Clinical trial NCT01999972: A Phase 1b Study Of Axitinib In Combination With Crizotinib In Patients With Advanced Solid Tumors
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Advanced Solid Tumors
Keywords: Carcinoma
Renal Cell
Lead sponsor: Pfizer
Sponsor class: INDUSTRY
First posted: 2013-12-03
Enrollment: 50
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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.

Primary outcomes:
measure: Dose-Escalation Part: Number of Participants With Dose-Limiting Toxicities (DLTs)
timeFrame: Cycle 1 (28 days)
Secondary outcomes:
measure: Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: 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)
measure: Number of Participants With Treatment-Related Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: 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)
measure: 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
timeFrame: 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)
measure: 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
timeFrame: Baseline up to end of treatment (up to 35 cycles in Part 1 and 35 cycles in Part 2, each cycle 28 days)
measure: 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
timeFrame: Baseline up to end of treatment (up to 35 cycles in Part 1 and 35 cycles in Part 2, each cycle 28 days)
measure: 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
timeFrame: 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)
measure: 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
timeFrame: 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)
measure: 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
timeFrame: 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)
measure: Number of Participants With Change From Baseline in Eastern Cooperative Oncology Group Performance Status (ECOG-PS) to Worst Value
timeFrame: Baseline, End of Treatment (up to Cycle 35 [for Part 1] and up to Cycle 35 [for Part 2], each cycle 28 days)
measure: Number of Participants With Maximum Increase From Baseline in QTc Interval
timeFrame: Baseline, End of Treatment (up to Cycle 35 [for Part 1] and up to Cycle 35 [for Part 2], each cycle 28 days)
measure: Maximum Observed Plasma Concentration (Cmax) of Axitinib and Crizotinib
timeFrame: 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
measure: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Axitinib and Crizotinib
timeFrame: 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
measure: Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of Axitinib and Crizotinib
timeFrame: 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
measure: Apparent Oral Clearance (CL/F) of Axitinib and Crizotinib
timeFrame: 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
measure: Apparent Volume of Distribution (Vz/F) of Axitinib and Crizotinib
timeFrame: 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
measure: Percentage of Participants With Objective Response
timeFrame: 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)
measure: Dose Expansion Part: Duration of Response
timeFrame: From first objective response until first recurrent, disease progression, or death, whichever occurred first (up to 35 cycles, each cycle 28 days)
measure: Dose Expansion Part: Progression-Free Survival (PFS)
timeFrame: From Baseline until disease progression or death, whichever occurred first (up to 35 cycles, each cycle 28 days)
measure: Dose Expansion Part Cohort 1: Levels of Serum Soluble Protein Biomarkers
timeFrame: Baseline, Cycle 2 Day 1, end of treatment (up to 35 cycles, each cycle 28 days)
measure: Dose Expansion Part Cohort 1: Change From Baseline in Serum Concentration of Circulating microRNAs (miRNA) at End of Treatment
timeFrame: Baseline, end of treatment (up to 35 cycles, each cycle 28 days)
measure: Dose Expansion Part Cohort 1: Percentage of c-MET Positive Tumor Cell at Baseline in Relation to Objective Response Rate (ORR)
timeFrame: Baseline
measure: Dose Expansion Part Cohort 1: Level of Plasma Soluble Protein Biomarker (c-MET)
timeFrame: 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)
measure: Dose Expansion Part Cohort 1: Ratio of Serum Soluble Protein Biomarkers Level to Baseline Biomarkers Level by Each Timepoint
timeFrame: Baseline, Cycle 2 Day 1, end of treatment (up to 35 cycles, each cycle 28 days)
Other outcomes:
Locations:
city: Chicago
country: United States
facility: University of Chicago Medical Center
state: Illinois
city: Indianapolis
country: United States
facility: Investigational Drug Services IUHSCC
state: Indiana
city: Indianapolis
country: United States
facility: IU Health University Hospital
state: Indiana
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Detroit
country: United States
facility: Wayne State University, Dept. of Oncology
state: Michigan
city: Minneapolis
country: United States
facility: University of Minnesota Health Clinics and Surgery Center
state: Minnesota
city: Minneapolis
country: United States
facility: University of Minnesota Medical Center, Fairview IDS Pharmacy
state: Minnesota
city: Minneapolis
country: United States
facility: University of Minnesota Medical Center, Fairview
state: Minnesota
city: Minneapolis
country: United States
facility: University of Minnesota Physicians Masonic Cancer Center
state: Minnesota
city: Cleveland
country: United States
facility: Cleveland Clinic Taussig Cancer Center Investigational Pharmacy
state: Ohio
city: Salt Lake City
country: United States
facility: Huntsman Cancer Hospital
state: Utah
city: Salt Lake City
country: United States
facility: Huntsman Cancer Institute
state: Utah
city: Salt Lake City
country: United States
facility: John A Moran Eye Center
state: Utah
city: Madison
country: United States
facility: University Station Ophthalmology Clinic
state: Wisconsin
city: Madison
country: United States
facility: University of Wisconsin Hospital and Clinics
state: Wisconsin
city: London
country: United Kingdom
facility: St Bartholomew's Hospital - Barts Health NHS Trust
city: London
country: United Kingdom
facility: The Royal Marsden NHS Foundation Trust, Royal Marsden Hospital
Study officials:
affiliation: Pfizer
name: Pfizer CT.gov Call Center
role: STUDY_DIRECTOR
References:
citation: Michaelson MD, Gupta S, Agarwal N, Szmulewitz R, Powles T, Pili R, Bruce JY, Vaishampayan U, Larkin J, Rosbrook B, Wang E, Murphy D, Wang P, Lechuga MJ, Valota O, Shepard DR. A Phase Ib Study of Axitinib in Combination with Crizotinib in Patients with Metastatic Renal Cell Cancer or Other Advanced Solid Tumors. Oncologist. 2019 Sep;24(9):1151-e817. doi: 10.1634/theoncologist.2018-0749. Epub 2019 Jun 6.