A Phase I Trial of the MET/ALK/ROS1 Inhibitor Crizotinib Combined with the VEGF Inhibitor Pazopanib in Patients with
Sarina A Piha-Paul1, Ecaterina E Dumbrava1, Binoj C Nair1
1Department of Investigational Cancer Therapeutics (A Phase I Clinical Trials Program), University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Background:
Crizotinib inhibits ALK, MET and ROS1 tyrosine kinases but the development of resistance to monotherapy is an issue. The anti-angiogenic properties of pazopanib could overcome crizotinib drug resistance. Additionally, the anti-angiogenic properties of crizotinib could augment the clinical efficacy of pazopanib.
Methods:
We evaluated the safety and responses in patients with advanced solid tumors treated with crizotinib and pazopanib.
Results:
Eighty-two patients (median age 53 years, range 18-78 years) were enrolled. The median number of prior systemic therapies was 3 (range, 0-8). We were able to dose escalate to dose level 8 (crizotinib 250 mg twice daily and pazopanib 800 mg daily) with no MTD identified. Grade 3 or 4 toxicities were seen in 32% of patients with the highest prevalence being fatigue (n=9, 11%), diarrhea (n=6, 7%), vomiting (n=3, 4%), anemia (n=2, 2%) and ALT increased (n=2, 2%). Of the 82 patients, 61 (74%) had measurable disease by RECISTv1.1 and reached first restaging (6 weeks). Partial response (PR) was observed in 6/61 (10%) patients, and stable disease (SD) lasting ≥6 months was observed in 10/61 patients (16%) (total = 16/61 (26%) of patients with SD ≥6 months/PR).
Conclusion:
Dose level 6 (crizotinib 200 mg twice daily and pazopanib 600 mg daily) was the most tolerable dosing of the combination and can be used in future studies. We also observed moderate clinical activity in patients with advanced solid tumors that had received numerous prior therapies.
Insights
This study investigated combining crizotinib and pazopanib in advanced solid tumors. Dose level 6 showed tolerable dosing and moderate clinical activity in heavily pre-treated patients.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- Crizotinib targets ALK, MET, and ROS1 tyrosine kinases, but resistance limits its efficacy.
- Pazopanib's anti-angiogenic properties may overcome crizotinib resistance and enhance its activity.
Observation:
- A Phase 1 trial evaluated safety and response of crizotinib plus pazopanib in 82 advanced solid tumor patients.
- Dose escalation reached level 8 (crizotinib 250mg BID, pazopanib 800mg daily) without identifying a maximum tolerated dose (MTD).
- Common Grade 3/4 toxicities included fatigue, diarrhea, vomiting, anemia, and elevated ALT.
Findings:
- Partial response (PR) was seen in 10% of evaluable patients, with 16% achieving stable disease (SD) for ≥6 months.
- Dose level 6 (crizotinib 200mg BID, pazopanib 600mg daily) was identified as the most tolerable combination dose.
- The combination demonstrated moderate clinical activity in patients with advanced solid tumors, including those with extensive prior therapies.
Implications:
- The combination of crizotinib and pazopanib warrants further investigation in future clinical studies.
- Identifying tolerable dosing regimens is crucial for advancing novel combination therapies in oncology.
- This combination may offer a treatment option for patients with advanced solid tumors who have exhausted other therapies.
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