The investigators hypothesize that inhibition of angiogenesis and PD-1 will be more effective than inhibition of PD-1 alone. The first step in pursuing proof of this hypothesis is to establish the safety and feasibility of combining ramucirumab with pembrolizumab, therefore the first part of this protocol is a de-escalation phase I trial of the combination of ramucirumab + pembrolizumab. 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 patients with recurrent/metastatic head and neck squamous cell carcinoma (RM-HNSCC). The second step in pursuing proof of this hypothesis is to establish the efficacy of ramucirumab (using the RP2D) with pembrolizumab. The second part of this protocol is a single arm phase II trial combining ramucirumab + pembrolizumab. The primary objective of the phase II trial is to determine the tumor response rates (complete response (CR) and partial response (PR)) of the treatment combination given as first line therapy in patients with RM-HNSCC.

Inclusion Criteria:

• Incurable 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 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.

• At least 18 years of age.

• Performance status 0-2 (ECOG).

• 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; 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
  • INR ≤ 1.5 x ULN (≤ 3.0 x ULN if on anticoagulation) and PTT ≤ 1.5 x ULN (<3 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 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 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 inter-current 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.
• 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.