Ramucirumab + Pembrolizumab for Head and Neck Cancer

(Rambro2 Trial)

Overseen By Douglas R. Adkins

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Washington University School of Medicine

Must not be taking: Corticosteroids, Antiplatelets, NSAIDs, others

Disqualifiers: PD-L1 negative, CNS metastases, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 3

Duration: 24 months

72 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, if you are on systemic corticosteroids, intense immunosuppressive therapy, or chronic antiplatelet therapy, you may need to adjust or stop these before starting the trial.

What data supports the effectiveness of the drug combination of Ramucirumab and Pembrolizumab for head and neck cancer?

Research shows that Pembrolizumab, one of the drugs in the combination, has been effective in treating head and neck cancer, especially in patients with high levels of PD-L1, a protein that can affect the immune system's ability to fight cancer. It has shown good tumor response and manageable side effects in several studies. ^{1 2 3 4 5}

Is the combination of Ramucirumab and Pembrolizumab safe for humans?

Pembrolizumab has been studied for head and neck cancer, showing some serious side effects like pneumonia, breathing problems, confusion, and immune system-related issues like inflammation of the lungs, liver, and thyroid problems. The safety of Ramucirumab in combination with Pembrolizumab specifically hasn't been detailed, but Pembrolizumab alone has a manageable safety profile in the context of head and neck cancer. ^{3 6 7 8 9}

How is the drug combination of Ramucirumab and Pembrolizumab unique for treating head and neck cancer?

The combination of Ramucirumab and Pembrolizumab is unique because it pairs an immune checkpoint inhibitor (Pembrolizumab) that helps the immune system attack cancer cells with another drug (Ramucirumab) that targets blood vessels feeding the tumor, potentially enhancing the overall anti-cancer effect. ^{1 2 6 10 11}

What is the purpose of this trial?

This is a phase 2 study investigating the efficacy of ramucirumab in combination with pembrolizumab compared to pembrolizumab monotherapy. Ramucirumab is a VEGFR-2 inhibitor believed to potentially enhance the efficacy of PD-1 inhibitors such as pembrolizumab.

Research Team

Douglas R. Adkins

Principal Investigator

Washington University School of Medicine

Eligibility Criteria

Adults with PD-L1 positive head and neck squamous-cell carcinoma, who haven't had systemic therapy for recurrent/metastatic cancer. They must have measurable disease, be in good physical condition (ECOG 0-1), have normal organ/blood function, agree to use contraception, and not be pregnant or breastfeeding. Excluded are those with negative PD-L1 status, recent surgeries or significant bleeding events, other cancers within a year (except certain skin cancers), serious illnesses or uncontrolled hypertension.

Inclusion Criteria

I am fully active or can carry out light work.

My kidney function, measured by creatinine levels, is within the normal range or adequately compensated.

My cancer can be measured by scans or physical exam.

Exclusion Criteria

I am not currently receiving radiation for brain metastases but finished it at least 2 weeks ago.

I haven't taken high doses of steroids or strong immune-weakening drugs in the last week.

My blood pressure has been high (>160/100 mmHg) despite treatment in the last month.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive ramucirumab and pembrolizumab or pembrolizumab monotherapy every 3 weeks for up to 35 cycles

24 months

Every 3 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

5 years

Treatment Details

Interventions

• Pembrolizumab
• Ramucirumab

Trial Overview The trial is testing the combination of Ramucirumab (a VEGFR-2 inhibitor) and Pembrolizumab versus Pembrolizumab alone in treating patients. It's a phase 2 study aimed at seeing if adding Ramucirumab can boost the effectiveness of Pembrolizumab in this type of cancer.

Participant Groups

Group I: Arm 1: Ramucirumab and Pembrolizumab Experimental Treatment 2 Interventions

Patients receive ramucirumab IV and pembrolizumab IV every 3 weeks. Cycles are 21 days in length. Treatment will continue until progression or unacceptable toxicity for up to 35 cycles of treatment.

Group II: Arm 2: Pembrolizumab monotherapy Active Control 1 Intervention

Patients receive pembrolizumab IV every 3 weeks. Cycles are 21 days in length. Treatment will continue until progression or unacceptable toxicity for up to 35 cycles of treatment.

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?

