Cabozantinib + Nivolumab for Endometrial Cancer

Recruiting at 36 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: Anticoagulants, CYP450 3A4 drugs

Disqualifiers: Active malignancy, Brain metastases, Hypertension, others

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

Prior Safety Data This treatment has passed at least one previous human trial

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

Compensation: Varies

Number of Visits: 1

Duration: Up to 1 year

84 Participants Needed

Trial Summary

What is the purpose of this trial?

This randomized phase II trial studies how well cabozantinib s-malate and nivolumab work in treating patients with endometrial cancer that has come back (recurrent) or spread to other places in the body (advanced or metastatic). Cabozantinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving cabozantinib and nivolumab may work better in treating endometrial cancer.

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

The trial does not specify if you need to stop taking your current medications, but it does exclude patients who are on certain medications like strong CYP450 3A4 inducers or inhibitors, and those requiring therapeutic doses of anticoagulants. It's best to discuss your current medications with the trial team to see if any adjustments are needed.

What data supports the effectiveness of the drug combination Cabozantinib and Nivolumab for endometrial cancer?

The combination of Cabozantinib and Nivolumab is being explored as a promising treatment strategy for endometrial cancer, as combining immunotherapy (like Nivolumab) and antiangiogenic agents (like Cabozantinib) has shown potential in treating this type of cancer. Additionally, PD-1 inhibitors, which include Nivolumab, have demonstrated activity in endometrial cancer, particularly in cases with certain genetic features. ^{1 2 3 4 5}

Is the combination of Cabozantinib and Nivolumab safe for humans?

The safety of Cabozantinib and Nivolumab in humans has been explored in various studies, but specific safety data for this combination in endometrial cancer is not detailed in the provided research. However, Cabozantinib and Nivolumab have been studied separately and in combination with other drugs, showing some common side effects like high blood pressure, fatigue, and nausea. ^{1 6 7 8 9}

How is the drug combination of Cabozantinib and Nivolumab unique for treating endometrial cancer?

This drug combination is unique because it combines an immunotherapy drug (nivolumab) with an antiangiogenic agent (cabozantinib), which targets blood vessel growth in tumors. This approach is promising for endometrial cancer, especially for patients who have not responded to previous immunotherapy treatments. ^{1 2 3 7 10}

Research Team

Stephanie Lheureux

Principal Investigator

University Health Network Princess Margaret Cancer Center LAO

Eligibility Criteria

This trial is for adults with advanced, recurrent, or metastatic endometrial cancer who've had at least one platinum-based chemotherapy. They must have measurable disease progression and not be on certain medications or have conditions like uncontrolled illnesses, other active cancers, known brain metastases, or a history of severe allergic reactions to the study drugs.

Inclusion Criteria

My cancer is in an advanced stage, has come back, or has spread from where it started.

I have been diagnosed with endometrial cancer.

MS/MMR result available at time of registration

Exclusion Criteria

I haven't had chemotherapy, biologic agents, or radiotherapy in the last 4 weeks.

My cancer has spread to my digestive system.

I have no active cancer other than endometrial cancer.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Patients receive cabozantinib s-malate and nivolumab or nivolumab alone, with cycles repeating every 28 days

Up to 1 year

Bi-weekly visits for nivolumab administration, monthly for cabozantinib

Follow-up

Participants are monitored for safety and effectiveness after treatment

30-37 days, then every 8-12 weeks

Regular follow-up visits

Treatment Details

Interventions

• Cabozantinib S-malate
• Nivolumab

Trial Overview The trial is testing the combination of Cabozantinib S-malate (a drug that blocks enzymes needed for tumor growth) and Nivolumab (an immunotherapy that helps the immune system attack cancer). It aims to see if this combo is more effective than current treatments in patients whose endometrial cancer has returned or spread.

Participant Groups

Group I: Arm B (nivolumab) Experimental Treatment 5 Interventions

Patients receive nivolumab as in Arm A. Patients may cross-over to Arm A at the time of disease progression. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan, MRI, and blood sample collection throughout the study and undergo biopsy at screening and optionally at follow up.

Group II: Arm A (cabozantinib s-malate, nivolumab) Experimental Treatment 6 Interventions

Patients receive cabozantinib s-malate PO QD on days 1-28 and nivolumab IV over 30 minutes on days 1 and 15, then on day 1 beginning cycle 5. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan, MRI, and blood sample collection throughout the study and undergo biopsy at screening and optionally at follow up.

Cabozantinib S-malate is already approved in United States, European Union for the following indications:

Approved in United States as Cabometyx for:

• Advanced renal cell carcinoma (RCC)
• Hepatocellular carcinoma (HCC)
• Locally advanced or metastatic differentiated thyroid cancer (DTC)

Approved in United States as Cometriq for:

• Medullary thyroid cancer

Approved in European Union as Cabometyx for:

• Advanced renal cell carcinoma (RCC)
• Hepatocellular carcinoma (HCC)
• Locally advanced or metastatic differentiated thyroid cancer (DTC)

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Findings from Research

In a phase II trial involving women with recurrent endometrial cancer, the combination of nivolumab and cabozantinib significantly improved progression-free survival (PFS) to a median of 5.3 months compared to 1.9 months for nivolumab alone, indicating enhanced efficacy of the combination therapy.

