Ramucirumab + Pembrolizumab for Head and Neck Cancer

Not currently recruiting at 1 trial location

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Washington University School of Medicine

Must not be taking: Steroids, Immunosuppressants

Disqualifiers: Cirrhosis, Autoimmune diseases, Hypertension, 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: 42

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the safety and effectiveness of combining two treatments, ramucirumab (Cyramza) and pembrolizumab (KEYTRUDA), for head and neck cancer that surgery or radiation cannot cure. Researchers believe that using both drugs together might be more effective than using just one. The trial seeks participants with specific types of head and neck cancer who haven't received certain treatments and cannot undergo surgery or radiation. Participants should have a cancer diagnosis that affects daily life, such as difficulty swallowing or ongoing pain. As a Phase 1, Phase 2 trial, this research aims to understand how the treatment works in people and measure its effectiveness in an initial, smaller group.

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 have had radiation, chemotherapy, or targeted therapy within 14 days of starting the trial, and you should not be on high-dose steroids or other immunosuppressive therapy within 7 days before the first dose of pembrolizumab.

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

Research has shown that using ramucirumab and pembrolizumab together appears safe for patients. One study found no major safety issues with this combination. Previous trials have demonstrated that patients tolerated this mix well. The main goal is to determine the optimal dose of ramucirumab to use with pembrolizumab. Pembrolizumab is already safely used for other conditions, indicating its potential safety in this combination as well. While more studies are ongoing, the combination currently looks promising in terms of safety. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard treatments for head and neck cancer, which often involve chemotherapy and radiation, the combination of Ramucirumab and Pembrolizumab offers a unique approach by targeting specific pathways in the cancer cells. Ramucirumab works by blocking the blood supply that tumors need to grow, while Pembrolizumab boosts the immune system's ability to detect and attack cancer cells. Researchers are excited about this treatment because it combines these two powerful mechanisms, potentially leading to more effective results and fewer side effects compared to traditional therapies.

What evidence suggests that the combination of ramucirumab and pembrolizumab could be an effective treatment for head and neck cancer?

Research has shown that pembrolizumab, when used alone, effectively treats head and neck cancer, particularly in patients with certain markers. In this trial, participants will receive a combination of pembrolizumab and ramucirumab. Combining these treatments might enhance effectiveness. One study showed that this combination led to a 60% overall response rate (ORR) for patients with specific cancer traits, meaning many experienced a reduction in tumor size. These early results suggest that the combination could be more effective than pembrolizumab alone for some patients with head and neck cancer. ^{1 6 7 8 9}

Who Is on the Research Team?

Douglas R Adkins, M.D.

Principal Investigator

Washington University School of Medicine

Are You a Good Fit for This Trial?

This trial is for adults with incurable head and neck squamous cell carcinoma (HNSCC) that can't be treated by surgery or radiation, or if the patient declines such treatments. Participants need to have certain blood counts and organ functions within specific ranges, no severe allergies to study agents, no recent heart attacks or strokes, and must not be pregnant. They should agree to use contraception and have not received certain therapies recently.

Inclusion Criteria

Adequate blood and organ function as defined: Absolute neutrophil count ≥ 1,500/mcL; Platelets ≥ 100,000/mcL; Hemoglobin ≥ 9.0 g/dL; Total bilirubin ≤ 1.5 mg/dL; AST(SGOT) ≤ 3 x institutional upper limit of normal (IULN) and ALT(SGPT) ≤ 3 x IULN. In the setting of liver metastases, AST < 5 x IULN and ALT < 5 x IULN; Creatinine ≤ 2 x ULN OR creatinine clearance ≥ 40 mL/min/1.73 m2; Urine protein to creatinine ratio (UPC) ≤ 1; INR ≤ 1.5 x ULN (≤ 3.0 x ULN if on anticoagulation) and PTT ≤ 1.5 x ULN (<3 x ULN if on anticoagulation); Women of childbearing potential and men must agree to use adequate contraception

Signed IRB approved written informed consent document

I am able to get out of my bed or chair and move around.

Exclusion Criteria

I have had PD-1 inhibitor therapy for incurable head and neck cancer.

I haven't had cancer treatment like radiation or chemotherapy in the last 14 days.

I haven't had major surgery or significant bleeding from the tumor site in the last 14 days.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase I Treatment

De-escalation phase to establish safety and recommended phase 2 dose (RP2D) of ramucirumab combined with pembrolizumab

2.5 months

Every 21 days (in-person)

Phase II Treatment

Single arm trial to determine tumor response rates of ramucirumab at RP2D with pembrolizumab

6 months

Every 21 days (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Pembrolizumab
• Ramucirumab

Trial Overview The trial tests combining Ramucirumab with Pembrolizumab versus Pembrolizumab alone in treating HNSCC. Phase I determines the safe dose of Ramucirumab when combined with Pembrolizumab while phase II evaluates how effective this combination is as a first-line treatment by looking at tumor response rates.

