Pelcitoclax + Cobimetinib for Recurrent Ovarian and Endometrial Cancers

Recruiting in Palo Alto (17 mi)

+6 other locations

Overseen by Joyce Liu, MD

Age: 18+

Sex: Female

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: National Cancer Institute (NCI)

Must be taking: Platinum-based therapy

Must not be taking: CYP3A4 inhibitors, CYP3A4 inducers

Disqualifiers: Uncontrolled illness, Retinal pathology, others

No Placebo Group

Trial Summary

What is the purpose of this trial?

This trial tests the safety and best dose of two drugs, pelcitoclax and cobimetinib, in patients with recurring ovarian and endometrial cancers. Pelcitoclax helps kill cancer cells, and cobimetinib slows their growth. The goal is to find an effective dose and observe how well the combination works in shrinking or stabilizing tumors.

Do I need to stop my current medications to join the trial?

The trial requires that you stop taking any medications that are strong inhibitors or inducers of CYP3A4 at least 7 days before starting the trial drugs. If you're on such medications, you'll need to discuss alternatives with your doctor.

What data supports the effectiveness of the drug Pelcitoclax + Cobimetinib for recurrent ovarian and endometrial cancers?

The research does not provide direct evidence for the effectiveness of Pelcitoclax + Cobimetinib in treating recurrent ovarian and endometrial cancers. However, it highlights the challenges in treating recurrent ovarian cancer and the potential of novel molecular targets and immunotherapy, which may indirectly support the exploration of new drug combinations like Pelcitoclax + Cobimetinib. ^{1 2 3 4 5}

What makes the drug Pelcitoclax + Cobimetinib unique for treating recurrent ovarian and endometrial cancers?

Pelcitoclax + Cobimetinib is unique because it combines two drugs that target specific pathways involved in cancer cell survival and growth, potentially offering a new approach for patients with recurrent ovarian and endometrial cancers who have limited options beyond standard chemotherapy. ^{2 3 4 6 7}

Research Team

Joyce Liu, MD

Principal Investigator

Dana-Farber - Harvard Cancer Center LAO

Eligibility Criteria

This trial is for adults with recurrent ovarian or endometrial cancer who've had platinum-based therapy and, if applicable, specific prior treatments based on their cancer type. They must be able to take oral meds, provide tissue samples if available, use contraception if needed, and have no other health issues that could interfere.

Inclusion Criteria

I have a history or symptoms of heart disease and need a heart function assessment.

My ovarian cancer worsened within 6 months after my last platinum treatment.

My cancer has returned or spread and cannot be surgically removed, with no standard treatments left.

Exclusion Criteria

I am allergic to medications similar to APG-1252 or cobimetinib.

I do not have any unmanaged ongoing illnesses.

I have a stomach or intestine condition that affects how I absorb pills.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive APG-1252 intravenously once a week and cobimetinib orally on days 1-21 of each 28-day cycle. Biopsies, blood collection, CT/MRI scans, and ECHO/MUGA are conducted throughout the trial.

28 days per cycle, repeated until disease progression or unacceptable toxicity

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessment of adverse events and progression-free survival.

Up to 30 days after removal from study therapy

Long-term Follow-up

Exploration of markers of response and resistance, and assessment of radiological response and RAS pathway signaling.

Up to 3 years

Treatment Details

Interventions

• APG-1252 (Protein Inhibitor)
• Cobimetinib (Kinase Inhibitor)

Trial Overview The trial tests a combo of two drugs: Pelcitoclax (APG-1252) which may help kill cancer cells by blocking certain proteins, and Cobimetinib which targets abnormal proteins in cancers with a BRAF gene mutation. The goal is to see if this drug duo can shrink or stabilize the tumors.

Participant Groups

Group I: Treatment (pelcitoclax, cobimetinib) Experimental Treatment 8 Interventions

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.

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Dr. Douglas R. Lowy

National Cancer Institute (NCI)

Chief Executive Officer since 2023

MD from New York University School of Medicine

Dr. Monica Bertagnolli

National Cancer Institute (NCI)

Chief Medical Officer since 2022

MD from Harvard Medical School

Findings from Research

Patients with recurrent ovarian cancer are categorized as either platinum-sensitive or platinum-resistant, which influences treatment options; platinum-sensitive patients often benefit from re-treatment with paclitaxel/platinum combinations, while platinum-resistant patients may receive single-agent therapies like altretamine or topotecan.

For platinum-sensitive patients with minimal residual disease, intensive intraperitoneal therapy with cisplatin and paclitaxel shows the most promise for long-term disease-free survival, highlighting the importance of tailored treatment strategies based on disease characteristics.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of refractory and recurrent ovarian cancer. Alberts, DS.[2005]

Ovarian cancer (OC) has a high mortality rate and is often diagnosed at advanced stages, particularly type II tumors, which are associated with poor prognosis and resistance to standard treatments like chemotherapy.

