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

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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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.