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Advanced Endometrial CarcinomaPhase 1NCT05691504

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

A Phase 1 study testing Biopsy Procedure, Biospecimen Collection and Cobimetinib in people with Advanced Endometrial Carcinoma and Metastatic Endometrial Carcinoma, run by National Cancer Institute (NCI) at 6 sites in United States.

Active, not recruiting

Under way, not looking for participants. Everyone needed has enrolled. The study is still running.

Official record

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Trial 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). Read more about this study

Who is it for?
Ages 18 years and older, women only
What is being tested?
Biopsy Procedure, Biospecimen Collection and Cobimetinib
Could I receive a placebo?
No, everyone receives an active treatment
How many people
42 participants
Where
6 sitesUnited States
Study dates
14 Sep 2023to 1 Feb 2027
Phase
Phase 1

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • Women only
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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)
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  • 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)

Who cannot join

  • 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
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  • 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

Trial locations and contacts

6 sites in 1 country.

6 sites in 1 country

United States6 sites

  • Emory University Hospital/Winship Cancer Institute

    Atlanta, Georgia, 30322

  • Johns Hopkins University/Sidney Kimmel Cancer Center

    Baltimore, Maryland, 21287

  • National Cancer Institute Developmental Therapeutics Clinic

    Bethesda, Maryland, 20892

  • National Institutes of Health Clinical Center

    Bethesda, Maryland, 20892

  • Dana-Farber Cancer Institute

    Boston, Massachusetts, 02215

  • Rutgers Cancer Institute of New Jersey

    New Brunswick, New Jersey, 08903

Other trials in United States

About this study

Official title: 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.

Read the detailed description

PRIMARY OBJECTIVE:

  1. To establish the recommended phase 2 dosing (RP2D) for combination pelcitoclax (APG-1252) and cobimetinib in advanced/recurrent endometrial and ovarian cancers.

SECONDARY OBJECTIVES:

  1. To observe and record anti-tumor activity. II. To assess the side effects associated with combination APG-1252 and cobimetinib in advanced/recurrent endometrial and ovarian cancers, as measured by treatment-emergent and treatment-related adverse events by Common Terminology Criteria for Adverse Events (CTCAE) criteria.

III. To assess the activity of combination APG-1252 and cobimetinib in advanced/recurrent endometrial and ovarian cancers, via measures of clinical activity, including response rate (RR), progression-free survival (PFS), clinical benefit rate (CBR), and duration of response (DoR).

TRANSLATIONAL OBJECTIVES:

  1. To evaluate the pharmacodynamic effects of combination APG-1252 and cobimetinib on BCL-xL activity, including BCL-xL:BAX and BCL-xL-BAK heterodimers, as measured by the National Clinical Laboratory Network (NCLN) apoptosis multiplex immunoassay.

II. To evaluate markers of response and resistance to APG-1252 and cobimetinib via whole exome sequencing and ribonucleic acid (RNA) sequencing obtained in pre-treatment/archival and on-treatment samples.

III. To explore the effect of combination APG-1252 and cobimetinib on RAS pathway signaling, as measured by the NCLN ERK/MEK multiple immunoassay, and the association between RAS pathway activation with activity of combination APG-1252 and cobimetinib.

IV. To explore markers of response and resistance to APG-1252 and cobimetinib through evaluation of BIM and MCL1 expression and RAS pathway signaling by reverse phase protein array (RPPA) and by BIM and pERK expression by immunohistochemistry.

  1. To determine pharmacokinetic (PK) parameters of APG-1252 and cobimetinib in combination.

VI. To investigate RAS allelic burden and resistance mutations in patients receiving combination APG-1252 and cobimetinib.

OUTLINE: This is a dose-escalation study of APG-1252 and cobimetinib followed by a dose-expansion study.

Patients receive APG-1252 intravenously (IV) once a week (Q7D). Patients also receive cobimetinib orally (PO) once a day (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 computed tomography (CT) and/or magnetic resonance (MRI) throughout the trial. Patients undergo echocardiography (ECHO) or multigated acquisition scan (MUGA) during screening and on study.

