A Phase 1 Study of APG-1252 (pelcitoclax) and cobimetinib in recurrent ovarian and endometrial cancers

This phase I trial tests the safety, side effects, and best dose of combination therapy
with pelcitoclax (APG-1252) and cobimetinib in treating patients with ovarian and
endometrial cancers that have come back after a period of improvement (recurrent).
APG-1252 is a drug that inhibits activity of proteins that prevent cell death, leading to
increased cell death and reduced cell growth. Cobimetinib is used in patients whose
cancer has a mutated (changed) form of a gene called BRAF. It is in a class of
medications called kinase inhibitors. It works by blocking the action of an abnormal
protein that signals cancer cells to multiply. This helps slow or stop the spread of
cancer cells. Giving APG-1252 in combination with cobimetinib may shrink or stabilize
tumor in patients with recurrent ovarian and endometrial cancers.

Inclusion Criteria:

- For dose escalation, patients must have histologically or cytologically confirmed
recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer, or
endometrial cancer that is metastatic or unresectable and for which standard
curative or palliative measures do not exist or are no longer effective. For
expansion, patients must have histologically or cytologically confirmed recurrent
epithelial ovarian, fallopian tube, or primary peritoneal cancer

- Prior lines:

- Patients must have received at least one prior line of platinum-based systemic
therapy. Platinum received together with radiation as a sensitizing agent is
not considered a systemic line of therapy

- Patients with low grade serous ovarian cancer must have received a prior MEK
inhibitor at a demonstrated therapeutic dose (i.e., trametinib 1mg daily or
higher; binimetinib 30mg twice daily or higher). Patients who have had prior
cobimetinib must have been able to tolerate cobimetinib at the dose and
schedule 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 directed
immunooncology (IO) therapy or be considered medically ineligible to receive
such therapy

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

- Age >= 18 years. Because no dosing or adverse event data are currently available on
the use of APG-1252 (pelcitoclax) in combination with cobimetinib in patients < 18
years 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) >= 50
ml/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 multigated
acquisition scan (MUGA)

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

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

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

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

- Patients with a prior or concurrent malignancy whose natural history or treatment
does not have the potential to interfere with the safety or efficacy assessment of
the investigational regimen are eligible for this trial

- Patients with known history or current symptoms of cardiac disease, or history of
treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac
function using the New York Heart Association Functional Classification. To be
eligible 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 reason
and 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 and
for the duration of study participation and for 2 weeks after completion of APG-1252
and cobimetinib administration. 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. Men treated or enrolled on this protocol must
also agree to use adequate contraception prior to the study, for the duration of
study participation, and 2 weeks after completion of APG-1252 and cobimetinib
administration

- Ability to understand and the willingness to sign a written informed consent
document. Participants with impaired decision-making capacity who have a
legally-authorized representative (LAR) and/or family member available will also be
eligible

- Patients must be willing to release archival tissue if available

- Patients on dose level 2 or higher in the escalation cohort and patients in the
expansion cohort must have measurable and biopsiable disease (in a lesion that is
not being utilized as a target lesion for Response Evaluation Criteria in Solid
Tumors [RECIST] assessment)

Exclusion Criteria:

- Potential trial participants should have recovered from clinically significant
adverse events of their most recent therapy/intervention prior to enrollment.
Patients who have previously received cancer-directed therapeutic agents with the
potential for CYP3A4 interaction will be eligible if at least 5 half-lives have
elapsed 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 or
biologic composition to APG-1252 or cobimetinib

- Patients receiving any medications or substances that are strong inhibitors or
inducers of CYP3A4 are ineligible. Strong inhibitors or inducers of CYP3A4 must be
discontinued 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 to
regularly consult a frequently-updated medical reference. As part of the
enrollment/informed consent procedures, the patient will be counseled on the risk of
interactions with other agents, and what to do if new medications need to be
prescribed or if the patient is considering a new over-the-counter medicine or
herbal product

- Patients with uncontrolled intercurrent illness

- Patients with evidence of retinal pathology on ophthalmologic examination; or
neurosensory retinal detachment, right ventricular outflow (RVO), or neovascular
macular degeneration

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

- Patients with prior exposure to BCL family inhibitors

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

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