Axitinib

Time in months from randomization to first documentation of objective tumor progression or death due to any cause. PFS calculated as (first event date minus date of randomization plus 1)/30.4. Tumor progression determined from oncologic assessment data (where it meets criteria for progressive disease \[PD\]), or from adverse event (AE) data (where outcome was "Death"). Progression using Response Evaluation Criteria in Solid Tumors (RECIST) is \>= 20 percent (%) increase in sum of longest diameter of target lesions; measurable increase in non-target lesion; appearance of new lesions.

Time in months from randomization to first documentation of objective tumor progression or death due to any cause. PFS calculated as (first event date minus date of randomization plus 1)/30.4. Tumor progression determined from oncologic assessment data (where it meets criteria for progressive disease \[PD\]), or from adverse event (AE) data (where outcome was "Death"). Progression using Response Evaluation Criteria in Solid Tumors (RECIST) is \>= 20 percent (%) increase in sum of longest diameter of target lesions; measurable increase in non-target lesion; appearance of new lesions.

PFS was defined as the time in months from start of study treatment to the first documentation of objective tumor progression of disease (PD) or to death due to any cause, whichever occurs first. PD was assessed by response evaluation criteria in solid tumors (RECIST) version 1.0. PD: \>=20 percent (%) increase in the sum of the longest dimensions (LD) of the target lesions taking as a reference the smallest sum of the LD recorded since the start of treatment or unequivocal progression in non-target lesions or the appearance of 1 or more new lesions. Occurrence of a pleural effusion or ascites was also considered PD if demonstrated by cytological investigation and it was not previously documented. New bone lesions not previously documented were considered PD if confirmed by computed tomography/magnetic resonance imaging or X-ray.

Time in weeks from randomization to date of death due to any cause. OS was calculated as (the death date minus the date of randomization plus 1) divided by 7. Death was determined from adverse event data (where outcome was death) or from follow-up contact data (where the participant current status was death).

over the total number of patients in a given cohort.

OS was defined as the time from the date of randomization to the date of death due to any cause. OS (in months) was calculated as (date of death - first randomization date +1)/30.4. For participants still alive at the time of the analysis, the OS time was censored on the last date they were known to be alive. All participants were followed up for survival at least every 3 months after discontinuing study treatment until at least two years after randomization of the last participant.

ORR was defined as the proportion of participants with objective response based assessment of complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST v1.0). CR was defined as complete disappearance of all target lesions and non-target disease. No new lesions. PR was defined as \>=30% decrease on study under baseline of the sum of longest diameters of all target lesions. No unequivocal progression of non-target disease. No new lesions.

Percentage of participants with objective response based on assessment of confirmed complete response (CR) or confirmed partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST). Confirmed response are those that persist on repeat imaging study at least 4 weeks after initial documentation of response. CR are those with disappearance of all target lesions. PR are those with at least 30 percent decrease in sum of the longest dimensions of target lesions taking as a reference the baseline sum longest dimensions.

Percentage of participants with objective response based assessment of confirmed CR or confirmed PR by the Independent Review Committee, according to Response Evaluation Criteria in Solid Tumors (RECIST Version 1.0). CR was defined as the disappearance of all target and nontarget lesions and no appearance of new lesions. PR was defined as at least a 30% decrease in the sum of the longest diameters of the targeted lesions. CR and PR had to be documented on 2 occasions separated by at least 4 weeks.

Percentage of participants with objective response based assessment of confirmed CR or confirmed PR by the investigator, according to Response Evaluation Criteria in Solid Tumors (RECIST Version 1.0). CR was defined as the disappearance of all target and nontarget lesions and no appearance of new lesions. PR was defined as at least a 30% decrease in the sum of the longest diameters of the targeted lesions. CR and PR had to be documented on 2 occasions separated by at least 4 weeks.

The AEs will be summarized and classified by body system and by treatment group. The type, incidence, severity, and causality of each AE, the duration of the event, and any required treatment interventions will be tabulated.

Dose escalation for this pilot study will be conducted using a CRM in which the probability of exceeding a blood selenium concentration of 45 µM on Day 14 is being modeled. Prior probabilities of exceeding a blood selenium concentration of 45 µM on Day 14 were estimated based on preclinical and preliminary data from the initial trial. A one parameter logistic model with intercept set at 3 and an initial value of 1 for the slope will be used to estimate the dose-concentration relationship through sequential recursive Bayesian assessment. The target probability of exceeding 45 µM is ≤20%.

