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Ramucirumab and Pembrolizumab in Treating Patients with Incurable Recurrent or Metastatic Head and Neck Squamous Cell Cancer

Trial Status: Closed to Accrual

This phase I / II trial studies the side effects and best dose of ramucirumab when given together with pembrolizumab and how well it works in treating patients with head and neck squamous cell cancer that has come back (recurrent) or has spread to other places in the body (metastatic) for which no treatment is currently available (incurable). Monoclonal antibodies, such as ramucirumab, may interfere with the ability of tumor cells to grow and spread. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body’s immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread.

Inclusion Criteria

  • Incurable RM-HNSCC, defined as RM disease not amenable to cure by surgery and/or radiation therapy or patient with HNSCC declines or is ineligible for curative therapy * In phase I, oral cavity, oropharynx, larynx, hypopharynx, nasopharynx, paranasal sinus, or salivary gland * In phase II, oral cavity, oropharynx, larynx or hypopharynx
  • Disease evaluation: * In phase I, evaluable or measurable disease * In phase II, measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
  • Prior Treatment: * For phase I, any number of lines of prior therapy for RM-HNSCC * For phase II, no prior systemic therapy for RM-HNSCC
  • Performance status 0-2 (Eastern Cooperative Oncology Group [ECOG])
  • Absolute neutrophil count >= 1,500/mcL
  • Platelets >= 100,000/mcL
  • Hemoglobin >= 9.0 g/dL
  • Total bilirubin =< 1.5 mg/dL
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) =< 3 x institutional upper limit of normal (IULN) and alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [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 m^2
  • Urine protein to creatinine ratio (UPC) =< 1; if UPC >= 1, then a 24-hour urine protein must be assessed; patients must have a 24-hour urine protein value < 1 g to be eligible
  • International normalized ratio (INR) =< 1.5 x ULN (=< 3.0 x ULN if on anticoagulation) and partial thromboplastin time (PTT) =< 1.5 x ULN (=< 3.0 x ULN if on anticoagulation) (patients are allowed to be on anticoagulation)
  • Women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control, abstinence) beginning 14 days prior to first dose of ramucirumab, through the dosing period, and for at least 28 days after
  • Signed Institutional Review Board (IRB) approved written informed consent document

Exclusion Criteria

  • Phase II: prior PD-1 inhibitor for treatment of incurable HNSCC. For phase I, prior PD-1 inhibitor therapy in the incurable setting is permitted
  • Radiation, chemotherapy, targeted or investigational therapy within 14 days of treatment start
  • Major surgery, presence of a non-healing, non-malignant ulcer within 14 days of treatment start; History of significant tumor site bleeding within 14 days of study consent
  • History of other malignancy =< 1 year previous with the exception of completely resected skin carcinoma or other cancers with a low risk of recurrence
  • Cirrhosis at a level of Child-Pugh B (or worse), cirrhosis of any degree with a history of hepatic encephalopathy or clinically meaningful ascites (from cirrhosis requiring diuretics or paracentesis)
  • Receiving any other investigational agents
  • Ongoing toxicity attributed to prior anti-cancer therapy that is > grade 1, except alopecia, anemia, fatigue or rash
  • Active central nervous system metastases: defined as currently receiving radiation therapy to metastatic central nervous system (CNS) disease. Once radiation therapy is completed, patients with CNS disease are eligible if they meet all other criteria for enrollment
  • History of severe allergic reactions attributed to agents used in the study
  • Serious uncontrolled intercurrent illness within the 3 months prior to study entry or psychiatric illness/social situations that would limit compliance with study requirements
  • Receiving systemic steroid therapy (in dosing exceeding 20 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of pembrolizumab
  • Has an active autoimmune disease (i.e. rheumatoid arthritis, lupus, Sjogren’s syndrome) that has required IV or subcutaneous systemic treatment in the past 6 months (excluding rituxin). Replacement therapy (i.e. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of system treatment
  • Gastrointestinal (GI) perforation or fistula within 6 months of first dose of protocol therapy
  • History of GI issues such as inflammatory bowel disease, ulcerative colitis, or Crohn’s disease
  • Poorly controlled hypertension (defined as high blood pressure measurements [systolic blood pressures of >= 160 mmHg or diastolic blood pressures of > 100 mmHg] documented during the two-week interval prior to enrollment). Initiation or adjustment of antihypertensive medications to control blood pressure is permitted prior to study entry
  • Arterial thromboembolic events (including but not limited to myocardial infarction, transient ischemic attack, cerebrovascular accident, or unstable angina) within 3 months prior to first dose of treatment
  • GI bleeding (grade 3 or 4) within 3 months prior to first dose
  • Pregnant and/or breastfeeding. Patient must have a negative serum pregnancy test within 7 days of first dose of treatment


Saint Louis
Siteman Cancer Center at Washington University
Contact: Douglas Ray Adkins
Phone: 314-747-8475


I. Determine the recommended phase II dose (RP2D) of ramucirumab combined with fixed dose pembrolizumab in patients with recurrent/metastatic head and neck squamous cell carcinoma (RM-HNSCC). (Phase I)

II. Determine the overall tumor response rate of ramucirumab + pembrolizumab as first line therapy in patients with RM-HNSCC. (Phase II)


I. Determine the adverse events (AE) profile of the combination of ramucirumab + pembrolizumab in patients with RM-HNSCC. (Phases I and II)

II. Determine duration of response (DOR), progression-free survival (PFS) and overall survival (OS) of patients with RM-HNSCC treated with ramucirumab + pembrolizumab. (Phase II)

III. Evaluate the quality of life (QOL) of RM-HNSCC patients receiving ramucirumab + pembrolizumab by Functional Assessment of Cancer Therapy Head and Neck (FACT H&N) and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30. (Phase II)


I. Collect and store pre-treatment tissue and blood specimens from patients for possible future correlative studies. (Phase II)

OUTLINE: This is a phase I, dose de-escalation study of ramucirumab followed by phase II study.

Patients receive ramucirumab intravenously (IV) over 1 hour and pembrolizumab IV over 30 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 28 days.

Trial Phase Phase I/II

Trial Type Treatment

Lead Organization
Siteman Cancer Center at Washington University

Principal Investigator
Douglas Ray Adkins

  • Primary ID 201809094
  • Secondary IDs NCI-2018-02080
  • ID NCT03650764