A Dose Escalation and Expansion Study of TRX518 in Combination With Cyclophosphamide Plus Avelumab in Advanced Solid Tumors

Inclusion Criteria:

* Advanced Solid Malignancies in Dose Escalation Parts 1 and 2:

  * Histologically documented metastatic or locally advanced, incurable solid malignancy.
  * At least one prior line of systemic therapy for metastatic or locally advanced disease.
* Advanced Triple Negative Breast Cancer (Dose Expansion):

  * Histologically proven invasive breast carcinoma with triple-negative receptor status.
  * At least 1 but no more than 2 prior lines of chemotherapy for metastatic or locally advanced disease.
* Advanced Hormone Receptor-Positive/Endocrine-Refractory Breast Cancer (Dose Expansion):

  * Histologically proven invasive breast carcinoma with hormone receptor+, HER2- status.
  * Only postmenopausal women are eligible. - Previously received at least 1 line of aromatase inhibitor ± cyclin dependent kinase 4 and 6 (CDK4/6) inhibitor therapy. Prior combination therapies of AI or selective estrogen receptor degrader (SERD \[fulvestrant\]) ± CDK 4/6 inhibitor or AI plus everolimus will be permitted. Up to 1 prior line of systemic chemotherapy for metastatic disease is allowed.
* Advanced Metastatic Castration-Resistant Prostate Cancer (Dose Expansion):

  * Histologically or cytologically confirmed prostate adenocarcinoma or poorly differentiated carcinoma of the prostate.
  * Surgically or medically castrated, with testosterone levels of \< 50 ng/dL (\< 2.0 nM). If a patient is being treated with LHRH agonists, this therapy must have been initiated at least 4 weeks prior to treatment start and must be continued throughout the study.
  * Patients must have received ≥1 androgen receptor (AR) signaling inhibitors and had disease progression RECIST v1.1 after no more than 1 prior chemotherapy for mCRPC.
* Advanced Platinum-Resistant Ovarian Cancer (Dose Expansion):

  * Histologically or cytologically confirmed diagnosis of metastatic, advanced, or recurrent platinum-resistant epithelial ovarian, primary peritoneal or fallopian tube cancer.
  * Platinum-resistant ovarian cancer defined as disease progression following a response within 180 days following the last administered dose of platinum therapy. Patients who have lack of response (SD) or disease progression while receiving the most recent platinum-based therapy are not eligible.
  * Received up to 3 lines of systemic therapy for platinum-sensitive disease, with the most recent regimen platinum-containing, and no prior systemic therapy for platinum-resistant or refractory disease.
* General:

  * Tumor tissue for mandatory pre-treatment and on-treatment biopsies.
  * One or more tumors measurable on radiographic imaging defined by RECIST 1.1.
  * Adult patients ≥18 years of age.
  * ECOG performance status (PS) score of 0 or 1.
  * Life expectancy of at least 12 weeks.
  * Disease-free of active second/secondary or prior malignancies for ≥2 years, with the exception of currently treated basal cell or squamous cell carcinoma of the skin or carcinoma in-situ of the cervix or breast.
  * Acceptable liver, renal, hematologic and coagulation function.

Exclusion Criteria:

* Hematologic malignancies or multiple myeloma.
* For the Dose Expansion cohorts the following cancers are not permitted:

  * Any of the following pure histologies of ovarian cancer: germ cell, sex cord stroma, carcinosarcoma, or sarcoma.
  * Small cell or pure neuroendocrine prostate carcinoma that has not yet been treated with at least one line of platinum-based chemotherapy (prostate adenocarcinoma with immunohistochemical neuroendocrine differentiation but without histological small cell that is naïve to platinum-based chemotherapy will be allowed.)
  * Inflammatory breast cancer.
* New York Heart Association Class III or IV cardiac disease, myocardial infarction within the past 6 months, or unstable arrhythmia.
* Cardiac function:

  * Known ejection fraction of \<50% by gated radionuclide study (e.g., multi-gated acquisition scan);
  * Fridericia-corrected QT interval (QTcF) \>470 msec (female) or \>450 msec (male), or history of congenital long QT syndrome;
  * Any ECG abnormality, including pericarditis, that in the Investigator's opinion, would preclude safe participation in the study.
* Active, uncontrolled bacterial, viral, or fungal infections within 7 days of study entry requiring systemic therapy.
* Active autoimmune disease that has required systemic treatment in the past 2 years. Replacement therapy (thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
* Known clinically important respiratory impairment.

  * History of (non-infectious) pneumonitis that required steroids or current pneumonitis.
  * History of interstitial lung disease.
* Clinically significant gastrointestinal disorders, such as perforation, gastrointestinal bleeding, or diverticulitis.
* Known to be human immunodeficiency virus (HIV) positive or have hepatitis B surface antigen (HBSAg) or hepatitis C antibodies (HCAb) unless hepatitis C virus (HCV) RNA is undetected/negative.
* History of major organ transplant (i.e., heart, lungs, liver, and kidney).
* History of an allogeneic bone marrow transplant.
* History of an autologous bone marrow transplant within 90 days of study entry.
* Symptomatic central nervous system (CNS) malignancy or metastasis. Patients with treated CNS metastases are eligible, provided their disease is radiographically stable, asymptomatic, and they are not currently receiving corticosteroids and/or anticonvulsants. Radiation must have been completed at least 14 days prior to study entry. Screening of asymptomatic patients without a history of CNS metastases is not required.
* Serious nonmalignant disease that could compromise protocol objectives in the opinion of the Investigator and/or the Sponsor.
* Pregnant or nursing women.