A Randomized Phase II Trial of Cabozantinib and Cabozantinib Plus Nivolumab Versus Standard Chemotherapy in Patients With Previously Treated Non-Squamous NSCLC
概览
- 阶段
- 2 期
- 干预措施
- Biospecimen Collection
- 疾病 / 适应症
- Metastatic Lung Non-Squamous Non-Small Cell Carcinoma
- 发起方
- National Cancer Institute (NCI)
- 入组人数
- 117
- 试验地点
- 1225
- 主要终点
- Progression-free survival (PFS) for patient population with non-squamous no-small cell lung cancer (NSCLC)
- 状态
- 进行中（未招募）
- 最后更新
- 昨天
概览
简要总结
This phase II trial compares cabozantinib alone and the combination of cabozantinib and nivolumab to standard chemotherapy in the treatment of patients with non-squamous non-small cell lung cancer (NSCLC). Cabozantinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Ramucirumab is a monoclonal antibody that may interfere with the ability of tumor cells to grow and spread. Chemotherapy drugs, such as docetaxel, gemcitabine hydrochloride, paclitaxel, and nab-paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving cabozantinib alone or in combination with nivolumab may be more effective than standard chemotherapy in treating patients with non-small cell lung cancer.
详细描述
PRIMARY OBJECTIVE: I. To determine whether cabozantinib alone, or the combination of nivolumab and cabozantinib, as compared to standard chemotherapy alone, extends progression-free survival (PFS) for this patient population with non squamous NSCLC. SECONDARY OBJECTIVES: I. To determine the overall survival for each arm of the trial. II. To evaluate the best overall radiographic response rate for each arm of the trial. III. To evaluate and describe the toxicity profile of monotherapy with cabozantinib, and the combination of nivolumab and cabozantinib in this patient population with non-squamous NSCLC. EXPLORATORY IMAGING OBJECTIVES: I. To describe time point tumor response assessment, overall best response, progression-free survival and overall survival using the conventional Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria and the exploratory revised CHOI criteria with all measurements performed by the central review. II. To compare the progression-free survival using the RECIST1.1 imaging response assessment measurements by site study personnel to those performed by central review. EXPLORATORY CORRELATIVE OBJECTIVE: I. To perform correlative biomarker research on tissue and blood biospecimens collected within this trial. OUTLINE: STEP 1: Patients are randomized to 1 of 3 arms. ARM A: Patients receive cabozantinib S-malate orally (PO) once daily (QD). Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients may continue to receive therapy after investigator-assessed RECIST 1.1 defined progression, including stable clinical and performance status and have potential for continued clinical benefit. ARM B: Patients receive cabozantinib S-malate PO QD and nivolumab intravenously (IV) over 30 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients may continue to receive therapy after investigator-assessed RECIST 1.1 defined progression, including stable clinical and performance status and have potential for continued clinical benefit. ARM C: Patients receive ramucirumab IV over 30-60 minutes and docetaxel IV over 1 hour on day 1, or docetaxel IV over 1 hour on days 1 and 8, or gemcitabine hydrochloride IV on days 1 and 8, or paclitaxel IV over 3 hours on day 1, or nab-paclitaxel IV over 30 minutes on days 1 and 8. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity and at the discretion of the treating physician. STEP 2: Patients in Arm C experiencing disease progression are assigned to Arm Z. ARM Z: Patients receive cabozantinib S-malate PO QD and nivolumab IV over 30 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients may continue to receive therapy after investigator-assessed RECIST 1.1 defined progression, including stable clinical and performance status and have potential for continued clinical benefit. Patients in all arms undergo echocardiogram (ECHO) as clinically indicated, computed tomography (CT) throughout the trial, and collection of blood on study. After the completion of study treatment, patients are followed up every 3 months for up to 3 years.
