Trial Title:
Testing the Combination of APG-1252 (Pelcitoclax) and Cobimetinib in Recurrent Ovarian and Endometrial Cancers
NCT ID:
NCT05691504
Condition:
Advanced Endometrial Carcinoma
Metastatic Endometrial Carcinoma
Metastatic Fallopian Tube Carcinoma
Metastatic Platinum-Resistant Ovarian Carcinoma
Metastatic Primary Peritoneal Carcinoma
Recurrent Endometrial Carcinoma
Recurrent Fallopian Tube Carcinoma
Recurrent Platinum-Resistant Ovarian Carcinoma
Recurrent Primary Peritoneal Carcinoma
Stage III Uterine Corpus Cancer AJCC v8
Stage IV Uterine Corpus Cancer AJCC v8
Conditions: Official terms:
Carcinoma
Endometrial Neoplasms
Ovarian Neoplasms
Carcinoma, Ovarian Epithelial
Fallopian Tube Neoplasms
Recurrence
Study type:
Interventional
Study phase:
Phase 1
Overall status:
Recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Procedure
Intervention name:
Biopsy
Description:
Undergo biopsy
Arm group label:
Treatment (pelcitoclax, cobimetinib)
Other name:
BIOPSY_TYPE
Other name:
Bx
Intervention type:
Procedure
Intervention name:
Biospecimen Collection
Description:
Undergo collection of blood
Arm group label:
Treatment (pelcitoclax, cobimetinib)
Other name:
Biological Sample Collection
Other name:
Biospecimen Collected
Other name:
Specimen Collection
Intervention type:
Drug
Intervention name:
Cobimetinib
Description:
Given PO
Arm group label:
Treatment (pelcitoclax, cobimetinib)
Other name:
Cotellic
Other name:
GDC 0973
Other name:
GDC-0973
Other name:
GDC0973
Other name:
MEK Inhibitor GDC-0973
Other name:
XL 518
Other name:
XL-518
Other name:
XL518
Intervention type:
Procedure
Intervention name:
Computed Tomography
Description:
Undergo CT
Arm group label:
Treatment (pelcitoclax, cobimetinib)
Other name:
CAT
Other name:
CAT Scan
Other name:
Computed Axial Tomography
Other name:
Computerized Axial Tomography
Other name:
Computerized axial tomography (procedure)
Other name:
Computerized Tomography
Other name:
Computerized Tomography (CT) scan
Other name:
CT
Other name:
CT Scan
Other name:
tomography
Intervention type:
Procedure
Intervention name:
Echocardiography
Description:
Undergo ECHO
Arm group label:
Treatment (pelcitoclax, cobimetinib)
Other name:
EC
Intervention type:
Procedure
Intervention name:
Magnetic Resonance Imaging
Description:
Undergo MRI
Arm group label:
Treatment (pelcitoclax, cobimetinib)
Other name:
Magnetic Resonance
Other name:
Magnetic Resonance Imaging (MRI)
Other name:
Magnetic resonance imaging (procedure)
Other name:
Magnetic Resonance Imaging Scan
Other name:
Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance
Other name:
MR
Other name:
MR Imaging
Other name:
MRI
Other name:
MRI Scan
Other name:
MRIs
Other name:
NMR Imaging
Other name:
NMRI
Other name:
Nuclear Magnetic Resonance Imaging
Other name:
sMRI
Other name:
Structural MRI
Intervention type:
Procedure
Intervention name:
Multigated Acquisition Scan
Description:
Undergo MUGA
Arm group label:
Treatment (pelcitoclax, cobimetinib)
Other name:
Blood Pool Scan
Other name:
Equilibrium Radionuclide Angiography
Other name:
Gated Blood Pool Imaging
Other name:
Gated Heart Pool Scan
Other name:
MUGA
Other name:
MUGA Scan
Other name:
Multi-Gated Acquisition Scan
Other name:
Radionuclide Ventriculogram Scan
Other name:
Radionuclide Ventriculography
Other name:
RNV Scan
Other name:
RNVG
Other name:
SYMA Scanning
Other name:
Synchronized Multigated Acquisition Scanning
Intervention type:
Drug
Intervention name:
Pelcitoclax
Description:
Given IV
Arm group label:
Treatment (pelcitoclax, cobimetinib)
Other name:
APG 1252
Other name:
APG-1252
Other name:
APG1252
Other name:
Bcl-2/Bcl-XL Inhibitor APG-1252
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.
Detailed description:
PRIMARY OBJECTIVE:
I. To establish the recommended phase 2 dosing (RP2D) for combination pelcitoclax
(APG-1252) and cobimetinib in advanced/recurrent endometrial and ovarian cancers.
SECONDARY OBJECTIVES:
I. 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:
I. 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.
V. 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.
Criteria for eligibility:
Criteria:
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
Gender:
Female
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
Emory University Hospital/Winship Cancer Institute
Address:
City:
Atlanta
Zip:
30322
Country:
United States
Status:
Recruiting
Contact:
Last name:
Site Public Contact
Phone:
404-778-1868
Investigator:
Last name:
Kristen Starbuck
Email:
Principal Investigator
Facility:
Name:
Johns Hopkins University/Sidney Kimmel Cancer Center
Address:
City:
Baltimore
Zip:
21287
Country:
United States
Status:
Recruiting
Contact:
Last name:
Site Public Contact
Phone:
410-955-8804
Email:
jhcccro@jhmi.edu
Investigator:
Last name:
Stephanie L. Gaillard
Email:
Principal Investigator
Facility:
Name:
National Cancer Institute Developmental Therapeutics Clinic
Address:
City:
Bethesda
Zip:
20892
Country:
United States
Status:
Recruiting
Contact:
Last name:
Site Public Contact
Phone:
800-411-1222
Investigator:
Last name:
Sarah Shin
Email:
Principal Investigator
Facility:
Name:
National Institutes of Health Clinical Center
Address:
City:
Bethesda
Zip:
20892
Country:
United States
Status:
Suspended
Facility:
Name:
Dana-Farber - Harvard Cancer Center LAO
Address:
City:
Boston
Zip:
02115
Country:
United States
Status:
Recruiting
Contact:
Last name:
Joyce F. Liu
Phone:
617-632-5269
Email:
joyce_liu@dfci.harvard.edu
Investigator:
Last name:
Joyce F. Liu
Email:
Principal Investigator
Facility:
Name:
Dana-Farber Cancer Institute
Address:
City:
Boston
Zip:
02215
Country:
United States
Status:
Recruiting
Contact:
Last name:
Site Public Contact
Phone:
877-442-3324
Investigator:
Last name:
Joyce F. Liu
Email:
Principal Investigator
Start date:
September 14, 2023
Completion date:
June 1, 2026
Lead sponsor:
Agency:
National Cancer Institute (NCI)
Agency class:
NIH
Source:
National Cancer Institute (NCI)
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05691504
