Combination Immunotherapy + Radiation for Cancer

Overseen By Alexis Mark, MS, CCRC

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Icahn School of Medicine at Mount Sinai

Must not be taking: Immunosuppressants, Steroids, Monoclonal antibodies, others

Disqualifiers: Immunodeficiency, Active infection, Autoimmune, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 3

56 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial investigates a combination of treatments to determine their effectiveness in fighting cancer. It includes low-dose radiation, two immune-boosting factors, and pembrolizumab, an immunotherapy drug already used for some cancers. The goal is to enhance the immune system's ability to target and destroy cancer cells. Suitable candidates have certain types of lymphoma, metastatic breast cancer, or head and neck cancer that do not require urgent treatment. As a Phase 1/Phase 2 trial, the research aims to understand how the treatment works in people and measure its effectiveness in an initial group, offering participants a chance to contribute to important cancer research.

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

The trial protocol does not specify if you need to stop your current medications. However, you cannot participate if you are on systemic steroid therapy or other immunosuppressive therapy within 7 days before the trial, or if you've had certain treatments like chemotherapy or radiotherapy recently. 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 has shown that the combination of Flt3L, Poly-ICLC, and Pembrolizumab is generally well-tolerated. Over 600 healthy volunteers and cancer patients have received doses of Poly-ICLC similar to those in this study, with excellent safety records reported. Poly-ICLC activates immune cells without causing major side effects.

For Flt3L, studies indicate it safely increases the number of immune cells, which is important for fighting cancer. Pembrolizumab, an antibody approved by the FDA for several cancers, is also part of this combination. It has been shown to be safe, though it may cause some side effects, which are usually manageable.

Overall, past research has demonstrated good safety for these treatments together. However, like any treatment, some side effects might occur. Discuss any concerns with the clinical trial team. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about this combination treatment for cancer because it brings together multiple innovative approaches. Unlike standard cancer treatments that often rely solely on chemotherapy or radiation, this therapy uses a combination of Flt3L, an immune system booster, Pembrolizumab, an immune checkpoint inhibitor, and Poly ICLC, a vaccine adjuvant, all alongside radiation. This unique mix aims to enhance the body’s immune response to target and destroy cancer cells more effectively. By activating different aspects of the immune system, this combination has the potential to improve outcomes for patients in ways that traditional treatments might not.

What evidence suggests that this trial's combination therapies could be effective for cancer?

Research has shown that each component of the combination therapy in this trial has potential in treating cancer. Participants will receive a combination of Flt3L, Pembrolizumab, Poly ICLC, and Radiation. Flt3L, a growth factor, increases immune cells, which are crucial for attacking cancer cells. Studies on Pembrolizumab, an antibody, have demonstrated its long-term effectiveness in treating several cancers, with survival rates reaching up to 22% in some cases. Poly ICLC strengthens the immune system, enhancing the body's response to tumors by increasing key immune cells. Together, these treatments aim to boost the body's natural defenses to fight cancer more effectively. ^{4 6 7 8 9}

Who Is on the Research Team?

Joshua Brody

Principal Investigator

Icahn School of Medicine at Mount Sinai

Are You a Good Fit for This Trial?

This trial is for adults with certain cancers like lymphoma, breast cancer, and head & neck cancer. It's not for those who've had recent cancer treatment or have active infections, autoimmune diseases needing treatment in the past year, known psychiatric/substance abuse issues that could affect participation, are pregnant/breastfeeding, or have untreated brain metastases.

Inclusion Criteria

My cancer is either iNHL, MBC, or HNSCC.

My lymphoma type is small lymphocytic.

Exclusion Criteria

I am not allergic to pembrolizumab, poly-ICLC, Flt3L, or their ingredients.

You have a current, active infection of Hepatitis B or Hepatitis C.

I haven't had cancer treatment with monoclonal antibodies in the last 28 days or have recovered from their side effects.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase 1 Treatment

Preliminary safety assessment with a modified 3 + 3 design to assess toxicity of the combination therapy

63 days

Multiple visits for treatment and monitoring

Phase 2 Treatment

Simon’s two-stage design to evaluate efficacy and safety in disease-specific cohorts

6 months

Regular visits for treatment and assessment

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 months

Imaging at 3-month intervals

What Are the Treatments Tested in This Trial?

Interventions

• Flt3L
• Pembrolizumab
• Poly ICLC
• Radiation

Trial Overview The trial tests a combo of low-dose radiation to shrink tumors and three drugs: Flt3L to boost immune cells; Poly-ICLC to activate them; Pembrolizumab (an FDA-approved antibody) via IV to help the immune system fight the tumor. The goal is seeing if this mix can better target and kill cancer cells.