研究者
入排标准
入选标准
- •RANDOMIZATION (STEP 1): Patient must be \>= 18 years of age
- •RANDOMIZATION (STEP 1): Patient must have pathologically confirmed non-squamous non-small cell lung carcinoma (NSCLC). Patients with NSCLC not otherwise specified (NOS) are eligible. Mixed tumors will be categorized by predominant cell type. If small cell elements are present, the patient is ineligible
- •RANDOMIZATION (STEP 1): Patient must have metastatic stage IVA or IVB disease (includes M1a, M1b, and M1c), according to the 8th edition of the lung cancer TNM classification system. Recurrent metastatic NSCLC ineligible for curative therapy (in the treating investigator's opinion) is also allowed
- •RANDOMIZATION (STEP 1): Patient's tumor must be known negative for EGFR tyrosine kinase inhibitor (TKI) sensitizing mutations (for example at a minimum, negative for EGFR Exon 19 deletions, EGFR exon 20 insertions, and Exon 21 L858R, L861Q mutations ) AND negative for ALK gene rearrangements (by fluorescence in situ hybridization \[FISH\], next generation sequencing \[NGS\], or immunohistochemistry \[IHC\]) by routine Clinical Laboratory Improvement Amendments (CLIA)- or Food and Drug Administration (FDA)-certified clinical testing methods. CLIA or FDA approved circulating tumor deoxyribonucleic acid (DNA) testing is acceptable as an alternative to tissue testing
- •RANDOMIZATION (STEP 1): Patient must have radiographic and/or clinical progression (per local investigator assessment) following one, but only one, line of platinum-based chemotherapy AND one, but only one, line of prior checkpoint inhibitor (anti-PD-1 or PD-L1) immunotherapy, either concurrently or sequentially in either order. A minimum of two doses of prior immunotherapy is required. Only one prior line of therapy is allowed if patients received chemotherapy and immunotherapy together (patients may not receive subsequent single agent chemotherapy), and greater than two prior lines of therapy are not allowed.
- •NOTE: Lines of therapy are defined by clinical or radiographic progression. For patients with recurrent metastatic NSCLC following treatment for stage 1-3 NSCLC, platinum-based chemotherapy received within 12 months of recurrence and/or immunotherapy received within 6 months of recurrence will meet the requirement for prior chemotherapy and/or immunotherapy but subsequent receipt of more immunotherapy and/or platinum-based chemotherapy is also allowed.
- •NOTE: Prior anti-VEGF antibody therapy (ie bevacizumab) is allowed. Prior ipilimumab, or investigational agents not excluded below, in combination with the required prior therapies above are allowed.
- •NOTE: Prior receipt of one or two lines of targeted therapy for ROS1, RET, MET, BRAF, ERBB2/HER2, or KRAS G12C positive NSCLC is allowed and will not count toward the line of therapy limit. However, progression is still required after chemotherapy and immunotherapy as above. Patients with ROS1, RET, MET positive NSCLC are strongly encouraged to get appropriate targeted therapy (such as crizotinib, entrectinib, lorlatinib, selpercatinib, pralsetinib, capmatinib, tepotinib, or another investigational, off-label, or approved agent directed against ROS1, RET, or MET positive NSCLC) prior to participation and will be stratified.
- •NOTE: No prior predominantly VEGFR directed TKI therapy (such as cabozantinib, lenvatinib, or sitravantinib) is allowed, except for the agents named above.
- •RANDOMIZATION (STEP 1): The investigator must document the intended chemotherapy regimen should their patient be randomized to Arm C (docetaxel and ramucirumab, OR single agent chemotherapy - docetaxel, gemcitabine, paclitaxel, nab-paclitaxel). The patient must not have received the selected chemotherapy agent previously for metastatic disease
排除标准
- 未提供
研究组 & 干预措施
Step 1, Arm C (standard chemotherapy)
Patients in Step 1, Arm C receive ramucirumab IV over 30-60 minutes and docetaxel IV over 1 hour on day 1, or docetaxel IV over 1 hour on days 1 and 8, or gemcitabine hydrochloride IV on days 1 and 8, or paclitaxel IV over 3 hours on day 1, or nab-paclitaxel IV over 30 minutes on days 1 and 8. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity and at the discretion of the treating physician. Patients also undergo ECHO as clinically indicated, CT throughout the trial, and collection of blood on study.