How Is the Trial Designed?

Group I: Phase II: Ramucirumab + Pembrolizumab Experimental Treatment 5 Interventions

-Patients will be treated with ramucirumab at the RP2D on Day 1 and SOC pembrolizumab (200 mg IV over 30 minutes) on Day 1 of each 21-day cycle.

Group II: Phase I: Ramucirumab + Pembrolizumab Experimental Treatment 3 Interventions

-Ramucirumab will be administered IV over 1 hour on Day 1 of each 21-day cycle. Pembrolizumab will be administered as per standard of care (IV at a dose of 200 mg over 30 minutes on Day 1 of each 21-day cycle). On Day 1, pembrolizumab will be given after ramucirumab.

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

Published Research Related to This Trial

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]

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]

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 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]

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]

In a phase Ia clinical trial involving 32 patients with advanced head and neck cancer, atezolizumab demonstrated a tolerable safety profile, with 66% of patients experiencing treatment-related adverse events, but no grade 5 events reported.

The treatment showed promising efficacy, with 22% of patients achieving objective responses and a median overall survival of 6.0 months, indicating potential benefits regardless of HPV status or PD-L1 expression levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and clinical activity of atezolizumab in head and neck cancer: results from a phase I trial. Colevas, AD., Bahleda, R., Braiteh, F., et al.[2022]

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 study involving 882 participants with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC), pembrolizumab alone significantly improved overall survival compared to cetuximab with chemotherapy, especially in patients with high PD-L1 expression (CPS of 20 or more).

Pembrolizumab combined with chemotherapy also showed improved overall survival compared to cetuximab with chemotherapy across all populations, indicating that pembrolizumab is an effective first-line treatment option for HNSCC, particularly for those with PD-L1 positivity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a randomised, open-label, phase 3 study. Burtness, B., Harrington, KJ., Greil, R., et al.[2021]

Citations

1. withpower.com withpower.com/trial/phase-2-carcinoma-9-2023-d0588

Ramucirumab + 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 ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT05980000?cond=%22Laryngeal%20Disease%22&intr=%22Pembrolizumab%22&viewType=Table&rank=6

NCT05980000 | Ramucirumab and Pembrolizumab vs ... This is a phase 2 study investigating the efficacy of ramucirumab in combination with pembrolizumab compared to pembrolizumab monotherapy.

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12571033/

Ramucirumab in combination with pembrolizumab for ... More than 800 000 new cases of head and neck squamous cell carcinoma (HNSCC) occur each year. Half of these patients will develop recurrent or metastatic ...

4. onclive.com onclive.com/view/ramucirumab-pembrolizumab-produces-encouraging-orr-in-recurrent-or-metastatic-hnscc

Ramucirumab/Pembrolizumab Produces Encouraging ... In 15 patients with a PD-L1 CPS of 20 or higher, the ORR was 60% with ramucirumab plus pembrolizumab; 2 patients had SD and 4 experienced PD.

5. nature.com nature.com/articles/s41698-025-01020-6

Inflammation and limited adaptive immunity predict worse ... Inflammation and limited adaptive immunity predict worse outcomes on immunotherapy in head and neck cancer. npj Precis. Onc. 9, 272 (2025) ...

6. clinicaltrials.gov clinicaltrials.gov/ct2/show/NCT03650764?term=Ramucirumab&draw=2&rank=5

Ramucirumab + Pembrolizumab in Patients With Recurrent ... The key objective of the phase I trial is to establish the safety and the recommended phase 2 dose (RP2D) of ramucirumab for this novel combination regimen in ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT05980000

NCT05980000 | Ramucirumab and Pembrolizumab vs ... This is a phase 2 study investigating the efficacy of ramucirumab in combination with pembrolizumab compared to pembrolizumab monotherapy.

8. ecancer.org ecancer.org/en/news/26559-asco-2025-ramucirumab-and-pembrolizumab-combo-does-not-improve-os-for-previously-treated-advanced-nsclc

ASCO 2025: Ramucirumab and pembrolizumab combo ... ... Data and Safety Monitoring Committee (DSMC) recommended that results be publicly released. The DSMC also reported that no safety concerns ...

9. sciencedirect.com sciencedirect.com/science/article/abs/pii/S1470204524002043

Articles Ramucirumab in combination with pembrolizumab ... Articles. Ramucirumab in combination with pembrolizumab for recurrent or metastatic head and neck squamous cell carcinoma: a single-centre, phase 1/2 trial.