Cabozantinib + Nivolumab for Endometrial Cancer

Not currently recruiting at 41 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to evaluate the effectiveness of combining cabozantinib and nivolumab for endometrial cancer that has returned or spread. Cabozantinib may block enzymes that promote cancer cell growth, while nivolumab, an immunotherapy, may enhance the immune system's ability to fight cancer. Participants with advanced endometrial cancer and recent disease progression after treatment may be suitable for this study. As a Phase 2 trial, this research focuses on assessing the treatment's effectiveness in an initial, smaller group of participants.

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.

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

Previous studies have tested cabozantinib s-malate in patients with various types of cancer. Some patients experienced side effects such as increased liver enzymes and fatigue, common with cancer treatments. However, it is not recommended for individuals with severe liver or kidney problems due to insufficient safety information for those groups.

Nivolumab has demonstrated acceptable safety in various studies. It has been used in patients with advanced endometrial cancer, and while side effects like tiredness and skin rash were reported, most were manageable. This drug enhances the immune system's ability to fight cancer.

Both treatments have been studied separately and have shown manageable safety profiles. While side effects can occur, they are often similar to those seen in other cancer treatments and can be managed by healthcare providers. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about using cabozantinib and nivolumab for endometrial cancer because these treatments offer a fresh approach compared to standard chemotherapy and hormonal therapies. Cabozantinib is a tyrosine kinase inhibitor that blocks the signals tumors use to grow blood vessels, potentially starving the cancer. Nivolumab is an immune checkpoint inhibitor that helps the immune system recognize and attack cancer cells more effectively. This combination could provide a one-two punch: cutting off the cancer's blood supply and boosting the body's immune response.

What evidence suggests that this trial's treatments could be effective for endometrial cancer?

Research has shown that using cabozantinib and nivolumab together may help treat endometrial cancer. In this trial, participants in Arm A will receive this combination, which has improved results for patients who have tried other treatments. Cabozantinib stops enzymes that help cancer grow, while nivolumab, an immunotherapy, helps the immune system attack cancer cells. Participants in Arm B will receive nivolumab alone, and evidence indicates it controls the disease in 76.9% of patients with advanced endometrial cancer. Together, these treatments might offer a stronger approach for managing recurring or advanced endometrial cancer. ^{6 7 8 9 10}

Who Is on the Research Team?

Stephanie Lheureux

Principal Investigator

University Health Network Princess Margaret Cancer Center LAO

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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 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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT03367741

Cabozantinib S-malate and Nivolumab in Treating Patients ... This randomized phase II trial studies how well cabozantinib s-malate and nivolumab work in treating patients with endometrial cancer that has come back ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/35288469/

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

3. withpower.com withpower.com/trial/phase-3-endometrial-neoplasms-2018-1377f

Cabozantinib + Nivolumab for Endometrial Cancer This randomized phase II trial studies how well cabozantinib s-malate and nivolumab work in treating patients with endometrial cancer that has come back ...

4. ipsen.com ipsen.com/press-releases/asco-2022-new-cabometyx-data-show-encouraging-results-in-monotherapy-and-in-combination-across-different-tumor-types-including-metastatic-non-small-cell-lung-cancer/

ASCO 2022: New Cabometyx® data show encouraging ... These data show that the therapeutic potential of Cabometyx as a key treatment option in a broad range of tumors is continuing to be realized.

5. targetedonc.com targetedonc.com/view/cabozantinib-nivolumab-combination-demonstrates-efficacy-in-nccrcc

Cabozantinib/Nivolumab Combination Demonstrates ... Previously, the combination of cabozantinib and nivolumab showed improved efficacy over sunitinib (Sutent) in patients with advanced ccRCC in the phase 3 ...

6. cabometyxhcp.com cabometyxhcp.com/rcc-treatment/monotherapy/safety

CABOSUN & METEOR show similar safety results for ... Laboratory abnormalities occurring in ≥25% of patients in the CABOMETYX arm of the METEOR trial · Grade 3-4 adverse reactions (ARs) occurring in >1% of patients ...

7. ema.europa.eu ema.europa.eu/en/documents/product-information/cometriq-epar-product-information_en.pdf

Cometriq, INN-Cabozantinib - European Medicines Agency Cabozantinib is not recommended for use in patients with severe hepatic impairment as safety and efficacy have not been established in this population. Patients ...

8. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2012/203756lbl.pdf

COMETRIQ™ (cabozantinib) Label - accessdata.fda.gov The safety of COMETRIQ was evaluated in 330 patients with progressive metastatic medullary thyroid cancer randomized to receive 140 mg COMETRIQ (n = 214) or ...

9. ema.europa.eu ema.europa.eu/en/documents/product-information/cabometyx-epar-product-information_en.pdf

Cabometyx, INN-Cabozantinib - EMA Cabozantinib is not recommended for use in patients with severe renal impairment as safety and efficacy have not been established in this population. Hepatic ...

10. clinicaltrials.gov clinicaltrials.gov/study/NCT01935934

Study Details | NCT01935934 | Cabozantinib S-Malate in ... This phase II trial studies how well cabozantinib s-malate works in treating patients with endometrial cancer that has come back (recurrent) or has spread ...