干预措施: Biospecimen Collection
Step 1, Arm A (cabozantinib S-malate)
Patients in Step 1, Arm A receive cabozantinib S-malate PO QD. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients may continue to receive therapy after investigator-assessed RECIST 1.1 defined progression, including stable clinical and performance status and have potential for continued clinical benefit. Patients also undergo ECHO as clinically indicated, CT throughout the trial, and collection of blood on study.
干预措施: Biospecimen Collection
Step 1, Arm A (cabozantinib S-malate)
Patients in Step 1, Arm A receive cabozantinib S-malate PO QD. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients may continue to receive therapy after investigator-assessed RECIST 1.1 defined progression, including stable clinical and performance status and have potential for continued clinical benefit. Patients also undergo ECHO as clinically indicated, CT throughout the trial, and collection of blood on study.
干预措施: Computed Tomography
Step 1, Arm B (cabozantinib S-malate, nivolumab)
Patients in Step 1, Arm B receive cabozantinib S-malate PO QD and nivolumab IV over 30 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients may continue to receive therapy after investigator-assessed RECIST 1.1 defined progression, including stable clinical and performance status and have potential for continued clinical benefit. Patients also undergo ECHO as clinically indicated, CT throughout the trial, and collection of blood on study.
干预措施: Echocardiography Test
Step 1, Arm C (standard chemotherapy)
Patients in Step 1, Arm C receive ramucirumab IV over 30-60 minutes and docetaxel IV over 1 hour on day 1, or docetaxel IV over 1 hour on days 1 and 8, or gemcitabine hydrochloride IV on days 1 and 8, or paclitaxel IV over 3 hours on day 1, or nab-paclitaxel IV over 30 minutes on days 1 and 8. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity and at the discretion of the treating physician. Patients also undergo ECHO as clinically indicated, CT throughout the trial, and collection of blood on study.
干预措施: Computed Tomography
Step 1, Arm C (standard chemotherapy)
Patients in Step 1, Arm C receive ramucirumab IV over 30-60 minutes and docetaxel IV over 1 hour on day 1, or docetaxel IV over 1 hour on days 1 and 8, or gemcitabine hydrochloride IV on days 1 and 8, or paclitaxel IV over 3 hours on day 1, or nab-paclitaxel IV over 30 minutes on days 1 and 8. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity and at the discretion of the treating physician. Patients also undergo ECHO as clinically indicated, CT throughout the trial, and collection of blood on study.
干预措施: Echocardiography Test
Step 2, Arm Z (cabozantinib S-malate, nivolumab)
Patients in Step 2, Arm Z receive cabozantinib S-malate PO QD and nivolumab IV over 30 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients may continue to receive therapy after investigator-assessed RECIST 1.1 defined progression, including stable clinical and performance status and have potential for continued clinical benefit. Patients also undergo ECHO as clinically indicated, CT throughout the trial, and collection of blood on study.
干预措施: Computed Tomography
Step 2, Arm Z (cabozantinib S-malate, nivolumab)
Patients in Step 2, Arm Z receive cabozantinib S-malate PO QD and nivolumab IV over 30 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients may continue to receive therapy after investigator-assessed RECIST 1.1 defined progression, including stable clinical and performance status and have potential for continued clinical benefit. Patients also undergo ECHO as clinically indicated, CT throughout the trial, and collection of blood on study.
干预措施: Biospecimen Collection
Step 2, Arm Z (cabozantinib S-malate, nivolumab)
Patients in Step 2, Arm Z receive cabozantinib S-malate PO QD and nivolumab IV over 30 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients may continue to receive therapy after investigator-assessed RECIST 1.1 defined progression, including stable clinical and performance status and have potential for continued clinical benefit. Patients also undergo ECHO as clinically indicated, CT throughout the trial, and collection of blood on study.