How Is the Trial Designed?

Group I: Combination therapy Experimental Treatment 4 Interventions

Vaccination with Flt3L, Radiation, and Poly ICLC combined with Pembrolizumab

Who Is Running the Clinical Trial?

Icahn School of Medicine at Mount Sinai

Lead Sponsor

Trials

933

Recruited

579,000+

Merck Sharp & Dohme LLC

Industry Sponsor

Trials

4,096

Recruited

5,232,000+

Chirfi Guindo

Merck Sharp & Dohme LLC

Chief Marketing Officer since 2022

Degree in Engineering from Ecole Centrale de Paris, MBA from New York University Stern School of Business

Robert M. Davis

Merck Sharp & Dohme LLC

Chief Executive Officer since 2021

JD from Northwestern University Pritzker School of Law, MBA from Northwestern University Kellogg Graduate School of Management, Bachelor's in Finance from Miami University

Celldex Therapeutics

Industry Sponsor

Trials

66

Recruited

5,900+

Anthony S. Marucci

Celldex Therapeutics

Chief Executive Officer since 2008

MBA from Columbia University, MHL from Brown University

Diane C. Young

Celldex Therapeutics

Chief Medical Officer since 2019

MD from Harvard Medical School, AB in Biochemical Sciences from Harvard University

Published Research Related to This Trial

Pembrolizumab is a monoclonal antibody that blocks the PD-1/PD-L1 interaction, which is crucial for preventing the immune system from attacking tumors, making it a key player in cancer immunotherapy.

It has been approved by the FDA for treating patients with advanced melanoma who have not responded to previous treatments, highlighting its efficacy in managing difficult cases of this aggressive cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New developments in the management of advanced melanoma - role of pembrolizumab. Improta, G., Leone, I., Donia, M., et al.[2020]

The combination of AMG 820 and pembrolizumab was found to have an acceptable safety profile, with 99.1% of patients experiencing adverse events, primarily grade ≥3, but only a small number of patients (3%) showed a partial response to treatment.

Despite some pharmacodynamic effects observed, such as increased PD-L1 expression and changes in immune cell populations, the combination did not demonstrate sufficient antitumor activity to warrant further investigation in the selected patient populations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of AMG 820, an anti-colony-stimulating factor 1 receptor antibody, in combination with pembrolizumab in adults with advanced solid tumors. Razak, AR., Cleary, JM., Moreno, V., et al.[2021]

Pembrolizumab, an immune checkpoint inhibitor, can cause pneumonitis in 1%-5% of patients, and this case report highlights an atypical presentation of this side effect in a patient with metastatic squamous cell carcinoma.

The patient was successfully treated with steroid therapy after ruling out other potential causes, leading to complete resolution of the pneumonitis, emphasizing the importance of recognizing and managing atypical cases of checkpoint inhibitor-pneumonitis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recurrent and atypical immune checkpoint inhibitor-induced pneumonitis. Jeon, WJ., Nguyen, J., Castillo, DR., et al.[2023]

Pembrolizumab, a PD-1 inhibitor used in cancer treatment, can lead to rare but serious immune-related adverse events, including type 1 diabetes mellitus, occurring in about 0.2% of cases.

A review of 42 cases revealed that patients may develop diabetic ketoacidosis during treatment, highlighting the need for blood glucose monitoring and awareness of this potential side effect among clinicians.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Programmed Cell Death-1 Inhibitor-Induced Type 1 Diabetes Mellitus. Clotman, K., Janssens, K., Specenier, P., et al.[2022]

In a phase 1b study involving 28 patients with myelodysplastic syndromes (MDS) resistant to hypomethylating agents, pembrolizumab demonstrated manageable safety, with 36% experiencing treatment-related adverse events, but no patients achieved a complete or partial response.

Despite the lack of significant tumor response, 19% of patients showed a complete response in bone marrow, and the median overall survival was 6 months, indicating some clinical activity in this challenging patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab for myelodysplastic syndromes after failure of hypomethylating agents in the phase 1b KEYNOTE-013 study. Garcia-Manero, G., Ribrag, V., Zhang, Y., et al.[2022]

Pembrolizumab (KEYTRUDA) was approved by the FDA for treating advanced melanoma, showing an overall response rate of 24% in a trial of 89 patients, with 86% of responses lasting at least 6 months.

While there are potential immune-mediated side effects, the benefits of prolonged tumor response durations were deemed to outweigh these risks, marking an improvement over existing treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Accelerated Approval of Pembrolizumab for Second-Line Treatment of Metastatic Melanoma. Chuk, MK., Chang, JT., Theoret, MR., et al.[2021]

Pembrolizumab, an immune checkpoint inhibitor, has been approved for treating relapsed MSI-H endometrial cancer after chemotherapy, showing promise in restoring anti-tumor immunity by blocking PD-1 interactions.

Despite encouraging response rates in MSI-H patients, over 50% do not respond to pembrolizumab, highlighting the need for better understanding of MSI status and identifying specific patient populations that may benefit from treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab as a single agent for patients with MSI-H advanced endometrial carcinoma. Turinetto, M., Lombardo, V., Pisano, C., et al.[2022]

Pembrolizumab is a monoclonal antibody that effectively blocks the PD-1 receptor on T cells, enhancing their ability to attack cancer cells, particularly in melanoma patients.

In a Phase I study involving 411 patients, pembrolizumab demonstrated high durable response rates with minimal toxicity, indicating its potential as a safe and effective treatment option for melanoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab joins the anti-PD-1 armamentarium in the treatment of melanoma. Hersey, P., Gowrishankar, K.[2017]

Pembrolizumab, an immunotherapy targeting PD-1, showed limited effectiveness in a patient with metastatic renal cell carcinoma, highlighting that only 20-40% of patients benefit from such treatments due to individual tumor biology and immune checkpoint diversity.

The patient's rapid disease progression during treatment may be linked to a lack of tumor-infiltrating lymphocytes (TILs) and the specific radiation dose and schedule used, which could affect the tumor microenvironment and the potential synergy with pembrolizumab.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immune biomarkers of treatment failure for a patient on a phase I clinical trial of pembrolizumab plus radiotherapy. Alexander, GS., Palmer, JD., Tuluc, M., et al.[2022]

Pembrolizumab, an immune checkpoint inhibitor, has shown significantly improved overall survival in patients with relapsed and/or metastatic head and neck squamous cell carcinoma compared to the standard EXTREME regimen, indicating a promising shift in treatment options.

This review highlights the importance of understanding the mechanisms of immune checkpoint inhibitors, including their interaction with the immune system and the challenges posed by tumor heterogeneity and PD-L1 expression, which are crucial for optimizing patient selection for treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Potential of Pembrolizumab in Metastatic or Recurrent Head and Neck Cancer: Evidence to Date. McCusker, MG., Orkoulas-Razis, D., Mehra, R.[2020]

This study provides the first clinical evidence that a combination of pembrolizumab and autologous cytokine-induced killer cells can lead to significant improvement in patients with advanced squamous non-small cell lung cancer.

The patient in this case experienced severe thrombocytopenia, highlighting the potential effectiveness of this treatment approach even in challenging clinical situations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rapid Response of Advanced Squamous Non-Small Cell Lung Cancer with Thrombocytopenia after First-Line Treatment with Pembrolizumab Plus Autologous Cytokine-Induced Killer Cells. Hui, Z., Zhang, X., Ren, B., et al.[2018]

Pembrolizumab (Keytruda) effectively blocks the PD-1 pathway, enhancing T-cell activity against tumors, which supports its role in promoting tumor regression and immune rejection.

Preclinical studies in cynomolgus monkeys showed that pembrolizumab has a favorable safety profile with no significant toxicological findings, aligning with its demonstrated safety and efficacy in human clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Biophysical and Immunological Characterization and In Vivo Pharmacokinetics and Toxicology in Nonhuman Primates of the Anti-PD-1 Antibody Pembrolizumab. Hutchins, B., Starling, GC., McCoy, MA., et al.[2021]

The combination of stereotactic body radiotherapy (SBRT) and pembrolizumab (SBRT+P) is safe for patients with large, advanced solid tumors, with only 7.2% experiencing dose-limiting toxicities in a study involving 97 patients.

Patients who showed a positive response to SBRT+P had significantly better overall survival rates, with a 1-year overall survival of 71% for responders, compared to 0% for nonresponders, highlighting the potential efficacy of this treatment approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Partial tumor irradiation plus pembrolizumab in treating large advanced solid tumor metastases. Korpics, MC., Onderdonk, BE., Dadey, RE., et al.[2023]

In a study involving 9 patients with resectable stage IIIA non-small cell lung cancer (NSCLC), the addition of pembrolizumab to neoadjuvant chemotherapy and radiotherapy resulted in a promising 67% overall response rate, with 4 patients achieving a pathologic complete response.

However, the trial faced significant safety concerns, with serious adverse events occurring in 7 patients, including 2 fatal events, leading to the study's closure due to higher-than-expected toxicities.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase 1 Study of Concurrent Neoadjuvant Pembrolizumab Plus Chemoradiation Followed by Consolidation Pembrolizumab in Patients With Resectable Stage IIIA NSCLC. Lemmon, CA., Videtic, GMM., Murthy, S., et al.[2022]

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