Phase 1
Completed N=24
A Phase 1b Study Of Axitinib In Combination With Crizotinib In Patients With Advanced Solid Tumors
Source: ClinicalTrials.gov NCT01999972 ↗Enrolled (actual)
24
Serious AEs
40.0%
Results posted
Jun 2019
Primary outcomePrimary: Dose-Escalation Part: Number of Participants With Dose-Limiting Toxicities (DLTs) — 0; 0; 0; 0 Participants
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.
Outcome Measures
| Outcome | Result | p-value |
|---|---|---|
| PRIMARY Dose-Escalation Part: Number of Participants With Dose-Limiting Toxicities (DLTs) |
0; 0; 0; 0 | — |
| SECONDARY Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) |
5; 3; 3; 10; 21; 7 | — |
| SECONDARY Number of Participants With Treatment-Related Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) |
4; 3; 3; 9; 21; 6 | — |
| SECONDARY 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 |
3; 3; 1; 8; 19; 6 | — |
| SECONDARY 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 |
1; 1; 0; 2; 10; 3 | — |
| SECONDARY 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 |
1; 1; 2; 3; 6; 1 | — |
| SECONDARY 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 |
115.7; 116.2; 124.8; 113.6; 131.4; 139.7 | — |
| SECONDARY 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 |
88.4; 81.2; 82.6; 80.9; 73.9; 77.4 | — |
| SECONDARY 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 |
74.96; 87.43; 78.46; 82.63; 86.54; 93.00 | — |
| SECONDARY Number of Participants With Change From Baseline in Eastern Cooperative Oncology Group Performance Status (ECOG-PS) to Worst Value |
0; 0; 0; 0; 3; 1 | — |
| SECONDARY Number of Participants With Maximum Increase From Baseline in QTc Interval |
2; 1; 2; 8; 16; 4 | — |
| SECONDARY Maximum Observed Plasma Concentration (Cmax) of Axitinib and Crizotinib |
8.777; 21.33; 31.31; 25.32; 40.21; 6.532 | — |
| SECONDARY Time to Reach Maximum Observed Plasma Concentration (Tmax) of Axitinib and Crizotinib |
2.09; 2.00; 2.48; 3.49; 2.00; 1.50 | — |
| SECONDARY Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of Axitinib and Crizotinib |
31.96; 105.9; 131.6; 93.22; 197.8; 34.87 | — |
| SECONDARY Apparent Oral Clearance (CL/F) of Axitinib and Crizotinib |
94.06; 28.32; 38.03; 53.70; 25.32; 86.03 | — |
| SECONDARY Apparent Volume of Distribution (Vz/F) of Axitinib and Crizotinib |
— | — |
| SECONDARY Percentage of Participants With Objective Response |
0; 0; 0; 0; 40.0; 14.3 | — |
| SECONDARY Dose Expansion Part: Duration of Response |
9.7; NA | — |
| SECONDARY Dose Expansion Part: Progression-Free Survival (PFS) |
5.6; NA | — |
| SECONDARY Dose Expansion Part Cohort 1: Levels of Serum Soluble Protein Biomarkers |
4.84; 3.81; 5.44; 9.59; 15.58; 11.95 | — |
| SECONDARY Dose Expansion Part Cohort 1: Change From Baseline in Serum Concentration of Circulating microRNAs (miRNA) at End of Treatment |
— | — |
| SECONDARY Dose Expansion Part Cohort 1: Percentage of c-MET Positive Tumor Cell at Baseline in Relation to Objective Response Rate (ORR) |
70.0; 85.0 | — |
| SECONDARY Dose Expansion Part Cohort 1: Level of Plasma Soluble Protein Biomarker (c-MET) |
640.0; 667.4; 694.8; 757.1; 678.2; 689.8 | — |
| SECONDARY Dose Expansion Part Cohort 1: Ratio of Serum Soluble Protein Biomarkers Level to Baseline Biomarkers Level by Each Timepoint |
0.90; 1.50; 1.62; 1.18; 0.748; 0.969 | — |
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.
Data sourced from ClinicalTrials.gov (NCT01999972). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication. Informational only — not medical advice.