干预措施: Echocardiography Test
Step 1, Arm C (standard chemotherapy)
Patients in Step 1, Arm C receive ramucirumab IV over 30-60 minutes and docetaxel IV over 1 hour on day 1, or docetaxel IV over 1 hour on days 1 and 8, or gemcitabine hydrochloride IV on days 1 and 8, or paclitaxel IV over 3 hours on day 1, or nab-paclitaxel IV over 30 minutes on days 1 and 8. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity and at the discretion of the treating physician. Patients also undergo ECHO as clinically indicated, CT throughout the trial, and collection of blood on study.
干预措施: Ramucirumab
Step 1, Arm B (cabozantinib S-malate, nivolumab)
Patients in Step 1, Arm B receive cabozantinib S-malate PO QD and nivolumab IV over 30 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients may continue to receive therapy after investigator-assessed RECIST 1.1 defined progression, including stable clinical and performance status and have potential for continued clinical benefit. Patients also undergo ECHO as clinically indicated, CT throughout the trial, and collection of blood on study.
干预措施: Biospecimen Collection
Step 1, Arm A (cabozantinib S-malate)
Patients in Step 1, Arm A receive cabozantinib S-malate PO QD. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients may continue to receive therapy after investigator-assessed RECIST 1.1 defined progression, including stable clinical and performance status and have potential for continued clinical benefit. Patients also undergo ECHO as clinically indicated, CT throughout the trial, and collection of blood on study.
干预措施: Echocardiography Test
Step 1, Arm B (cabozantinib S-malate, nivolumab)
Patients in Step 1, Arm B receive cabozantinib S-malate PO QD and nivolumab IV over 30 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients may continue to receive therapy after investigator-assessed RECIST 1.1 defined progression, including stable clinical and performance status and have potential for continued clinical benefit. Patients also undergo ECHO as clinically indicated, CT throughout the trial, and collection of blood on study.
干预措施: Cabozantinib S-malate
Step 1, Arm B (cabozantinib S-malate, nivolumab)
Patients in Step 1, Arm B receive cabozantinib S-malate PO QD and nivolumab IV over 30 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients may continue to receive therapy after investigator-assessed RECIST 1.1 defined progression, including stable clinical and performance status and have potential for continued clinical benefit. Patients also undergo ECHO as clinically indicated, CT throughout the trial, and collection of blood on study.
干预措施: Computed Tomography
Step 1, Arm B (cabozantinib S-malate, nivolumab)
Patients in Step 1, Arm B receive cabozantinib S-malate PO QD and nivolumab IV over 30 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients may continue to receive therapy after investigator-assessed RECIST 1.1 defined progression, including stable clinical and performance status and have potential for continued clinical benefit. Patients also undergo ECHO as clinically indicated, CT throughout the trial, and collection of blood on study.
干预措施: Nivolumab
Step 1, Arm C (standard chemotherapy)
Patients in Step 1, Arm C receive ramucirumab IV over 30-60 minutes and docetaxel IV over 1 hour on day 1, or docetaxel IV over 1 hour on days 1 and 8, or gemcitabine hydrochloride IV on days 1 and 8, or paclitaxel IV over 3 hours on day 1, or nab-paclitaxel IV over 30 minutes on days 1 and 8. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity and at the discretion of the treating physician. Patients also undergo ECHO as clinically indicated, CT throughout the trial, and collection of blood on study.
干预措施: Docetaxel
Step 1, Arm C (standard chemotherapy)
Patients in Step 1, Arm C receive ramucirumab IV over 30-60 minutes and docetaxel IV over 1 hour on day 1, or docetaxel IV over 1 hour on days 1 and 8, or gemcitabine hydrochloride IV on days 1 and 8, or paclitaxel IV over 3 hours on day 1, or nab-paclitaxel IV over 30 minutes on days 1 and 8. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity and at the discretion of the treating physician. Patients also undergo ECHO as clinically indicated, CT throughout the trial, and collection of blood on study.
