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

Trial Summary

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.

What data supports the idea that Combination Immunotherapy + Radiation for Cancer is an effective treatment?

The available research shows that combining immunotherapy with radiation can be effective for treating certain cancers. For example, in a study involving patients with advanced solid tumors, those who received a combination of radiation and the drug pembrolizumab had a higher response rate in irradiated tumors compared to non-irradiated ones. Additionally, the study found that patients who responded to this combination treatment had a better chance of surviving for at least a year. This suggests that the combination of immunotherapy and radiation can improve outcomes for cancer patients compared to some other treatments. ^{1 2 3 4 5}

What safety data exists for the combination of immunotherapy and radiation in cancer treatment?

The safety data for pembrolizumab (Keytruda), a key component of the combination therapy, indicates that while it is effective, it can cause immune-related adverse events (irAEs) such as pneumonitis, colitis, hepatitis, hypophysitis, thyroid disorders, and rare cases of type 1 diabetes mellitus. In clinical trials, pneumonitis occurred in 1%-5% of patients. Common adverse reactions include fatigue, cough, nausea, pruritus, rash, decreased appetite, constipation, arthralgia, and diarrhea. Preclinical studies in nonhuman primates showed no toxicologic findings of significance, suggesting a manageable safety profile. However, in a study on myelodysplastic syndromes, treatment-related adverse events were reported in 36% of patients, with some leading to treatment discontinuation. ^{6 7 8 9 10}

Is the drug Flt3L, Pembrolizumab, Poly ICLC a promising treatment for cancer?

Yes, the drug Pembrolizumab, part of the combination treatment, is promising for cancer. It helps the immune system fight cancer by blocking a protein that stops immune cells from attacking cancer cells. Studies show it works well in treating certain types of cancer, like melanoma and endometrial cancer, especially when combined with other treatments like radiation. ^{2 11 12 13 14}

What is the purpose of this trial?

This is a combination of 4 therapies, three of which are used to treat a single "target site" of your cancer (such as a lymph node or a single tumor), and the 4th is given directly into the blood stream (intravenous or "IV"). 1. Radiation: The target site --lymph node or tumor (the one what will be injected) --will get two small treatments of radiation. Radiation is often times used to shrink and kill tumors in patients with certain types of lymphoma, breast cancer and head and neck cancer, however, the dose of radiation that you will receive --one dose on day one of the clinical trial and one dose on day two --is 10 to 20 time less radiation that you would receive for treatment of these cancers. 2. Flt3L/CDX-301 is an immune cell growth factor, similar to white blood cell growth factors (Neupogen or Neulasta) or red blood cell growth factors (EPO or Epogen) that you may have received to help protect your blood cells previously. Flt3L causes your body to make more immune cells, specifically a type of immune cell called "dendritic cells". 3. Poly-ICLC is an immune cell activating factor. Its function is to turn on the immune cells that have been brought to the tumor by Flt3L. 4. Pembrolizumab is an antibody (a type of human protein) that is being tested to see if it will allow the body's immune system to kill your tumor cells. Pembrolizumab is approved for use by the U.S. Food and Drug Administration (FDA) for the treatment of adult patients with many different types of cancer including head and neck cancer. Pembrolizumab is not FDA approved to treat patients with non-Hodgkin's lymphoma or metastatic breast cancer, as it has not been effective at treating these cancers when used alone. While most people do not have immediate side effects when this medication is given, it has the ability to cause side effects for.

Research Team

Joshua Brody

Principal Investigator

Icahn School of Medicine at Mount Sinai

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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

Findings from Research

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, 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]

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]

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, 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 (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, 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]

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]

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, 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 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]

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]

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]

References

1. England 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. [2021]

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

Pembrolizumab as a single agent for patients with MSI-H advanced endometrial carcinoma. [2022]

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

Partial tumor irradiation plus pembrolizumab in treating large advanced solid tumor metastases. [2023]

4. New Zealand pubmed.ncbi.nlm.nih.gov

Potential of Pembrolizumab in Metastatic or Recurrent Head and Neck Cancer: Evidence to Date. [2020]

5. Switzerland 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. [2018]

6. England pubmed.ncbi.nlm.nih.gov

Recurrent and atypical immune checkpoint inhibitor-induced pneumonitis. [2023]

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

FDA Approval Summary: Accelerated Approval of Pembrolizumab for Second-Line Treatment of Metastatic Melanoma. [2021]

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

Programmed Cell Death-1 Inhibitor-Induced Type 1 Diabetes Mellitus. [2022]

9. United States 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. [2021]

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

Pembrolizumab for myelodysplastic syndromes after failure of hypomethylating agents in the phase 1b KEYNOTE-013 study. [2022]

11. England pubmed.ncbi.nlm.nih.gov

Immune biomarkers of treatment failure for a patient on a phase I clinical trial of pembrolizumab plus radiotherapy. [2022]

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

Pembrolizumab joins the anti-PD-1 armamentarium in the treatment of melanoma. [2017]

13. United States 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. [2022]

14. New Zealand pubmed.ncbi.nlm.nih.gov

New developments in the management of advanced melanoma - role of pembrolizumab. [2020]