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Report for Clinical Trial NCT04310007

Developed by Shray Alag, 2020.
SNP Clinical Trial Gene

A Randomized Phase II Trial of Cabozantinib and Cabozantinib Plus Nivolumab Versus Standard Chemotherapy in Patients With Previously Treated Non-Squamous NSCLC

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.

NCT04310007 Metastatic Lung Non-Squamous Non-Small Cell Carcinoma Recurrent Lung Non-Squamous Non-Small Cell Carcinoma Stage III Lung Cancer AJCC v8 Stage IIIA Lung Cancer AJCC v8 Stage IIIB Lung Cancer AJCC v8 Stage IIIC Lung Cancer AJCC v8 Stage IVA Lung Cancer AJCC v8 Unresectable Lung Non-Squamous Non-Small Cell Carcinoma
MeSH:Carcinoma Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Carcinoma Neoplasm of the lung Non-small cell lung carcinoma

7 Interventions

Name: Cabozantinib S-malate

Description: Given PO
Type: Drug
Group Labels: 3

Arm A (cabozantinib S-malate) Arm B (cabozantinib S-malate, nivolumab) Arm C (standard chemotherapy,cabozantinib S-malate, nivolumab)

Name: Docetaxel

Description: Given IV
Type: Drug
Group Labels: 1

Arm C (standard chemotherapy,cabozantinib S-malate, nivolumab)

Name: Gemcitabine Hydrochloride

Description: Given PO
Type: Drug
Group Labels: 1

Arm C (standard chemotherapy,cabozantinib S-malate, nivolumab)

Name: Nab-paclitaxel

Description: Given IV
Type: Drug
Group Labels: 1

Arm C (standard chemotherapy,cabozantinib S-malate, nivolumab)

Name: Nivolumab

Description: Given IV
Type: Biological
Group Labels: 2

Arm B (cabozantinib S-malate, nivolumab) Arm C (standard chemotherapy,cabozantinib S-malate, nivolumab)

Name: Paclitaxel

Description: Given IV
Type: Drug
Group Labels: 1

Arm C (standard chemotherapy,cabozantinib S-malate, nivolumab)

Name: Ramucirumab

Description: Given IV
Type: Biological
Group Labels: 1

Arm C (standard chemotherapy,cabozantinib S-malate, nivolumab)


Primary Outcomes

Description: 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%.

Measure: Progression-free survival (PFS) for patient population with non-squamous no-small cell lung cancer (NSCLC)

Time: After 58 events (From time of randomization to documented disease progression [site review of imaging] or death from any cause, whichever occurs first)

Secondary Outcomes

Description: The final analysis of OS will be performed when the full information of PFS is reached (i.e., 58 events for each of the two primary comparisons). OS will be tested in a hierarchical fashion if the primary comparison of PFS between treatment arms is statistically significant, using a log rank test stratified on the randomization stratification factors with a one-sided type I error rate of 10%. Estimates of OS, 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. OS will be further tested in a hierarchical fashion if the comparison of PFS between the two experimental arms is statistically significant. Point estimates of all endpoints will be accompanied by the corresponding two-sided 80% confidence intervals. Subset analyses of PFS and OS by treatment arm will be estimated and compared within subsets.

Measure: Overall survival (OS) for each arm

Time: 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

Description: Will be evaluated via Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. Response rates (complete response [CR] + partial response [PR]) and toxicity will be compared using Fisher's exact tests with a one-sided type I error rate of 10%; multivariable logistic regression modeling will be used to adjust for the effect of any covariates that are associated with these categorical outcomes. Modeling procedures will implement backward selection; variables significant at the 0.10 level in the univariate setting will be chosen for inclusion in an initial full model, and at each step the least significant variable will be removed from the model. Only those covariates with p < 0.05 will remain in any final models, unless there are factors identified by the study team as crucial to model interpretation. Point estimates of all endpoints will be accompanied by the corresponding two-sided 80% confidence intervals.

Measure: Best objective response for each arm

Time: Every 6 weeks for the first year on study, and then every 12 weeks after year one

Description: Will be determined using the Common Terminology Criteria for Adverse Events (CTCAE) criteria. Response rates (complete response [CR] + pathologic response [PR]) and toxicity will be compared using Fisher's exact tests with a one-sided type I error rate of 10%; multivariable logistic regression modeling will be used to adjust for the effect of any covariates that are associated with these categorical outcomes. Modeling procedures will implement backward selection; variables significant at the 0.10 level in the univariate setting will be chosen for inclusion in an initial full model, and at each step the least significant variable will be removed from the model. Only those covariates with p < 0.05 will remain in any final models, unless there are factors identified by the study team as crucial to model interpretation. Point estimates of all endpoints will be accompanied by the corresponding two-sided 80% confidence intervals.

Measure: Toxicity profile of monotherapy with cabozantinib, and the combination of nivolumab and cabozantinib

Time: Up to 3 years after completion of study treatment

Other Outcomes

Description: The measurement of each time point will be performed using the revised CHOI criteria will be only applied to arms A, B, and T, which will include anti-angiogenic therapy. Both the RECIST1.1 and revised CHOI criteria will assess the overall best response as CR, partial PR, stable disease (SD), or progressive disease (PD). Their concordance will be assessed using the weighted Cohen's kappa coefficient (k) with quadratic weights. As a rule of thumb, the level of concordance between the two criteria will be considered poor (k <0), slight (k 0-0.20), fair (k 0.21-0.40), moderate (k 0.41-0.60), substantial (k 0.61-0.80), and almost perfect (k 0.81 - 1).

Measure: The RECIST1.1 response at each time point

Time: Every 6 weeks for the first year on study, and then every 12 weeks after year one

Description: The progression status and the progression time will be assessed in agreement. The progression status is a binary measurement and the agreement will be assessed using the Cohen's kappa coefficient. For progression time, will assess the temporal agreement using the method developed by Zeng et al.

Measure: Agreement between central view and site review in terms of progression-free survival

Time: After the completion of study treatment

Description: Correlative biomarker research will be performed on tissue and blood specimens collected within this trial.

Measure: Correlative biomarker research

Time: After the completion of study treatment

Purpose: Treatment

Allocation: Randomized

Parallel Assignment


There are 2 SNPs

SNPs


1 L858R

If small cell elements are present the patient is ineligible - ELIGIBILITY CRITERIA FOR STEP 0 (PRE-REGISTRATION): Patient's tumor(s) must be tested and known negative for EGFR TKI sensitizing mutations (EGFR Exon 19 deletions, L858R, L861Q, G719X) and ALK gene rearrangements (by FISH, NGS, or IHC) by routine Clinical Laboratory Improvement Act (CLIA)-certified clinical testing methods. --- L858R ---


2 L861Q

If small cell elements are present the patient is ineligible - ELIGIBILITY CRITERIA FOR STEP 0 (PRE-REGISTRATION): Patient's tumor(s) must be tested and known negative for EGFR TKI sensitizing mutations (EGFR Exon 19 deletions, L858R, L861Q, G719X) and ALK gene rearrangements (by FISH, NGS, or IHC) by routine Clinical Laboratory Improvement Act (CLIA)-certified clinical testing methods. --- L858R --- --- L861Q ---



HPO Nodes


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