Safety of Clofarabine With Multiagent Chemotherapy in Childhood Acute Lymphoblastic Leukemia (Vandevol)

A Phase I Dose Escalation Study of Clofarabine Given in Combination With Multi-agent Therapy for Remission Induction in Pediatric Patients With Acute Lymphoblastic Leukemia in First Relapse or Refractory to First Line Therapy -

The purpose of this study is to determine Maximum Tolerated Dosage (MTD), Dosage Limited Toxicities (DLT), and the Rate Phase 2 Dosage of clofarabine when used in combination with etoposide, asparaginase, mitoxantrone and dexamethasone and to assess the feasibility and safety of this combination regimen to treat children with high risk relapsed or refractory acute lymphoblastic leukemia (ALL).

Study Overview

• Status: Completed
• Conditions: Acute Lymphoid Leukemia Relapse; Acute Lymphoid Leukemia Relapse After Bone Marrow Transplant
• Intervention / Treatment: Drug: Clofarabine

Detailed Description

I.3 Primary Objectives :

To determine the MTD of escalating doses of clofarabine starting from 20 mg/m2/day to 40 mg/m2/day from day 1 to day 5, as a replacement of cytarabine as part of a combination of etoposide, asparaginase, mitoxantrone and dexamethasone (VANDA regimen).

I.4 Secondary Objectives :

1. To determine the safety and tolerability of clofarabine when used in combination with etoposide, asparaginase, mitoxantrone and dexamethasone (VANDA regimen) and determine the duration, seriousness, and relationship of adverse events that occur during the treatment and follow-up periods ; we search DLT
2. To determine the Overall Response rate (OR) (Complete Remission + Complete Remission without platelet's normalization) of clofarabine plus etoposide ,asparaginase, mitoxantrone and dexamethasone (VANDA regimen) in pediatric patients with refractory or relapsed ALL at the established clofarabine RP2D.
3. To document the rate of Partial Response[s] in the study population
4. To document time-to-event parameters, including duration of remission, Event Free Survival (EFS), 4-month EFS, and overall survival (OS).

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 1

Contacts and Locations

Study Locations

• France
  • Besançon, France, 25000
    • Besançon University Hospital
  • Lille, France, 59037
    • Lille University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 23 years (ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• 1 to 21 years old at the date of acute lymphoblastic leukemia initial diagnosis
• Very early medullary first relapse occurring during the first 18th months after complete remission OR patients with second relapse OR a relapse occurring 6 months or more after myeloablative stem cell transplantation will be eligible.
• Have a Karnofsky Performance Status (KPS) of ≥70 for patients >10 years of age or a Lansky Performance Status (LPS) of ≥60 for patients ≤10 years of age.
• No concomitant malignant disease.
• No active uncontrolled infection.
• Have adequate renal and hepatic functions
• absence of concomitant severe cardiovascular disease, i.e. congestive heart failure
• Female patients of childbearing potential must have a negative serum pregnancy test within 2 weeks prior to enrollment.
• Male and female patients must use an effective contraceptive method during the study and for a minimum of 6 months after study treatment.

Exclusion Criteria:

• Current concomitant chemotherapy, radiation therapy, or immunotherapy other than as specified in the protocol.
• Use of any investigational agent within 30 days.
• Known hypersensitivity to clofarabine or excipients.
• Known hypersensitivity to mitoxantrone, etoposide or excipients.
• Allergy to both E Coli-Asparaginase and Erwinia Asparaginase
• Prior transplant less than 6 months ago.
• Trisomy 21
• Have any other severe concurrent disease, or have a history of serious organ dysfunction or disease involving the heart, kidney, liver, or other organ system that may place the patient at undue risk to undergo treatment.
• Patients with a systemic fungal, bacterial, viral, or other infection not controlled (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antibiotics or other treatment).
• Pregnant or lactating patients.
• Any significant concurrent disease, illness, or psychiatric disorder that would compromise patient safety or compliance, interfere with consent, study participation, follow up, or interpretation of study results.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
maximum tolerated dose of clofarabine in combination with etoposide, asparaginase, mitoxantrone and dexamethasone	within the 40 days after the chemotherapy

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
efficacy of clofarabine used in combination with etoposide, asparaginase, mitoxantrone and dexamethasone	Complete remission rate and minimal residual disease level	40 days after the chemotherapy
Event free survival		4 months

Collaborators and Investigators

• Sponsor: University Hospital, Lille
• Collaborators: Assistance Publique - Hôpitaux de Paris; Hospices Civils de Lyon; Central Hospital, Nancy, France; University Hospital, Bordeaux; Saint-Louis Hospital, Paris, France; Centre Hospitalier Universitaire de Besancon; Rennes University Hospital; University Hospital, Toulouse; Nantes University Hospital; University Hospital, Marseille
• Investigators: Principal Investigator: Brigitte Nelken, MD PhD, Lille Unıversity Hospital, Lille, France; Study Chair: Pıerre S Rohrlich, MD, PhD, Besançon University Hospital

Study record dates

Study Major Dates

• Study Start: January 1, 2010
• Primary Completion (ACTUAL): June 1, 2012
• Study Completion (ACTUAL): June 1, 2013

Study Registration Dates

• First Submitted: January 17, 2011
• First Submitted That Met QC Criteria: January 17, 2011
• First Posted (ESTIMATE): January 19, 2011

Study Record Updates

• Last Update Posted (ESTIMATE): December 9, 2014
• Last Update Submitted That Met QC Criteria: December 8, 2014
• Last Verified: December 1, 2014

More Information

Terms related to this study

• Keywords: relapse; childhood; Acute lymphoblastic leukemia; clofarabine
• Additional Relevant MeSH Terms: Pathologic Processes; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Disease Attributes; Leukemia; Recurrence; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Dexamethasone; Etoposide; Clofarabine; Asparaginase; Mitoxantrone
• Other Study ID Numbers: 2009-010826-20; 2008_40/0905 (OTHER: Sponsor)