Imatinib Mesylate, Gemcitabine, and Capecitabine in Treating Patients With Advanced Solid Tumors

Phase 1

Completed

• Conditions: Unspecified Adult Solid Tumor, Protocol Specific
• Interventions: Drug: capecitabine; Drug: gemcitabine hydrochloride; Drug: imatinib mesylate; Genetic: mutation analysis; Genetic: nucleic acid sequencing; Genetic: polymerase chain reaction

• Registration Number: NCT00483366
• Lead Sponsor: University of Nebraska

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.

Study Timeline

• Study Start: 2006-08-15
• Study First Submitted: 2007-06-06
• Study First Submitted QC: 2007-06-06
• Study First Posted: 2007-06-07
• Primary Completion: 2009-01-30
• Study Completion: 2011-03-29
• Status Verified: 2023-09
• Last Update Submitted: 2023-09-12
• Last Update Posted: 2023-09-14

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 13

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)

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Imatinib/Gemcitabine/Capecitabine	gemcitabine hydrochloride	Patients will be accrued on cohorts of three per dose level starting at dose level 0. Accrual to higher dose levels will depend on toxicity occurrence. Dose limiting toxicity (DLT) will be determined after cycle two for each patient. Schema: Imatinib days 1 - 5 and days 8 - 12 Gemcitabine on days 3 and 10 Capecitabine on days 1 - 14 Doses: Imatinib 400 mg/d fixed dose Gemcitabine 450 mg/m2; 550 mg/m2; 675 mg/m2; 825 mg/m2; 1000 mg/m2 Capecitabine 500 mg/m2; 600 mg/m2 bid; 725 mg/m2; 850 mg/m2 Treatment cycle: 21-days Treatment duration: Until disease progression or unacceptable toxicity defined in protocol.
Imatinib/Gemcitabine/Capecitabine	imatinib mesylate	Patients will be accrued on cohorts of three per dose level starting at dose level 0. Accrual to higher dose levels will depend on toxicity occurrence. Dose limiting toxicity (DLT) will be determined after cycle two for each patient. Schema: Imatinib days 1 - 5 and days 8 - 12 Gemcitabine on days 3 and 10 Capecitabine on days 1 - 14 Doses: Imatinib 400 mg/d fixed dose Gemcitabine 450 mg/m2; 550 mg/m2; 675 mg/m2; 825 mg/m2; 1000 mg/m2 Capecitabine 500 mg/m2; 600 mg/m2 bid; 725 mg/m2; 850 mg/m2 Treatment cycle: 21-days Treatment duration: Until disease progression or unacceptable toxicity defined in protocol.
Imatinib/Gemcitabine/Capecitabine	mutation analysis	Patients will be accrued on cohorts of three per dose level starting at dose level 0. Accrual to higher dose levels will depend on toxicity occurrence. Dose limiting toxicity (DLT) will be determined after cycle two for each patient. Schema: Imatinib days 1 - 5 and days 8 - 12 Gemcitabine on days 3 and 10 Capecitabine on days 1 - 14 Doses: Imatinib 400 mg/d fixed dose Gemcitabine 450 mg/m2; 550 mg/m2; 675 mg/m2; 825 mg/m2; 1000 mg/m2 Capecitabine 500 mg/m2; 600 mg/m2 bid; 725 mg/m2; 850 mg/m2 Treatment cycle: 21-days Treatment duration: Until disease progression or unacceptable toxicity defined in protocol.
Imatinib/Gemcitabine/Capecitabine	nucleic acid sequencing	Patients will be accrued on cohorts of three per dose level starting at dose level 0. Accrual to higher dose levels will depend on toxicity occurrence. Dose limiting toxicity (DLT) will be determined after cycle two for each patient. Schema: Imatinib days 1 - 5 and days 8 - 12 Gemcitabine on days 3 and 10 Capecitabine on days 1 - 14 Doses: Imatinib 400 mg/d fixed dose Gemcitabine 450 mg/m2; 550 mg/m2; 675 mg/m2; 825 mg/m2; 1000 mg/m2 Capecitabine 500 mg/m2; 600 mg/m2 bid; 725 mg/m2; 850 mg/m2 Treatment cycle: 21-days Treatment duration: Until disease progression or unacceptable toxicity defined in protocol.
Imatinib/Gemcitabine/Capecitabine	polymerase chain reaction	Patients will be accrued on cohorts of three per dose level starting at dose level 0. Accrual to higher dose levels will depend on toxicity occurrence. Dose limiting toxicity (DLT) will be determined after cycle two for each patient. Schema: Imatinib days 1 - 5 and days 8 - 12 Gemcitabine on days 3 and 10 Capecitabine on days 1 - 14 Doses: Imatinib 400 mg/d fixed dose Gemcitabine 450 mg/m2; 550 mg/m2; 675 mg/m2; 825 mg/m2; 1000 mg/m2 Capecitabine 500 mg/m2; 600 mg/m2 bid; 725 mg/m2; 850 mg/m2 Treatment cycle: 21-days Treatment duration: Until disease progression or unacceptable toxicity defined in protocol.
Imatinib/Gemcitabine/Capecitabine	capecitabine	Patients will be accrued on cohorts of three per dose level starting at dose level 0. Accrual to higher dose levels will depend on toxicity occurrence. Dose limiting toxicity (DLT) will be determined after cycle two for each patient. Schema: Imatinib days 1 - 5 and days 8 - 12 Gemcitabine on days 3 and 10 Capecitabine on days 1 - 14 Doses: Imatinib 400 mg/d fixed dose Gemcitabine 450 mg/m2; 550 mg/m2; 675 mg/m2; 825 mg/m2; 1000 mg/m2 Capecitabine 500 mg/m2; 600 mg/m2 bid; 725 mg/m2; 850 mg/m2 Treatment cycle: 21-days Treatment duration: Until disease progression or unacceptable toxicity defined in protocol.

Primary Outcome Measures

Name	Time	Method
Maximum tolerated dose of gemcitabine hydrochloride and capecitabine when combined with imatinib mesylate	By the end of cycle 2	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.
Dose-limiting Toxicity	By the end of cycle 2.	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

Name	Time	Method
Antitumor activity	Following response assessment.	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

Trial Locations

Locations (1)

UNMC Eppley Cancer Center at the University of Nebraska Medical Center; 🇺🇸 Omaha, Nebraska, United States