Cabozantinib + Dostarlimab for Gynecologic Cancers

Overseen By Margaret A Thomas, MPH

Age: 18+

Sex: Female

Trial Phase: Phase 1 & 2

Sponsor: University of Alabama at Birmingham

Must not be taking: Anticoagulants, Platelet inhibitors

Disqualifiers: Brain metastases, Uncontrolled hypertension, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: Unknown

Duration: 6 months

37 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new combination of treatments for gynecologic cancers that have returned after treatment. It combines Cabozantinib, which blocks blood vessels from nourishing tumors, and Dostarlimab, an immunotherapy drug that helps the immune system attack cancer cells. The goal is to determine if these two drugs work better together than individually. The trial seeks participants diagnosed with carcinosarcoma, a type of cancer, who have already undergone at least one chemotherapy treatment. As a Phase 1, Phase 2 trial, this research aims to understand how the treatment works in people and to measure its effectiveness in an initial, smaller group.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot have had certain cancer treatments or radiation therapy recently. You also cannot take certain blood thinners like warfarin, but some others are allowed if stable.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that cabozantinib has been studied in various gynecologic cancers and is generally well-tolerated by patients. In real-world use, it has consistently proven safe for other conditions like liver cancer. Dostarlimab, an immunotherapy drug, targets specific proteins on cancer cells. It has shown promise in treating endometrial cancer and received FDA approval for this purpose. Although limited safety data exist on using cabozantinib and dostarlimab together, both drugs have been well-tolerated individually in other studies, suggesting they might be safe when combined. As this trial is in its early stages, the primary focus is on assessing safety, with close monitoring of any side effects. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about Cabozantinib and Dostarlimab for gynecologic cancers because they target the cancer in innovative ways compared to standard treatments like chemotherapy and surgery. Cabozantinib works by inhibiting certain proteins that help cancer cells grow and spread, while Dostarlimab is an immune checkpoint inhibitor that helps the immune system better recognize and attack cancer cells. This combination not only aims to reduce tumor growth but also enhances the body's natural defenses against cancer, offering a potentially more effective and comprehensive approach to treating gynecologic cancers.

What evidence suggests that the combination of Cabozantinib and Dostarlimab could be effective for gynecologic cancers?

This trial will evaluate the combination of Cabozantinib and Dostarlimab for treating recurring gynecologic carcinosarcoma. Research has shown that combining these drugs might be effective. In one study, Cabozantinib, when used with another drug, helped shrink tumors in 21% of patients with ovarian cancer. Cabozantinib blocks a pathway that tumors use to grow blood vessels, potentially stopping cancer growth. Dostarlimab is an immunotherapy drug that helps the immune system identify and fight cancer cells. Together, these drugs may enhance the immune system's ability to attack tumors in gynecologic cancers. ^{1 3 5 6 7}

Are You a Good Fit for This Trial?

This trial is for adults with recurrent gynecologic carcinosarcoma who've had at least one chemotherapy treatment. They must have a certain level of hemoglobin, white blood cells, and platelets, no serious illnesses or recent surgeries, and can't be pregnant or breastfeeding. Participants need to agree to use contraception and not have used certain drugs recently.

Inclusion Criteria

Capable of understanding and complying with the protocol requirements and must have signed the informed consent document

My blood tests show my organs and bone marrow are working well.

My cancer is a type called carcinosarcoma.

Exclusion Criteria

I cannot swallow pills.

Medical or psychological impediment to probable compliance with the protocol

I have not had major surgery recently.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Cabozantinib 40 mg by mouth every day + Dostarlimab 500 mg intravenous every 3 weeks followed by maintenance therapy: Cabozantinib 40 mg by mouth every day + Dostarlimab 1000 mg intravenous every 6 weeks

6 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Cabozantinib
• Dostarlimab

Trial Overview The study tests Cabozantinib (a drug that inhibits blood vessel growth in tumors) combined with Dostarlimab (an immunotherapy drug) on patients with recurring gynecological cancers. It aims to see if this combination improves the body's immune response against cancer cells.

How Is the Trial Designed?

