Clinical trial NCT00483366: Imatinib Mesylate, Gemcitabine, and Capecitabine in Treating Patients With Advanced Solid Tumors
Official title: Phase I Study of Imatinib, Gemcitabine and Capecitabine in Patients With Solid Tumors
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Unspecified Adult Solid Tumor, Protocol Specific
Keywords: unspecified adult solid tumor, protocol specific
Lead sponsor: University of Nebraska
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2007-06-07
Enrollment: 13
Sex: ALL
Minimum age (years): 19
Maximum age (years): 120
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: RATIONALE: Imatinib mesylate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as gemcitabine and capecitabine, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving imatinib mesylate together with gemcitabine and capecitabine may kill more tumor cells.

PURPOSE: This phase I trial is studying the side effects and best dose of gemcitabine and capecitabine when given together with imatinib mesylate in treating patients with advanced solid tumors.

Detailed description: OBJECTIVES:

Primary

* Determine the maximum tolerated dose of gemcitabine hydrochloride and capecitabine when combined with imatinib mesylate in patients with advanced solid tumors.
* Determine the toxicity of this regimen in these patients.

Secondary

* Explore the antitumor activity of this regimen in these patients.

OUTLINE: This is a dose-escalation study of gemcitabine and capecitabine.

Patients receive oral imatinib mesylate once daily on days 1-5 and 8-12, gemcitabine hydrochloride IV on days 3 and 10, and oral capecitabine twice daily on days 1-14. Treatment repeats every 21 days for at least 2 courses in the absence of progressive disease or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of gemcitabine hydrochloride and capecitabine until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.

Existing paraffin-embedded tissue blocks from patients diagnosed with melanoma or renal cell carcinoma will be assessed for c-kit mutations by polymerase chain reaction and direct sequencing of both juxtamembrane domains (exons 9 and 11) and tyrosine kinase domain (exon 13 and 17). (Begins 12-11-2008)

PROJECTED ACCRUAL: Closed to patient accrual 12/11/2008.

Eligibility criteria: Inclusion Criteria:

* Histologically confirmed solid tumor, meeting 1 of the following criteria:

  * Failed standard therapy and subsequent line therapy
  * Disease for which no standard therapy exists
* Any number of prior therapies are allowed provided standard treatment options have either been exhausted or are unable to be administered, in the opinion of the treating physician
* Measurable or nonmeasurable disease

  * Measurable disease is defined as ≥ 1 unidimensionally measurable lesion ≥ 20 mm by CT scan or ≥ 10 mm by spiral CT scan
  * Nonmeasurable disease is defined as all other lesions, including small lesions (\< 20 mm by conventional techniques or \< 10 mm by spiral CT scan) and truly nonmeasurable lesions, including the following:

    1. Leptomeningeal disease
    2. Bone lesions
    3. Ascites
    4. Pleural or pericardial effusion
    5. Lymphangitis cutis/pulmonis
    6. Abdominal masses that are not confirmed and followed by imaging techniques
    7. Cystic lesions
* Brain metastases allowed provided both of the following are true:

  * Patient has undergone resection and/or radiotherapy and does not require steroids
  * No evidence of disease progression by CT scan or MRI at least 4 weeks after completion of steroids, surgery, and/or radiotherapy
* ECOG performance status 0-2
* Absolute neutrophil count ≥ 1,500/mm³
* Platelet count ≥ 100,000/mm³
* Hemoglobin ≥ 8.5 g/dL (epoetin alfa supplementation allowed)
* Bilirubin ≤ 1.5 times upper limit of normal (ULN) (except if due to Gilbert's syndrome)
* AST and ALT ≤ 2.5 times ULN
* Creatinine \< 1.5 times ULN
* Fertile patients must use effective barrier method contraception during and for 3 months after completion of study treatment
* Must be able to tolerate oral intake for the administration of imatinib mesylate and capecitabine
* Prior treatment with gemcitabine hydrochloride, capecitabine, or imatinib mesylate allowed provided all three drugs were not used in combination simultaneously
* Prior radiotherapy allowed provided the lesion treated is not used to assess response and has not demonstrated progression after treatment
* At least 2 weeks since prior radiotherapy
* More than 2 weeks since prior major surgery
* At least 4 weeks since prior systemic therapy (6 weeks for nitrosoureas) and recovered
* More than 4 weeks since prior packed red blood cell transfusions
* Concurrent bisphosphonate therapy allowed for skeletal metastases provided therapy is started before study entry

Exclusion Criteria:

* Not pregnant or nursing/negative pregnancy test
* No active serious infections
* No known allergy or hypersensitivity to study drugs or their formulation
* No comorbidity or condition which would preclude study participation
* No other primary malignancy within the past 5 years except basal cell skin cancer, cervical carcinoma in situ, or another primary malignancy that is not currently clinically significant or requires active intervention
* No prior radiotherapy to ≥ 25% of the bone marrow
* No concurrent anticoagulation therapy with warfarin

  * Therapeutic anticoagulation with low-molecular weight heparin or heparin allowed
  * Mini-dose warfarin (e.g., 1 mg/day) for prophylaxis of central venous catheter thrombosis allowed at the discretion of the treating physician
* No other concurrent anticancer agents, including chemotherapy and biologic agents
* No other concurrent investigational drugs
* No concurrent routine systemic corticosteroid therapy (corticosteroid therapy may only be administered after consultation with the principal investigator)
* No other malignant disease
* No New York Heart Association class III-IV cardiac disease
* No congestive heart failure
* No myocardial infarction within the past 6 months
* No known chronic liver disease (e.g., chronic active hepatitis or cirrhosis)
* No known HIV infection
* No prior radiotherapy to ≥ 25% of the bone marrow
* No concurrent anticoagulation therapy with warfarin

  * Therapeutic anticoagulation with low-molecular weight heparin or heparin allowed
  * Mini-dose warfarin (e.g., 1 mg/day) for prophylaxis of central venous catheter thrombosis allowed at the discretion of the treating physician
* No other concurrent anticancer agents, including chemotherapy and biologic agents
* No other concurrent investigational drugs
* No concurrent routine systemic corticosteroid therapy (corticosteroid therapy may only be administered after consultation with the principal investigator)

Primary outcomes:
measure: Maximum tolerated dose of gemcitabine hydrochloride and capecitabine when combined with imatinib mesylate
timeFrame: By the end of cycle 2
measure: Dose-limiting Toxicity
timeFrame: By the end of cycle 2.
Secondary outcomes:
measure: Antitumor activity
timeFrame: Following response assessment.
Other outcomes:
Locations:
city: Omaha
country: United States
facility: UNMC Eppley Cancer Center at the University of Nebraska Medical Center
state: Nebraska
Study officials:
affiliation: University of Nebraska
name: Ralph Hauke, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Nebraska
name: Elizabeth C. Reed, MD
role: STUDY_CHAIR
References: