Ramucirumab + Pembrolizumab in Patients With Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma

Washington University School of Medicine43 enrolled

Overview

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. Three participants will be treated at each dose level. De-escalation to the next dose level will occur if 2 or more participants experience dose-limiting toxicities (DLTs) attributable to ramucirumab during cycle 1. 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.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Head and Neck Squamous Cell Carcinoma

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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.

Outcomes

Primary Outcomes

Recommended Phase 2 Dose (RP2D) of Ramucirumab Combined With Fixed Dose Pembrolizumab (Phase I Participants Only)

-The RP2D of ramucirumab is defined as the highest dose level at which fewer than 2 participants of a cohort of three participants experience a dose-limiting toxicity (DLT) during the first cycle.

Time frame: Completion of first cycle of treatment (each cycle is 21 days) for all participants enrolled in Phase I portion of study (estimated to be 2.5 months)

Objective Response Rate of Ramucirumab and Pembrolizumab (Phase II Participants Only)

* Objective response rate = number of participants with complete response + partial response as measured per RECIST 1.1 * Complete response (CR)=Disappearance of all target lesions and non-target lesions along with normalizations of tumor marker level. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. * Partial response (PR)=At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.

Time frame: Through completion of treatment (median length of follow-up 162 days, full range 1-2240 days)

Secondary Outcomes

Adverse Event Profile of the Combination of Ramucirumab and Pembrolizumab (Phase I and II Participants) as Measured by the Frequency of Adverse Events

-The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for all toxicity reporting.

Time frame: Through 28 days after completion of treatment (median length of follow-up 183 days, full range 14-2240 days)

Duration of Response (Phase II Participants Only)

-Duration of response: The duration of response is measured from the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started).

Time frame: Through completion of follow-up (median length of follow-up of 445 days, full range 14-2240 days)

Kaplan-Meier Estimate of Median Progression-free Survival (PFS) (Phase II Participants Only)

* PFS is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first. * Progressive disease: At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progressions).

Time frame: Through completion of follow-up (median length of follow-up of 445 days, full range 14-2240 days)

Kaplan-Meier Estimate of Median Overall Survival (OS) (Phase II Participants Only)

OS is defined as the duration of time from start of treatment to time of death (or last follow-up alive).

Time frame: Through completion of follow-up (median length of follow-up of 445 days, full range 14-2240 days)

Changes in Quality of Life as Measured by Functional Assessment of Cancer Therapy-Head and Neck (FACT-H&N) (Phase II Participants Only)

* Includes 39 questions: 7 in physical well-being, 6 in emotional well-being, 7 in functional well-being, and 12 in head \& neck * Scored from 0 (not at all) to 4 (very much) * Higher scores indicated worse physical and emotional well-being and better social/family and functional well-being * The FACT-H\&N Total Score (range 0-148) measures the sum of the physical, social, emotional, functional, and HNCS domains * The maximum score of 148 reflects the best quality of life.