Metronomic Cyclophosphamide With Pembrolizumab in Checkpoint Inhibitor Refractory Melanoma
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 14
- 试验地点
- 1
- 主要终点
- Objective Response Rate (ORR) by RECIST v1.1
研究概览
简要总结
This is a phase 2, single-arm, open label clinical trial determining efficacy of Cyclophosphamide and Pembrolizumab in subjects with melanoma.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 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
- •Age ≥18 years at the time of signing informed consent form (ICF)
- •Patients must have unresectable Stage III or Stage IV non-ocular melanoma per American Joint Committee on Cancer 8th Edition Staging Criteria not amenable to local therapy
- •Participants must have measurable disease by RECIST v1.1 criteria as assessed by investigator/ radiology. Lesions situated in a previously irradiated area are considered measurable if progression has been shown in such lesions.
- •Participants must have Eastern Cooperative Group (ECOG) performance status score of 0, 1 or 2 at screening visit.
- •Life expectancy of at least 12 weeks
- •Adequate bone marrow, liver, and renal function
- •Hemoglobin ≥9.0 g/dL
- •Platelets ≥100/mm3
- •ANC ≥1.5/mm3
- •Creatinine Clearance ≥ 30mL/min Cockcroft-Gault CrCl, mL/min = (140 - age) × (weight, kg) × (0.85 if female) / (72 × Cr, mg/dL).
- •AST and ALT less than 3 times the Upper Limit of Normal or less than 5 times the Upper Limit of normal with liver metastases. T Bilirubin < 3.1 mg/dL.
- •Has progressed on a prior PD-1/PD-L1 treatment
- •Recovered from toxicities of pembrolizumab to Grade ≤1, excluding endocrine toxicities
- •Prior Receipt of PD-1/PD-L1 therapy within 9 weeks prior to the first dose of the investigational therapy.
- •Women of childbearing potential must have had a negative pregnancy test performed within 7 days prior to the start of treatment
- •Females of childbearing potential and males must be willing and able to use an adequate method of contraception to avoid pregnancy for the duration of the study.
- •Male and female participants of childbearing potential who are sexually active with a non-sterilized partner must agree to use highly effective methods of birth control from the trial screening date until 3 months after the final dose of study intervention; cessation of birth control after this point shall be discussed with a responsible physician.
- •Pregnant or lactating women are prohibited from enrolling in this study.
- •Male participants are not allowed to donate sperm from the time of enrollment until 6 months after administration of study interventions.
排除标准
- •Participants with a diagnosis of ocular or metastatic uveal melanoma
- •Participants with a history of a malignant disease other than those being treated in this study. The following exceptions are permitted:
- •Malignancies that were treated curatively and have not recurred within 2 years. Shorter intervals can be considered after discussion with the Principal Investigator.
- •Completely resected basal cell and squamous cell skin cancers.
- •Any malignancy considered to be indolent and that has never required therapy, such as chronic lymphocytic leukemia.
- •Completely resected carcinoma in situ of any type
- •Participants ineligible to be retreated with pembrolizumab due to a treatment-related AE while on a prior anti-PD(L)-1 regimen that led to discontinuation of that prior therapy and would thus prevent retreatment or with an immune-related adverse event (irAE) of grade 3 or greater
- •Participants with known untreated or symptomatic central nervous system (CNS) metastases and/or carcinomatous meningitis. NOTE: Participants with previously treated brain metastases may participate provided ALL of the following apply:
- •Treated CNS lesions are radiographically stable (without evidence of progression for ≥ 28 days prior to the first dose of study intervention) after intervention (eg, surgery and/or radiation).
- •Neurologically stable and on stable dose of ≤ 10mg of prednisone equivalent steroids for at least 7 days prior to the first dose of study intervention.
- •Any prior investigational or standard cancer therapy, with exception of PD-1/PD-L1 (includes nivolumab + Relatlimab) therapy, chemotherapy or radiation within 6-9 weeks of the first dose of the investigational therapy (see Inclusion Criteria)
- •Presence of B-RAF driver mutation without prior receipt of BRAF +/- MEK inhibitors, unless patient declines BRAF +/-MEK inhibition for any reason or is unable to tolerate BRAF and/or MEK inhibitors.
