Combination ONC201 and Atezolizumab for the Treatment of Metastatic or Recurrent Obesity-Driven Endometrial Cancer

Inclusion Criteria

• Ability to understand and willingness to sign a written informed consent obtained to participate in the study and Health Insurance Portability and Accountability Act (HIPAA) authorization for release of personal health information
• Age >= 18 years at the time of consent
• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1, or 2
• Histologically confirmed metastatic or recurrent EC (endometrioid, carcinosarcoma, serous, clear cell, adeno-squamous and mixed histologies)
• Subjects must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension in accordance with Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1
• Availability of at least 12 unstained slides from archival formalin-fixed paraffin-embedded (FFPE) tumor tissue. Available archived tissue biopsies will be provided for correlative studies
• Must have radiographic disease progression after at least 1 line of systemic cytotoxic therapy for metastatic disease or with progression within 12 months of completing adjuvant chemotherapy
• Life expectancy of at least 3 months
• Hemoglobin (Hgb) >= 9 g/dL (within 14 days prior to initiating study treatment) (subjects may be transfused to meet this criterion)
• White blood cell (WBC) > 3,000/mcL (within 14 days prior to initiating study treatment)
• Lymphocytes >= 500/mcL (within 14 days prior to initiating study treatment)
• Absolute neutrophil count (ANC) > 1,500/mcL (within 14 days prior to initiating study treatment)
• Platelets > 100,000/mcL without transfusion (within 14 days prior to initiating study treatment)
• Serum albumin >= 25 g/L (2.5 g/dL) (within 14 days prior to initiating study treatment)
• Creatinine =< 1.5 x upper limit of normal (ULN) OR calculated creatinine clearance > 60 mL/min/1.73 m^2 for subjects with creatinine levels above ULN calculated using Calvert formula (within 14 days prior to initiating study treatment)
• Total bilirubin =< 1.5 x upper limit of normal (ULN) (within 14 days prior to initiating study treatment). Subjects with Gilbert's syndrome: serum bilirubin =< 3 x ULN
• Aspartate aminotransferase (AST) =< 2.5 x upper limit of normal (ULN) with the following exceptions: Subjects with documented liver metastases: AST =< 5 x ULN (within 14 days prior to initiating study treatment)
• Alanine aminotransferase (ALT) =< 2.5 x upper limit of normal (ULN) with the following exceptions: Subjects with documented liver metastases: ALT =< 5 x ULN (within 14 days prior to initiating study treatment)
• Alkaline phosphatase (ALP) =< 2.5 x upper limit of normal (ULN) with the following exceptions: Subjects with documented liver or bone metastases: ALP =< 5 x ULN (within 14 days prior to initiating study treatment)
• International normalized ratio (INR) or activated partial thromboplastin time (aPTT) =<1.5 x ULN unless participant is receiving anticoagulant therapy as long as prothrombin time (PT) or aPTT is within therapeutic range of intended use of anticoagulants (within 14 days prior to initiating study treatment)
• Females of childbearing potential must have a negative serum or urine pregnancy test within 3 days (72 hours) prior to study treatment. NOTE: Females are considered of childbearing potential unless they are surgically sterile (have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are naturally postmenopausal for at least 12 consecutive months. Documentation of postmenopausal status must be provided
• Subjects must be surgically sterile or be postmenopausal or must agree to use effective contraception during the period of the trial and for at least 5 months after completion of treatment
• For subjects receiving therapeutic anticoagulation, they must be on a stable anticoagulant regimen
• Subjects is willing and able to comply with study procedures based on the judgement of the investigator or protocol designee
• Subjects with prior or concurrent malignancies of the same or different tumor type whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational drug are eligible for enrollment at the discretion of the treating physician

