Cemiplimab + Ziv-Aflibercept for Uveal Melanoma

Overseen by Ahmad Tarhini, MD, PhD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: H. Lee Moffitt Cancer Center and Research Institute

Must not be taking: Corticosteroids, Immunosuppressants

Disqualifiers: Pregnancy, Autoimmune disorders, Heart disease, others

No Placebo Group

Prior Safety Data

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

This trial is testing a combination of two drugs, Cemiplimab and Ziv-Aflibercept, to treat patients with metastatic uveal melanoma. Cemiplimab helps the immune system fight cancer, while Ziv-Aflibercept stops tumors from getting the blood they need to grow. The goal is to see if this combination can shrink or stop the growth of tumors.

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

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot be on systemic corticosteroids or other immunosuppressants, and you must not have had another investigational drug or systemic intervention for uveal melanoma within 4 weeks of starting the study drugs.

What data supports the effectiveness of the drug combination Cemiplimab and Ziv-Aflibercept for uveal melanoma?

The research does not provide direct evidence for the effectiveness of Cemiplimab and Ziv-Aflibercept in treating uveal melanoma. However, it mentions that new therapies are being developed for uveal melanoma, and the use of immune system-targeting treatments like tebentafusp has shown some success in improving survival. ^{1 2 3 4 5}

Is the combination of Cemiplimab and Ziv-Aflibercept safe for humans?

Ziv-Aflibercept has been studied for safety in eye conditions, showing it is generally safe when injected into the eye for conditions like age-related macular degeneration and retinal diseases. However, this information is specific to eye treatments and may not fully apply to other uses or combinations with Cemiplimab. ^{6 7 8 9 10}

What makes the drug combination of Cemiplimab and Ziv-Aflibercept unique for treating uveal melanoma?

This drug combination is unique because it combines Cemiplimab, an immune checkpoint inhibitor, with Ziv-Aflibercept, a VEGF inhibitor, to target both the immune system and blood vessel growth in uveal melanoma, a cancer that typically responds poorly to immune therapies alone. ^{2 6 8 11 12}

Research Team

Ahmad Tarhini, MD, PhD

Principal Investigator

Moffitt Cancer Center

Eligibility Criteria

Adults with metastatic uveal melanoma can join this trial. They should have a life expectancy over 3 months, an ECOG performance status of 0-1 (fully active or restricted in physically strenuous activity but ambulatory), measurable disease, and normal organ/marrow function. Women must use effective contraception, as must men who agree to use condoms. Prior treatments for melanoma are allowed except for bevacizumab, aflibercept, or cemiplimab.

Inclusion Criteria

Patients must have a disease that can be measured using specific guidelines.

I am fully active or can carry out light work.

For Women of childbearing potential: use of highly effective contraception for at least 2 or more menstrual cycles prior to screening and agreement to use such a method during study participation and for at least 180 days after the end of study drugs administration

Exclusion Criteria

You have had a solid organ transplant, except for corneal transplants.

I have had lung inflammation due to immune response in the last 5 years.

I have undergone invasive medical procedures.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Cemiplimab 350 mg IV every 3 weeks and Ziv-Aflibercept 4 mg/kg IV every 2 weeks for metastatic uveal melanoma

3 weeks per cycle

1 visit every 2 weeks (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

5 years

Treatment Details

Interventions

• Cemiplimab (Checkpoint Inhibitor)
• Ziv-Aflibercept (Angiogenesis Inhibitor)

Trial Overview The study is testing the safety and effectiveness of combining Cemiplimab with Ziv-Aflibercept to see if they can shrink tumors or halt their growth in patients with metastatic uveal melanoma.

Participant Groups

Group I: Cemiplimab + Ziv-Aflibercept Experimental Treatment 2 Interventions

One cycle consists of 3 weeks during which: Cemiplimab 350 mg administered IV every 3 weeks given with Ziv-Aflibercept 4 mg/kg administered IV every 2 weeks.

Cemiplimab is already approved in Canada, Brazil for the following indications:

Approved in Canada as Libtayo for:

• Cutaneous squamous cell carcinoma (CSCC)
• Non-small cell lung cancer (NSCLC)

Approved in Brazil as Libtayo for:

• Cutaneous squamous cell carcinoma (CSCC)

Who Is Running the Clinical Trial?

