Cabozantinib + Pembrolizumab for Melanoma

Overseen By Yousef Zakharia, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: John Rieth

Must not be taking: Corticosteroids, CYP3A4 inducers/inhibitors

Disqualifiers: Ocular melanoma, CNS metastases, 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: 6

28 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial requires a 2-week washout period (time without taking certain medications) for those who have taken BRAF and/or MEK inhibitors. Additionally, you cannot take certain medications like strong CYP3A4 inducers or inhibitors close to the start of the trial. Other medications may also need to be stopped, but the protocol does not specify all details.

What data supports the effectiveness of the drug pembrolizumab for melanoma?

Pembrolizumab has been shown to improve treatment outcomes in advanced melanoma, performing better than another drug called ipilimumab. It has also been approved for use in patients with advanced melanoma, showing it can help control the disease. ^{1 2 3 4 5}

Is the combination of Cabozantinib and Pembrolizumab safe for treating melanoma?

Pembrolizumab, also known as KEYTRUDA, has been shown to be generally safe in humans with advanced melanoma, with common side effects including fatigue, rash, itching, and diarrhea. Less common side effects can include thyroid issues, inflammation of the colon, liver, or lungs. While specific safety data for the combination with Cabozantinib is not provided, Pembrolizumab alone has a favorable safety profile. ^{2 6 7 8 9}

How is the drug combination of Cabozantinib and Pembrolizumab unique for treating melanoma?

The combination of Cabozantinib and Pembrolizumab is unique because it pairs a tyrosine kinase inhibitor (Cabozantinib) with an immune checkpoint inhibitor (Pembrolizumab), potentially enhancing the immune system's ability to fight melanoma by targeting different pathways. This approach is novel compared to traditional treatments that often focus on a single mechanism. ^{1 2 6 10 11}

What is the purpose of this trial?

This trial is testing a combination of two drugs to treat adults with advanced melanoma that cannot be surgically removed. One drug stops cancer cells from growing, and the other helps the immune system attack the cancer. The combination of pembrolizumab and ipilimumab is being tested for its effectiveness and safety in treating advanced melanoma.

Research Team

John Rieth, MD

Principal Investigator

University of Iowa

Eligibility Criteria

Adults with advanced melanoma who can swallow pills, have measurable lesions, and haven't had certain treatments for their cancer recently. They must understand the study and agree to provide tissue samples. Women of childbearing age need a negative pregnancy test.

Inclusion Criteria

I can care for myself and have a life expectancy of more than 12 weeks.

I haven't been treated for advanced melanoma, except possibly BRAF/MEK inhibitors.

My melanoma cannot be removed by surgery and is either stage IIIc or IV.

Exclusion Criteria

I have not had any cancer other than skin, cervical, or in situ cancers in the last 2 years.

I haven't taken any tyrosine kinase inhibitor medication in the last 2 weeks.

I have had treatments targeting PD-1, PD-L1, or PD-L2 for advanced melanoma, but not within the last 6 months if it was for preventing cancer return.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase 1b Treatment

Establish the recommended Phase 2 dose of cabozantinib in combination with pembrolizumab and assess safety and tolerability

Up to 2 years

Pembrolizumab administered every 3 weeks

Phase 2 Treatment

Evaluate the preliminary efficacy of the established dose of cabozantinib in combination with pembrolizumab

Up to 2 years

Pembrolizumab administered every 3 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Cabozantinib
• Pembrolizumab

Trial Overview The trial is testing the combination of two drugs, Cabozantinib and Pembrolizumab, to see how safe they are together and if they work well against advanced melanoma.

Participant Groups

Group I: Cabozantinib and pembrolizumab Experimental Treatment 2 Interventions

Cabozantinib will be administered in the tablet form, at three dose levels: 40, 20 and 60 mg per day. Pembrolizumab will be administered as an intravenous infusion at a fixed dose of 200 mg once every 3 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?

John Rieth

Lead Sponsor

Trials

4

Recruited

70+

Yousef Zakharia

Lead Sponsor

Trials

5

Recruited

160+

University of Iowa

Collaborator

Trials

486

Recruited

934,000+

Exelixis

Industry Sponsor

Trials

126

Recruited

20,500+

Michael M. Morrissey

Exelixis

Chief Executive Officer since 2010

PhD in Chemistry from Harvard University, BSc in Chemistry from the University of Wisconsin

Vicki L. Goodman

Exelixis

Chief Medical Officer since 2022

MD

Findings from Research

In a post hoc analysis of the KEYNOTE-006 study involving 555 patients with advanced melanoma, both ipilimumab and BRAF ± MEK inhibitors showed antitumor activity as subsequent therapies after pembrolizumab, with overall response rates (ORR) of 17.5% for ipilimumab and 30.5% for BRAF ± MEK inhibitors.

Patients who had not previously received BRAF ± MEK inhibitors showed a significantly higher ORR of 43.2% when treated with these agents after pembrolizumab, indicating that prior treatment status may influence the effectiveness of subsequent therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antitumor activity of ipilimumab or BRAF ± MEK inhibition after pembrolizumab treatment in patients with advanced melanoma: analysis from KEYNOTE-006. Long, GV., Arance, A., Mortier, L., et al.[2022]

Pembrolizumab (Keytruda) is the first anti-PD-1 therapy approved in the US for treating advanced malignant melanoma, specifically for patients who have progressed after prior treatments.

It is designed to target the PD-1 protein, enhancing the immune system's ability to fight cancer, and is currently under review for approval in the EU.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab: first global approval. Poole, RM.[2021]

In a randomized trial comparing FDA-approved immune checkpoint inhibitors for advanced melanoma, pembrolizumab showed significantly better treatment outcomes than ipilimumab.

This study is notable as it is the first to directly compare these two therapies as first-line treatments, highlighting pembrolizumab's potential as a more effective option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab superior to ipilimumab in melanoma. [2017]

In a phase 3 trial involving 706 patients with unresectable stage III or IV melanoma, the combination of epacadostat and pembrolizumab did not show any significant improvement in progression-free survival or overall survival compared to pembrolizumab alone.

The most common serious side effects were similar between the two groups, with no treatment-related deaths reported, indicating that the combination therapy was generally safe but ineffective in enhancing treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Epacadostat plus pembrolizumab versus placebo plus pembrolizumab in patients with unresectable or metastatic melanoma (ECHO-301/KEYNOTE-252): a phase 3, randomised, double-blind study. Long, GV., Dummer, R., Hamid, O., et al.[2020]

In a phase 3 trial involving 1,019 patients with resected high-risk stage III melanoma, pembrolizumab significantly improved recurrence-free survival compared to placebo, with a 1-year rate of 75.4% versus 61.0%.

While pembrolizumab was effective, it was associated with a higher rate of severe adverse events (14.7% vs. 3.4% in the placebo group), including one treatment-related death, indicating the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adjuvant Pembrolizumab versus Placebo in Resected Stage III Melanoma. Eggermont, AMM., Blank, CU., Mandala, M., et al.[2022]

Pembrolizumab, an anti-PD-1 antibody, has shown significant efficacy in treating advanced melanoma, demonstrating superior progression-free survival compared to chemotherapy in Phase II trials and improved overall survival in Phase III trials.

The treatment is generally well tolerated with a favorable safety profile, though common side effects include fatigue and rash, while less frequent but serious immune-related adverse events can occur.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab in the management of metastatic melanoma. Spain, L., Younger, E., Hatipoglu, E., et al.[2020]

Pembrolizumab (KEYTRUDA) was approved by the FDA for treating unresectable or metastatic melanoma based on two clinical trials involving 1,374 patients, showing significant improvements in overall survival compared to ipilimumab, with hazard ratios indicating a reduced risk of death.