Exclusion Criteria

• Prior treatment with ONC201
• Prior treatment with CD137 agonists (including anti−CTLA-4)
• Subjects who have received treatment of immunotherapy within 28 days or 2 halflives of the drug (whichever is longer) before the first study drug administration (Cycle 1 day 1 [C1D1])
• Treatment with another investigational agent or participation in another clinical trial within the last 28 days prior to initiating protocol therapy
• Subjects who have had chemotherapy or radiotherapy within 4 weeks prior to study treatment or those who have not recovered from adverse events due to agents administered more than 4 weeks prior to initiating protocol therapy
• Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of protocol therapy * Subjects receiving prophylactic antibiotics (e.g., to prevent a urinary tract infection or chronic obstructive pulmonary disease exacerbation) are eligible for the study
• Treatment with systemic immunostimulatory agents (including, but not limited to, interferon and interleukin 2 [IL-2]) within 4 weeks or 5 half-lives of the drug (whichever is longer) prior to initiation of protocol therapy
• Treatment with systemic immunosuppressive medication (including, but not limited to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti−tumor necrosis factor alpha [TNF-a] agents) within 2 weeks prior to initiation of protocol therapy, or anticipation of need for systemic immunosuppressive medication during study treatment, with the following exceptions: * Subjects who received acute, low-dose systemic immunosuppressant medication or a one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of corticosteroids for a contrast allergy) may be eligible for the study after Principal Investigator review and approval. * Subjects who received mineralocorticoids (e.g., fludrocortisone), corticosteroids for chronic obstructive pulmonary disease (COPD) or asthma, or low-dose corticosteroids for orthostatic hypotension or adrenal insufficiency are eligible for the study
• Has received a live vaccine within 30 days prior to the first dose of protocol therapy, or anticipation of need for such a vaccine during study treatment or within 5 months after the final doses of study drugs. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette–Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist) are live attenuated vaccines and are not allowed
• Receiving therapeutic agents known to prolong QT interval will be excluded, however the use of Zofran is permitted
• Concomitant use of potent CYP3A4/5 inhibitors or inducers during the treatment phase of the study and within 72 hours prior to starting study drug administration
• Subject is receiving prohibited medications or treatments as listed in the protocol that cannot be discontinued/replaced by an alternative therapy
• History of leptomeningeal disease
• Uncontrolled tumor-related pain * Subjects requiring pain medication must be on a stable regimen at study entry * Symptomatic lesions (e.g., bone metastases or metastases causing nerve impingement) amenable to palliative radiotherapy should be treated prior to enrollment. Subjects should be recovered from the effects of radiation. There is no required minimum recovery period * Asymptomatic metastatic lesions that would likely cause functional deficits or intractable pain with further growth (e.g., epidural metastasis that is not currently associated with spinal cord compression) should be considered for loco-regional therapy if appropriate prior to enrollment
• Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently). Subjects with indwelling catheters (e.g., PleurX) are allowed
• Uncontrolled or symptomatic hypercalcemia (ionized calcium > 1.5 mmol/L, calcium > 12 mg/dL or corrected serum calcium > ULN)
• Has a known history of active TB (Bacillus Tuberculosis)
• Severe infection within 4 weeks prior to initiation of study treatment, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia
• Immunocompromised subjects (e.g., subjects who are known to be serologically positive for human immunodeficiency virus (HIV) * Subjects with HIV will be allowed to participate if they have controlled HIV (CD4+ counts > 200 cells/uL). Subjects must be tested within 28 days of starting
• Known active Hepatitis B virus (HBV) or Hepatitis C virus (HCV) infection whose disease is uncontrolled * If positive for HBV, core antibody or surface antigen, subject will be allowed to participate with HBV prophylaxis * If positive for HCV exposure or active infection, subject will be allowed to participate with pharmacotherapy and monitoring for liver function abnormalities * Tests for HBV and HCV within 1 year of starting treatment are acceptable
• Active or history of autoimmune disease or immune deficiency, including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, or multiple sclerosis, with the following exceptions: * Subjects with a history of autoimmune-related hypothyroidism who are on thyroid-replacement hormone are eligible for the study * Subjects with controlled Type 1 diabetes mellitus who are on an insulin regimen are eligible for the study * Subjects with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g., subjects with psoriatic arthritis are excluded) are eligible for the study provided all of following conditions are met: ** Rash must cover < 10% of body surface area ** Disease is well controlled at baseline and requires only low-potency topical corticosteroids ** No occurrence of acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high-potency or oral corticosteroids within the previous 12 months
• History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan * History of radiation pneumonitis in the radiation field (fibrosis) is permitted
• History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or fusion proteins
• Known hypersensitivity to Chinese hamster ovary cell products or to any component of the atezolizumab formulation
• Known allergy or hypersensitivity to any component of the ONC201 formulation
• Prior allogeneic stem cell or solid organ transplantation
• The subjects who has not recovered to baseline or Common Terminology Criteria for Adverse Events (CTCAE) =< Grade 1 from related toxicity to all prior therapies will be excluded. Subjects with non-serious adverse events such as alopecia, fatigue, weakness, loss of appetite and nausea that are nonsignificant will not be excluded
• The subject is unable to swallow ONC201 in either capsule or Ora-Sweet formulation
• Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of ONC201 (uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection)
• Subjects with symptomatic brain metastases are excluded
• Uncontrolled intercurrent illness including, but not limited to ongoing or active infection requiring systemic treatment. Any of the following in the previous 6 months: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, cerebrovascular accident, transient ischemic attack or symptomatic pulmonary embolism
• Known history of cardiac arrhythmias including atrial fibrillation, tachyarrhythmias, or bradycardia, unless arrhythmia is controlled and cardiology has cleared all subjects with these arrythmias to receive ONC201 and atezolizumab
• Active inflammatory gastrointestinal disease, chronic diarrhea (unless related to underlying malignancy or prior related treatment) or history of abdominal fistula, gastrointestinal perforation, peptic ulcer disease, or intra-abdominal abscess within 6 months prior to initiation of protocol therapy. Gastroesophageal reflux disease under treatment with proton pump inhibitors is allowed
• Pregnant or breast feeding or intention to become pregnant during study treatment or within 5 months after the last dose of study treatment
• Significant cardiovascular disease (such as New York Heart Association Class II or greater cardiac disease, myocardial infarction, or cerebrovascular accident) within 3 months prior to initiation of protocol therapy, unstable arrhythmia, or unstable angina or has a history of symptomatic congestive heart failure (e.g. congestive heart failure defined as New York Heart Association [NYHA] Class III or IV functional status)
• Major surgical procedure, other than for diagnosis, within 4 weeks prior to initiation of protocol therapy, or anticipation of need for a major surgical procedure during the study
• Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration, or may interfere with the interpretation of study results, or in the judgment of the investigator would make the subject inappropriate for entry into the study
• Subjects who are receiving drugs acting on the dopamine pathway (as agonists or antagonists), have a diagnosis that would increase risk of toxicity (e.g., Parkinson’s), or have concurrent medications with overlapping toxicities (e.g., tardive dyskinesia)