Patients are followed for up to 30 days after removal from study therapy.

Being tested
Biopsy Procedure, Biospecimen Collection, Cobimetinib, Computed Tomography, Echocardiography Test
Medical subject headings
Endometrial Neoplasms, Fallopian Tube Neoplasms, Carcinosarcoma

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Biopsy ProcedureProcedure or surgery

    Also called Biopsy, BIOPSY_TYPE, Bx

    Undergo biopsy

  • Biospecimen CollectionProcedure or surgery

    Also called Biological Sample Collection, Biospecimen Collected, Sample Collection, Specimen Collection

    Undergo collection of blood

  • CobimetinibDrug

    Also called Cotellic, GDC 0973, GDC-0973, GDC0973

    Given PO

  • Computed TomographyProcedure or surgery

    Also called CAT, CAT Scan, Computed Axial Tomography, Computerized Axial Tomography

    Undergo CT

  • Echocardiography TestProcedure or surgery

    Also called EC, Echocardiography

    Undergo ECHO

  • Magnetic Resonance ImagingProcedure or surgery

    Also called Magnetic Resonance, Magnetic Resonance Imaging (MRI), Magnetic resonance imaging (procedure), Magnetic Resonance Imaging Scan

    Undergo MRI

  • Multigated Acquisition ScanProcedure or surgery

    Also called Blood Pool Scan, Equilibrium Radionuclide Angiography, Gated Blood Pool Imaging, Gated Heart Pool Scan

    Undergo MUGA

  • PelcitoclaxDrug

    Also called APG 1252, APG-1252, APG1252, Bcl-2/Bcl-XL Inhibitor APG-1252

    Given IV

Study groups in NCT05691504
Study groupRoleWhat they receive
Treatment (pelcitoclax, cobimetinib)ExperimentalPatients 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.
Receives: Procedure: Biopsy Procedure; Procedure: Biospecimen Collection; Drug: Cobimetinib; Procedure: Computed Tomography; Procedure: Echocardiography Test; Procedure: Magnetic Resonance Imaging; Procedure: Multigated Acquisition Scan; Drug: Pelcitoclax

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Maximum tolerable dose

    Will be identified using a Bayesian optimal interval design.

    Measured: Up to 28 days after the beginning of the treatment cycle

  2. 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,

    Measured: At completion of the dose escalation phase

  3. 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.

    Measured: During the first cycle of therapy (28 days)

Secondary outcomes (6)

  1. Radiological response

    Will be assessed by Response Evaluation Criteria in Solid Tumors version 1.1 criteria and will be graded as complete response (CR), partial response (PR), stable disease (SD) and progressive disease.

    Measured: Up to 3 years

  2. Incidence of adverse events

    Will be graded according to National Cancer Institute CTCAE, version 5.0. Toxicities will be summarized by maximum grade and by treatment dose level. Incidence rate of each toxicity will be reported with 95% exact confidence intervals.

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

  3. Response rate (RR)

    Proportion of participants with CR + PR will be summarized by frequencies and percentages, by dose level.

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

  4. Progression-free survival

    Will be summarized using Kaplan-Meier curves by dose-level (for dose levels with sufficient sample size to permit estimation).

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

  5. Clinical benefit rate

    Proportion of participants whose response is CR + PR + SD > 24 weeks will be summarized by frequencies and percentages, by dose level.

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

  6. Duration of response (DoR)

    Median DoR will be reported with ranges.

    Measured: From the time measurement criteria are met for CR or PR until the first date that recurrent or progressive disease is objectively documents, assessed up to 30 days after removal from study or until death, whichever occurs first

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted20 Jan 2023
  2. Study start14 Sep 2023
  3. Primary completion1 Feb 2027 (estimated)
  4. Study completion1 Feb 2027 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
42 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT05691504
Sponsor's protocol ID
NCI-2022-11033
Other IDs
NCI-2022-11033, 10597, 10597, UM1CA186709
Status last verified
Oct 2026
First submitted
18 Jan 2023
Last updated
9 Oct 2026
Results posted
No
Data monitoring committee
No
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
Yes: NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page

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