Trial Outcomes & Findings for Phase I/II Trial of Alectinib and Bevacizumab in Patients With Advanced, Anaplastic Lymphoma Kinase (ALK)-Positive, Non-Small Cell Lung Cancer (NCT NCT02521051)

Phase I/II Trial of Alectinib and Bevacizumab in Patients With Advanced, Anaplastic Lymphoma Kinase (ALK)-Positive, Non-Small Cell Lung Cancer

The recommended phase II doses for the combination of alectinib and bevacizumab will be defined as either a) the highest dosage cohort in which less than 1/3 of patients experience a dose-limiting toxicity or b) alectinib at the previously defined recommended phase II dose (600 mg twice daily PO) as a single agent plus bevacizumab at the highest tolerated dose (15 mg/kg IV every 21 days) investigated in this indication - whichever is the lower dose. Dose-limiting toxicities (DLTs) were defined as adverse events (AEs) occurring within the first cycle of treatment (21 days) attributed to the study drugs.

The recommended phase II doses for the combination of alectinib and bevacizumab will be defined as either a) the highest dosage cohort in which less than 1/3 of patients experience a dose-limiting toxicity or b) alectinib at the previously defined recommended phase II dose (600 mg twice daily PO) as a single agent plus bevacizumab at the highest tolerated dose (15 mg/kg IV every 21 days) investigated in this indication - whichever is the lower dose. Dose-limiting toxicities (DLTs) were defined as adverse events (AEs) occurring within the first cycle of treatment (21 days) attributed to the study drugs.

In the phase II portion of the study, we aim to further investigate the safety and tolerability of alectinib plus bevacizumab at the RP2Ds as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. The combination of alectinib and bevacizumab will be deemed unsafe if 2 or more participants are observed to have grade 2 or higher, central nervous system (CNS) intracranial hemorrhagic events.

Objective response rate (ORR) is defined as the percentage of participants with complete response (CR) or partial response (PR), evaluated using a modified Response Evaluation Criteria In Solid Tumors (RECIST) criteria for CNS response: * CR = Disappearance of all target lesions. Any pathological lymph node must have reduction in short axis to less than 10 mm. * PR = At least a 30% decrease in the sum of the longest diameters of target lesions, taking as reference the baseline sum diameters.

Disease control rate (DCR) is the percentage of participants with intracranial complete response (CR), partial response (PR), and stable disease (SD), evaluated using a modified Response Evaluation Criteria In Solid Tumors (RECIST) criteria for CNS response: * CR = Disappearance of all target lesions. Any pathological lymph node must have reduction in short axis to less than 10 mm. * PR = At least a 30% decrease in the sum of the longest diameters of target lesions, taking as reference the baseline sum diameters. * SD = Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the baseline sum diameters. * PD = At least a 20% increase in the sum of the longest diameters of target lesions, taking as reference the baseline sum diameters. At least a 5 mm absolute increase in the sum of all lesions. The appearance of one or more new lesions also qualifies as PD.

Progression-free survival (PFS) is defined as the time from the start of study treatment to the date of progressive disease (PD) in the central nervous system (CNS) or death due to CNS disease. PD is evaluated using a modified Response Evaluation Criteria In Solid Tumors (RECIST) criteria for CNS response: \* PD = At least a 20% increase in the sum of the longest diameters of target lesions, taking as reference the baseline sum diameters. At least a 5 mm absolute increase in the sum of all lesions. The appearance of one or more new lesions also qualifies as PD.

Objective response rate (ORR) is defined as the percentage of participants with intra- and extra-cranial complete response (CR) or partial response (PR), evaluated using Response Evaluation Criteria In Solid Tumors (RECIST) criteria version 1.1. * CR = Disappearance of all target lesions. Any pathological lymph node must have reduction in short axis to less than 10 mm. * PR = At least a 30% decrease in the sum of the longest diameters of target lesions, taking as reference the baseline sum diameters.

Disease control rate (DCR) is the percentage of participants with intra- and extra-cranial complete response (CR), partial response (PR), and stable disease (SD), evaluated using Response Evaluation Criteria In Solid Tumors (RECIST) criteria version1.1: * CR = Disappearance of all target lesions. Any pathological lymph node must have reduction in short axis to less than 10 mm. * PR = At least a 30% decrease in the sum of the longest diameters of target lesions, taking as reference the baseline sum diameters. * SD = Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the baseline sum diameters. * PD = At least a 20% increase in the sum of the longest diameters of target lesions, taking as reference the baseline sum diameters. At least a 5 mm absolute increase in the sum of all lesions. The appearance of one or more new lesions also qualifies as PD.

Progression-free survival (PFS) is defined as the time from the start of study treatment to the date of progressive disease (PD) or death due to any cause. PD is evaluated using Response Evaluation Criteria In Solid Tumors (RECIST) criteria version1.1: \- PD = At least a 20% increase in the sum of the longest diameters of target lesions, taking as reference the baseline sum diameters. At least a 5 mm absolute increase in the sum of all lesions. The appearance of one or more new lesions also qualifies as PD.

The European Organization for Research and Treatment of Cancer quality of life questionnaire (EORTC QLQ-C30) is designed to measure cancer patients' physical, psychological and social functions. The questionnaire is composed of functional scales, symptom scales, a global health status/quality of life (QOL) scale. All of the scales range in score from 0 to 100. A summary score is calculated as the average of all scores. High score for functional scales mean high level of functioning. High score for global health status means high quality of life. High score for symptom scales mean high level of problems.

The European Organization for Research and Treatment of Cancer quality of life questionnaire has a brain cancer nodule (EORTC QLQ-BN20) developed for patients undergoing chemotherapy or radiotherapy. It includes 20 items, 13 of which aggregate into four scales assessing future uncertainty, visual disorder, motor dysfunction, and communication deficit. The remaining single items assess other disease symptoms (e.g. headaches and seizures) and treatment toxic effects (e.g. hair loss). Raw scores items were computed and subsequently transformed linearly to a 0-100 scale. A higher score represents worse quality of life.