APX005M and Doxorubicin in Treating Patients with Advanced Soft Tissue Sarcoma

Inclusion Criteria

• Histologically confirmed soft tissue sarcoma excluding Kaposi sarcoma and gastrointestinal stromal tumor (GIST) and for which anthracycline monotherapy would be considered appropriate, standard of care treatment. Patients with well-differentiated liposarcoma who have histologic evidence of a dedifferentiated component are eligible. A pathology report documenting one of the above histologic diagnoses must be obtained; however, pathology review at Columbia University Medical Center (CUMC) is not required for this study. * Amendment 4 (12/14/2020) restricts further enrollment to patients with the following sarcoma subtypes. A total of 10 patients will be enrolled with each of the following sarcoma subtypes for the entire study, inclusive of patients enrolled prior to Amendment 4: ** Dedifferentiated liposarcoma ** Leiomyosarcoma ** Myxofibrosarcoma/undifferentiated pleomorphic sarcoma
• Disease must be locally advanced and unresectable or metastatic (that is, considered not amenable to curative surgery or radiation)
• Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) criteria version 1.1
• Patients must be age 18 years or older.
• Patients must demonstrate an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and be considered an appropriate candidate for anthracycline chemotherapy. There is no limit on prior lines of systemic therapy received. Treatment naive patients may be enrolled
• Absolute neutrophil count (ANC) >= 1,500/mm^3
• Hemoglobin >= 9 g/dL
• Platelet count >= 100,000/mm^3
• Creatinine =< 1.5 times upper limit of normal OR calculated creatinine clearance > 45 mL/min * NOTE: Upper limit of normal is defined by the clinical laboratory performing the test. Using the lean body mass formula (Modified Cockcroft Gault)
• Total bilirubin =< upper limit of normal * NOTE: Upper limit of normal is defined by the clinical laboratory performing the test. If transaminase elevation and/or bilirubin elevation is attributed to the presence of liver metastases, a total bilirubin =< 2.5 times the upper limit of normal and an aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 times the upper limit of normal are permissible. Patients with an elevated bilirubin that is attributed to an inherited disorder, such as Gilbert’s disease, may be enrolled at the discretion of the principal investigator
• AST/ALT =< 1.5 times upper limit of normal * NOTE: Upper limit of normal is defined by the clinical laboratory performing the test. If transaminase elevation and/or bilirubin elevation is attributed to the presence of liver metastases, a total bilirubin =< 2.5 times the upper limit of normal and an AST and ALT =< 2.5 times the upper limit of normal are permissible. Patients with an elevated bilirubin that is attributed to an inherited disorder, such as Gilbert’s disease, may be enrolled at the discretion of the principal investigator
• International normalized ratio (INR) =< 1.5 times upper limit of normal * NOTE: Upper limit of normal is defined by the clinical laboratory performing the test. For patients receiving anticoagulants, coagulation parameters must be within the expected parameters for that particular agent
• Prothrombin time (PT) and partial thromboplastin time (PTT) =< 1.5 times upper limit of normal * NOTE: Upper limit of normal is defined by the clinical laboratory performing the test. For patients receiving anticoagulants, coagulation parameters must be within the expected parameters for that particular agent
• Patients must have normal left ventricular systolic function, as demonstrated by a transthoracic echocardiogram or multigated acquisition scan (MUGA) scan at screening, as defined by the laboratory performing the test
• Women of child-bearing potential and all men must agree to use adequate contraception (hormonal or barrier method of birth control, abstinence) prior to study entry and for the duration of study participation. A woman is considered of non-childbearing potential if she is age >= 60, has been amenorrheic for >= 12 months with a follicle stimulating hormone (FSH) >= 40 IU/L, or has undergone hysterectomy, ligation of the fallopian tubes or surgical removal of both ovaries. Any woman not meeting these criteria is considered of child-bearing potential. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. All patients treated or enrolled on this protocol must agree to use adequate contraception prior to the study, for the duration of study participation, and for 4 months after completion of study drug administration
• Ability to understand and willingness to sign a written informed consent document
• After the safety lead-in phase is complete, the next consecutive 10 patients enrolled on the study must have a site of tumor tissue which is amenable to image-guided biopsy by interventional radiology with at most minimal risk to the patient. These 10 patients will be required to undergo tumor biopsy at screening and while on treatment. However, if a patient is otherwise eligible for the study but does not have a suitable tumor site amenable to biopsy at minimal risk, that patient may still be enrolled on the study without undergoing biopsy procedures. Such a patient would not count towards the 10 paired biopsies planned for the study

