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

Study Overview
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Brief Summary
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Despite the success of anti-angiogenic therapy in multiple treatment settings, a fraction of patients are refractory to vascular endothelial growth factor (VEGF) inhibitor treatment, while the majority of patients will eventually develop evasive resistance. It is proposed that mesenchymal-epithelial transition factor (c-MET) and its ligand hepatocyte growth factor (HGF or scatter factor) contribute to VEGF inhibitor resistance, such that combining a c-MET inhibitor with a VEGF inhibitor will provide additional clinical activity compared to VEGF inhibitor alone. This hypothesis will be tested using the cMET/ALK inhibitor, crizotinib, in combination with the VEGF inhibitor, axitinib.Since this will be the first study of axitinib given in combination with crizotinib, the study will primarily assess the safety and tolerability of the combination regimen.

Official Title
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A PHASE 1B, OPEN LABEL, DOSE ESCALATION STUDY TO EVALUATE SAFETY, PHARMACOKINETICS AND PHARMACODYNAMICS OF AXITINIB (AG-013736) IN COMBINATION WITH CRIZOTINIB (PF-02341066) IN PATIENTS WITH ADVANCED SOLID TUMORS

Conditions
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Advanced Solid Tumors

Intervention / Treatment
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* Drug: axitinib
* Drug: crizotinib
* Drug: axitinib
* Drug: crizotinib
* Drug: axitinib
* Drug: crizotinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis - Dose Escalation Phase: Histologically or cytologically confirmed diagnosis of advanced solid tumor that is resistant to standard therapy or for which no standard therapy is available. Diagnosis - Dose Expansion Phase: Histologically or cytologically confirmed advanced RCC with a component of clear cell subtype Dose Expansion Phase: at least one measureable lesion as defined by RECIST [Response Evaluation Criterion in Solid Tumors] version 1.1. ECOG [Eastern Cooperative Oncology Group] Performance Status 0 or 1. Exclusion Criteria: Major surgery <4 weeks or radiation therapy <2 weeks of patient registration. History of or known active seizure disorder, brain metastases, spinal cord compression, or carcinomatous meningitis, or new evidence of brain or leptomeningeal disease. Dose Expansion Phase only: diagnosis of any other malignancy within 2 years prior to registration.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Axitinib in combination with crizotinib, escalation phase<br>Dose Escalation Advanced solid tumor that is resistant to standard therapy or for which no standard therapy is available | Drug: axitinib<br>* Axitinib: tablets, dosage range 2 - 5 mg, given orally twice daily on a continuous dosing schedule in 28 days cycles.<br>Drug: crizotinib<br>* Crizotinib: capsules, dosage range 200-250 mg, given orally twice daily or every day on a continuous dosing schedule in 28 days cycle.<br>|
| Experimental: Expansion Phase Cohort 1<br>Dose Expansion, Cohort 1: axitinib in combination with crizotinib Advanced renal cell cancer [RCC] with no prior systemic therapy | Drug: axitinib<br>* Axitinib: tablets, dosage be defined based on Arm 1 results, given orally twice daily on a continuous dosing schedule in 28 days cycles.<br>Drug: crizotinib<br>* Crizotinib: capsules, dosage be defined based on Arm 1 results, given orally twice daily or every day on a continuous dosing schedule in 28 days cycle.<br>|
| Experimental: Expansion Phase Cohort 2<br>Dose Expansion, Cohort 2: axitinib in combination with crizotinib Advanced renal cell cancer with at least one but no more than two prior systemic treatment regimens directed at advanced RCC | Drug: axitinib<br>* Axitinib: tablets, dosage be defined based on Arm 1 results, given orally twice daily on a continuous dosing schedule in 28 days cycles.<br>Drug: crizotinib<br>* Crizotinib: capsules, dosage be defined based on Arm 1 results, given orally twice daily or every day on a continuous dosing schedule in 28 days cycle.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose-Escalation Part: Number of Participants With Dose-Limiting Toxicities (DLTs) | 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. | Cycle 1 (28 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | 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. | 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) | 
| Number of Participants With Treatment-Related Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | 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. | 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) | 
