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A Phase I Pharmacokinetic Study of STI571 in Patients With Advanced Malignancies and Varying Degrees of Renal Dysfunction for the CTEP-Sponsored Organ Dysfunction Working Group

Phase 1
16 Years
Not Enrolling
Malignant Neoplasm, Unspecified Adult Solid Tumor, Protocol Specific

Thank you

Trial Information

A Phase I Pharmacokinetic Study of STI571 in Patients With Advanced Malignancies and Varying Degrees of Renal Dysfunction for the CTEP-Sponsored Organ Dysfunction Working Group


I. To establish the maximum tolerated dose (MTD) of STI571 for cohorts of patients with
varying degrees of renal dysfunction (normal, mild, moderate, and severe).

II. To determine the effects of renal dysfunction on the plasma pharmacokinetics and
pharmacodynamics of STI571.

III. To evaluate the safety of STI571 in patients with various degrees of renal dysfunction.

OUTLINE: This is a dose-escalation study. Patients are stratified according to creatinine
clearance (at least 60 mL/min vs 40-59 mL/min vs 20-39 mL/min vs less than 20 mL/min vs any
creatinine clearance and undergoing dialysis).

Patients receive oral imatinib mesylate once or twice daily on days 1 and 4-28. Courses
repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients in each stratum receive escalating doses of imatinib mesylate until
the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding
that at which at least 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.

PROJECTED ACCRUAL: Approximately 60-69 patients (about 12 per stratum) will be accrued for
this study.

Inclusion Criteria:

- Patients must have histologically or cytologically confirmed malignancy, which is
metastatic or unresectable and for which standard curative or palliative measures do
not exist or are no longer effective; the following tumor types are eligible:

- (Note: All patients with normal renal function should be referred first to
higher priority national trials under cooperative group or Novartis sponsorship;
these studies include the Intergroup S0033 trial in GIST tumors and NABTC-9908
trial for gliomas; Novartis is also sponsoring ongoing clinical trials in
pediatric patients with Philadelphia chromosome - positive acute lymphocytic
leukemia and chronic myelogenous leukemia; for complete listing of other trials
and sites collaborating investigators are encouraged to verify status of current
national trials on the NCI - Physician Data Query [PDQ] system)

- Patients with all hematological malignancies are eligible (such as myeloma,
leukemia and lymphoma patients) provided the patient(s) have exhausted curative
intent or life prolonging therapy and meet other eligibility in terms of blood
counts; patients with Philadelphia chromosome - positive leukemia should be
enrolled on other NCI or Novartis sponsored trials, if possible

- Any solid tumor patient with abnormal renal dysfunction and including 12
patients with normal renal function (controls for pharmacokinetics) with an
emphasis on patients with gastrointestinal stromal tumors (GIST) and including
patients with glioma; patients with glioma who require corticosteroids or
anticonvulsants must be on a stable dose of corticosteroids and seizure free for
one month prior to enrollment

- (Note: Slots will be retained for patients with CML or other Philadelphia
chromosome-positive leukemia or GIST tumors beyond the initial dose level
cohorts, since these tumor types have greater potential to respond to therapy);
every effort should be made to enroll patients with glioma or GIST on available
cooperative group trials first

- Prior chemotherapy, radiation therapy, hormonal therapy and immunotherapy are
allowed, including prior therapy with STI571; there is no ceiling on number of prior

- ECOG performance status =< 2, (Karnofsky >= 60%) and a life expectancy of at least 3

- Leukocytes >= 3,000/uL, OR

- Absolute neutrophil count >= 1,500/uL

- Platelets >= 100,000/uL

- Total bilirubin within normal institutional limits

- AST (SGOT)/ALT (SGPT) =< 1.5 times the institutional upper limit of normal

- Patients with abnormal kidney function will be allowed and will be grouped

- Patients with gliomas and brain metastases, who require corticosteroids or
anticonvulsants must be on a stable dose of corticosteroids and seizure free for one
month prior to enrollment; patients with brain metastasis should have had brain

- The effects of STI571 on the developing human fetus at the recommended therapeutic
dose are unknown; for this reason and because STI571 is known to be teratogenic,
women of childbearing potential and men must agree to use adequate contraception
(hormonal or barrier method of birth control) prior to study entry and for the
duration of study participation; since interaction with STI571 and oral
contraceptives is possible, a barrier method should be used and oral contraceptives
should not be the only method; a negative pregnancy test is required prior to
starting therapy for women of child bearing age; should a woman become pregnant or
suspect she is pregnant while participating in this study, she should inform her
treating physician immediately

- Pregnancy: STI571 may be harmful to the developing fetus; therefore, for patients
enrolled on the study, contraceptive methods are recommended, and since interactions
with the metabolism of some oral contraceptives cannot be excluded at present, an
additional or alternative effective method of contraception, (e.g., barrier method)
should be used

- Breast feeding: STI571 may be harmful to nursing infants secondary to STI571
treatment of the mother' breastfeeding should be discontinued if the mother is
treated with STI571

- Ability to understand and the willingness to sign a written informed consent form

- Patients must be capable of following instructions regarding study medication,
completion of medication diaries, or have a caregiver who will be responsible for
administering study medication and completing medication diaries

Exclusion Criteria:

- Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for
nitrosoureas or mitomycin C) prior to study enrollment (excluding hydroxyurea if
hydroxyurea was administered to patients with leukemia to maintain a lower WBC
count); in the case of leukemic patients on maintenance hydroxyurea, patients may not
receive hydroxyurea within 24 hours prior to initiation of therapy

- Patients undergoing therapy with other investigational agents; patients on
therapeutic doses of warfarin are excluded

- Patients who have had liver, kidney, lung transplants or taking FK-506, cyclosporine
as an immunosuppressive agent; these agents may cause increased toxicity with STI571

- Uncontrolled intercurrent illness including but not limited to ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements

- Pregnant and nursing women are excluded from this study because STI571 is an agent
with the potential for teratogenic or abortifacient effects; because there is an
unknown but potential risk for adverse events in nursing infants secondary to
treatment of the mother with STI571, breastfeeding should be discontinued if the
mother is treated with STI571

- Because patients with immune deficiency are at increased risk of lethal infections,
when treated with marrow-suppressive therapy, HIV-positive patients receiving
combination anti-retroviral therapy are excluded from the study because of possible
pharmacokinetic interactions with STI571

- Patients receiving renal dialysis treatments while on the study will be enrolled in
two cohorts per the schema

- Patients must not have had a major surgery (e.g., thoracotomy, intra-abdominal
surgery) within 14 days prior to registration

- Patients with unstable or untreated (irradiated) brain metastases should be excluded

Type of Study:


Study Design:

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Maximum tolerated dose (MTD) of imatinib mesylate, based on the National Cancer Institute Common Toxicity Criteria (NCI CTC) v2.0

Outcome Description:

Toxicities will be tabulated and summarized by organ systems.

Outcome Time Frame:

Up to 4 weeks

Safety Issue:


Principal Investigator

Afshin Dowlati

Investigator Role:

Principal Investigator

Investigator Affiliation:

Case Western Reserve University


United States: Food and Drug Administration

Study ID:




Start Date:

September 2001

Completion Date:

Related Keywords:

  • Malignant Neoplasm
  • Unspecified Adult Solid Tumor, Protocol Specific
  • Neoplasms



Case Western Reserve University Cleveland, Ohio  44106