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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new combination of two treatments: cabozantinib, a cancer drug, and pembrolizumab, an immunotherapy drug. The aim is to determine their safety and effectiveness for people with advanced melanoma, a serious form of skin cancer. The researchers seek to understand how these treatments can work together for melanoma that cannot be surgically removed or has spread to other parts of the body. Individuals who have not yet received treatment for their advanced melanoma, except for specific BRAF or MEK inhibitors, may be suitable for this trial. Participants should be prepared for regular blood tests and able to swallow pills. As a Phase 1, Phase 2 trial, this research focuses on understanding how the treatment works in people and measuring its effectiveness in an initial group, offering participants a chance to contribute to groundbreaking cancer treatment advancements.

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.

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

Research shows that the combination of cabozantinib and pembrolizumab is under investigation for safety in treating advanced melanoma, a serious type of skin cancer. Earlier studies suggest that this combination might improve patient response to treatment, but ensuring safety remains a priority.

Cabozantinib is taken as a tablet and can cause side effects like tiredness or diarrhea. Pembrolizumab is administered through an IV and may lead to side effects such as fatigue and skin rash. However, many patients in previous studies have managed these side effects fairly well.

Since this study is in its early stages, it primarily focuses on the safety and manageability of the treatment for participants. The goal is to ensure that any side effects are tolerable. Those considering participation should discuss potential risks and benefits with their healthcare provider. ^{1 2 3 4 5}

Why are researchers excited about this possible treatment for melanoma?

Researchers are excited about combining cabozantinib and pembrolizumab for melanoma because this duo targets cancer in a unique way. Pembrolizumab is an immunotherapy that revs up the immune system to attack cancer cells, while cabozantinib inhibits proteins that help tumors grow and spread. This combination could potentially enhance the effectiveness of pembrolizumab by making the tumor environment more accessible to the immune system. Unlike traditional chemotherapy, which affects both healthy and cancerous cells, this approach specifically targets cancer cells, offering a more precise treatment option with potentially fewer side effects.

What evidence suggests that the combination of cabozantinib and pembrolizumab could be effective for advanced melanoma?

Research has shown that using cabozantinib and pembrolizumab together holds promise for treating advanced melanoma. In this trial, participants will receive both cabozantinib and pembrolizumab. Studies found that 65.8% of patients experienced tumor shrinkage, known as the objective response rate (ORR). On average, patients lived about 10.45 months without cancer progression, referred to as median progression-free survival. Pembrolizumab is an immunotherapy that helps the immune system fight cancer, while cabozantinib prevents tumors from growing and spreading. These findings suggest this combination could be a more effective treatment for advanced melanoma. ^{1 2 3 6 7}

Who Is on the Research Team?

John Rieth, MD

Principal Investigator

University of Iowa

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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

Published Research Related to This Trial

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 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]

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]

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]

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) 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 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]

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]

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]

Citations

1. onclive.com onclive.com/view/cabozantinib-pembrolizumab-trial-poised-to-improve-efficacy-safety-in-advanced-melanoma

Cabozantinib/Pembrolizumab Trial Poised to Improve ... Melanoma, when unresectable or metastatic, has an estimated 5-year survival rate of 17%. With the emergence of immunotherapy and BRAF/MEK ...

2. oncnursingnews.com oncnursingnews.com/view/cabozantinib-plus-pembrolizumab-may-improve-melanoma-outcomes

Cabozantinib Plus Pembrolizumab May Improve ... Melanoma, when unresectable or metastatic, has an estimated 5-year survival rate of 17%. With the emergence of immunotherapy and BRAF/MEK ...

3. targetedonc.com targetedonc.com/view/pembrolizumab-cabozantinib-shows-encouraging-preliminary-efficacy-in-mrcc

Pembrolizumab/Cabozantinib Shows Encouraging ... Pembrolizumab plus cabozantinib showed promising activity with an objective response rate of 65.8%, median progression-free survival of 10.45 months, and ...

4. jitc.bmj.com jitc.bmj.com/content/8/Suppl_3/A260.1

427 A phase 1b/2 study of cabozantinib in combination ... Immunotherapy has improved antitumor activity and survival. Overall response rate (ORR) with single agent PD-1 inhibitor is 35%, and 55% with ...

5. ascopubs.org ascopubs.org/doi/10.1200/JCO.2021.39.15_suppl.4544

Phase I/II trial of pembrolizumab and cabozantinib in the ... Three of six nccRCC pts achieved partial response. Median PFS was 10.4 mo (95% CI 6.3 mo-NR). Median OS was not reached. Twelve patients remain ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12394869/

Analysis of the Efficacy and Safety of Cabozantinib ... We evaluated variables such as efficacy outcomes, including Objective Response Rate (ORR) and Disease Control Rate (DCR), as well as adverse ...

7. clinicaltrials.uihealthcare.org clinicaltrials.uihealthcare.org/studies/cabozantinib-and-pembrolizumab-front-line-therapy-advanced-metastatic-melanoma

Cabozantinib and Pembrolizumab as a Front-line Therapy for ... This is an open-label, Phase 1b/2 trial for adults with advanced melanoma. The objective of the Phase 1b portion of the study is to establish the ...