- Determine the maximum tolerated dose of dasatinib combined with lapatinib ditosylate.
- Describe the toxicities associated with this treatment combination.
- Assess the pharmacokinetic interaction of lapatinib ditosylate and dasatinib.
- Assess the effect of the lapatinib ditosylate and dasatinib combination on circulating tumor cells and on osteoclast precursor activation.
- Study the association of clinical (toxicity and/or tumor response or activity) with the pharmacokinetic parameters, and/or biologic (pharmacodynamic) results.
- Describe the responses of this treatment combination.
OUTLINE: This is a multicenter study.
- Cohort I (determination of maximum tolerated dose [MTD]): Patients receive oral dasatinib and oral lapatinib ditosylate once daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
- Cohort II (treatment at the MTD): Patients receive oral dasatinib once daily on days 1 and 9-28, and oral lapatinib ditosylate once daily on days 2-28 of course 1. For all subsequent courses, patients receive oral dasatinib and oral lapatinib ditosylate once daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Tissue and blood samples are collected periodically for pharmacokinetic and correlative studies. Samples are analyzed for biomarkers, circulating tumor cells, tyrosine phosphorylated or total MAP-K, EGFR, Her2, and FAK, among other potential markers of activity and/or response by immunofluorescence. Circulating osteoclasts are also assessed by flow cytometry.
After completion of treatment study, patients are followed for 3 months.
- Histologically confirmed advanced solid tumor
- Unresectable disease
- Must be refractory to or have refused all standard treatment for the disease
- Willing to provide the biologic specimens (cohort II only)
- No known standard therapy for disease that is not refractory to treatment that is potentially curative or definitely capable of extending life expectancy
- No CNS metastases that are not stable for at least 4 weeks prior to registration based on imaging, clinical assessment, and use of steroids
- No uncontrolled pleural or pericardial effusion of any grade
- ECOG performance status 0-2
- Life expectancy ≥ 12 weeks.
- Absolute neutrophil count ≥ 1,500/μL
- Platelet count ≥ 100,000/μL
- Total bilirubin ≤ upper limit of normal (ULN)
- AST ≤ 3 times ULN (5 times ULN if liver involvement)
- Creatinine ≤ 1.5 times ULN
- Hemoglobin ≥ 9.0 g/dL
- Potassium and magnesium must be within normal limits
- LVEF > 50% by ECHO
- Able to swallow pills
- Not pregnant or nursing
- Negative pregnancy test
- Fertile patients must use effective contraception during and for at least 4 weeks after completion of study therapy
- Uncontrolled infection
- New York Heart Association classification III or IV
- Seizure disorder
- Uncontrolled angina, congestive heart failure, or myocardial infarction within the past 6 months
- Diagnosed congenital long-QT syndrome
- History of clinically significant ventricular arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or torsades de pointes)
- Prolonged QTc interval on pre-entry electrocardiogram (> 450 msec)
- Hypokalemia or hypomagnesemia that cannot be corrected
- Diagnosed congenital bleeding disorders (e.g., von Willebrand disease)
- Diagnosed acquired bleeding disorder within one year (e.g., acquired anti-factor VIII antibodies)
- Ongoing or recent (≤ 3 months prior to registration) significant gastrointestinal bleeding
- Gastrointestinal conditions that may interfere with drug absorption such as ulcerative colitis, Crohn disease, and short bowel syndrome
PRIOR CONCURRENT THERAPY:
- More than 4 weeks since prior chemotherapy (6 weeks for nitrosoureas and mitomycin C) and recovered
- More than 4 weeks since prior immunotherapy, or biologic therapy (i.e., bevacizumab, trastuzumab [Herceptin®], or cetuximab)
- More than 4 weeks since prior molecular target agents (i.e., erlotinib hydrochloride, sunitinib malate, sorafenib tosylate, gefitinib, imatinib mesylate)
- More than 4 weeks since prior radiotherapy
- No prior radiotherapy to > 25% of bone marrow
- No other concurrent chemotherapy, immunotherapy, radiotherapy, or any ancillary therapy considered investigational
- No concurrent therapy with a CYP3A4 inhibitor or inducer
- No concurrent prophylactic colony-stimulating factors
Last updated: 07/29/2011