistics. Among patients in the dose escalation portion of the study. | Baseline up to safety FU visit ((Up to approximately 17 months) | 
| Categorical summary of ECG parameters | Number of participants with notable ECG values will be summarized. Among patients in the dose escalation portion of the study. | Baseline up to safety FU visit (Up to approximately 17 months) | 
| Number of participants with abnormal laboratory results | The number of participants with following laboratory abnormalities meeting any of the Grades 1 to 4 classified according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) toxicity grading version 5.0. Among patients in the dose escalation portion of the study. | Baseline up to safety FU visit (Up to approximately 17 months) | 
| Number of participants with dose modifications | The number of drug administrations with dose reduction, infusion held or permanently withdrawn. Among patients in the dose escalation portion of the study. | First dose to last dose (Up to approximately 16 months) | 
| Percentage of patients with objective response | The percentage of patients with confirmed objective response (complete response [CR] + partial response [PR]) as defined by RECIST [Response Evaluation Criteria in Solid Tumors] v 1.1 criteria. Confirmed responses are those that persist on repeat imaging study ≥4 weeks after initial documentation of response. Patients in the dose escalation and dose expansion of the study. | Initiation of treatment up to progression or initiation of new anti-cancer therapy or discontinuation from study (Up to approximately 20 months) | 
| Mean and changes from baseline in weight | Mean and changes from baseline in weight will be summarized with continuous descriptive statistics. Among patients in the dose escalation portion of the study. | Baseline up to safety FU visit (Up to approximately 17 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants with Treatment Emergent Adverse Events (TEAE) and Serious Adverse Events (SAE) | An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship with the study treatment. TEAE was defined as an AE with onset date occurring during the on-treatment period. SAE was defined as one of the following: was fatal or life-threatening; resulted in persistent or significant disability/incapacity; constituted a congenital anomaly/birth defect; was medically significant; required inpatient hospitalization or prolongation of existing hospitalization. AEs included all SAEs and non-SAEs. Among patients in the dose expansion portion of the study. | From the first dose of study treatment through minimum (30 days + last dose of study treatment, start day of new anti-cancer drug therapy - 1 day) (Up to approximately 20 months) | 
| Mean and Changes from baseline in blood pressure | Mean and changes from baseline in blood pressure will be summarized with continuous descriptive statistics. Among patients in the dose expansion portion of the study. | Baseline up to safety FU visit (Up to approximately 20 months) | 
| Categorical summary of ECG parameters | Number of participants with notable ECG values will be summarized. Among patients in the dose expansion portion of the study. | Baseline up to safety FU visit (Up to approximately 20 months) | 
| Number of participants with abnormal laboratory results | The number of participants with following laboratory abnormalities meeting any of the Grades 1 to 4 classified according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) toxicity grading version 5.0. Among patients in the dose expansion portion of the study. | Baseline up to safety FU visit (Up to approximately 20 months) | 
| Number of participants with dose modifications | The number of drug administrations with dose reduction, infusion held or permanently withdrawn. Among patients in the dose expansion portion of the study. | First dose to last dose (Up to approximately 20 months) | 
| Progression-free survival (PFS) | PFS is defined as time from the first dose of study treatment to the first documentation of objective tumor progression or to death due to any cause, whichever occurs first. Median PFS with 95% CI will be summarized using the Kaplan-Meier method. Patients in the dose escalation and dose expansion of the study. | Initiation of treatment up to progression or initiation of new anti-cancer therapy or discontinuation from study (Up to approximately 20 months) | 
| Overall Survival (OS) | OS is defined as time from the first dose of study treatment to death due to any cause. Median OS with 95% CI will be summarized using the Kaplan-Meier method. Patients in the dose escalation and dose expansion of the study. | From initiation of treatment until discontinuation from study (Up to approximately 29 months) | 
| Disease control rate (DCR) | DCR is defined as the percent of participants with a confirmed complete response (CR), confirmed partial response (PR) or stable disease (SD). Patients in the dose escalation and dose expansion of the study. | Initiation of treatment up to progression or initiation of new anti-cancer therapy or discontinuation from study (Up to approximately 20 months) | 
| Duration of response (DOR) | DOR is defined for participants with an OR per RECIST version 1.1, as the time from the first documentation of objective tumor response to the first documentation of objective tumor progression or death due to any cause, whichever occurs first. Median DOR with 95% CI will be summarized using the Kaplan-Meier method. Patients in the dose escalation and dose expansion of the study. | Date of first documentation of an objective response to progression or initiation of new anti-cancer therapy or discontinuation from study (Up to approximately 20 months) | 
| Time to disease progression (TTP) | TTP is defined as time from the first dose of study treatment to the first documentation of objective tumor progression. Median TTP with 95% CI will be summarized using the Kaplan-Meier method. Patients in the dose escalation and dose expansion of the study. | Initiation of treatment up to progression or initiation of new anti-cancer therapy or discontinuation from study (Up to approximately 20 months) | 
| Duration of disease control (DDC) | DDC is defined as the time from the first dose to the date of documented progression or death of any cause and will be calculated for patients who achieve a CR, PR or SD. Median DDC with 95% CI will be summarized using the Kaplan-Meier method. Patients in the dose escalation and dose expansion of the study. | Initiation of treatment up to progression or initiation of new anti-cancer therapy or discontinuation from study (Up to approximately 20 months) | 
| Time to new metastatic lesions appearance | Time to new metastases is defined as the time from the first dose to a new metastatic lesion appearance. Patients who progress or die without new metastases will be censored at their date of progression or death. Median time to event with 95% CI will be summarized using the Kaplan-Meier method. Patients in the dose escalation and dose expansion of the study. | Initiation of treatment up to progression or initiation of new anti-cancer therapy or discontinuation from study (Up to approximately 20 months) | 
| Number of participants with a worsening of ECOG (Eastern Cooperative Oncology Group) status from baseline | ECOG Performance Status will be assessed as described in the protocol Appendix A. Patients in the dose escalation and dose expansion of the study. | Baseline up to safety FU visit (Up to approximately 20 months) | 
| Number of participants with a worsening of European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (EORTC QLQ-C30) | Characterize the change of patient-reported outcomes (PRO) using the EORTC QLQ-C30 questionnaire. Scale is 0 to 100. Higher score for the functioning scales and global health status denote a better level of functioning (i.e. a better state of the patient), while higher scores on the symptom and single-item scales indicate a higher level of symptoms (i.e. a worse state of the patient). Patients in the dose escalation and dose expansion of the study. | Baseline up to safety FU visit (Up to approximately 20 months) | 
| Mean and changes from baseline in weight | Mean and changes from baseline in weight will be summarized with continuous descriptive statistics. Among patients in the dose escalation portion of the study. | Baseline up to safety FU visit (Up to approximately 20 months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Leiomyosarcoma, Pleomorphic sarcoma, Myxofibrosarcoma, Liposarcoma, Angiosarcoma, Epithelioid sarcoma