Randomized Phase 2 Trial of Gemcitabine + Carboplatin + Nivolumab Versus Gemcitabine + Oxaliplatin + Nivolumab in Cisplatin-ineligible Patients With Metastatic Urothelial Cancer
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- 入组人数
- 49
- 试验地点
- 6
- 主要终点
- Objective Response Rate (ORR)
研究概览
简要总结
This is a randomized phase 2 trial of gemcitabine + carboplatin + nivolumab or gemcitabine + oxaliplatin + nivolumab for the treatment of cisplatin-ineligible patients with metastatic urothelial cancer. Randomization will be stratified on the lymph node only (and/or unresectable primary) metastatic status.
详细描述
Patients will be randomized to Arm A: gemcitabine plus carboplatin plus nivolumab versus Arm B: gemcitabine plus oxaliplatin plus nivolumab. Randomization will be stratified on the metastasis status (lymph node only vs. the rest). Patients on both treatment arms will receive up to 6 cycles of combination therapy in the absence of prohibitive adverse effects or disease progression. Patients with at least stable disease at the completion of 6 cycles of treatment may continue "maintenance" single agent nivolumab for up to 12 cycles. Patients who require discontinuation of chemotherapy (i.e., gemcitabine plus carboplatin or gemcitabine plus oxaliplatin) prior to Cycle 6, but who have at least stable disease, may be considered for ongoing treatment with single-agent nivolumab on the "maintenance" phase after discussion with the sponsor-investigator.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
盲法说明
Open-label
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
- •Subject must meet all the following applicable inclusion criteria to participate in this study:
- •Written informed consent and HIPAA authorization for release of personal health information prior to registration. NOTE: HIPAA authorization may be included in the informed consent or obtained separately.
- •Age ≥ 18 years at the time of consent.
- •Eastern Cooperative Oncology Group (ECOG) performance status of = 2
- •Able to comply with the study protocol, in the investigator's judgment.
- •Histologically documented, locally advanced (T4b, any N; or any T, N 2-3) or metastatic urothelial carcinoma (mUC) (M1, Stage IV) (also termed TCC or UCC of the urinary tract; including renal pelvis, ureters, urinary bladder, and urethra) Patients with mixed histologies are required to have a dominant transitional cell pattern. Locally advanced bladder cancer must be inoperable on the basis of involvement of pelvic sidewall or adjacent viscera (clinical Stage T4b) or bulky nodal metastasis (N2-N3).
- •Measurable disease, as defined by RECIST v1.1
- •Representative formalin-fixed paraffin-embedded (FFPE) tumor specimens (metastatic specimens preferable but if not available primary tumor specimens that are at least muscle-invasive are acceptable) in paraffin blocks (blocks preferred) or at least 15 unstained slides. If archival tissue is not available, subjects may be considered for enrollment on a case by case basis after discussion with the sponsor-investigator.
- •No prior chemotherapy for inoperable locally advanced or mUC. For patients who received prior adjuvant/neoadjuvant chemotherapy or chemo-radiation for urothelial carcinoma, a treatment-free interval > 12 months between the last treatment administration and the date of recurrence is required in order to be considered treatment naive in the metastatic setting.
- •Cisplatin-ineligible as defined by at least one of the following:
- •Calculated creatinine clearance ≥ 30 (Cockroft-Gault)
- •ECOG performance status of 2 or greater
- •CTCAE v4 Grade ≥ 2 audiometric hearing loss
- •Demonstrate adequate organ function. All screening labs to be obtained within 28 days prior to registration:
- •Hematological:
- •Absolute Neutrophil Count (ANC) ≥ 1.5 x 10^9/L
- •Hemoglobin (Hgb) ≥ 9 g/dL
- •Platelets ≥ 100 x 10^9/L
- •Calculated creatinine clearance ≥ 30 mL/min (Cockroft-Gault)
- •Bilirubin ≤ 1.5 × upper limit of normal (ULN) (except subjects with Gilbert Syndrome, who can have total bilirubin < 3.0 mg/dL)
- •Aspartate aminotransferase (AST) ≤ 3 × ULN
- •Alanine aminotransferase (ALT) ≤ 3 × ULN
- •Women of childbearing potential must have a negative serum or urine pregnancy.
- •Women of childbearing potential (WOCBP) and male subjects must use appropriate method(s) of contraception as stated for the timeline below. Male subjects are not required to use contraception as outlined in protocol.
排除标准
- •Subjects meeting any of the criteria below may not participate in the study:
- •Active infection requiring systemic therapy.
- •Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while the mother is being treated on study).
- •Any serious or uncontrolled medical disorder that, in the opinion of the site investigator, may increase the risk associated with study participation or study drug administration, impair the ability of the subject to receive protocol therapy, or interfere with the interpretation of study results.
- •Prior malignancy active within the previous 3 years except for locally curable cancers that have been apparently cured.
- •Subjects with active, known or suspected autoimmune disease. Subjects with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.
- •Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
- •Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways.
- •Grade ≥ 2 neuropathy (NCI CTCAE version 4).
- •Known positive result for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (RNA) or hepatitis C antibody (HCV antibody) indicating acute or chronic infection. Testing at screening is not required.
- •Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).
- •Evidence of interstitial lung disease or active, non-infectious pneumonitis.
- •Significant cardiovascular disease, such as New York Heart Association cardiac disease (Class III or greater), myocardial infarction within 3 months prior to randomization, unstable arrhythmias, or unstable angina.
- •Known left ventricular ejection fraction (LVEF) < 40% Patients with known coronary artery disease, congestive heart failure not meeting the above criteria, or LVEF 40%-50% must be on a stable medical regimen that is optimized in the opinion of the treating physician, in consultation with a cardiologist if appropriate.
- •Solid organ or tissue transplant including stem cell transplant
研究组 & 干预措施
Arm A
Gemcitabine plus carboplatin plus nivolumab
干预措施: Gemcitabine (Drug)
Arm A
Gemcitabine plus carboplatin plus nivolumab
干预措施: Nivolumab (Drug)
Arm A
Gemcitabine plus carboplatin plus nivolumab
干预措施: Carboplatin (Drug)
Arm B
Gemcitabine plus oxaliplatin plus nivolumab
干预措施: Nivolumab (Drug)
Arm B
Gemcitabine plus oxaliplatin plus nivolumab
干预措施: Gemcitabine (Drug)
Arm B
Gemcitabine plus oxaliplatin plus nivolumab
干预措施: Oxaliplatin (Drug)
结局指标
主要结局
Objective Response Rate (ORR)
时间窗: Up to a maximum of 50 months
Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST): Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Progressive Disease (PD) \>= 20% increase in tumor burden relative to nadir or the appearance of one or more new lesions; Stable Disease (SD), not meet criteria for CR/PR/PD. ORR is defined as the percentage of patients who achieve a response (confirmed PR or CR) according to RECIST 1.1.
次要结局
- Duration of Response (DOR)(Up to a maximum of 50 months)
- Adverse Events(AE had been recorded from time of signed informed consent until 30 days after discontinuation of study drug(s) or until a new anti-cancer treatment starts, whichever occurs first, up to a maximum of 19 months.)
- Overall Survival (OS)(Up to a maximum of 53 months)
- Progression-Free Survival (PFS)(Up to maximum of 50 months)
研究者
Matthew Galsky
Sponsor-Investigator
Hoosier Cancer Research Network