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Soft Tissue Sarcoma

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Doxorubicin

Liposomal doxorubicin

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Patients will be treated with doxorubicin and APX005M in 21 day cycles. All patients receive the same treatment (there is no "placebo" arm). After completing 8 cycles of study treatment, patients without evidence of disease progression or unacceptable toxicity may continue treatment with APX005M alone. Doxorubicin will not be continued beyond cycle 8 due to the risk for cardiac toxicity from cumulative dosing.

Doxorubicin is an anthracycline antibiotic with antineoplastic activity 75 mg/m2 IV day 1 (21 day cycles)

APX005M is a CD40 agonistic monoclonal antibody 0.3 mg/kg IV day 1 (21 day cycles)

APX005M

Alexander Wei, MD

This phase II clinical trial will evaluate the safety and efficacy of adding APX005M (a CD40 agonistic monoclonal antibody) to doxorubicin for the treatment of patients with advanced soft tissue sarcoma. The investigators believe that doxorubicin, which is currently the standard of care for most advanced sarcomas, could work better when combined with APX005M, which is a type of immunotherapy.

Doxorubicin, a chemotherapy, is currently considered standard-of-care treatment for most advanced soft tissue sarcomas. This study will assess the safety and efficacy of combining APX005M, a novel immunomodulatory drug, together with standard of care doxorubicin, for the treatment of patients with advanced soft tissue sarcoma. APX005M is an agonistic monoclonal antibody targeting the CD40 receptor and may have favorable effects on certain types of immune cells in sarcoma tumors, particularly macrophages.

The primary objective is to determine the objective response rate. Secondary objectives include further evaluation of safety and efficacy. A subset of patients will undergo tumor biopsies at baseline and while on study treatment to help understand how the drug combination works and to evaluate how the composition of immune cells in the tumor changes after the treatment.

APX005M and Doxorubicin in Advanced Sarcoma

A Phase II Trial Evaluating APX005M (a CD40 Agonistic Monoclonal Antibody) in Combination With Standard-of-Care Doxorubicin for the Treatment of Advanced Sarcomas

The percentage of patients achieving a partial or complete response as measured by imaging assessments from study treatment

A safety-lead in phase will be conducted during which a small number of patients will be treated and monitored closely for certain side effects. If these side effects are seen, the dose of doxorubicin will be adjusted and the study treatment reassessed among another small number of patients. The purpose of the safety lead-in phase is to establish a safe and tolerable dose combination ("the recommended dose") which will be used during the remainder of the study.

Patients on the study will be assessed at regular intervals during clinical visits and through laboratory testing to monitor side effects from the study treatment.

The mean time to either disease progression or death, whichever comes first, for patients on the study

Objective response rate in patients with dedifferentiated liposarcoma, leiomyosarcoma, and myxofibrosarcoma/undifferentiated pleomorphic sarcoma. The confirmed ORR per RECIST version 1.1. criteria will be evaluated in the group of patients with these 3 sarcoma subtypes and within each of these subtypes.

Apexigen America, Inc.

Alexander Z. Wei, MD

Assistant Professor of Medicine

Hemangiosarcoma

Epithelioid Sarcoma

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

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.

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.

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.

Ontorpacept (TTI-621) will be administered by intravenous infusion.

Ontorpacept (TTI-621)

75 mg/m\^2 by intravenous infusion in 21-day cycles for a maximum of six cycles.

Pfizer CT.gov Call Center

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.

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.

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

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

Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.

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.

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.

Number of participants with notable ECG values will be summarized.

Among patients in the dose escalation portion of the study.

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.

The number of drug administrations with dose reduction, infusion held or permanently withdrawn.

Among patients in the dose escalation portion of the study.

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.

Mean and changes from baseline in weight will be summarized with continuous descriptive statistics.

Among patients in the dose escalation portion of the study.

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.

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.

Number of participants with notable ECG values will be summarized.

Among patients in the dose expansion portion of the study.

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.

The number of drug administrations with dose reduction, infusion held or permanently withdrawn.

Among patients in the dose expansion portion of the study.

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.

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.

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.

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.

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.

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.

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.

ECOG Performance Status will be assessed as described in the protocol Appendix A.

Patients in the dose escalation and dose expansion of the study.

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.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
APX005M and Doxorubicin in Advanced Sarcoma	NCT03719430	Soft Tissue Sar...	Doxorubicin APX005M	18 Years -	Columbia University
APX005M and Doxorubicin in Advanced Sarcoma	NCT03719430	Soft Tissue Sar...	Doxorubicin APX005M	18 Years -	Columbia University
A Study to Learn About the Study Medicine (Called Ontorpacept or TTI-621) Given Alone and in Combination With Doxorubicin in People With Leiomyosarcoma	NCT04996004	Leiomyosarcoma	Ontorpacept (TT... Doxorubicin	18 Years -	Pfizer
A Study to Learn About the Study Medicine (Called Ontorpacept or TTI-621) Given Alone and in Combination With Doxorubicin in People With Leiomyosarcoma	NCT04996004	Leiomyosarcoma	Ontorpacept (TT... Doxorubicin	18 Years -	Pfizer
A Study to Learn About the Study Medicine (Called Ontorpacept or TTI-621) Given Alone and in Combination With Doxorubicin in People With Leiomyosarcoma	NCT04996004	Leiomyosarcoma	Ontorpacept (TT... Doxorubicin	18 Years -	Pfizer

Spots Global Cancer Trial Database for pleomorphic sarcoma