DLT was defined as any of the following adverse events (AEs) occurring in the first two cycles of treatment which were attributable to one or both the study drugs: 1) Grade 4 neutropenia, 2) Febrile neutropenia lasting greater than (\>) 1 hour, 3) Grade greater than or equal to (\>=) 3 neutropenia with infection, 4) Grade \>=3 thrombocytopenia with bleeding, 4) Grade 4 thrombocytopenia, 5) Any grade \>=3 non-hematologic: non-laboratory toxicities despite maximum supportive therapy or hypertension despite maximal medical therapy, 6) Grade \>=3 non-hematologic toxicities resulted in hospitalisation or medical intervention 7) Inability to complete at least 75 percent (%) of axitinib dosing or 2 infusions of pembrolizumab within the DLT observation period (up to 42 days) due to treatment related toxicity. Severity of AEs was graded according to NCI (National Cancer Institute) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.

Toxicity as per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.03. DLT defined as any following events attributable to any (axitinib or crizotinib) or both agents in combination: hematologic (Grade 4 neutropenia, absolute neutrophil count\<1000/mm\^3 with single temperature of \>38.3 degrees celsius or sustained temperature of 38 degrees celsius for \>1 hour; \>=Grade 3 neutropenic infection; \>=Grade 3 thrombocytopenia with bleeding; Grade 4 thrombocytopenia), non-hematologic (\>=Grade 3 toxicities \[except asymptomatic hypophosphatemia, hyperuricemia without signs, symptoms of gout, and tumor lysis syndrome\], nausea, vomiting or diarrhea persisted at Grade 3 or 4 despite maximal medical therapy; Grade 3 hypertension if persistent despite anti-hypertensives); In asymptomatic participant, Grade 3 QTc prolongation (QTc\>=501 msec) if persisted after correcting reversible causes, and failure to deliver \>=75 percent (%) of dose of each study drug.

DLT = Grade (GR) 2 proteinuria; GR3 nonhematological toxicity (NHT) (excluding alopecia and those that can be controlled with appropriate treatment) for greater than or equal to (\>=)7 days, GR3 thrombocytopenia with active bleeding; GR \>=3 febrile neutropenia (NP) or NP infection; GR 3 or 4 nausea, vomiting or diarrhea despite anti-emetics, anti-diarrheals; GR4 NHT, thrombocytopenia, NP for \>=7 days; \>= 1/2 teaspoon per day hemoptysis; any treatment related toxicity with \>3 consecutive days of capecitabine or 5 consecutive days of axitinib missed doses per cycle; delayed toxicity recovery \>14 days.

AUCinf is obtained from AUC (0 - t) plus AUC (t - infinity).

Plasma decay half-life is the time measured for the plasma concentration to decrease by one half.

AUC (0 - ∞) = Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - ∞). It is obtained from AUC (0 - t) plus AUC (t - ∞).

Number of participants with any adverse events, adverse events graded as Common Terminology Criteria for Adverse Events Version 3.0 (CTCAE) Grade 3 or higher, serious adverse events, and adverse events resulted in discontinuation.

MTD defined as the dose level at which more than 1 out of 6 participants experienced a dose limiting toxicity (DLT). DLT included grade (Gr) 4 neutropenia or thrombocytopenia, greater than or equal to (\>=) Gr 3 nonhematological toxicities or \>=0.5 teaspoon/day hemoptysis or \>=2 gram /24 hours proteinuria or inability to resume background chemotherapy or axitinib (AG-013736) dosing within 14 days of stopping due to treatment related toxicity.

Time in days from start of study treatment to first documentation of objective tumor progression or death due to cancer, whichever comes first. TTP was calculated as first event date minus the date of first dose of study medication plus 1. Tumor progression was determined from oncologic assessment data (where data meet the criteria for progressive disease \[PD\]).

MTD is defined as the dose level at which "no more than 1 of 6 participants experience dose-limiting toxicity (DLT) following de-escalation from the maximum administered dose (MAD)." DLT includes grade (Gr) 2 or greater gastrointestinal toxicities, Gr 3 anemia, nonhematological toxicities (excluding nausea, vomiting, and diarrhea) or Gr 4 neutropenia, thrombocytopenia and inability to resume axitinib (AG-013736) dosing within 14 days of stopping due to treatment related toxicity.