Ipilimumab and Gemcitabine for Advanced Pancreas Cancer: A Phase Ib Study
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 21
- 试验地点
- 1
- 主要终点
- Number of Dose Limiting Toxicities (DLTs) Seen in Patients With Pancreas Adenocarcinoma Treated With Ipilimumab and Gemcitabine Combination in Order to Define the Maximum Tolerated Dose (MTD)
研究概览
简要总结
This phase I trial studies the side effects and best dose of ipilimumab when given together with gemcitabine hydrochloride in treating patients with stage III-IV or recurrent pancreatic cancer that cannot be removed by surgery. Monoclonal antibodies, such as ipilimumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or tumor-killing substances to them. Drugs used in chemotherapy, such as gemcitabine hydrochloride, work in different ways to kill tumor cells or stop them from growing. Giving monoclonal antibody therapy together with chemotherapy may kill more tumor cells.
详细描述
OUTLINE: This is a dose-escalation study of ipilimumab.
INDUCTION: Patients receive ipilimumab intravenously (IV) over 90 minutes in weeks 1, 4, 7, and 10, and gemcitabine hydrochloride IV over 30 minutes in weeks 1-7 and 9-11.
MAINTENANCE: Beginning in week 22, patients receive ipilimumab IV over 90 minutes once every 12 weeks and gemcitabine hydrochloride IV over 30 minutes once weekly for 3 weeks. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Treatment modifications may apply according to response.
After completion of study treatment, patients are followed up monthly for 6 months and then every 3 months.
研究设计
- 研究类型
- Interventional
- 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
- •Willing and able to give written informed consent
- •Histologic or cytologic diagnosis of pancreas adenocarcinoma advanced or recurrent (stage III or IV) that is unresectable; histologic or cytologic pathology from any prior surgery is sufficient for diagnosis
- •Must have measurable disease by modified WHO criteria
- •White blood cells (WBC) >= 2000/uL
- •Absolute neutrophil count (ANC) >= 1500/uL
- •Platelets >= 100 x 10^3/uL
- •Hemoglobin >= 9 g/dL (>= 80 g/L; may be transfused)
- •Creatinine =< 2.0 x upper limit of normal (ULN)
- •Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 x ULN
- •Bilirubin =< 2.0 x ULN, (except patients with Gilbert's Syndrome, who must have a total bilirubin less than 3.0 mg/dL)
- •No active or chronic infection with human immunodeficiency virus (HIV), hepatitis B, or hepatitis C
- •Performance status: Eastern Cooperative Oncology Group (ECOG) 0-1
- •Prior systemic therapy for advanced pancreas cancer with gemcitabine is prohibited; prior gemcitabine with radiotherapy for localized pancreas cancer is allowed provided disease is present outside of the radiated field; prior gemcitabine as adjuvant therapy to surgical resection is allowed provided 3 months or greater has elapsed between the last dose of gemcitabine and the detection of recurrent disease
- •Women of childbearing potential (WOCBP) must be using an adequate method of contraception to avoid pregnancy throughout the study and for up to 26 weeks after the last dose of investigational product, in such a manner that the risk of pregnancy is minimized; WOCBP include any female who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or is not post-menopausal; post-menopause is defined as: amenorrhea >= 12 consecutive months without another cause, or for women with irregular menstrual periods and taking hormone replacement therapy (HRT), a documented serum follicle stimulating hormone (FSH) level >= 35 mIU/mL; women who are using oral contraceptives, other hormonal contraceptives (vaginal products, skin patches, or implanted or injectable products), or mechanical products such as an intrauterine device or barrier methods (diaphragm, condoms, spermicides) to prevent pregnancy, or are practicing abstinence or where their partner is sterile (eg, vasectomy) should be considered to be of childbearing potential
- •WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotrophin [HCG]) within 72 hours before the start of ipilimumab
- •Men of fathering potential must be using an adequate method of contraception to avoid conception throughout the study (and for up to 26 weeks after the last dose of investigational product) in such a manner that the risk of pregnancy is minimized
- •Patients on stable anticoagulation are eligible for enrollment; for patients on warfarin, prothrombin time (PT)/international normalized ratio (INR) should be monitored every 2 weeks during induction therapy, monthly thereafter, or more frequent as clinically indicated
排除标准
- •Any other malignancy from which the patient has been disease-free for less than 5 years, with the exception of adequately treated and cured basal or squamous cell skin cancer, superficial bladder cancer or carcinoma in situ of the cervix
- •Autoimmune disease: Patients with a history of inflammatory bowel disease, including ulcerative colitis and Crohn's Disease, are excluded from this study, as are patients with a history of symptomatic disease (eg, rheumatoid arthritis, systemic progressive sclerosis [scleroderma], systemic lupus erythematosus, autoimmune vasculitis [eg, Wegener's Granulomatosis]); motor neuropathy considered of autoimmune origin (e.g. Guillain-Barre Syndrome and Myasthenia Gravis)
- •Any underlying medical or psychiatric condition, which in the opinion of the investigator will make the administration of ipilimumab hazardous or obscure the interpretation of adverse events (AEs), such as a condition associated with frequent diarrhea
- •Any non-oncology vaccine therapy used for prevention of infectious diseases (for up to 1 month before or after any dose of ipilimumab)
- •A history of prior treatment with ipilimumab or prior tumor necrosis factor receptor superfamily, member 9 (CD137) agonist or cytotoxic T-lymphocyte-associated protein 4 (CTLA4) inhibitor or agonist
- •Concomitant therapy with any of the following: interleukin (IL)2, interferon, or other non-study immunotherapy regimens; immunosuppressive agents; other investigation therapies; or chronic use of systemic corticosteroids
- •WOCBP who are unwilling or unable to use an acceptable method of contraception to avoid pregnancy for their entire study period and for at least 8 weeks after cessation of study drug, or have a positive pregnancy test at baseline, or are pregnant or breastfeeding
- •Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) for treatment of either a psychiatric or physical (eg, infectious) illness
- •Patients with symptoms of partial or complete bowel obstruction and recent (within 6 month) history of fistula, intra-abdominal abscess or bowel perforation
- •Patients with a history or evidence of central nervous system (CNS) disease, including brain tumor, seizures not controlled with standard medical therapy or any brain metastases
- •Patients currently receiving radiation therapy or those having received radiation within 4 weeks of study entry
- •Patients with any known active infection or known history of tuberculosis
研究组 & 干预措施
Treatment (monoclonal antibody, chemotherapy)
INDUCTION: Patients receive ipilimumab IV over 90 minutes in weeks 1, 4, 7, and 10 and gemcitabine hydrochloride IV over 30 minutes in weeks 1-7 and 9-11.
