Combination Chemotherapy in Treating Young Patients With Relapsed or Refractory Acute Leukemia

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

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.

Study Overview

• Status: Completed
• Conditions: Leukemia
• Intervention / Treatment: Drug: dexamethasone; Drug: thiotepa; Biological: filgrastim; Drug: topotecan hydrochloride; Drug: vinorelbine tartrate; Drug: clofarabine

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.

• Study Type: Interventional
• Enrollment (Actual): 23
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • New York
    • New York, New York, United States, 10065
      • Memorial Sloan-Kettering Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 28 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Clofarabine; This is a single arm phase I clinical trial to assess safety (morbidity and mortality) of a novel leukemia re-induction regimen. The first component of this trial is a phase I dose escalation study to determine the maximum tolerated dose (MTD) of the novel agent Clofarabine, when used in combination with topotecan, vinorelbine, thiotepa and dexamethasone. A total of three dose levels will be explored in this study.

Drug: dexamethasone; Drug: thiotepa; Biological: filgrastim; Drug: topotecan hydrochloride; Drug: vinorelbine tartrate; Drug: clofarabine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Overall survival	2 years
Progression-free survival	2 years
Maximum tolerated dose of clofarabine	2 years

Collaborators and Investigators

• Sponsor: Memorial Sloan Kettering Cancer Center
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Peter G. Steinherz, MD, Memorial Sloan Kettering Cancer Center; Principal Investigator: Neerav Shukla, MD, Memorial Sloan Kettering Cancer Center

Study record dates

Study Major Dates

• Study Start: April 1, 2007
• Primary Completion (Actual): November 1, 2013
• Study Completion (Actual): November 1, 2013

Study Registration Dates

• First Submitted: April 18, 2007
• First Submitted That Met QC Criteria: April 18, 2007
• First Posted (Estimate): April 19, 2007

Study Record Updates

• Last Update Posted (Estimate): November 14, 2013
• Last Update Submitted That Met QC Criteria: November 13, 2013
• Last Verified: November 1, 2013

More Information

Terms related to this study

• Keywords: recurrent adult acute myeloid leukemia; recurrent adult acute lymphoblastic leukemia; recurrent childhood acute lymphoblastic leukemia; recurrent childhood acute myeloid leukemia; acute undifferentiated leukemia
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Leukemia; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Anti-Inflammatory Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Phytogenic; Topoisomerase Inhibitors; Topoisomerase I Inhibitors; Dexamethasone; Clofarabine; Vinorelbine; Topotecan; Thiotepa
• Other Study ID Numbers: 07-012; MSKCC-07012