Washington University School of Medicine

Lead Sponsor

Trials

2,027

Recruited

2,353,000+

Eli Lilly and Company

Industry Sponsor

Trials

2,708

Recruited

3,720,000+

Dr. Daniel Skovronsky

Eli Lilly and Company

Chief Medical Officer since 2018

MD from Harvard Medical School

David A. Ricks

Eli Lilly and Company

Chief Executive Officer since 2017

BSc from Purdue University, MBA from Indiana University

Findings from Research

In a study involving 133 patients with locally advanced squamous cell carcinoma of the head and neck, pembrolizumab combined with radiotherapy did not show a significant improvement in locoregional control or survival compared to the standard treatment of cetuximab with radiotherapy.

However, patients receiving pembrolizumab experienced significantly lower toxicity, with only 74% reporting severe adverse events compared to 92% in the cetuximab group, suggesting it may be a safer option for patients unfit for high-dose cisplatin.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab versus cetuximab concurrent with radiotherapy in patients with locally advanced squamous cell carcinoma of head and neck unfit for cisplatin (GORTEC 2015-01 PembroRad): a multicenter, randomized, phase II trial. Tao, Y., Biau, J., Sun, XS., et al.[2023]

In a study of 38 patients with p16+ oropharyngeal squamous cell carcinoma, there was a 76% agreement in PD-L1 combined positive scores (CPS) between primary tumors and lymph node metastases, indicating variability in scoring between these specimens.

The interobserver agreement for CPS scoring was fair to substantial, suggesting that additional evaluations may be necessary to ensure accurate scoring, especially for patients who might benefit from immunotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Programmed Death Ligand-1 Combined Positive Score Concordance and Interrater Reliability in Primary Tumors and Synchronous Lymph Node Metastases in Resected Cases of p16+ Oropharyngeal Squamous Cell Carcinoma. Kaur, A., Kuchta, K., Watkin, W., et al.[2023]

In a phase 3 study involving 495 patients with recurrent or metastatic head-and-neck squamous cell carcinoma, pembrolizumab demonstrated a median overall survival of 8.4 months, compared to 6.9 months for standard-of-care treatments, indicating a significant improvement in survival rates.

Pembrolizumab was associated with fewer severe treatment-related adverse events (13%) compared to standard-of-care therapies (36%), suggesting a better safety profile for patients receiving pembrolizumab.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab versus methotrexate, docetaxel, or cetuximab for recurrent or metastatic head-and-neck squamous cell carcinoma (KEYNOTE-040): a randomised, open-label, phase 3 study. Cohen, EEW., Soulières, D., Le Tourneau, C., et al.[2019]

In a phase III trial, pembrolizumab, a single-agent treatment, showed significant effectiveness in patients with head and neck tumors that had high PD-L1 expression, leading to deep and lasting responses.

This study highlights the potential of pembrolizumab as a first-line therapy for this specific group of cancer patients, suggesting a targeted approach based on PD-L1 levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembro Ups Survival in PD-L1-positive HNSCC. [2019]

In a study with 882 patients over a median follow-up of 45 months, pembrolizumab and pembrolizumab-chemotherapy showed significant improvements in overall survival compared to cetuximab-chemotherapy for recurrent/metastatic head and neck squamous cell carcinoma, particularly in patients with high PD-L1 expression (CPS ≥ 20).

The analysis also indicated that patients who received pembrolizumab-based therapies had favorable outcomes in subsequent treatments, with improved progression-free survival on next-line therapies, highlighting the long-term efficacy of pembrolizumab in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab With or Without Chemotherapy in Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma: Updated Results of the Phase III KEYNOTE-048 Study. Harrington, KJ., Burtness, B., Greil, R., et al.[2023]

Pembrolizumab (KEYTRUDA) received accelerated FDA approval for treating recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) based on a study of 174 patients, showing an objective response rate of 16% and a duration of response ranging from 2.4 to 27.7 months.

The safety profile included serious adverse reactions such as pneumonia and respiratory failure, but the overall benefit-risk assessment was deemed acceptable, marking pembrolizumab as the first new treatment option for HNSCC since 2006.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Pembrolizumab for the Treatment of Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma with Disease Progression on or After Platinum-Containing Chemotherapy. Larkins, E., Blumenthal, GM., Yuan, W., et al.[2019]

Pembrolizumab, an immune checkpoint inhibitor, has been approved by the FDA for treating platinum-refractory recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC), offering a new option with potentially improved efficacy compared to traditional chemotherapy and EGFR inhibitors.

