A Phase 1b Study Of Axitinib In Combination With Crizotinib In Patients With Advanced Solid Tumors

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.

Time frame: Cycle 1 (28 days)

Population: Per protocol analysis set:all enrolled participants who received at least 1 dose of study drug, experienced either DLT during first cycle,or completed first cycle observation period.Participants who lost to follow up before receiving at least 75% of planned first cycle dose due to reasons other than treatment-related AEs were not evaluable for DLT.

Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Apparent oral clearance was obtained by dividing study drug dose with AUCtau, where AUCtau was area under the plasma concentration-time curve from time zero to the quantifiable concentration at the end of dosing interval. Data of this outcome measure was not planned to be analyzed for Cohort 2 in dose expansion part, as pre-specified in protocol.

Time frame: Axitinib: Pre-dose (0 hour [hr]), 1, 2, 3, 4, 6, 8 hrs post-dose at Lead-in Day 7, Cycle 1 Day 15; Crizotinib: pre-dose (0 hr), 1, 2, 3, 4, 6, 8 hrs post-dose at Cycle 1 Day 15

Population: The PK parameter analysis population was defined as all treated participants who had at least 1 of the PK parameters of interest of any of the study drugs.

Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Apparent volume of distribution after oral dose (Vz/F) is influenced by the fraction absorbed.

Time frame: Axitinib: Pre-dose (0 hour [hr]), 1, 2, 3, 4, 6, 8 hrs post-dose at Lead-in Day 7, Cycle 1 Day 15; Crizotinib: pre-dose (0 hr), 1, 2, 3, 4, 6, 8 hrs post-dose at Cycle 1 Day 15

Population: Data for this outcome measure was not collected due to change in planned analysis.

Area under the plasma concentration versus time-curve from time zero to end of dosing interval (AUCtau), where dosing interval was 12 hours. Data of this outcome measure was not planned to be analyzed for Cohort 2 in dose expansion part, as pre-specified in protocol.

Time frame: Axitinib: Pre-dose (0 hour [hr]), 1, 2, 3, 4, 6, 8 hrs post-dose at Lead-in Day 7, Cycle 1 Day 15; Crizotinib: pre-dose (0 hr), 1, 2, 3, 4, 6, 8 hrs post-dose at Cycle 1 Day 15

Population: The PK parameter analysis population was defined as all treated participants who had at least 1 of the PK parameters of interest of any of the study drugs.

Time frame: Baseline; Day 1 and 15 of Cycle 1; Day 1 of Cycles 2, 4, 6, 12, 24; and end of treatment (any time up to a maximum duration of 35 cycles in Part 1 and 35 cycles in Part 2, each cycle 28 days)

Population: Safety analysis set included all enrolled participants who received at least 1 dose of axitinib or crizotinib. Here, '0' in the number analyzed field signifies that none of the participant were evaluable at specified time point.

Time frame: Baseline; Day 1 and 15 of Cycle 1; Day 1 of Cycles 2, 4, 6, 12, 24; and end of treatment (any time up to a maximum duration of 35 cycles in Part 1 and 35 cycles in Part 2, each cycle 28 days)

Population: Safety analysis set included all enrolled participants who received at least 1 dose of axitinib or crizotinib. Here, '0' in the number analyzed field signifies that none of the participant were evaluable at specified time point.

Time frame: Baseline; Day 1 and 15 of Cycle 1; Day 1 of Cycles 2, 4, 6, 12, 24; and end of treatment (up to a maximum duration of 35 cycles in Part 1 and 35 cycles in Part 2, each cycle 28 days)

Population: Safety analysis set included all enrolled participants who received at least 1 dose of axitinib or crizotinib. Here, '0' in the number analyzed field signifies that none of the participant were evaluable at specified time point.

Time frame: Baseline, end of treatment (up to 35 cycles, each cycle 28 days)

Population: This outcome measure was not analyzed because of a change in planned analysis, due to the lack of strong evidence available supporting testing a hypothesis in the small sample set.

