Imatinib Mesylate, Gemcitabine, and Capecitabine in Treating Patients With Advanced Solid Tumors (Closed to Accrual 12/11/2008) - Full Text View

Purpose

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.

Condition	Intervention	Phase
Unspecified Adult Solid Tumor, Protocol Specific	Drug: capecitabine Drug: gemcitabine hydrochloride Drug: imatinib mesylate Genetic: mutation analysis Genetic: nucleic acid sequencing Genetic: polymerase chain reaction	Phase 1

Study Type:	Interventional
Study Design:	Intervention Model: Single Group Assignment Masking: Open Label Primary Purpose: Treatment
Official Title:	Phase I Study of Imatinib, Gemcitabine and Capecitabine in Patients With Solid Tumors

Resource links provided by NLM:

MedlinePlus related topics: Cancer

Drug Information available for: Gemcitabine Gemcitabine hydrochloride Imatinib Capecitabine Imatinib mesylate

U.S. FDA Resources

Further study details as provided by University of Nebraska:

Primary Outcome Measures:

Maximum tolerated dose of gemcitabine hydrochloride and capecitabine when combined with imatinib mesylate [ Time Frame: By the end of cycle 2 ] [ Designated as safety issue: Yes ]
Cohorts of 3 starting at dose level 0. The imatinib dose is fixed. The dose of capecitabine is initially fixed and the dose of gemcitabine is increased 1 dose level. For the subsequent cohort, the dose of gemcitabine will be fixed and the dose of capecitabine advanced to the next dose level. 3 patients will be treated on the initial schedule. If no dose-limiting toxicities related to drug are observed and no patients require dose mods by the end of cycle 2, then 3 patients will be treated on the next schedule.
Toxicity [ Time Frame: By the end of cycle 2. ] [ Designated as safety issue: Yes ]
Cohorts of 3 starting at dose level 0. The imatinib dose is fixed. The dose of capecitabine is initially fixed and the dose of gemcitabine is increased 1 dose level. For the subsequent cohort, the dose of gemcitabine will be fixed and the dose of capecitabine advanced to the next dose level. 3 patients will be treated on the initial schedule. If no dose-limiting toxicities related to drug are observed and no patients require dose mods by the end of cycle 2, then 3 patients will be treated on the next schedule.

Secondary Outcome Measures:

Antitumor activity [ Time Frame: Following response assessment. ] [ Designated as safety issue: No ]
Deidentified melanoma samples will be sent to our collaborator at Ohio State, Dr. Christopher Corless, who is a recognized expert in this field. Renal cell samples will be assayed here at our institution

Estimated Enrollment:	56
Study Start Date:	August 2006
Estimated Primary Completion Date:	December 2016 (Final data collection date for primary outcome measure)

Intervention Details:

Dose level Capecitabine

-1 400 mg/m2 bid

0 500 mg/m2 bid

500 mg/m2 bid
600 mg/m2 bid
600 mg/m2 bid
725 mg/m2 bid
725 mg/m2 bid
850 mg/m2 bid
850 mg/m2 bid

Dose level Gemcitabine

-1 400 mg/m2 0 450 mg/m2

550 mg/m2
550 mg/m2
675 mg/m2
675 mg/m2
825 mg/m2
825 mg/m2
1000 mg/m2

Dose level Imatinib

-1 400 mg/d 0 400 mg/d

400 mg/d
400 mg/d
400 mg/d
400 mg/d
400 mg/d
400 mg/d
400 mg/d

C-kit mutations will be assessed on existing paraffin-embedded blocks by Polymerase Chain Reaction and direct sequencing of both juxtamembrane domains (exons 9 and 11) and the tyrosine kinase domain (exons 13 and 17). Every ABI sequence will be compared to a NCBI Human KIT gene nucleotide sequence and will be blast using a NCBI Standard Nucleotide Blast Search to determine the presence of mutation within a particular exon.

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

Ages Eligible for Study:	19 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

DISEASE CHARACTERISTICS:

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:
  - Bone lesions
  - Leptomeningeal disease
  - Ascites
  - Pleural or pericardial effusion
  - Lymphangitis cutis/pulmonis
  - Abdominal masses that are not confirmed and followed by imaging techniques
  - 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

PATIENT CHARACTERISTICS:

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
Not pregnant or nursing
Negative pregnancy test
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
No active serious infections
No known allergy or hypersensitivity to study drugs or their formulation
No comorbidity or condition which, in the opinion of the investigator, 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 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

PRIOR CONCURRENT THERAPY:

See Disease Characteristics
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
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)
Concurrent bisphosphonate therapy allowed for skeletal metastases provided therapy is started before study entry

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00483366

Locations

United States, Nebraska
UNMC Eppley Cancer Center at the University of Nebraska Medical Center
Omaha, Nebraska, United States, 68198-6805

Sponsors and Collaborators

University of Nebraska

National Cancer Institute (NCI)

Investigators

Principal Investigator:	Ralph Hauke, MD	University of Nebraska
Study Chair:	Elizabeth C. Reed, MD	University of Nebraska

More Information

Additional Information:

Clinical trial summary from the National Cancer Institute's PDQ® database This link exits the ClinicalTrials.gov site

No publications provided

Responsible Party:	Ralph Hauke, M.D., UNMC Eppley Cancer Center at the University of Nebraska Medical Center
ClinicalTrials.gov Identifier:	NCT00483366 History of Changes
Other Study ID Numbers:	163-06, P30CA036727, UNMC-16306
Study First Received:	June 6, 2007
Last Updated:	July 22, 2010
Health Authority:	United States: Federal Government

Keywords provided by University of Nebraska:

unspecified adult solid tumor, protocol specific

Additional relevant MeSH terms:

Neoplasms
Gemcitabine
Capecitabine
Fluorouracil
Imatinib
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents

Therapeutic Uses
Antiviral Agents
Anti-Infective Agents
Enzyme Inhibitors
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Radiation-Sensitizing Agents
Protein Kinase Inhibitors

ClinicalTrials.gov processed this record on May 23, 2013