Ziv-aflibercept + Pembrolizumab for Cancer

Recruiting at 8 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: National Cancer Institute (NCI)

Must not be taking: Immunosuppressants, Steroids

Disqualifiers: Immunodeficiency, Active autoimmune, Brain 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: Unknown

Duration: Up to 2 years

78 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This phase I trial studies the side effects and best dose of ziv-aflibercept when given together with pembrolizumab in treating patients with solid tumors that that may have spread from where it first started to nearby tissue, lymph nodes, or distant parts of the body (advanced). Ziv-afibercept works by decreasing blood and nutrient supply to the tumor, which may result in shrinking the tumor. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving ziv-aflibercept together with pembrolizumab may be a better treatment for patients with advanced solid tumors.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot participate if you have had chemotherapy, targeted therapy, or radiotherapy within 4 weeks before the study, or if you are on certain immunosuppressive therapies. It's best to discuss your specific medications with the trial team.

Is the combination of Ziv-aflibercept and Pembrolizumab safe for humans?

Pembrolizumab (also known as KEYTRUDA) has been shown to be generally safe in humans, with common side effects including tiredness, rash, itching, and diarrhea. Ziv-aflibercept (also known as Zaltrap) has been used safely in combination with other treatments for cancer, but it can increase some chemotherapy-related side effects. Both drugs have been tested in various conditions, showing a favorable safety profile. ^{1 2 3 4 5}

What makes the drug combination of Ziv-aflibercept and Pembrolizumab unique for cancer treatment?

This drug combination is unique because it combines Ziv-aflibercept, which inhibits blood vessel growth in tumors, with Pembrolizumab, an immune checkpoint inhibitor that helps the immune system attack cancer cells. This dual approach targets both the tumor's blood supply and enhances the body's immune response against cancer. ^{2 6 7 8 9}

What data supports the effectiveness of the drug combination Ziv-aflibercept and Pembrolizumab for cancer?

Pembrolizumab has shown effectiveness in treating non-small cell lung cancer by helping the immune system attack cancer cells. Ziv-aflibercept has been effective in improving survival in patients with metastatic colorectal cancer when used with other chemotherapy drugs. ^{1 6 8 10 11}

Who Is on the Research Team?

Frank S Hodi

Principal Investigator

Dana-Farber - Harvard Cancer Center LAO

Are You a Good Fit for This Trial?

Adults with advanced solid tumors, specifically melanoma, renal cancer, ovarian cancer or colorectal cancer that's spread and is resistant to certain treatments. Participants must have adequate organ function, no more than two prior therapies for metastatic disease, and not be pregnant or breastfeeding. They should agree to use contraception and not have a history of severe autoimmune diseases or other conditions that could interfere with the trial.

Inclusion Criteria

Ability to understand and the willingness to sign a written informed consent document

Your hemoglobin level is at least 9 g/dL or 5.6 mmol/L.

My cancer is resistant to PD-1 treatment.

Exclusion Criteria

I haven't had severe GI bleeding or uncontrollable blood clot issues in the last 3 months.

I have a history of cancer.

I am on a full dose of Coumadin for blood thinning.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive pembrolizumab and ziv-aflibercept intravenously. Cycles repeat every 2 weeks for up to 2 years in the absence of disease progression or unacceptable toxicity.

Up to 2 years

Bi-weekly visits for drug administration

Follow-up

Participants are monitored for safety and effectiveness after treatment completion, including CT scans, MRIs, blood sample collection, and tumor biopsy.

12 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Pembrolizumab
• Ziv-Aflibercept

Trial Overview The trial is testing the combination of ziv-aflibercept (which cuts off blood supply to tumors) with pembrolizumab (an immunotherapy drug). It aims to find the safest dose while observing how well this combo works against advanced cancers by leveraging the body's immune system.

How Is the Trial Designed?

Group I: Treatment (pembrolizumab and ziv-aflibercept) Experimental Treatment 6 Interventions

Patients receive pembrolizumab intravenously (IV) over approximately 30 minutes and ziv-aflibercept IV over 1-2 hours on day 1. Cycles repeat every 2 weeks for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan, MRI, blood sample collection and tumor biopsy throughout the study.