This review discusses the pharmacology and tolerability of pembrolizumab, emphasizing its mechanism of action by blocking the PD-1 receptor, which may enhance the immune response against HNSCC tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab and its use in the treatment of recurrent or metastatic head and neck cancer. Sheth, S., Weiss, J.[2019]

In a study of 167 patients with recurrent/metastatic squamous cell carcinoma of the head and neck treated with pembrolizumab, the median overall survival was 22.7 months and progression-free survival was 5.1 months for those receiving pembrolizumab alone, indicating significant efficacy.

The presence of immune-related adverse events (irAEs) was associated with better progression-free survival, suggesting that these side effects may serve as important prognostic factors in treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of Pembrolizumab in Recurrent/Metastatic Squamous Cell Head and Neck Carcinoma: A Multicenter Retrospective Study. Okada, T., Fushimi, C., Matsuki, T., et al.[2023]

In a phase 1b trial involving 60 patients with recurrent or metastatic squamous cell carcinoma of the head and neck, pembrolizumab was found to be well tolerated, with only 17% experiencing severe drug-related adverse events and no drug-related deaths.

The treatment showed clinically meaningful antitumor activity, with an overall response rate of 18%, and particularly higher in HPV-positive patients at 25%, indicating its potential as a viable therapy for advanced head and neck cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and clinical activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-012): an open-label, multicentre, phase 1b trial. Seiwert, TY., Burtness, B., Mehra, R., et al.[2022]

In a phase IB study involving 59 patients with locally advanced head and neck squamous cell carcinoma, the combination of pembrolizumab with cisplatin-based chemoradiotherapy was found to be safe, with a high completion rate of treatment and only 8.8% of patients experiencing immune-related adverse events.

The treatment showed promising efficacy, with complete response rates of 85.3% for HPV-positive and 78.3% for HPV-negative patients, suggesting that this combination warrants further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and Efficacy of Pembrolizumab With Chemoradiotherapy in Locally Advanced Head and Neck Squamous Cell Carcinoma: A Phase IB Study. Powell, SF., Gold, KA., Gitau, MM., et al.[2022]

The Phase III trial KEYNOTE-412 is designed to evaluate the efficacy and safety of pembrolizumab, an immune checkpoint inhibitor, when used alongside chemoradiation therapy (CRT) in patients with locally advanced head and neck squamous cell carcinoma (HNSCC).

Previous Phase Ib studies have indicated that combining pembrolizumab with CRT is safe and feasible, supporting its potential use in this larger trial to improve treatment outcomes for patients with locally advanced HNSCC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab given concomitantly with chemoradiation and as maintenance therapy for locally advanced head and neck squamous cell carcinoma: KEYNOTE-412. Machiels, JP., Tao, Y., Burtness, B., et al.[2021]

References

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

Pembrolizumab versus cetuximab concurrent with radiotherapy in patients with locally advanced squamous cell carcinoma of head and neck unfit for cisplatin (GORTEC 2015-01 PembroRad): a multicenter, randomized, phase II trial. [2023]

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

Programmed Death Ligand-1 Combined Positive Score Concordance and Interrater Reliability in Primary Tumors and Synchronous Lymph Node Metastases in Resected Cases of p16+ Oropharyngeal Squamous Cell Carcinoma. [2023]

3. England pubmed.ncbi.nlm.nih.gov

Pembrolizumab versus methotrexate, docetaxel, or cetuximab for recurrent or metastatic head-and-neck squamous cell carcinoma (KEYNOTE-040): a randomised, open-label, phase 3 study. [2019]

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

Pembro Ups Survival in PD-L1-positive HNSCC. [2019]

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

Pembrolizumab With or Without Chemotherapy in Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma: Updated Results of the Phase III KEYNOTE-048 Study. [2023]

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

FDA Approval Summary: Pembrolizumab for the Treatment of Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma with Disease Progression on or After Platinum-Containing Chemotherapy. [2019]

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

Pembrolizumab and its use in the treatment of recurrent or metastatic head and neck cancer. [2019]

8. Greece pubmed.ncbi.nlm.nih.gov

Effects of Pembrolizumab in Recurrent/Metastatic Squamous Cell Head and Neck Carcinoma: A Multicenter Retrospective Study. [2023]

9. England pubmed.ncbi.nlm.nih.gov

Safety and clinical activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-012): an open-label, multicentre, phase 1b trial. [2022]

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

Safety and Efficacy of Pembrolizumab With Chemoradiotherapy in Locally Advanced Head and Neck Squamous Cell Carcinoma: A Phase IB Study. [2022]

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

Pembrolizumab given concomitantly with chemoradiation and as maintenance therapy for locally advanced head and neck squamous cell carcinoma: KEYNOTE-412. [2021]