Testing the Combination of APG-1252 (Pelcitoclax) and Cobimetinib in Recurrent Ovarian and Endometrial Cancers

Inclusion Criteria:

• For dose escalation, patients must have histologically or cytologically confirmedrecurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer, orendometrial cancer that is metastatic or unresectable and for which standardcurative or palliative measures do not exist or are no longer effective. Forexpansion, patients must have histologically or cytologically confirmed recurrentepithelial ovarian, fallopian tube, or primary peritoneal cancer

• Prior lines:

• Patients must have received at least one prior line of platinum-based systemictherapy. Platinum received together with radiation as a sensitizing agent isnot considered a systemic line of therapy

• Patients with low grade serous ovarian cancer must have received a prior MEKinhibitor at a demonstrated therapeutic dose (i.e., trametinib 1mg daily orhigher; binimetinib 30mg twice daily or higher). Patients who have had priorcobimetinib must have been able to tolerate cobimetinib at the dose andschedule they would receive it on study

• Patients with microsatellite instability (MSI) or mismatch repair deficient (dMMR) endometrial cancer must have received prior PD-1 or PD-L1 directedimmunooncology (IO) therapy or be considered medically ineligible to receivesuch therapy

• Patients with ovarian cancer must have platinum-resistant disease (progressionwithin 6 months of last receipt of platinum)

• Age >= 18 years. Because no dosing or adverse event data are currently available onthe use of APG-1252 (pelcitoclax) in combination with cobimetinib in patients < 18years of age, children are excluded from this study

• Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)

• Absolute neutrophil count >= 1,500/mcL

• Platelets >= 100,000/mcL

• Hemoglobin > 9 g/dL

• Total bilirubin =< 1.5 x institutional upper limit of normal (ULN)

• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) < 3 x institutional ULN

• Creatinine =< 1.5 x institutional ULN OR glomerular filtration rate (GFR) >= 50ml/min (based on the calculated Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) glomerular filtration rate estimation

• Left ventricular ejection fraction (LVEF) >= institutional lower limit of normal (LLN) (or above 50%, whichever is higher) by echocardiogram (ECHO) or multigatedacquisition scan (MUGA)

• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviraltherapy (that are not excluded) with undetectable viral load within 6 months areeligible for this trial

• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBVviral load must be undetectable on suppressive therapy, if indicated

• Patients with a history of hepatitis C virus (HCV) infection must have been treatedand cured. For patients with HCV infection who are currently on treatment, they areeligible if they have an undetectable HCV viral load

• Patients with treated brain metastases are eligible if follow-up brain imaging aftercentral nervous system (CNS)-directed therapy shows no evidence of progression byscan and stable off systemic steroids for at least 4 weeks

• Patients with a prior or concurrent malignancy whose natural history or treatmentdoes not have the potential to interfere with the safety or efficacy assessment ofthe investigational regimen are eligible for this trial

• Patients with known history or current symptoms of cardiac disease, or history oftreatment with cardiotoxic agents, should have a clinical risk assessment of cardiacfunction using the New York Heart Association Functional Classification. To beeligible for this trial, patients should be class 2B or better

• Patients should be able to swallow oral therapy

• The effects of APG-1252 on the developing human fetus are unknown. For this reasonand because other therapeutic agents used in this trial are known to be teratogenic,women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry andfor the duration of study participation and for 2 weeks after completion of APG-1252and cobimetinib administration. Should a woman become pregnant or suspect she ispregnant while she or her partner is participating in this study, she should informher treating physician immediately. Men treated or enrolled on this protocol mustalso agree to use adequate contraception prior to the study, for the duration ofstudy participation, and 2 weeks after completion of APG-1252 and cobimetinibadministration

• Ability to understand and the willingness to sign a written informed consentdocument. Participants with impaired decision-making capacity who have alegally-authorized representative (LAR) and/or family member available will also beeligible

• Patients must be willing to release archival tissue if available

• Patients on dose level 2 or higher in the escalation cohort and patients in theexpansion cohort must have measurable and biopsiable disease (in a lesion that isnot being utilized as a target lesion for Response Evaluation Criteria in SolidTumors [RECIST] assessment)

Exclusion Criteria:

• Potential trial participants should have recovered from clinically significantadverse events of their most recent therapy/intervention prior to enrollment.Patients who have previously received cancer-directed therapeutic agents with thepotential for CYP3A4 interaction will be eligible if at least 5 half-lives haveelapsed before enrollment

• Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > grade 1) with the exception of alopecia

• Patients who are receiving any other investigational agents

• History of allergic reactions attributed to compounds of similar chemical orbiologic composition to APG-1252 or cobimetinib

• Patients receiving any medications or substances that are strong inhibitors orinducers of CYP3A4 are ineligible. Strong inhibitors or inducers of CYP3A4 must bediscontinued at least 7 days prior to the first dose of APG-1252 and cobimetinib.Because the lists of these agents are constantly changing, it is important toregularly consult a frequently-updated medical reference. As part of theenrollment/informed consent procedures, the patient will be counseled on the risk ofinteractions with other agents, and what to do if new medications need to beprescribed or if the patient is considering a new over-the-counter medicine orherbal product

• Patients with uncontrolled intercurrent illness

• Patients with evidence of retinal pathology on ophthalmologic examination; orneurosensory retinal detachment, right ventricular outflow (RVO), or neovascularmacular degeneration

• Pregnant women are excluded from this study because APG-1252 is an agent with thepotential for teratogenic or abortifacient effects. Because there is an unknown butpotential risk for adverse events in nursing infants secondary to treatment of themother with APG-1252, breastfeeding should be discontinued if the mother is treatedwith APG-1252. These potential risks may also apply to other agents used in thisstudy

• Patients with prior exposure to BCL family inhibitors

• Patients with any gastrointestinal (GI) disorder that may affect absorption ofcobimetinib and other oral medications in the opinion of the treating investigator,such as malabsorption syndrome, major bowel or stomach resection, evidence of smallor large bowel obstruction within the past 3 months

• Patients who have a dependence on IV fluids or total parenteral nutrition