A Prospective Phase I and II Trial of Ramucirumab + Pembrolizumab in Patients With Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 43
- 试验地点
- 1
- 主要终点
- Recommended phase 2 dose (RP2D) of ramucirumab combined with fixed dose pembrolizumab (Phase I patients only)
研究概览
简要总结
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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.
研究组 & 干预措施
Phase II: Ramucirumab (10 mg/kg) + Pembrolizumab
Participants enrolled in the Phase II portion received 10 mg/kg intravenous ramucirumab which was the recommended phase 2 dose (RP2D) determined during the Phase I portion on Day 1. Pembrolizumab was administered as per standard of care (SOC) IV at a dose of 200 mg on Day 1. Each cycle was 21 days.
干预措施: Ramucirumab (Drug)
Phase II: Ramucirumab (10 mg/kg) + Pembrolizumab
Participants enrolled in the Phase II portion received 10 mg/kg intravenous ramucirumab which was the recommended phase 2 dose (RP2D) determined during the Phase I portion on Day 1. Pembrolizumab was administered as per standard of care (SOC) IV at a dose of 200 mg on Day 1. Each cycle was 21 days.
干预措施: Pembrolizumab (Drug)
Phase I Dose Level 1 : Ramucirumab (10 mg/kg) + Pembrolizumab
Participants enrolled in Phase I Dose Level 1 received 10 mg/kg ramucirumab administered intravenously (IV) on Day 1. Pembrolizumab was administered as per standard of care (SOC) IV at a dose of 200 mg on Day 1. Each cycle was 21 days.
干预措施: Ramucirumab (Drug)
Phase I Dose Level 1 : Ramucirumab (10 mg/kg) + Pembrolizumab
Participants enrolled in Phase I Dose Level 1 received 10 mg/kg ramucirumab administered intravenously (IV) on Day 1. Pembrolizumab was administered as per standard of care (SOC) IV at a dose of 200 mg on Day 1. Each cycle was 21 days.
干预措施: Pembrolizumab (Drug)
结局指标
主要结局
Recommended phase 2 dose (RP2D) of ramucirumab combined with fixed dose pembrolizumab (Phase I patients only)
时间窗: Completion of first cycle of treatment for all patients 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 patients of a cohort of three patients experience a dose-limiting toxicity (DLT) during the first cycle.
Overall tumor response rate of ramucirumab and pembrolizumab (Phase II patients only)
时间窗: Through 28 days after completion of treatment (estimated to be 6 months)
* Overall tumor response rate = number of participants with complete response + partial response * Complete response (CR)=Disappearance of all target lesions. 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.
Recommended Phase 2 Dose (RP2D) of Ramucirumab Combined With Fixed Dose Pembrolizumab (Phase I Participants Only)
时间窗: 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)
时间窗: 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.
次要结局
- Adverse event profile of the combination of ramucirumab and pembrolizumab (Phase I and II patients) as measured by the frequency of adverse events(Through 28 days after completion of treatment (estimated to be 6 months))
- Changes in quality of life as measured by FACT H&N (Phase II patients only)(Baseline, start of cycle 2, and start of cycle 5 (estimated to be 12 weeks))
- Duration of overall response (Phase II patients only)(Through 28 days after completion of treatment (estimated to be 6 months))
- Overall survival (OS) (Phase II patients only)(Through 28 days after completion of treatment (estimated to be 6 months))
- Progression-free survival (PFS) (Phase II patients only)(Through 28 days after completion of treatment (estimated to be 6 months))
- Changes in quality of life as measured by EORTC QLQ-C30 (Phase II patients only)(Baseline, start of cycle 2, and start of cycle 5 (estimated to be 12 weeks))
- 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))
- 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))
- 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))
- 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))
- 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))
- 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))
- 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))
- 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))
- 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))
- 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))