Plasma soluble protein biomarker included c-MET. Biomarker analysis was not planned to be performed in dose escalation part and Cohort 2 of dose expansion part, as pre-specified in protocol.

Time frame: Baseline; Day 1 and 15 of Cycle 1; Day 1 of Cycles 2, 3, 5; end of treatment (up to 35 cycles, each cycle 28 days)

Population: Plasma soluble protein biomarker analysis set included all enrolled participants who received at least one dose of any study drug, and had at least one biomarker parameter from the corresponding assay sample with at least one baseline biomarker measurement.

Serum soluble protein biomarkers included angiopoietin-2, Hepatocyte Growth Factor (HGF), Vascular Endothelial Growth Factor Receptor 3 (VEGFR 3). Biomarker analysis was not planned to be performed in dose escalation part and Cohort 2 of dose expansion part, as pre-specified in protocol.

Time frame: Baseline, Cycle 2 Day 1, end of treatment (up to 35 cycles, each cycle 28 days)

Population: Serum soluble protein biomarker analysis set included all enrolled participants who received at least one dose of any study drug, and had at least one biomarker parameter from the corresponding assay sample with at least one baseline biomarker measurement.

Percentage of c-MET positive tumor cell for objective response (complete response \[CR\] + partial response \[PR\]) is reported. Objective response was defined as CR and PR. CR was defined as disappearance of all lesions (target and/or non target). PR were 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, with non target lesions not increased or absent. Biomarker analysis was not planned to be performed in dose escalation part and Cohort 2 of dose expansion part, as pre-specified in protocol.

Time frame: Baseline

Population: Tumor Immunohistochemistry (IHC) analysis set included all enrolled participants who received at least one dose of any study drug, and had at least one biomarker parameter from the corresponding assay sample with at least one baseline biomarker measurement, and had confirmed objective response (CR+PR).

Serum soluble protein biomarkers included angiopoietin-2, Hepatocyte Growth Factor (HGF), Vascular Endothelial Growth Factor Receptor 3 (VEGFR3). Ratio=value of serum soluble protein biomarkers at each time point to the value at baseline. Biomarker analysis was not planned to be performed in dose escalation part and Cohort 2 of dose expansion part, as pre-specified in protocol.

Time frame: Baseline, Cycle 2 Day 1, end of treatment (up to 35 cycles, each cycle 28 days)

Population: Serum soluble protein biomarker analysis set: all enrolled participants who received at least 1 dose of any study drug, had at least 1 biomarker parameter from corresponding assay sample with at least 1 baseline biomarker measurement. Here, 'number of participants analyzed' signifies those participants who were evaluable for this outcome measure.

Duration of response (as per Response Evaluation Criteria in Solid Tumors \[RECIST\] version 1.1) was defined as the time (in months) from first documentation of objective tumor response (complete response \[CR\] or partial response \[PR\]) until the first date that recurrent, progressive disease, or death (whichever occurred first). CR was defined as disappearance of all lesions (target and/or non target). PR were 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, with non target lesions not increased or absent. Progression was defined as \>= 20 percent increase in sum of longest diameter of target lesions; measurable increase in non-target lesion; appearance of new lesions.

Time frame: From first objective response until first recurrent, disease progression, or death, whichever occurred first (up to 35 cycles, each cycle 28 days)

Population: Subset of response evaluable analysis set included all participants with overall objective response of CR or PR who received at least 1 dose of axitinib and crizotinib and had baseline tumor assessment. Data for this outcome measure was not planned to be collected and analyzed for dose escalation part, as pre specified in protocol.

PFS (as per Response Evaluation Criteria in Solid Tumors \[RECIST\] version 1.1) was defined as the time (in months) from start of study treatment to first documentation of objective tumor progression or death due to any cause, whichever occurred first. PFS (in months) was calculated as (first event date minus date of first dose of study medication plus 1) divided by 30.44. Progression was defined as \>= 20 percent increase in sum of longest diameter of target lesions; measurable increase in non-target lesion; appearance of new lesions. PFS was not estimated in Dose Expansion Cohort 2 due to small sample size.

