Dasatinib and Lapatinib Ditolsylate in Treating Patients With Advanced Solid Tumors That Cannot Be Removed By Surgery

Phase I Trial of the Combination of Dasatinib and Lapatinib

RATIONALE: Dasatinib and lapatinib ditoslylate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

PURPOSE: This phase I trial is studying the side effects and best dose of dasatinib and lapatinib ditoslylate when given together in treating patients with advanced solid tumors that cannot be removed by surgery.

Study Overview

• Status: Completed
• Conditions: Unspecified Adult Solid Tumor, Protocol Specific
• Intervention / Treatment: Drug: dasatinib; Drug: lapatinib ditosylate; Other: pharmacological study; Other: laboratory biomarker analysis

Detailed Description

PRIMARY OBJECTIVES:

I. To determine the maximally tolerated dose of dasatinib combined with lapatinib.

II. To describe the toxicities associated with this treatment combination. III. To assess the pharmacokinetic interaction of lapatinib and dasatinib. IV. To assess the effect of the lapatinib and dasatinib combination on circulating tumor cells and on osteoclast precursor activation.

V. To study the association of clinical (toxicity and/or tumor response or activity) with the pharmacokinetic parameters, and/or biologic (pharmacodynamic) results.

VI. To describe the responses of this treatment combination.

OUTLINE: This is a multicenter, phase I, dose-escalation study. COHORT I: Patients receive oral dasatinib and oral lapatinib ditosylate once daily on days 1-28.

COHORT II: 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. In all subsequent courses patients receive oral dasatinib and oral lapatinib ditosylate once daily on days 1-28.

In both cohorts courses repeat every 28 days, in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed for 3 months.

• Study Type: Interventional
• Enrollment (Actual): 27
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Scottsdale, Arizona, United States, 85259
      • Mayo Clinic in Arizona
  • Florida
    • Jacksonville, Florida, United States, 32224-9980
      • Mayo Clinic in Florida
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Histologic proof of cancer that is now unresectable and refractory to or refused all standard treatment for the disease
• Please contact study investigator and/or consult protocol document for specific details on laboratory criteria
• Ability to provide informed consent
• Willingness to return to Mayo Clinic for follow up
• Life expectancy >= 12 weeks
• Negative serum pregnancy test done =< 7 days prior to registration for women of childbearing potential only
• Echocardiogram with ejection fraction > 50%
• ECOG performance status (PS) 0-2
• Able to swallow pills whole (patients with feeding tubes may be eligible if whole pills can be taken and tolerated through the feeding tube)
• Willingness to provide the biologic specimens as required by the protocol for Cohort II, (MTD) patients only

Exclusion Criteria:

• Failure to fully recover from acute, reversible effects of prior chemotherapy regardless of interval since last treatment
• Pregnant women
• Any of the following prior therapies: chemotherapy =< 4 weeks prior to registration; mitomycin C/nitrosoureas =< 6 weeks prior to registration; immunotherapy =< 4 weeks prior to registration; biologic therapy =< 4 weeks prior to registration
• Patients who have been treated with Avastin, Herceptin, or Erbitux are eligible if last treatment is >= 4 weeks; molecularly targeted agents (erlotinib, sunitinib, sorafenib, gefitinib, imatinib) =< 4 weeks prior to registration; radiation therapy =< 4 weeks prior to registration; radiation to > 25% of bone marrow
• CNS metastases that are not stable for at least 4 weeks prior to registration based on imaging, clinical assessment, and use of steroids
• Men or women of childbearing potential who are unwilling to employ adequate contraception throughout the study and until 4 weeks following study
• Other concurrent chemotherapy, immunotherapy, radiotherapy, or any ancillary therapy considered investigational (utilized for a non-FDA-approved indication and in the context of a research investigation)
• Current therapy with a CYP3A4 inhibitor or inducer
• Known standard therapy for the patient's disease that is not refractory to treatment that is potentially curative or definitely capable of extending life expectancy
• Uncontrolled pleural or pericardial effusion of any grade
• Uncontrolled angina, congestive heart failure or MI within 6 months prior to registration
• Diagnosed congenital long QT syndrome
• Any 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)
• Subjects with potassium or magnesium that are not within normal limits and cannot be corrected prior to registration
• New York Heart Association classification III or IV
• 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
• Prophylactic use of colony-stimulating factors during the study is not allowed
• Diagnosed congenital bleeding disorders (e.g., von Willebrand's disease)
• G.I conditions that may interfere with drug absorption such as Ulcerative Colitis, Crohn's Disease, and Short Bowel Syndrome
• Active hepatic or biliary disease (with the exception of patients with Gilbert's syndrome, asymptomatic gallstones, liver metastases or stable chronic liver disease per investigator's assessment)
• Nursing women
• Uncontrolled infection
• Seizure disorder

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm I; Patients receive oral dasatinib and lapatinib ditosylate once daily on days 1-28.	Drug: dasatinib; Given orally; Other Names: BMS-354825; Sprycel; Drug: lapatinib ditosylate; Given orally; Other Names: Tykerb; Lapatinib; GSK572016; GW-572016; GW2016; Other: pharmacological study; Correlative study (cohort II only); Other Names: pharmacological studies; Other: laboratory biomarker analysis; Correlative study (cohort II only)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Adverse events profile
Toxicity profile per NCI CTCAE v3.0
Response profile	Every 4 weeks
Time until any treatment-related toxicity, time until treatment-related grade 3+ toxicity, and time until hematologic nadirs (WBC, ANC, platelets)
Time to progression and time to treatment failure
Laboratory correlates

Collaborators and Investigators

• Sponsor: Mayo Clinic
• Collaborators: National Cancer Institute (NCI)

Study record dates

Study Major Dates

• Study Start (Actual): August 1, 2008
• Primary Completion (Actual): December 18, 2014
• Study Completion (Actual): December 18, 2014

Study Registration Dates

• First Submitted: April 18, 2008
• First Submitted That Met QC Criteria: April 18, 2008
• First Posted (Estimate): April 21, 2008

Study Record Updates

• Last Update Posted (Actual): March 23, 2017
• Last Update Submitted That Met QC Criteria: March 21, 2017
• Last Verified: April 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Dasatinib; Lapatinib
• Other Study ID Numbers: MC0616 (Other Identifier: Mayo Clinic); P30CA015083 (U.S. NIH Grant/Contract); NCI-2009-01197 (Registry Identifier: CTRP (Clinical Trial Reporting Program))