Recent advances in molecular biology and the exploration of immunotherapy are promising for improving treatment options for recurrent and refractory OC, highlighting the importance of identifying prognostic and predictive biomarkers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New Achievements from Molecular Biology and Treatment Options for Refractory/Relapsed Ovarian Cancer-A Systematic Review. Bachmann, C.[2023]

The combination of pembrolizumab and carboplatin was found to be well-tolerated and showed activity in patients with recurrent platinum-resistant ovarian cancer, with a median overall survival of 11.3 months.

Patients with a higher ratio of peripheral CD8+PD1+Ki67+ T cells to tumor burden had significantly longer overall survival, suggesting this ratio could help identify those who may benefit more from this treatment approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab with low-dose carboplatin for recurrent platinum-resistant ovarian, fallopian tube, and primary peritoneal cancer: survival and immune correlates. Liao, JB., Gwin, WR., Urban, RR., et al.[2022]

Pembrolizumab and dostarlimab, immune checkpoint inhibitors, have been approved for treating advanced recurrent endometrial cancer in patients with specific molecular subgroups, particularly those with mismatch repair deficiency (MMRd) or microsatellite instability-high (MSI-H) status, based on data from 15 studies involving 1609 patients.

The combination of pembrolizumab or dostarlimab with lenvatinib has shown efficacy in patients with mismatch repair proficient/microsatellite stable (MMRp/MSS) endometrial cancer, highlighting the importance of biomarker assessment to optimize treatment strategies for different molecular phenotypes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immune Checkpoint Inhibitors Targeting the PD-1/PD-L1 Pathway in Advanced, Recurrent Endometrial Cancer: A Scoping Review with SWOT Analysis. Johnson, RL., Ganesan, S., Thangavelu, A., et al.[2023]

Advanced epithelial ovarian cancer responds well to first-line chemotherapy, with 70-80% of patients showing a response, but most eventually relapse and develop chemoresistant disease.

New treatment options, including topoisomerase I inhibitors and immunotherapy, are being explored for patients with recurrent ovarian cancer, highlighting the need for clinical trials to improve outcomes, especially for those with platinum-resistant disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Salvage chemotherapy for epithelial ovarian carcinoma. Christian, MC., Trimble, EL.[2015]

In a study of 101 women with recurrent endometrial, cervical, and ovarian cancer treated with immunotherapy, prior antibiotic use (pABX) was linked to a significantly lower response rate, progression-free survival (PFS), and overall survival (OS) compared to those who did not use antibiotics.

Specifically, women who received pABX had a PFS of only 2.9 months and an OS of 9.3 months, while those without antibiotics had a PFS of 8.9 months and an OS of 19.9 months, indicating that prior antibiotic use may negatively impact the effectiveness of immunotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of antibiotic treatment on immunotherapy response in women with recurrent gynecologic cancer. Chambers, LM., Michener, CM., Rose, PG., et al.[2021]

Atezolizumab, a PD-L1 inhibitor, was well tolerated in patients with advanced ovarian and uterine cancers, with no new safety concerns and mostly mild treatment-related adverse events.

Preliminary results showed anti-tumor activity in some patients, with long durations of response, suggesting that atezolizumab may be a promising treatment option for these cancers, especially in those with high microsatellite instability.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety, clinical activity and biomarker assessments of atezolizumab from a Phase I study in advanced/recurrent ovarian and uterine cancers. Liu, JF., Gordon, M., Veneris, J., et al.[2019]

References

1. United States pubmed.ncbi.nlm.nih.gov

Treatment of refractory and recurrent ovarian cancer. [2005]

2. Switzerland pubmed.ncbi.nlm.nih.gov

New Achievements from Molecular Biology and Treatment Options for Refractory/Relapsed Ovarian Cancer-A Systematic Review. [2023]

3. England pubmed.ncbi.nlm.nih.gov

Pembrolizumab with low-dose carboplatin for recurrent platinum-resistant ovarian, fallopian tube, and primary peritoneal cancer: survival and immune correlates. [2022]

4. Switzerland pubmed.ncbi.nlm.nih.gov

Immune Checkpoint Inhibitors Targeting the PD-1/PD-L1 Pathway in Advanced, Recurrent Endometrial Cancer: A Scoping Review with SWOT Analysis. [2023]

5. United States pubmed.ncbi.nlm.nih.gov

Salvage chemotherapy for epithelial ovarian carcinoma. [2015]

6. United States pubmed.ncbi.nlm.nih.gov

Impact of antibiotic treatment on immunotherapy response in women with recurrent gynecologic cancer. [2021]

7. United States pubmed.ncbi.nlm.nih.gov

Safety, clinical activity and biomarker assessments of atezolizumab from a Phase I study in advanced/recurrent ovarian and uterine cancers. [2019]