Head and Neck Squamous Cell Carcinoma
Conditions
Brief summary
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.
Interventions
DRUGRamucirumab
Ramucirumab is an investigational agent for this trial and will be supplied by Lilly Oncology, free of charge to the patient
DRUGPembrolizumab
Pembrolizumab is commercially available
Sponsors
Washington University School of Medicine
Eli Lilly and Company
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Recommended Phase 2 Dose (RP2D) of Ramucirumab Combined With Fixed Dose Pembrolizumab (Phase I Participants Only) | 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) | -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. |
| Objective Response Rate of Ramucirumab and Pembrolizumab (Phase II Participants Only) | Through completion of treatment (median length of follow-up 162 days, full range 1-2240 days) | * 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Adverse Event Profile of the Combination of Ramucirumab and Pembrolizumab (Phase I and II Participants) as Measured by the Frequency of Adverse Events | Through 28 days after completion of treatment (median length of follow-up 183 days, full range 14-2240 days) | -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. |
| Duration of Response (Phase II Participants Only) | Through completion of follow-up (median length of follow-up of 445 days, full range 14-2240 days) | -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). |
| Kaplan-Meier Estimate of Median Progression-free Survival (PFS) (Phase II Participants Only) | Through completion of follow-up (median length of follow-up of 445 days, full range 14-2240 days) | * 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). |
| Kaplan-Meier Estimate of Median Overall Survival (OS) (Phase II Participants Only) | Through completion of follow-up (median length of follow-up of 445 days, full range 14-2240 days) | OS is defined as the duration of time from start of treatment to time of death (or last follow-up alive). |
| Changes in Quality of Life as Measured by Functional Assessment of Cancer Therapy-Head and Neck (FACT-H&N) (Phase II Participants Only) | Baseline, start of cycle 2 (each cycle is 21 days), and start of cycle 5 (estimated to be 12 weeks) | * 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. |
| Changes in Quality of Life as Measured by Functional Assessment of Cancer Therapy-Head and Neck Trial Outcome Index (FACT-H&N TOI) (Phase II Participants Only) | Baseline, start of cycle 2 (each cycle is 21 days), and start of cycle 5 (estimated to be 12 weeks) | * 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 TOI (range 0-96) measures the total score for the physical, functional, and HNCS domains but excludes the emotional and social domains * The maximum score of 96 reflects the best quality of life. |
| Changes in Quality of Life as Measured by Functional Assessment of Cancer Therapy-General (FACT-G) (Phase II Participants Only) | Baseline, start of cycle 2 (each cycle is 21 days), and start of cycle 5 (estimated to be 12 weeks) | * Includes 27 questions: 7 in physical well-being, 6 in emotional well-being, 7 in functional well-being, 7 in social well-being. * 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-G Total Score (range 0-108) measures the sum of the physical, social, emotional, and functional domains but excludes the HNCS domain * The maximum score of 108 reflects the best quality of life. |
| Changes in Quality of Life as Measured by The European Organisation for Research and Treatment of Cancer Core Questionnaire (EORTC QLQ-30) - Global Health Status (Phase II Participants Only) | Baseline, start of cycle 2 (each cycle is 21 days), and start of cycle 5 (estimated to be 12 weeks) | EORTC QLQ-C30: this has a total score, one general quality of life (QoL), and one "within the last week" subscale, as well as a general health item and a single overall QoL item. This study does not use current empirical guidelines for the EORTC-QLQ-30 global score with the understanding that both the magnitude and variance of scores vary considerably from patient to patient, from one time point to another and by such factors as disease condition, age, and comorbidity. The participants can choose from 1-4 with 1 being Not At All and 4 being Very Much. A high scale score represents a higher response level but these differ based on the type of sub-scale. Per the QLQ-C30 scoring manual, a high score for the global health status / QoL represents a high QoL, The total score range was 0-100. |
| Changes in Quality of Life as Measured by The European Organisation for Research and Treatment of Cancer Core Questionnaire (EORTC QLQ-30) - Functional Scale (Phase II Participants Only) | Baseline, start of cycle 2 (each cycle is 21 days), and start of cycle 5 (estimated to be 12 weeks) | EORTC QLQ-C30: this has a total score, one general quality of life (QoL), and one "within the last week" subscale, as well as a general health item and a single overall QoL item. This study does not use current empirical guidelines for the EORTC-QLQ-30 global score with the understanding that both the magnitude and variance of scores vary considerably from patient to patient, from one time point to another and by such factors as disease condition, age, and comorbidity. The participants can choose from 1-4 with 1 being Not At All and 4 being Very Much. A high scale score represents a higher response level but these differ based on the type of sub-scale. Per the QLQ-C30 scoring manual, high score for a functional scale represents a high / healthy level of functioning. The total score range was 0-100. |
| Changes in Quality of Life as Measured by The European Organisation for Research and Treatment of Cancer Core Questionnaire (EORTC QLQ-30) - Symptom Scale (Phase II Participants Only) | Baseline, start of cycle 2 (each cycle is 21 days), and start of cycle 5 (estimated to be 12 weeks) | EORTC QLQ-C30: this has a total score, one general quality of life (QoL), and one "within the last week" subscale, as well as a general health item and a single overall QoL item. This study does not use current empirical guidelines for the EORTC-QLQ-30 global score with the understanding that both the magnitude and variance of scores vary considerably from patient to patient, from one time point to another and by such factors as disease condition, age, and comorbidity. The participants can choose from 1-4 with 1 being Not At All and 4 being Very Much. A high scale score represents a higher response level but these differ based on the type of sub-scale. Per the QLQ-C30 scoring manual, a high score for a symptom scale / item represents a high level of symptomatology / problems. The total score range was 0-100. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORDouglas R Adkins, M.D.
Washington University School of Medicine
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 64 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 43 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 38 Participants |
| Region of Enrollment United States | 43 participants |
| Sex: Female, Male Female | 4 Participants |
| Sex: Female, Male Male | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 3 / 3 | 32 / 37 |
| other Total, other adverse events | 3 / 3 | 37 / 37 |
| serious Total, serious adverse events | 2 / 3 | 26 / 37 |
Outcome results
None listed