H. Lee Moffitt Cancer Center and Research Institute

Lead Sponsor

Trials

576

Recruited

145,000+

Regeneron Pharmaceuticals

Industry Sponsor

Trials

690

Recruited

948,000+

Founded

1988

Headquarters

Tarrytown, USA

Known For

Precision medicine

Top Products

Dupixent, EYLEA, Libtayo, Praluent

Leonard Schleifer

Regeneron Pharmaceuticals

Chief Executive Officer since 1988

MD and PhD in Medicine

George Yancopoulos

Regeneron Pharmaceuticals

Chief Medical Officer since 1997

MD from Harvard Medical School

Genzyme, a Sanofi Company

Industry Sponsor

Trials

528

Recruited

186,000+

David Meeker

Genzyme, a Sanofi Company

Chief Executive Officer since 2011

MD from the University of Vermont Medical School, Advanced Management Program at Harvard Business School

Jean-Paul Kress

Genzyme, a Sanofi Company

Chief Medical Officer since 2015

MD from Faculte Necker-Enfants Malades, Paris

Findings from Research

In a study of 64 patients with metastatic uveal melanoma treated with a combination of CTLA-4 and PD-1 inhibitors, the overall response rate was 15.6%, with a median overall survival of 16.1 months, indicating that this combination therapy may be the most effective option currently available for this difficult-to-treat cancer.

Despite a significant number of patients experiencing severe treatment-related adverse events (39.1%), the tolerability of this combined therapy appears to be better than that seen in trials for cutaneous melanoma, suggesting a potentially safer profile for patients with uveal melanoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined immune checkpoint blockade for metastatic uveal melanoma: a retrospective, multi-center study. Heppt, MV., Amaral, T., Kähler, KC., et al.[2023]

Uveal melanoma, a rare and aggressive form of melanoma, has shown poor responses to traditional immune checkpoint inhibitors, highlighting the need for new treatment strategies.

Tebentafusp, a first-in-class bi-specific fusion protein therapy, has demonstrated a significant overall survival benefit in patients with uveal melanoma compared to standard treatment options, marking a promising advancement in this challenging cancer type.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Review of bi-specific therapies in uveal melanoma. Orloff, M., Seedor, R., Sato, T.[2023]

Current adjuvant therapies for uveal melanoma have not been effective in preventing metastasis, highlighting the need for new treatment strategies.

New approaches are focusing on using genetic criteria to tailor immunotherapy and targeted treatments for patients at risk, with ongoing clinical trials exploring these innovative therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adjuvant Therapy of Uveal Melanoma: Current Status. Triozzi, PL., Singh, AD.[2022]

Uveal melanoma, the most common eye cancer in adults, has a significant risk of metastasis, with up to 50% of patients developing metastases within 15 years after treatment of the primary tumor.

Current systemic therapies for uveal melanoma have limited efficacy, but ongoing research is exploring new candidate drugs, including bortezomib and MEK inhibitors, to improve treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New therapeutic agents in uveal melanoma. Velho, TR., Kapiteijn, E., Jager, MJ.[2012]

Tebentafusp demonstrated a significantly higher median overall survival (mOS) of 22.4 months compared to combined immune checkpoint blockade (ICB) which had an mOS of 15.7 months, based on a systematic review of 55 studies involving 2,682 patients.

While the median progression-free survival (mPFS) was similar across treatment groups, tebentafusp showed a strong advantage in overall survival, with population-adjusted hazard ratios indicating it is more effective than combined ICB in extending patient survival.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Is tebentafusp superior to combined immune checkpoint blockade and other systemic treatments in metastatic uveal melanoma? A comparative efficacy analysis with population adjustment. Petzold, A., Steeb, T., Wessely, A., et al.[2023]

A study involving 12 patients showed that a single intravitreal injection of ziv-aflibercept for treating choroidal neovascularization due to age-related macular degeneration was safe, with no serious ocular or systemic adverse events reported after 30 days.

While there was only a slight improvement in best-corrected visual acuity after treatment, the absence of significant side effects suggests that ziv-aflibercept could be a viable low-cost alternative for macular disease therapy, especially in resource-limited settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

SHORT-TERM SAFETY PROFILE OF INTRAVITREAL ZIV-AFLIBERCEPT. Chhablani, J., Narayanan, R., Mathai, A., et al.[2022]

In a study of 60 patients receiving an average of 8.4 intravitreal injections of ziv-aflibercept over a mean follow-up of 9.2 months, significant improvements in best-corrected visual acuity (BCVA) and reductions in central macular thickness (CMT) were observed, indicating the treatment's efficacy for retinal disease.

The treatment was found to be safe, with no significant increases in intraocular pressure, no progression of lens opacities, and only one case of mild transient iritis, suggesting that repeated injections of ziv-aflibercept are well-tolerated.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term safety and efficacy of ziv-aflibercept in retinal diseases. Mansour, AM., Ashraf, M., Dedhia, CJ., et al.[2022]

Ziv-aflibercept is a recombinant fusion protein effective in treating metastatic colorectal carcinoma and shows promise for off-label use in chorioretinal vascular conditions, supported by extensive clinical data.