| Number of Participants With Grade 3 or Higher Adverse Events (AEs) as Graded by National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE) Version 4.03 | 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. | 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) | 
| Number of Participants With Clinically Significant Laboratory Abnormalities Based on National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE) Version 4.03: Hematological Test Abnormalities | 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. | Baseline up to end of treatment (up to 35 cycles in Part 1 and 35 cycles in Part 2, each cycle 28 days) | 
| Number of Participants With Clinically Significant Laboratory Abnormalities Based on National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE) Version 4.03: Biochemistry Test Abnormalities | 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. | Baseline up to end of treatment (up to 35 cycles in Part 1 and 35 cycles in Part 2, each cycle 28 days) | 
| Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at Day 1, 15 of Cycle 1, Day 1 of Cycles 2, 4, 6, 12, 24 and End of Treatment Visit |  | 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) | 
| Change From Baseline in Pulse Rate at Day 1, 15 of Cycle 1, Day 1 of Cycles 2, 4, 6, 12, 24 and End of Treatment |  | 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) | 
| Change From Baseline in Body Weight at Day 1, 15 of Cycle 1, Day 1 of Cycles 2, 4, 6, 12, 24 and End of Treatment |  | 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) | 
| Number of Participants With Change From Baseline in Eastern Cooperative Oncology Group Performance Status (ECOG-PS) to Worst Value | 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. | Baseline, End of Treatment (up to Cycle 35 [for Part 1] and up to Cycle 35 [for Part 2], each cycle 28 days) | 
| Number of Participants With Maximum Increase From Baseline in QTc Interval | 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. | Baseline, End of Treatment (up to Cycle 35 [for Part 1] and up to Cycle 35 [for Part 2], each cycle 28 days) | 
| Maximum Observed Plasma Concentration (Cmax) of Axitinib and Crizotinib | Data of this outcome measure was not planned to be analyzed for Cohort 2 in dose expansion part, as pre-specified in protocol. | 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 | 
| Time to Reach Maximum Observed Plasma Concentration (Tmax) of Axitinib and Crizotinib | Data of this outcome measure was not planned to be analyzed for Cohort 2 in dose expansion part, as pre-specified in protocol. | 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 | 
| Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of Axitinib and Crizotinib | 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. | 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 | 
| Apparent Oral Clearance (CL/F) of Axitinib and Crizotinib | 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. | 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 | 
| Apparent Volume of Distribution (Vz/F) of Axitinib and Crizotinib | 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. | 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 | 
| Percentage of Participants With Objective Response | 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. | 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) | 
| Dose Expansion Part: Duration of Response | 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. | From first objective response until first recurrent, disease progression, or death, whichever occurred first (up to 35 cycles, each cycle 28 days) | 
| Dose Expansion Part: Progression-Free Survival (PFS) | 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. | From Baseline until disease progression or death, whichever occurred first (up to 35 cycles, each cycle 28 days) | 
| Dose Expansion Part Cohort 1: Levels of Serum Soluble Protein Biomarkers | 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. | Baseline, Cycle 2 Day 1, end of treatment (up to 35 cycles, each cycle 28 days) | 
| Dose Expansion Part Cohort 1: Change From Baseline in Serum Concentration of Circulating microRNAs (miRNA) at End of Treatment |  | Baseline, end of treatment (up to 35 cycles, each cycle 28 days) | 
| Dose Expansion Part Cohort 1: Percentage of c-MET Positive Tumor Cell at Baseline in Relation to Objective Response Rate (ORR) | 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. | Baseline | 
| Dose Expansion Part Cohort 1: Level of Plasma Soluble Protein Biomarker (c-MET) | 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. | 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) | 
| Dose Expansion Part Cohort 1: Ratio of Serum Soluble Protein Biomarkers Level to Baseline Biomarkers Level by Each Timepoint | 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. | Baseline, Cycle 2 Day 1, end of treatment (up to 35 cycles, each cycle 28 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Carcinoma, Renal Cell