The study identified specific immune cell profiles that may predict treatment response, particularly in patients previously treated with immunotherapy, suggesting that immune profiling could help tailor future treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Translational randomized phase II trial of cabozantinib in combination with nivolumab in advanced, recurrent, or metastatic endometrial cancer. Lheureux, S., Matei, DE., Konstantinopoulos, PA., et al.[2023]

The phase III RUBY and NRG-GY018 trials demonstrated that women with newly diagnosed or first-recurrent advanced endometrial cancer benefit from combining a PD-1 inhibitor (dostarlimab or pembrolizumab) with standard chemotherapy.

This combination treatment significantly prolonged progression-free survival, and there was a positive trend in overall survival, indicating its potential effectiveness in managing this type of cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

ICI-Chemo New Standard for Endometrial Cancer. [2023]

PD-1 and PD-L1 inhibitors have shown effectiveness in treating ovarian, endometrial, and cervical cancers, particularly in cases of mismatch repair-deficient endometrial cancers, which exhibit the highest response rates.

Testing for mismatch repair deficiency or high microsatellite instability is recommended for all women with progressive gynecologic cancers to determine eligibility for treatment with pembrolizumab, a PD-1 inhibitor.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Role of PD-1 Checkpoint Inhibition in Gynecologic Malignancies. Garcia, C., Ring, KL.[2022]

A survey of oncologists in Italy revealed that while there is a good understanding of new treatments for endometrial cancer (EC), such as dostarlimab for MSI high patients, these innovations are not fully integrated into clinical practice, with only 13.3% performing all necessary molecular tests.

After the approval of dostarlimab, 75.6% of clinicians preferred it for second-line treatment in MSI high advanced EC patients, indicating a significant shift in treatment choice, while 77.8% plan to use lenvatinib plus pembrolizumab for MSS patients once approved.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Management of Metastatic Endometrial Cancer: Physicians' Choices Beyond the First Line. A MITO Survey. Giannone, G., Castaldo, D., Tuninetti, V., et al.[2022]

The combination of lenvatinib and pembrolizumab shows significant clinical benefits for patients with endometrial carcinoma, with a safety profile consistent with each drug's individual use, primarily involving manageable side effects like hypertension and hypothyroidism.

Effective management of lenvatinib's common adverse events is crucial to maximize its efficacy, as most side effects can be prevented or mitigated through proactive monitoring and intervention during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Optimizing the use of lenvatinib in combination with pembrolizumab in patients with advanced endometrial carcinoma. Lorusso, D., Danesi, R., Locati, LD., et al.[2023]

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]

The combination of lenvatinib and pembrolizumab is effective for treating advanced endometrial carcinoma, particularly in patients who have not responded to prior therapies, with manageable safety profiles similar to each drug used alone.

Common adverse reactions include hypothyroidism (51% incidence), fatigue, hypertension, and nausea, which typically occur within the first 10 weeks of treatment and can be effectively managed with dose adjustments and supportive care.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Characterization and Management of Adverse Reactions in Patients with Advanced Endometrial Carcinoma Treated with Lenvatinib Plus Pembrolizumab. Makker, V., Taylor, MH., Oaknin, A., et al.[2022]

The combination of lenvatinib and pembrolizumab significantly improved treatment outcomes for patients with advanced endometrial cancer compared to chemotherapy, regardless of tumor characteristics, based on data from Study-309/KEYNOTE-775.

Common adverse reactions included hypothyroidism, hypertension, and fatigue, with effective management strategies involving patient education, monitoring, and appropriate dose adjustments to minimize treatment interruptions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Characterization and Management of Adverse Reactions in Patients With Advanced Endometrial Cancer Receiving Lenvatinib Plus Pembrolizumab. Colombo, N., Lorusso, D., Monk, BJ., 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]

References

1. England pubmed.ncbi.nlm.nih.gov

Translational randomized phase II trial of cabozantinib in combination with nivolumab in advanced, recurrent, or metastatic endometrial cancer. [2023]

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

ICI-Chemo New Standard for Endometrial Cancer. [2023]

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

The Role of PD-1 Checkpoint Inhibition in Gynecologic Malignancies. [2022]

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

Uterine serous carcinoma. [2022]

5. Switzerland pubmed.ncbi.nlm.nih.gov

Management of Metastatic Endometrial Cancer: Physicians' Choices Beyond the First Line. A MITO Survey. [2022]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Optimizing the use of lenvatinib in combination with pembrolizumab in patients with advanced endometrial carcinoma. [2023]

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

Anticancer Activity of the Combination of Cabozantinib and Temozolomide in Uterine Sarcoma. [2022]

8. England pubmed.ncbi.nlm.nih.gov

Characterization and Management of Adverse Reactions in Patients with Advanced Endometrial Carcinoma Treated with Lenvatinib Plus Pembrolizumab. [2022]

9. England pubmed.ncbi.nlm.nih.gov

Characterization and Management of Adverse Reactions in Patients With Advanced Endometrial Cancer Receiving Lenvatinib Plus Pembrolizumab. [2023]

10. United States 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). [2021]