MAINTENANCE: Beginning in week 22, patients receive ipilimumab IV over 90 minutes once every 12 weeks and gemcitabine hydrochloride IV over 30 minutes once weekly for 3 weeks. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Treatment modifications may apply according to response.
干预措施: ipilimumab (Biological)
Treatment (monoclonal antibody, chemotherapy)
INDUCTION: Patients receive ipilimumab IV over 90 minutes in weeks 1, 4, 7, and 10 and gemcitabine hydrochloride IV over 30 minutes in weeks 1-7 and 9-11.
MAINTENANCE: Beginning in week 22, patients receive ipilimumab IV over 90 minutes once every 12 weeks and gemcitabine hydrochloride IV over 30 minutes once weekly for 3 weeks. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Treatment modifications may apply according to response.
干预措施: gemcitabine hydrochloride (Drug)
Treatment (monoclonal antibody, chemotherapy)
INDUCTION: Patients receive ipilimumab IV over 90 minutes in weeks 1, 4, 7, and 10 and gemcitabine hydrochloride IV over 30 minutes in weeks 1-7 and 9-11.
MAINTENANCE: Beginning in week 22, patients receive ipilimumab IV over 90 minutes once every 12 weeks and gemcitabine hydrochloride IV over 30 minutes once weekly for 3 weeks. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Treatment modifications may apply according to response.
干预措施: laboratory biomarker analysis (Other)
结局指标
主要结局
Number of Dose Limiting Toxicities (DLTs) Seen in Patients With Pancreas Adenocarcinoma Treated With Ipilimumab and Gemcitabine Combination in Order to Define the Maximum Tolerated Dose (MTD)
时间窗: During the 12 weeks of Induction Therapy
Dose limiting toxicity (DLT) will be monitored by calculating the Bayesian predictive probability of a DLT given the data to date. All toxicities will be summarized in a descriptive manner as to type, frequency, attribution and timing by dose level. Safety will be evaluated for all treated patients using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0 where grading is as follows: Mild (grade 1) Moderate (grade 2) Severe (grade 3) Life-threatening (grade 4) Fatal (grade 5) In general a DLT will be defined as any any of the following drug-related toxicities: Febrile neutropenia with grade 3/4 neutropenia Asymptomatic grade 4 neutropenia more than 7 days Grade 3 thrombocytopenia with grade 3-4 hemorrhage or grade 4 thrombocytopenia Non-hematologic toxicity grade 3 or 4 (with some protocol specified exceptions) DLTs will be used to determine the MTD for the expansion cohort of the study. \*AST = Aspartate transamina
次要结局
- Response Rate Using Immune-related Response Criteria (irRC) in Patients With Pancreas Adenocarcinoma Treated With Ipilimumab and Gemcitabine Combination(Every 12 weeks during treatment with a 12 week induction and then 28 day maintenance cycles. Range of cycles completed (including induction cycle) 0-10)
- Recovery of Tumor Immune Surveillance: T-cell Response to Defined Pancreatic Cancer Tumor Antigens(Prior to ipilimumab infusion at weeks 1, 4, 7, and 10, and then every 12 weeks starting at week 13 where range of cycles including induction cycle was 0-10 (Induction cycle = 12 weeks, maintenance cycle = 28 days))
- Time to Progression Patients With Pancreas Adenocarcinoma Treated With Ipilimumab and Gemcitabine Combination Who Progress While on Treatment(Every 12 weeks during treatment with a 12 week induction and then 28 day maintenance cycles. Range of cycles completed (including induction cycle) 0-10)
- Progression Free Survival (PFS) in Patients With Pancreas Adenocarcinoma Treated With Ipilimumab and Gemcitabine Combination(Every 12 weeks during treatment with a 12 week induction and then 28 day maintenance cycles. Range of cycles completed (including induction cycle) 0-10)
- Overall Survival (OS) in Patients With Pancreas Adenocarcinoma Treated With Ipilimumab and Gemcitabine Combination(Every 12 weeks during treatment with a 12 week induction and then 28 day maintenance cycles. Range of cycles completed (including induction cycle) 0-10)
研究者
Mary Mulcahy
Mary Mulcahy, MD
Northwestern University