Pembrolizumab is already approved in United States, European Union, United Kingdom for the following indications:

Approved in United States as KEYTRUDA for:

• Head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1
• Melanoma
• Non-small cell lung cancer (NSCLC)
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Hepatocellular carcinoma
• Renal cell carcinoma
• Cervical cancer
• Endometrial carcinoma

Approved in European Union as KEYTRUDA for:

• Head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1
• Melanoma
• Non-small cell lung cancer (NSCLC)
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Hepatocellular carcinoma
• Renal cell carcinoma
• Cervical cancer
• Endometrial carcinoma

Approved in United Kingdom as KEYTRUDA for:

• Untreated metastatic or unresectable recurrent head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1

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

Aflibercept combined with FOLFIRI significantly improved overall survival in patients with metastatic colorectal cancer (mCRC) previously treated with oxaliplatin, showing median survival of 12.5 months compared to 11.7 months with placebo.

The treatment effect of aflibercept was consistent across various patient subgroups, including those with or without prior bevacizumab treatment, indicating its broad efficacy in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Aflibercept versus placebo in combination with fluorouracil, leucovorin and irinotecan in the treatment of previously treated metastatic colorectal cancer: prespecified subgroup analyses from the VELOUR trial. Tabernero, J., Van Cutsem, E., Lakomý, R., et al.[2022]

In a phase II trial involving 15 patients with resectable non-small cell lung cancer (NSCLC), neoadjuvant treatment with pembrolizumab showed a major pathologic response in 27% of patients, indicating promising antitumor activity before surgery.

The treatment was found to be feasible and safe, with only 33% of patients experiencing moderate adverse events, and no postoperative mortality, suggesting that pembrolizumab does not compromise surgical outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant anti-programmed death-1 immunotherapy by pembrolizumab in resectable non-small cell lung cancer: First clinical experience. Eichhorn, F., Klotz, LV., Kriegsmann, M., et al.[2022]

Intravitreal injections of ziv-aflibercept (IVI-ZA) over 48 weeks were found to be safe, with no significant changes in electroretinogram results or any systemic or ocular complications in the seven patients with diabetic macular edema (DME).

The treatment led to a significant improvement in best-corrected visual acuity (BCVA) after the first injection, which was maintained throughout the study, and a notable decrease in central retinal thickness (CRT), indicating its efficacy in managing DME.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intravitreal Ziv-Aflibercept for Diabetic Macular Edema: 48-Week Outcomes. de Andrade, GC., de Oliveira Dias, JR., Maia, A., et al.[2019]

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]

Aflibercept, an anti-angiogenic drug, was approved in Europe for use with FOLFIRI in adults with metastatic colorectal cancer that has progressed after oxaliplatin treatment, showing improved overall survival (13.5 months vs 12.06 months) in the VELOUR Phase III trial.

While aflibercept enhances survival rates, it also increases the risk of specific side effects related to anti-VEGF therapy and some chemotherapy-related toxicities, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Aflibercept (Zaltrap(®)) approved in metastatic colorectal cancer]. André, T., Chibaudel, B.[2013]

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]

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 of 26 patients with refractory diabetic macular edema (DME), ziv-aflibercept treatment led to significant improvements in visual acuity and macular thickness after switching from previous anti-VEGF therapies.

No adverse ocular or systemic side effects were reported, indicating that ziv-aflibercept is a safe option for patients who did not respond to other treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and Efficacy of Ziv-Aflibercept in the Treatment of Refractory Diabetic Macular Edema. Ashraf, M., Kayal, HE., Souka, AAR.[2022]

Citations

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

Evaluation of efficacy and safety markers in a phase II study of metastatic colorectal cancer treated with aflibercept in the first-line setting. [2022]

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

Ziv-aflibercept: a novel angiogenesis inhibitor for the treatment of metastatic colorectal cancer. [2022]

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

Aflibercept and Docetaxel versus Docetaxel alone after platinum failure in patients with advanced or metastatic non-small-cell lung cancer: a randomized, controlled phase III trial. [2022]

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

Aflibercept versus placebo in combination with fluorouracil, leucovorin and irinotecan in the treatment of previously treated metastatic colorectal cancer: prespecified subgroup analyses from the VELOUR trial. [2022]

5. Ireland pubmed.ncbi.nlm.nih.gov

Neoadjuvant anti-programmed death-1 immunotherapy by pembrolizumab in resectable non-small cell lung cancer: First clinical experience. [2022]

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

Intravitreal Ziv-Aflibercept for Diabetic Macular Edema: 48-Week Outcomes. [2019]

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

Pembrolizumab in the management of metastatic melanoma. [2020]

8. France pubmed.ncbi.nlm.nih.gov

[Aflibercept (Zaltrap(®)) approved in metastatic colorectal cancer]. [2013]

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

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

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

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

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

Safety and Efficacy of Ziv-Aflibercept in the Treatment of Refractory Diabetic Macular Edema. [2022]