Time frame: From Baseline until disease progression or death, whichever occurred first (up to 35 cycles, each cycle 28 days)

Population: Response-evaluable analysis set included all participants who received at least 1 dose of axitinib and crizotinib and had an adequate baseline tumor assessment. Data for this outcome measure was not planned to be collected and analyzed for dose escalation part, as pre specified in protocol.

Data of this outcome measure was not planned to be analyzed for Cohort 2 in dose expansion part, as pre-specified in protocol.

Time frame: Axitinib: Pre-dose (0 hour [hr]), 1, 2, 3, 4, 6, 8 hrs post-dose at Lead-in Day 7, Cycle 1 Day 15; Crizotinib: pre-dose (0 hr), 1, 2, 3, 4, 6, 8 hrs post-dose at Cycle 1 Day 15

Population: Pharmacokinetic (PK) parameter analysis population was defined as all treated participants who had at least 1 of the PK parameters of interest of any of the study drugs.

ECOG-PS: used to assess how disease affected the daily living abilities of participant. It ranges on the scale from: 0-5 (0=fully active/able to carry on all pre-disease activities without restriction;1=restricted in physically strenuous activity but ambulatory/able to carry out light/sedentary work;2=ambulatory \[for more than (\>)50%of waking hours\], capable of all self-care but unable to carry out any work activities;3=capable of limited self-care, confined to bed or chair \[for \>50% of waking hours\];4=completely disabled, not capable of any self-care, totally confined to bed or chair;5= dead, higher score=more functional impairment) and changes to worst status scores were presented. Baseline value=value collected prior to first dose of study drug on Cycle 1 Day 1. Worst post-baseline value=worst value between first dose of any study drug and end of treatment (EOT) visit. Shift to low refers to lower than Baseline value; shift to high refers to higher than baseline value for ECOG-PS.

Time frame: Baseline, End of Treatment (up to Cycle 35 [for Part 1] and up to Cycle 35 [for Part 2], each cycle 28 days)

Population: Safety analysis set included all enrolled participants who received at least 1 dose of axitinib or crizotinib.

Laboratory parameters included hematological and biochemistry parameters. Biochemistry parameters/abnormalities included alanine aminotransferase, alkaline phosphatase, aspartate aminotransferase, bilirubin (total), creatinine, hypercalcemia, hyperglycemia, hyperkalemia, hypermagnesemia, hypernatremia, hypoalbuminemia, hypocalcemia, hypoglycemia, hypokalemia, hypomagnesemia, hyponatremia, hypophosphatemia and gamma glutamyl transferase Number of participants with biochemistry test abnormalities by grades (NCI CTCAE version 4.03) were reported. Grade 1= mild; Grade 2= moderate; Grade 3= severe and Grade 4= life-threatening or disabling.

Time frame: Baseline up to end of treatment (up to 35 cycles in Part 1 and 35 cycles in Part 2, each cycle 28 days)

Population: Safety analysis set included all enrolled participants who received at least 1 dose of axitinib or crizotinib. Here, Overall number of participants analyzed signifies those participants who were evaluable for this outcome measure and Number Analyzed signifies number of participants evaluable for specified rows.

Laboratory parameters included hematological and biochemistry parameters. Hematological parameters included haemoglobin (anemia, haemoglobin increased), lymphocytes (lymphopenia, lymphocyte count increased), neutrophils, platelets and white blood cells. Number of participants with hematological abnormalities by grades (as per NCI CTCAE version 4.03) were reported. Grade 1= mild; Grade 2= moderate; Grade 3= severe and Grade 4= life-threatening or disabling.