- •Participants with a known history of chronic viral infections as indicated below. If patients do not have a known history, testing is not required during the screening period to confirm the patient has an active infection.
- •Known HBV infection defined as hepatitis B surface antigen reactive. NOTE: Participants with HBV infection on stable anti-viral therapy for > 4 weeks prior to the planned first study intervention and viral load confirmed as undetectable during Screening may be eligible.
- •Known active HCV infection defined as detectable HCV RNA (qualitative) infection. NOTE: History of HCV is not exclusionary if participant has received curative treatment and viral load is confirmed as undetectable during Screening.
- •Active HIV infection. Those with HIV infections on combination antiretroviral medications with stable CD4 count >200/microliters as measured within screening time period. If the patient does not have a known history of HIV, then testing is not required during screening to confirm presence or absence of HIV.
- •Positive serum pregnancy test
- •Participants with out-of-range screening laboratory values as defined below. NOTE: Hematology evaluations must be performed >7 days from any blood transfusion. Or blood product transfusion or from any dose of hematologic growth factor.
- •Glomerular filtration rate (calculated using the Chronic Kidney Disease Epidemiology Collaboration formula) < 30 mL/min
- •Total bilirubin > 1.5 × ULN; participants with Gilbert's syndrome are excluded if total bilirubin > 3.0 × ULN; or direct bilirubin > 1.5 × ULN
- •Albumin < 3.0 g/dL
- •Absolute lymphocyte count < 0.5 × 10^9/L
- •Participants with a history of allogeneic tissue/solid organ transplant
研究组 & 干预措施
Pembrolizumab + Cyclophosphamide
Pembrolizumab 200mg IV every 21 days or 400 mg IV every 42 days Cyclophosphamide 50mg PO daily on days 1-14 every 21 days for melanoma patients
干预措施: Pembrolizumab (Drug)
Pembrolizumab + Cyclophosphamide
Pembrolizumab 200mg IV every 21 days or 400 mg IV every 42 days Cyclophosphamide 50mg PO daily on days 1-14 every 21 days for melanoma patients
干预措施: Cyclophosphamide (Drug)
结局指标
主要结局
Objective Response Rate (ORR) by RECIST v1.1
时间窗: Up to 3 years
Sum of Complete Response (CR) and Partial Response (PR) by RECIST v 1.1. Per Response Evaluation Criteria in Solid Tumors Criteria (RECIST v1.1): Complete Response (CR) is defined as the disappearance of all target lesions; Partial Response (PR) is defined as a 30% decrease in the sum of diameters of target lesions. ORR = CR + PR
Number of Patients with Adverse Events
时间窗: Up to 3 years
Number of Patients who received at least one dose of Pembrolizumab with Cyclophosphamide with any reported Adverse Events (AEs) using the CTCAE version 5.0 for reporting of nonhematologic AEs and modified criteria for hematologic AEs.
Number of Patients with Immune Related Adverse Events
时间窗: Up to 3 years
Number of Patients who received at least one dose of Pembrolizumab with Cyclophosphamide with reported immune related AEs (irAEs) using the CTCAE version 5.0 for reporting of nonhematologic AEs and modified criteria for hematologic AEs.
Number of Patients who Discontinued Treatment Due to Reported Adverse Events
时间窗: Up to 3 years
Number of Patients who received at least one dose of Pembrolizumab with Cyclophosphamide requiring discontinuation of therapy due to reported AEs using the CTCAE version 5.0 for reporting of nonhematologic AEs and modified criteria for hematologic AEs..
Comparative Analysis of Immune Cells
时间窗: Up to 3 years
Mean, median, percentage and total counts of immune T cell subsets pre-treatment and after 2 three-week cycles of metronomic cyclophosphamide and pembrolizumab.
次要结局
- Overall Survival(Up to 3 years)
- Objective Response Rate (ORR) by iRECIST(Up to 3 years)
- Clinical Benefit Rate(Up to 3 years)
- Duration of Response(Up to 3 years)
- Progression Free Survival(Up to 3 years.)
研究者
Warren Chow
HS Clinical Professor and Associate Director for Clinical Science
University of California, Irvine