干预措施: Paclitaxel
Step 2, Arm Z (cabozantinib S-malate, nivolumab)
Patients in Step 2, Arm Z receive cabozantinib S-malate PO QD and nivolumab IV over 30 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients may continue to receive therapy after investigator-assessed RECIST 1.1 defined progression, including stable clinical and performance status and have potential for continued clinical benefit. Patients also undergo ECHO as clinically indicated, CT throughout the trial, and collection of blood on study.
干预措施: Cabozantinib S-malate
Step 2, Arm Z (cabozantinib S-malate, nivolumab)
Patients in Step 2, Arm Z receive cabozantinib S-malate PO QD and nivolumab IV over 30 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients may continue to receive therapy after investigator-assessed RECIST 1.1 defined progression, including stable clinical and performance status and have potential for continued clinical benefit. Patients also undergo ECHO as clinically indicated, CT throughout the trial, and collection of blood on study.
干预措施: Nivolumab
Step 1, Arm A (cabozantinib S-malate)
Patients in Step 1, Arm A receive cabozantinib S-malate PO QD. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients may continue to receive therapy after investigator-assessed RECIST 1.1 defined progression, including stable clinical and performance status and have potential for continued clinical benefit. Patients also undergo ECHO as clinically indicated, CT throughout the trial, and collection of blood on study.
干预措施: Cabozantinib S-malate
Step 1, Arm C (standard chemotherapy)
Patients in Step 1, Arm C receive ramucirumab IV over 30-60 minutes and docetaxel IV over 1 hour on day 1, or docetaxel IV over 1 hour on days 1 and 8, or gemcitabine hydrochloride IV on days 1 and 8, or paclitaxel IV over 3 hours on day 1, or nab-paclitaxel IV over 30 minutes on days 1 and 8. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity and at the discretion of the treating physician. Patients also undergo ECHO as clinically indicated, CT throughout the trial, and collection of blood on study.
干预措施: Nab-paclitaxel
Step 1, Arm C (standard chemotherapy)
Patients in Step 1, Arm C receive ramucirumab IV over 30-60 minutes and docetaxel IV over 1 hour on day 1, or docetaxel IV over 1 hour on days 1 and 8, or gemcitabine hydrochloride IV on days 1 and 8, or paclitaxel IV over 3 hours on day 1, or nab-paclitaxel IV over 30 minutes on days 1 and 8. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity and at the discretion of the treating physician. Patients also undergo ECHO as clinically indicated, CT throughout the trial, and collection of blood on study.
干预措施: Gemcitabine Hydrochloride
结局指标
主要结局
Progression-free survival (PFS) for patient population with non-squamous no-small cell lung cancer (NSCLC)
时间窗: After 58 events (From time of randomization to documented disease progression [site review of imaging] or death from any cause, whichever occurs first)
The final analysis of PFS will be performed when the full information of PFS is reached (i.e., 58 events for each of the two primary comparisons). The two primary comparisons of PFS will each use a logrank test stratified on the randomization stratification factors with a one-sided type I error rate of 10%. Estimates of PFS including medians and confidence intervals, will be calculated using the Kaplan-Meier method. Cox proportional hazards models, stratified, on the same factors, will be used to estimate the treatment hazard ratios. At the final analyses, in the event that both primary PFS comparisons of the combination of nivolumab with cabozantinib and cabozantinib alone versus the standard chemotherapy are statistically significant, PFS will be compared between the two experimental arms (combination of nivolumab with cabozantinib versus \[vs.\] cabozantinib alone), using a stratified log rank test with a one-sided type I error rate of 10%.
次要结局
- Best objective response for each arm(Every 6 weeks for the first year on study, and then every 12 weeks after year one)
- Overall survival (OS) for each arm(From time of randomization to documented disease progression (site review of imaging) or death from any cause, whichever occurs first, assessed up to 3 years)
- Toxicity profile of monotherapy with cabozantinib, and the combination of nivolumab and cabozantinib(Up to 3 years after completion of study treatment)