Group I: Cabo + Dostarlimab Experimental Treatment 1 Intervention

Cabozantinib 40 mg by mouth every day + Dostarlimab 500 mg intravenous every 3 weeks followed by maintenance therapy: Cabozantinib 40 mg by mouth every day + Dostarlimab 1000 mg intravenous every 6 weeks

Cabozantinib is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Cabometyx for:

• Renal cell carcinoma
• Hepatocellular carcinoma

Approved in United States as Cabometyx for:

• Renal cell carcinoma
• Hepatocellular carcinoma

Approved in Canada as Cabometyx for:

• Renal cell carcinoma
• Hepatocellular carcinoma

Approved in Japan as Cabometyx for:

• Renal cell carcinoma

Who Is Running the Clinical Trial?

University of Alabama at Birmingham

Lead Sponsor

Trials

1,677

Recruited

2,458,000+

Published Research Related to This Trial

Dostarlimab (JEMPERLI) is a PD-1 monoclonal antibody that has received rapid FDA approval for treating adult patients with mismatch repair deficient (dMMR) recurrent or advanced endometrial cancer, showing promising tumor response rates.

A clinical trial (NCT04165772) reported a remarkable 100% remission rate for rectal cancer patients treated with Dostarlimab, highlighting the potential of matching tumor genetics with targeted therapies, and the trial is ongoing for other cancer types like gastric, prostate, and pancreatic cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dostarlimab: A Review. Costa, B., Vale, N.[2022]

In a phase 2 trial involving 70 ovarian carcinoma patients, cabozantinib showed a 21% objective response rate at week 12, with a median progression-free survival of 5.5 months, indicating its potential effectiveness in treating this type of cancer.

The treatment was associated with manageable side effects, with 70% of patients experiencing tumor regression, although 37% required dose reductions due to adverse events like diarrhea and hypertension.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase 2 randomised discontinuation trial of cabozantinib in patients with ovarian carcinoma. Vergote, IB., Smith, DC., Berger, R., et al.[2019]

Cabozantinib and temozolomide both significantly reduced the growth and viability of uterine sarcoma cells, with the combination of the two drugs showing even greater effectiveness in promoting cell death and inhibiting tumor growth.

In mouse models, the combined treatment of cabozantinib and temozolomide led to a significant reduction in tumor size, indicating a synergistic effect that supports further clinical trials for this combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anticancer Activity of the Combination of Cabozantinib and Temozolomide in Uterine Sarcoma. Noh, JJ., Cho, YJ., Ryu, JY., et al.[2022]

In a phase 3 trial involving 494 patients with advanced or recurrent endometrial cancer, dostarlimab combined with chemotherapy significantly improved progression-free survival, especially in patients with mismatch repair-deficient (dMMR) tumors, showing a 61.4% survival rate at 24 months compared to 15.7% for placebo.

Overall survival at 24 months was also better with dostarlimab (71.3%) compared to placebo (56.0%), indicating its efficacy as a treatment option, although it was associated with a higher incidence of severe adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dostarlimab for Primary Advanced or Recurrent Endometrial Cancer. Mirza, MR., Chase, DM., Slomovitz, BM., et al.[2023]

Dostarlimab-gxly (Jemperli) has received accelerated approval from the FDA for treating adults with mismatch repair deficient recurrent or advanced endometrial cancer and solid tumors, indicating its potential effectiveness in these specific cancer types.

This approval highlights the importance of targeted therapies in oncology, particularly for patients with specific genetic markers that may influence treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New Drug for Mismatch Repair Deficient Endometrial Cancer and Solid Tumors. Aschenbrenner, DS.[2023]

Dostarlimab is a monoclonal antibody that targets the PD-1 receptor and has been approved for treating adult patients with mismatch repair deficient recurrent or advanced endometrial cancer based on promising results from the GARNET trial.

The approval of dostarlimab in the EU and USA marks a significant milestone in cancer treatment, highlighting its potential efficacy in targeting specific cancer types.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dostarlimab: First Approval. Markham, A.[2021]

Cabozantinib showed minimal efficacy in treating recurrent clear cell ovarian, fallopian tube, or primary peritoneal cancer, with only 23% of patients achieving progression-free survival of 6 months or more, and no objective tumor responses observed in a study of 13 patients over 19 months.

