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

NCT05691504 | Active Not Recruiting Phase 1 FDA Drug

• 3 other identifiers: NCI-2022-1103310597UM1CA186709
• Study Type: interventional
• Target: 42
• Locations: 1 country
• Sites: 6

Brief Summary

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.

Conditions

Recurrent Primary Peritoneal Carcinoma; Metastatic Primary Peritoneal Carcinoma; Stage III Uterine Corpus Carcinoma or Carcinosarcoma AJCC v8; Recurrent Endometrial Carcinoma; Metastatic Platinum-Resistant Ovarian Carcinoma; Metastatic Endometrial Carcinoma; Metastatic Fallopian Tube Carcinoma; Recurrent Platinum-Resistant Ovarian Carcinoma; Advanced Endometrial Carcinoma; Recurrent Fallopian Tube Carcinoma; Stage IV Uterine Corpus Carcinoma or Carcinosarcoma AJCC v8

Outcome Measures

Primary Outcomes (3)

• Maximum tolerable dose

  Will be identified using a Bayesian optimal interval design.

  Up to 28 days after the beginning of the treatment cycle

• Recommended phase 2 dose

  The dose level chosen based on safety, tolerability, efficacy, pharmacokinetics (PK), and pharmacodynamic (PD) data collected during the dose escalation portion of the study,

  At completion of the dose escalation phase

• Incidence of dose-limiting toxicities (DLTs)

  The toxicity of the combination will be assessed using Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 criteria. Participants enrolled to the dose escalation will be observed during the first cycle of therapy for adverse events consistent with a DLT definition.

  During the first cycle of therapy (28 days)

Secondary Outcomes (6)

• Radiological response

  Up to 3 years

• Incidence of adverse events

  Up to 30 days after removal from study or until death, whichever occurs first

• Response rate (RR)

  Up to 30 days after removal from study or until death, whichever occurs first

• Progression-free survival

  From study enrollment until the identification of disease progression or death, assessed up to 30 days after removal from study

• Clinical benefit rate

  Up to 30 days after removal form study or death, whichever occurs first

Other Outcomes (6)

• Pharmacodynamic effects of combination APG-1252 (pelcitoclax) and cobimetinib on BCL-xL activity

  Up to 3 years

• Markers of response and resistance to APG-1252 and cobimetinib via sequencing

  Up to 3 years

• Effect of combination APG-1252 and cobimetinib on RAS pathway signaling

  Up to 3 years

Study Arms (1)

Treatment (pelcitoclax, cobimetinib)

EXPERIMENTAL

Patients receive APG-1252 IV Q7D. Patients also receive cobimetinib PO QD on days 1-21 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo biopsy and collection of blood on study and undergo CT and/or MRI throughout the trial. Patients undergo ECHO or MUGA during screening and on study.

Procedure: Biopsy Procedure; Procedure: Biospecimen Collection; Drug: Cobimetinib; Procedure: Computed Tomography; Procedure: Echocardiography Test; Procedure: Magnetic Resonance Imaging; Procedure: Multigated Acquisition Scan; Drug: Pelcitoclax

Interventions

Biopsy Procedure PROCEDURE

Undergo biopsy

Also known as: Biopsy, BIOPSY_TYPE, Bx

Treatment (pelcitoclax, cobimetinib)

Biospecimen Collection PROCEDURE

Undergo collection of blood

Also known as: Biological Sample Collection, Biospecimen Collected, Sample Collection, Specimen Collection

Treatment (pelcitoclax, cobimetinib)

Cobimetinib DRUG

Given PO

Also known as: Cotellic, GDC 0973, GDC-0973, GDC0973, MEK Inhibitor GDC-0973, XL 518, XL-518, XL518

Treatment (pelcitoclax, cobimetinib)

Echocardiography Test PROCEDURE

Undergo ECHO

Also known as: EC, Echocardiography

Treatment (pelcitoclax, cobimetinib)

Computed Tomography PROCEDURE

Undergo CT

Also known as: CAT, CAT Scan, Computed Axial Tomography, Computerized Axial Tomography, Computerized axial tomography (procedure), Computerized Tomography, Computerized Tomography (CT) scan, CT, CT Scan, Diagnostic CAT Scan, Diagnostic CAT Scan Service Type, tomography

Treatment (pelcitoclax, cobimetinib)

Magnetic Resonance Imaging PROCEDURE

Undergo MRI

Also known as: Magnetic Resonance, Magnetic Resonance Imaging (MRI), Magnetic resonance imaging (procedure), Magnetic Resonance Imaging Scan, Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance, MR, MR Imaging, MRI, MRI Scan, MRIs, NMR Imaging, NMRI, Nuclear Magnetic Resonance Imaging, sMRI, Structural MRI

Treatment (pelcitoclax, cobimetinib)

Multigated Acquisition Scan PROCEDURE

Undergo MUGA

Also known as: Blood Pool Scan, Equilibrium Radionuclide Angiography, Gated Blood Pool Imaging, Gated Heart Pool Scan, MUGA, MUGA Scan, Multi-Gated Acquisition Scan, Radionuclide Ventriculogram Scan, Radionuclide Ventriculography, RNV Scan, RNVG, SYMA Scanning, Synchronized Multigated Acquisition Scanning

Treatment (pelcitoclax, cobimetinib)

Pelcitoclax DRUG

Given IV

Also known as: APG 1252, APG-1252, APG1252, Bcl-2/Bcl-XL Inhibitor APG-1252

Treatment (pelcitoclax, cobimetinib)

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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)

You may not qualify if:

• 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

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (6)

Emory University Hospital/Winship Cancer Institute

Atlanta, Georgia, 30322, United States

Location

Johns Hopkins University/Sidney Kimmel Cancer Center

Baltimore, Maryland, 21287, United States

Location

National Cancer Institute Developmental Therapeutics Clinic

Bethesda, Maryland, 20892, United States

Location

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

Location

Dana-Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

Rutgers Cancer Institute of New Jersey

New Brunswick, New Jersey, 08903, United States

Location

MeSH Terms

Conditions

Endometrial Neoplasms; Fallopian Tube Neoplasms; Carcinosarcoma

Interventions

Biopsy; Specimen Handling; cobimetinib; Magnetic Resonance Spectroscopy; pelcitoclax

Condition Hierarchy (Ancestors)

Uterine Neoplasms; Genital Neoplasms, Female; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Uterine Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases; Fallopian Tube Diseases; Adnexal Diseases; Neoplasms, Complex and Mixed; Neoplasms by Histologic Type; Sarcoma; Neoplasms, Connective and Soft Tissue

Intervention Hierarchy (Ancestors)

Cytodiagnosis; Cytological Techniques; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Diagnostic Techniques, Surgical; Surgical Procedures, Operative; Investigative Techniques; Spectrum Analysis; Chemistry Techniques, Analytical

Study Officials

• Joyce F Liu

  Dana-Farber - Harvard Cancer Center LAO

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 18, 2023
• First Posted: January 20, 2023
• Study Start: September 14, 2023
• Primary Completion (Estimated): February 1, 2027
• Study Completion (Estimated): February 1, 2027
• Last Updated: May 13, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will share

Locations

US (6)