Exclusion Criteria

• Patients must not have received treatment with any chemotherapy, immunotherapy, radiotherapy or an investigational agent for malignancy within the 21 days preceding cycle 1 day 1 treatment. Patients may not have received treatment with a small molecule targeted anti-cancer agent within 14 days preceding cycle 1 day 1 provided this represents at least 7 half-lives for that agent. If patients have received combinations of the above agents, the longest washout should be observed. Furthermore, toxic effects from any prior therapy (except alopecia) must have resolved to =< grade 1 by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0 or to the patient’s baseline by the time of cycle 1 day 1 treatment. Endocrinopathies attributed to prior immunotherapy treatment which are well controlled on replacement therapy are not an exclusion, provided the patient meets all other eligibility criteria.
• Patients may not be receiving any other investigational agent for any purpose
• Patients may not have received prior treatment with: * Any anthracycline chemotherapy * Any CD40 agonist
• Patients may not have received prior radiotherapy of the mediastinal, pericardial or whole pelvis areas at any time
• Patients may not have active, known or suspected autoimmune disease with the exceptions of well-controlled: * Asthma or allergic rhinitis, * Vitiligo, * Type 1 diabetes mellitus, * Psoriasis, or * Hypothyroidism
• Patients may not be receiving chronic systemic steroid therapy in excess of physiologic/ replacement doses (e.g. prednisone =< 10 mg/day is acceptable), or any other form of immunosuppressive medication within 14 days prior to cycle 1 day 1
• Patients with symptomatic brain metastases may not be enrolled. Those subjects with untreated brain metastases =< 1 cm who are asymptomatic and for whom there are no plans for surgery, radiation or corticosteroid use may be considered eligible at the discretion of the principal investigator. Subjects with brain metastases that have been treated and are stable for at least 30 days are eligible if asymptomatic and not receiving corticosteroids. Screening for brain metastases is not required and should not be routinely pursued given their uncommon incidence in sarcoma. However, if a patient with known central nervous system (CNS) disease is enrolled on the study, proper follow-up imaging to assess the status of this CNS disease should be performed at the time of study-specified response assessment imaging
• Patients may not have: * Uncontrolled intercurrent illness including, but not limited to congestive heart failure, unstable angina pectoris, uncontrolled cardiac arrhythmias, uncontrolled diabetes mellitus or uncontrolled psychiatric illness that would limit compliance with study requirements in the opinion of the investigator * Angioplasty, cardiac stenting, or myocardial infarction within 6 months of cycle 1 day 1 * Any thromboembolic event within 1 month prior to cycle 1 day 1 * Any active coagulopathy * Any clinically serious, active infection requiring treatment with antibiotics within 14 days prior to cycle 1 day 1 * Major surgery within 28 days of cycle 1 day 1
• Patients may not have a history of another primary cancer, with the exception of: * Curatively treated non-melanomatous skin cancer * Curatively treated cervical carcinoma in-situ * Other primary cancers treated with curative intent, no known active disease and no treatment administered within 2 years prior to cycle 1 day 1 * Other cancers considered indolent and for which no treatment is anticipated, in the opinion of the principal investigator
• Patients may not be pregnant or nursing. Pregnant women are excluded from this study because of the teratogenic effects of doxorubicin and possible effects from APX005M. For all women of childbearing potential, a negative pregnancy test must be documented 7 days or less prior to cycle 1 day 1 treatment. A woman is considered of non-childbearing potential if she is age >= 60, has been amenorrheic for >= 12 months with an FSH >= 40 IU/L, or has undergone hysterectomy, ligation of the fallopian tubes or surgical removal of both ovaries. Any woman not meeting this criteria is considered of child-bearing potential. Because there is an unknown but potential risk for adverse events to nursing infants secondary to treatment of the mother with study agents, breastfeeding must be discontinued prior to cycle 1 day 1
• Patients may not have known human immunodeficiency virus (HIV) or hepatitis A, B or C infection; however, screening tests for these infections are not required