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Updated: Aug 10, 2026
Development and Maintenance of a Preclinical Patient Derived Tumor Xenograft Model for the Investigation of Novel Anti-Cancer Therapies
Published on: September 30, 2016
A phase 1 study of intermittently administered pazopanib in combination with continuous daily dosing of lapatinib in
H Henary1, G C George, J Wheler
1Departments of Investigational Cancer Therapeutics (Phase I Program), Clinical Center for Targeted Therapy, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Box 455, Houston, TX, 77030, USA.
Purpose:
Preclinically, pazopanib/lapatinib combination acted synergistically to suppress the activity of multiple tyrosine kinases, including VEGFR-1, 2, 3, PDGFR and c-kit (pazopanib), HER1/EGFR and HER2 (lapatinib), and several other tyrosine kinases including c-Met through, plausibly, network inhibition effects. Clinically, continuous dosing of pazopanib/lapatinib combination was associated with a higher response rate than with lapatinib monotherapy, with poor tolerance. We explored multiple intermittent dose levels of pazopanib combined with continuous daily dosing of lapatinib in patients with solid tumors.
Methods:
The present study used a phase 1, modified 3 + 3, dose-escalation design to evaluate the safety and tolerability of the combination of orally received pazopanib once every other day with continuous daily dosing of lapatinib for 28 days. In the expansion phase, tumor response was evaluated in patients with specific genetic alterations (HER2 amplification, HER2 mutation, c-Met amplification, c-Met mutation, and EGFR mutation).
Results:
Twenty-four patients were treated. The most common drug-related adverse events were fatigue 7/24 (29%), skin rash 5/21 (21%), and diarrhea 3/24 (17%), with 4/24 (16%) patients experiencing grade ≥3 drug-related adverse events. Escalation to the FDA-approved dose (800 mg daily for pazopanib and 1500 mg every day for lapatinib) was not feasible due to toxicities. Pazopanib 200 mg every other day + lapatinib 500 mg daily was considered the maximum tolerated dose (MTD). No tumor response was observed, including in patients with the specific molecular genetic alterations tested.
Conclusion:
Every other day dosing of pazopanib combined with daily lapatinib was tolerated at the established MTD, but no complete or partial tumor responses were observed at these dose levels.
Insights
Intermittent pazopanib with lapatinib showed good tolerability in solid tumor patients but did not yield tumor responses. This combination therapy, while manageable, did not demonstrate clinical efficacy in this phase 1 trial.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- Pazopanib and lapatinib target multiple tyrosine kinases involved in cancer progression.
- Previous studies indicated synergistic preclinical activity and potential clinical benefit of pazopanib/lapatinib, but continuous dosing showed poor tolerance.
- Exploring intermittent dosing strategies is crucial for improving the therapeutic index of combination cancer therapies.
Purpose of the Study:
- To evaluate the safety and tolerability of an intermittent dosing schedule of pazopanib combined with continuous daily lapatinib in patients with solid tumors.
- To determine the maximum tolerated dose (MTD) of this combination therapy.
- To assess preliminary tumor response in patients with specific genetic alterations.
Main Methods:
- A phase 1, modified 3 + 3 dose-escalation study was conducted.
- Patients received oral pazopanib every other day with continuous daily lapatinib for 28-day cycles.
- Tumor response was evaluated in an expansion phase for patients with HER2, c-Met, or EGFR alterations.
Main Results:
- Twenty-four patients were treated, with fatigue, skin rash, and diarrhea as common adverse events.
- The maximum tolerated dose (MTD) was determined to be pazopanib 200 mg every other day plus lapatinib 500 mg daily.
- No complete or partial tumor responses were observed, even in patients with targeted genetic alterations.
Conclusions:
- The intermittent pazopanib and daily lapatinib combination was tolerated at the MTD.
- Despite preclinical rationale and manageable toxicity, this specific dosing regimen did not show clinical efficacy in patients with solid tumors.
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