Patients receiving pembrolizumab also experienced significant improvements in progression-free survival, although some immune-mediated adverse reactions like hypothyroidism and pneumonitis were noted, highlighting the importance of monitoring for side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Pembrolizumab for the Treatment of Patients with Unresectable or Metastatic Melanoma. Barone, A., Hazarika, M., Theoret, MR., et al.[2022]

In a study of 103 Chinese patients with advanced melanoma, pembrolizumab demonstrated a 16.7% objective response rate, indicating its effectiveness as a second-line treatment, particularly in aggressive melanoma subtypes.

The treatment was well tolerated, with 84.5% of patients experiencing treatment-related adverse events, but only a small percentage (8.7%) had severe side effects, and no treatment-related deaths occurred.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase Ib Study of Pembrolizumab as Second-Line Therapy for Chinese Patients With Advanced or Metastatic Melanoma (KEYNOTE-151). Si, L., Zhang, X., Shu, Y., et al.[2020]

In a study of 655 patients with advanced melanoma, pembrolizumab showed a 5-year overall survival rate of 34%, with even better outcomes (41%) for treatment-naive patients, indicating its long-term efficacy.

The treatment was generally well-tolerated, with 86% of patients experiencing treatment-related adverse events, but only 7.8% discontinued due to these effects, suggesting a manageable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Five-year survival outcomes for patients with advanced melanoma treated with pembrolizumab in KEYNOTE-001. Hamid, O., Robert, C., Daud, A., et al.[2023]

Pembrolizumab, a PD-1 inhibitor, has demonstrated clinical effectiveness in treating various solid tumors, particularly in patients with PD-L1-positive non-small-cell lung cancer and unresectable/metastatic melanoma.

Early-phase trials and ongoing studies are focused on further confirming the clinical benefits of pembrolizumab in thoracic malignancies, highlighting its potential as a significant treatment option in cancer therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab for the treatment of thoracic malignancies: current landscape and future directions. Karim, S., Leighl, N.[2017]

The maximum tolerated doses (MTDs) for the combination of pembrolizumab and trametinib were established, with concurrent dosing showing a lower objective response rate (0%) compared to intermittent dosing (27%).

While the combination treatment had manageable safety profiles, with 31% of patients experiencing grade 3/4 treatment-related adverse events in the concurrent group, the overall antitumor activity was limited, suggesting that this combination may not be highly effective for solid tumors and BRAF wild-type melanoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

KEYNOTE-022: Pembrolizumab with trametinib in patients with BRAF wild-type melanoma or advanced solid tumours irrespective of BRAF mutation. Maio, M., Carlino, MS., Joshua, AM., et al.[2022]

References

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

Antitumor activity of ipilimumab or BRAF ± MEK inhibition after pembrolizumab treatment in patients with advanced melanoma: analysis from KEYNOTE-006. [2022]

2. New Zealand pubmed.ncbi.nlm.nih.gov

Pembrolizumab: first global approval. [2021]

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

Pembrolizumab superior to ipilimumab in melanoma. [2017]

4. England pubmed.ncbi.nlm.nih.gov

Epacadostat plus pembrolizumab versus placebo plus pembrolizumab in patients with unresectable or metastatic melanoma (ECHO-301/KEYNOTE-252): a phase 3, randomised, double-blind study. [2020]

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

Adjuvant Pembrolizumab versus Placebo in Resected Stage III Melanoma. [2022]

6. England pubmed.ncbi.nlm.nih.gov

Pembrolizumab in the management of metastatic melanoma. [2020]

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

FDA Approval Summary: Pembrolizumab for the Treatment of Patients with Unresectable or Metastatic Melanoma. [2022]

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

A Phase Ib Study of Pembrolizumab as Second-Line Therapy for Chinese Patients With Advanced or Metastatic Melanoma (KEYNOTE-151). [2020]

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

Five-year survival outcomes for patients with advanced melanoma treated with pembrolizumab in KEYNOTE-001. [2023]

10. England pubmed.ncbi.nlm.nih.gov

Pembrolizumab for the treatment of thoracic malignancies: current landscape and future directions. [2017]

11. England pubmed.ncbi.nlm.nih.gov

KEYNOTE-022: Pembrolizumab with trametinib in patients with BRAF wild-type melanoma or advanced solid tumours irrespective of BRAF mutation. [2022]