Studies indicate that ziv-aflibercept is safe and effective, with no significant differences in outcomes between lower and higher doses, making it a cost-effective anti-VEGF treatment option, particularly beneficial for low- and middle-income countries.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ziv-aflibercept: A cost-effective, off-label, highly potent antagonist of vascular endothelial growth factor. Mansour, AM., Stewart, MW., Farah, ME., et al.[2023]

In a study involving 21 eyes from 20 patients, single intravitreal injections of 2 mg ziv-aflibercept were found to be safe, with no reports of worsening vision, pain, or intraocular inflammation after the procedure.

While there were no significant changes in best-corrected visual acuity, the treatment led to a significant reduction in central subfield thickness of the macula, indicating potential efficacy in managing choroidal neovascular membranes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

SHORT-TERM SAFETY OF 2 MG INTRAVITREAL ZIV-AFLIBERCEPT. Chhablani, J., Dedhia, CJ., Peguda, HK., et al.[2022]

In a study of 6 patients with macular edema due to central retinal vein occlusion, treatment with intravitreal ziv-aflibercept led to significant improvements in visual acuity and reductions in central macular thickness over 12 months.

No safety issues were reported, such as uveitis or cataract progression, suggesting that ziv-aflibercept is a safe and effective treatment option, especially in resource-limited settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

One-year outcomes of ziv-aflibercept for macular edema in central retinal vein occlusion. Eldeeb, M., Chan, EW., Dedhia, CJ., et al.[2022]

In a phase 3 trial involving 378 patients with metastatic uveal melanoma, treatment with tebentafusp led to a significant increase in overall survival at 1 year (73%) compared to the control group (59%), demonstrating its efficacy as a new treatment option.

Tebentafusp was associated with manageable treatment-related adverse events, primarily cytokine-mediated and skin-related, which decreased in severity after initial doses, indicating a favorable safety profile with no treatment-related deaths reported.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Overall Survival Benefit with Tebentafusp in Metastatic Uveal Melanoma. Nathan, P., Hassel, JC., Rutkowski, P., et al.[2022]

Ziv-aflibercept, an analogue of aflibercept, has shown a similar safety profile to existing treatments for neovascular age-related macular degeneration (nAMD), effectively maintaining or improving best-corrected visual acuity (BCVA) and reducing retinal fluid and central foveal thickness (CFT).

Clinical trials indicate that ziv-aflibercept is also effective in treating other neovascular conditions like diabetic macular edema (DME) and retinal vein occlusion (RVO), but further randomized studies are necessary to confirm its efficacy specifically for nAMD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intravitreal Ziv-Aflibercept: A Comprehensive Review. Barmas-Alamdari, D., D'Souza, HS., Kapoor, KG., et al.[2019]

References

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

Combined immune checkpoint blockade for metastatic uveal melanoma: a retrospective, multi-center study. [2023]

2. England pubmed.ncbi.nlm.nih.gov

Review of bi-specific therapies in uveal melanoma. [2023]

3. Switzerland pubmed.ncbi.nlm.nih.gov

Adjuvant Therapy of Uveal Melanoma: Current Status. [2022]

4. Greece pubmed.ncbi.nlm.nih.gov

New therapeutic agents in uveal melanoma. [2012]

5. Netherlands pubmed.ncbi.nlm.nih.gov

Is tebentafusp superior to combined immune checkpoint blockade and other systemic treatments in metastatic uveal melanoma? A comparative efficacy analysis with population adjustment. [2023]

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

SHORT-TERM SAFETY PROFILE OF INTRAVITREAL ZIV-AFLIBERCEPT. [2022]

7. England pubmed.ncbi.nlm.nih.gov

Long-term safety and efficacy of ziv-aflibercept in retinal diseases. [2022]

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

Ziv-aflibercept: A cost-effective, off-label, highly potent antagonist of vascular endothelial growth factor. [2023]

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

SHORT-TERM SAFETY OF 2 MG INTRAVITREAL ZIV-AFLIBERCEPT. [2022]

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

One-year outcomes of ziv-aflibercept for macular edema in central retinal vein occlusion. [2022]

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

Overall Survival Benefit with Tebentafusp in Metastatic Uveal Melanoma. [2022]

12. England pubmed.ncbi.nlm.nih.gov

Intravitreal Ziv-Aflibercept: A Comprehensive Review. [2019]