Time frame: Baseline up to end of treatment (up to 35 cycles in Part 1 and 35 cycles in Part 2, each cycle 28 days)

Population: Safety analysis set included all enrolled participants who received at least 1 dose of axitinib or crizotinib. Here, Overall number of participants analyzed signifies those participants who were evaluable for this outcome measure.

An AE was any untoward medical occurrence in participant who received study drug without regard to possibility of causal relationship. Grade 3 (severe) events=unacceptable or intolerable events, significantly interrupting usual daily activity, require systemic drug therapy/other treatment. Grade 4 (Life-threatening) events caused participant to be in imminent danger of death. Grade 5 = death. Treatment-emergent were events between first dose of study drug and until 28 days after last dose that were absent before treatment or that worsened relative to pretreatment state. AEs included both serious and non-serious adverse events.

Time frame: First dose of study drug until 28 days after last dose (up to 35 cycles in Part 1 and 35 cycles in Part 2, each cycle 28 days)

Population: Safety analysis set included all enrolled participants who received at least 1 dose of axitinib or crizotinib.

Triplicate 12-lead ECG measurements (each recording separated by approximately 2 minutes) were performed and average was calculated. The time corresponding to beginning of depolarization to repolarization of the ventricles (QT interval) was adjusted for RR interval using QT and RR from each ECG by Fridericia's formula (QTcF = QT divided by cube root of RR) and by Bazette's formula (QTcB = QT divided by square root of RR). Number of participants with maximum increase from baseline of less than (\<) 30 milliseconds (msec), 30 to \<60 msec and greater than or equal to (\>=) 60 msec were reported.

Time frame: Baseline, End of Treatment (up to Cycle 35 [for Part 1] and up to Cycle 35 [for Part 2], each cycle 28 days)

Population: Safety analysis set included all enrolled participants who received at least 1 dose of axitinib or crizotinib.

An AE was any untoward medical occurrence in a participant who received study drugs (crizotinib and axitinib) without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent were events between first dose of study drug and until 28 days after last dose that were absent before treatment or that worsened relative to pretreatment state. AEs included both serious and non-serious adverse events.

Time frame: First dose of study drug until 28 days after last dose (up to 35 cycles in Part 1 and 35 cycles in Part 2, each cycle 28 days)

Population: Safety analysis set included all enrolled participants who received at least 1 dose of axitinib or crizotinib.

Treatment-related AE was any untoward medical occurrence attributed to study drugs (crizotinib and axitinib) in a participant who received study drugs. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent were events between first dose of study drug and until 28 days after last dose that were absent before treatment or that worsened relative to pretreatment state. AEs included both serious and non-serious adverse events.

Time frame: First dose of study drug until 28 days after last dose (up to 35 cycles in Part 1 and 35 cycles in Part 2, each cycle 28 days)

Population: Safety analysis set included all enrolled participants who received at least 1 dose of axitinib or crizotinib.

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 \[RECIST\] version1.1 were reported. Confirmed responses were those that persisted on repeat imaging study at least 4 weeks after initial documentation of response. CR was defined as disappearance of all lesions (target and/or non target). PR were 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, with non target lesions not increased or absent.

Time frame: From Baseline until disease progression or death, whichever occurred first (up to 35 cycles in Part 1 and 35 cycles in Part 2, each cycle 28 days)

Population: Response-evaluable analysis set included all participants who received at least 1 dose of axitinib and crizotinib and had an adequate baseline tumor assessment.

Data of this outcome measure was not planned to be analyzed for Cohort 2 in dose expansion part, as pre-specified in protocol.

Time frame: Axitinib: Pre-dose (0 hour [hr]), 1, 2, 3, 4, 6, 8 hrs post-dose at Lead-in Day 7, Cycle 1 Day 15; Crizotinib: pre-dose (0 hr), 1, 2, 3, 4, 6, 8 hrs post-dose at Cycle 1 Day 15

Population: The PK parameter analysis population was defined as all treated participants who had at least 1 of the PK parameters of interest of any of the study drugs.