Clinical trial NCT00462787: Combination Chemotherapy in Treating Young Patients With Relapsed or Refractory Acute Leukemia
Official title: A Phase I Dose Escalation Trial of Clofarabine in Addition to Topotecan, Vinorelbine, Thiotepa, and Dexamethasone in Pediatric Patients With Relapsed or Refractory Acute Leukemia
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Leukemia
Keywords: acute undifferentiated leukemia
recurrent childhood acute lymphoblastic leukemia
recurrent childhood acute myeloid leukemia
recurrent adult acute lymphoblastic leukemia
recurrent adult acute myeloid leukemia
Lead sponsor: Memorial Sloan Kettering Cancer Center
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2007-04-19
Enrollment: 23
Sex: ALL
Maximum age (years): 28
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: RATIONALE: Drugs used in chemotherapy, such as clofarabine, topotecan, vinorelbine, thiotepa, and dexamethasone, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more cancer cells.

PURPOSE: This phase I trial is studying the side effects and best dose of clofarabine when given together with topotecan, vinorelbine, thiotepa, and dexamethasone in treating young patients with relapsed or refractory acute leukemia.

Detailed description: OBJECTIVES:

* Determine the maximum tolerated dose of clofarabine when administered in combination with topotecan hydrochloride, vinorelbine ditartrate, thiotepa, and dexamethasone in young patients with relapsed or refractory acute leukemia.
* Evaluate the antileukemic potential of this regimen in these patients.
* Evaluate the incidence and severity of treatment-related morbidity and mortality in patients treated with this regimen.
* Develop a new reinduction treatment regimen that will result in a patient clinical response with as little residual disease as possible to permit a bone marrow transplantation while in subsequent remission; maintain the response long enough to identify an appropriate stem cell donor; and permit the patient to undergo a stem cell transplantation free of infections and without vital organ dysfunction.

OUTLINE: This is a nonrandomized, prospective, dose-escalation study of clofarabine.

Patients receive topotecan hydrochloride IV continuously over 120 hours on days 0-4; vinorelbine ditartrate over 6-10 minutes on days 0, 7, and 14; thiotepa IV over 4 hours on day 2; clofarabine IV over 2 hours on days 3-7; and oral or IV dexamethasone 3 times daily on days 3 and 7-13 and then on day 3 only thereafter. Patients also receive filgrastim (G-CSF) subcutaneously once daily beginning on day 8 and continuing until blood counts recover. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of clofarabine until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose at which 2 of 6 patients experience dose-limiting toxicity OR the dose preceding that at which 2 of 3 patients experience dose-limiting toxicity. At least 6 patients are treated at the MTD.

After completion of study treatment, patients are followed once a week for 4 weeks, twice a month for 6 months, and then once a month for 2 years.

PROJECTED ACCRUAL: A total of 23 patients will be accrued for this study.

Eligibility criteria: DISEASE CHARACTERISTICS:

* Must have 1 of the following diagnoses:

  * Acute lymphoblastic leukemia (ALL) meeting 1 of the following criteria:

    * Refractory to initial induction with two or more standard regimens
    * Relapsed \< 24 months after first complete response on a high-risk protocol OR refractory to one standard reinduction regimen
    * Second or greater relapse
  * Acute myeloid leukemia, acute biphenotypic leukemia, or acute undifferentiated leukemia meeting 1 of the following criteria:

    * Refractory to initial induction
    * First or greater relapse
* Must have \> 20% bone marrow blasts, or evidence of recurrent disease at an extramedullary site
* No symptomatic CNS disease

  * Patients with asymptomatic CNS disease are eligible with the approval of the principal investigator

PATIENT CHARACTERISTICS:

* Karnofsky performance status (PS) 70-100% OR Lansky PS 70-100%
* AST and ALT \< 4 times upper limit of normal
* Bilirubin \< 2.0 mg/dL (unless liver involvement)
* Creatinine within normal range for age OR creatinine clearance \> 60 mL/min/1.73 m\^2
* Adequate cardiac function (either asymptomatic with no prior risk factors, or if symptomatic, left ventricular ejection fraction \> 50% at rest)
* Not pregnant or nursing
* Negative pregnancy test
* Fertile patients must use effective contraception
* No active uncontrolled viral, bacterial, or fungal infection

PRIOR CONCURRENT THERAPY:

* See Disease Characteristics
* No prior clofarabine
* More than 2 weeks since prior systemic chemotherapy

  * At least 7 days since prior chemotherapy for patients with rapidly progressive disease and recovered

Primary outcomes:
measure: Maximum tolerated dose of clofarabine
timeFrame: 2 years
measure: Overall survival
timeFrame: 2 years
measure: Progression-free survival
timeFrame: 2 years
Secondary outcomes:
Other outcomes:
Locations:
city: New York
country: United States
facility: Memorial Sloan-Kettering Cancer Center
state: New York
Study officials:
affiliation: Memorial Sloan Kettering Cancer Center
name: Peter G. Steinherz, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Memorial Sloan Kettering Cancer Center
name: Neerav Shukla, MD
role: PRINCIPAL_INVESTIGATOR
References: