Ziv-aflibercept + Pembrolizumab for Cancer

Not currently 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores new ways to treat advanced solid tumors that may have spread. Researchers are testing two drugs, ziv-aflibercept (an anti-cancer medication) and pembrolizumab (an immunotherapy drug), to assess their effectiveness in shrinking tumors and enhancing the immune system's ability to fight cancer. The trial seeks participants with specific types of cancer, including melanoma, renal cell carcinoma, ovarian cancer, colorectal cancer, or sarcoma, who have experienced resistance to certain treatments and have measurable disease. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new combination therapy.

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

Research shows that the combination of ziv-aflibercept and pembrolizumab is generally well-tolerated. Studies with patients who have advanced solid tumors indicate that this combination has an acceptable safety profile, meaning most people do not experience severe side effects.

Common side effects include fatigue, nausea, and changes in blood pressure, but these effects are often manageable. Both ziv-aflibercept and pembrolizumab are already used in other treatments, and their individual safety is well understood, adding confidence to their combined use.

In summary, existing research suggests that this treatment combination is safe for humans, with manageable side effects. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of ziv-aflibercept and pembrolizumab for cancer treatment because it offers a unique approach compared to current options. Most cancer treatments focus on either inhibiting cancer growth or boosting the immune system. Ziv-aflibercept blocks blood vessel growth that tumors need to thrive, while pembrolizumab enhances the immune system's ability to detect and destroy cancer cells. This dual action not only targets the cancer directly but also empowers the body’s natural defenses, potentially leading to more effective and longer-lasting results.

What evidence suggests that this trial's treatments could be effective for advanced solid tumors?

Research has shown that combining ziv-aflibercept and pembrolizumab may help treat advanced solid tumors. Ziv-aflibercept stops the blood supply to tumors, potentially shrinking them. Pembrolizumab boosts the immune system to attack cancer cells. Studies have found that this combination can effectively fight tumors. Participants in this trial will receive both ziv-aflibercept and pembrolizumab. Patients in earlier studies experienced manageable side effects and some positive results, suggesting this treatment could be effective. ^{1 2 3 4 6}

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

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]

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]

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]

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]

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]

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]

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]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38236249/

Ziv-aflibercept plus pembrolizumab in patients with advanced ... This study investigated the combination of ziv-aflibercept anti-angiogenic therapy with pembrolizumab in patients with advanced melanoma resistant to anti-PD-1 ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT02298959

Testing the PD-1 Antibody, MK3475, Given With Ziv- ... 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 ...

3. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/35264434/

Phase IB study of ziv-aflibercept plus pembrolizumab in ... The combination of ziv-aflibercept and pembrolizumab demonstrated an acceptable safety profile with antitumor activity in solid tumors.

4. jitc.bmj.com jitc.bmj.com/content/10/3/e003569

Phase IB study of ziv-aflibercept plus pembrolizumab in ... The combination of ziv-aflibercept and pembrolizumab demonstrated an acceptable safety profile with antitumor activity in solid tumors.

5. link.springer.com link.springer.com/article/10.1007/s00262-023-03593-2

Ziv-aflibercept plus pembrolizumab in patients with ... We previously reported favorable clinical outcomes in patients with a number of solid tumors who were treated with ziv-aflibercept (at 2–4 mg/kg) ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT00357760

Ziv-Aflibercept in Treating Patients With Metastatic or ... This randomized phase II trial studies how well ziv-aflibercept (VEGF Trap) works in treating patients with kidney cancer that has spread from the primary ...