The treatment was associated with significant safety concerns, including thromboembolic events in multiple patients, highlighting the need for careful monitoring of side effects during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of single-agent cabozantinib in patients with recurrent clear cell ovarian, primary peritoneal or fallopian tube cancer (NRG-GY001). Konstantinopoulos, PA., Brady, WE., Farley, J., et al.[2023]

Cabozantinib shows potential efficacy in treating endometrial cancer, with a 14% response rate and a median progression-free survival (PFS) of 4.8 months in patients with endometrioid histology, and a 12% response rate with a median PFS of 4.0 months in serous histology patients.

The treatment was associated with significant side effects, including hypertension and gastrointestinal issues, with a notable increase in response rates observed in patients with specific genetic mutations (CTNNB1, KRAS, PTEN/PIK3CA), suggesting that genomic profiling may enhance treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II Trial of Cabozantinib in Recurrent/Metastatic Endometrial Cancer: A Study of the Princess Margaret, Chicago, and California Consortia (NCI9322/PHL86). Dhani, NC., Hirte, HW., Wang, L., et al.[2021]

Dostarlimab showed significant antitumor activity in patients with advanced endometrial cancer, achieving an objective response rate (ORR) of 43.5% in those with dMMR/MSI-H disease, compared to 14.1% in those with proficient/stable disease, indicating its potential effectiveness in specific cancer subtypes.

The treatment had a manageable safety profile, with most adverse events being mild to moderate (grade 1-2), and no deaths attributed to the drug, suggesting it is a safe option for patients with advanced endometrial cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and antitumor activity of dostarlimab in patients with advanced or recurrent DNA mismatch repair deficient/microsatellite instability-high (dMMR/MSI-H) or proficient/stable (MMRp/MSS) endometrial cancer: interim results from GARNET-a phase I, single-arm study. Oaknin, A., Gilbert, L., Tinker, AV., et al.[2022]

In a study involving 111 patients with recurrent ovarian cancer, cabozantinib showed a median progression-free survival (PFS) of 5.3 months, which was similar to the 5.5 months achieved with weekly paclitaxel, indicating comparable initial treatment effectiveness.

However, cabozantinib had worse outcomes in overall survival (OS), event-free survival (EFS), and overall response rate (ORR) compared to paclitaxel, along with increased gastrointestinal side effects, leading to the conclusion that cabozantinib is not recommended for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A randomized phase II study of cabozantinib versus weekly paclitaxel in the treatment of persistent or recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer: An NRG Oncology/Gynecologic Oncology Group study. Matulonis, UA., Sill, MW., Makker, V., et al.[2020]

Citations

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Cabozantinib and Dostarlimab in Recurrent Gynecologic ... Immunotherapy has gained a significant amount of attention recently, but its efficacy as a single agent in gynecological cancers has been disappointing.

2. withpower.com withpower.com/trial/phase-2-carcinoma-2023-ae47d

Cabozantinib + Dostarlimab for Gynecologic Cancers In a phase 2 trial involving 70 ovarian carcinoma patients, cabozantinib showed a 21% objective response rate at week 12, with a median progression-free ...

3. careacross.com careacross.com/clinical-trials/trial/NCT05559879

Cabozantinib and Dostarlimab in Recurrent Gynecologic ... In this study, Cabozantinib (VEGF inhibitor) and Dostarlimab (immunotherapeutic drug) will be admnistered as a combination to patients with recurrent ...

4. jpccr.eu jpccr.eu/Dostarlimab-as-a-promising-immunotherapy-for-endometrial-cancer-treatment-literature,172403,0,2.html

Dostarlimab as a promising immunotherapy for ... Clinical outcome and biomarker assessments of a multi-centre phase II trial assessing niraparib with or without dostarlimab in recurrent endometrial carcinoma.

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8921950/

Translational randomized phase II trial of cabozantinib in ... Adding cabozantinib to nivolumab significantly improved outcomes in heavily pretreated endometrial cancer. A subgroup of immunotherapy- ...

6. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2023-06286

Cabozantinib plus Dostarlimab for Treatment of Recurrent ... This phase Ib/II trial tests the safety and how well cabozantinib and dostarlimab works in treating patients with a specific gynecologic cancer, ...

7. academic.oup.com academic.oup.com/oncolo/advance-article/doi/10.1093/oncolo/oyaf252/8229573?searchresult=1

Real-world clinical outcomes of cabozantinib as a second-line ... Cabozantinib shows consistent effectiveness and safety in the 2L HCC setting following prior TKIs or IO-based regimens in real-world clinical ...