Clofarabine, Etoposide, and Mitoxantrone for Relapsed and Refractory Acute Leukemias

NCT ID: NCT00882076

Last Updated: 2019-07-24

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE1
• Total Enrollment: 22 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2009-03-31
• Study Completion Date: 2011-03-31

Brief Summary

The purpose of this study is to establish toxicity and a maximum tolerated dose recommended phase 2 dose of Clofarabine in combination with Etoposide and Mitoxantrone for therapy of relapsed or refractory acute leukemias. The investigators will observe responses with these therapy agents and assess the impact of Clofarabine interacting with Etoposide in induction of DNA strand breaks.

Detailed Description

This will be a phase I study with a standard 3x3 design. Patients will proceed to treatment through a series of cohorts with the three drugs being delivered over five days beginning with a dose of Etoposide 100 mg/m2 on days 1-5,Mitoxantrone 8 mg/m2 days 1-3, and clofarabine at 20 mg/m2 IV on days 2-6. Presuming this and subsequent cohorts are tolerable and no more than 1 patient per cohort develops DLT, MTD patients will be treated in cohorts of 3-6 patients up to a final dose level of Etoposide 100 mg/m2 on days 1-5,Mitoxantrone 8 mg/m2 days 1-5, and Clofarabine at 30 mg/m2 IV on days 2-6. Patients failing to enter remission may receive 4 days of therapy with Etoposide 100 mg/m2 on days 1-4,Mitoxantrone 8 mg/m2 days 1-2 or 1-4,and Clofarabine at 20-30 mg/m2 IV on days 1-4. According to established definitions for dose limiting toxicity a recommended phase II dose will be established. After this is established the final cohort will be expanded to 15 patients.

Conditions

Leukemia

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: FACTORIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Treatment Cohort 1

Etoposide (Days 1-5) 100 mg/m2; Mitoxantrone (Days 1-3) 8 mg/m2 (3 doses); Clofarabine (Days 2-6) 20 mg/m2

Group Type: EXPERIMENTAL

Clofarabine

Intervention Type: DRUG

For Treatment Clofarabine will be administered on Days 2-6 at the dose of 20mg/m2 in Cohort 1, 25mg/m2 in Cohort 2 and 30mg/m2 in Cohort 3 and 4 and 10mg/m2 in Cohort 0 (In the event of excessive DLT in Treatment Cohort 1). For Retreatment Clofarabine will be administered on Days 1-4 at the dose of 20mg/m2 in Cohort 1, 25mg/m2 in Cohort 2 and 30mg/m2 in Cohort 3 and 4 and 10mg/m2 in Cohort 0 (In the event of excessive DLT in Retreatment Cohort 1).

Mitoxantrone

Intervention Type: DRUG

For Treatment Mitoxantrone will be administered on Days 1-3 at the dose of 8mg/m2 in Cohort 1, 2, 3 and on Days 1-5 for Cohort 4 and on Days 1-3 8mg/m2 in Cohort 0 (In the event of excessive DLT in Treatment Cohort 1). For Retreatment Mitoxantrone will be administered on Days 1-2 (2 doses) at the dose of 8mg/m2 in Cohort 1, 2 and 3 and on Days 1-4 (4 doses) at the dose of 8mg/m2 in Cohort 4, and on Days 1-2 (2 doses) at the dose of 8mg/m2 in Cohort 0 (In the event of excessive DLT in Retreatment Cohort 1).

Etoposide

Intervention Type: DRUG

For Treatment Etoposide will be administered on Days 1-5 at the dose of 100mg/m2 in Cohort 1, 2, 3, 4 and Cohort 0 (in the event of excessive DLT in Treatment Cohort 1). For Retreatment Etoposide will be administered on Days 1-4 at the dose of 100mg/m2 in Cohort 1, 2, 3, 4 and Cohort 0 (in the event of excessive DLT in Retreatment Cohort 1).

Treatment Cohort 2

Etoposide (Days 1-5) 100 mg/m2; Mitoxantrone (Days 1-3) 8 mg/m2; Clofarabine (Days 2-6) 25 mg/m2

Group Type: EXPERIMENTAL

Clofarabine

Intervention Type: DRUG

For Treatment Clofarabine will be administered on Days 2-6 at the dose of 20mg/m2 in Cohort 1, 25mg/m2 in Cohort 2 and 30mg/m2 in Cohort 3 and 4 and 10mg/m2 in Cohort 0 (In the event of excessive DLT in Treatment Cohort 1). For Retreatment Clofarabine will be administered on Days 1-4 at the dose of 20mg/m2 in Cohort 1, 25mg/m2 in Cohort 2 and 30mg/m2 in Cohort 3 and 4 and 10mg/m2 in Cohort 0 (In the event of excessive DLT in Retreatment Cohort 1).

Mitoxantrone

Intervention Type: DRUG

For Treatment Mitoxantrone will be administered on Days 1-3 at the dose of 8mg/m2 in Cohort 1, 2, 3 and on Days 1-5 for Cohort 4 and on Days 1-3 8mg/m2 in Cohort 0 (In the event of excessive DLT in Treatment Cohort 1). For Retreatment Mitoxantrone will be administered on Days 1-2 (2 doses) at the dose of 8mg/m2 in Cohort 1, 2 and 3 and on Days 1-4 (4 doses) at the dose of 8mg/m2 in Cohort 4, and on Days 1-2 (2 doses) at the dose of 8mg/m2 in Cohort 0 (In the event of excessive DLT in Retreatment Cohort 1).

Etoposide

Intervention Type: DRUG

For Treatment Etoposide will be administered on Days 1-5 at the dose of 100mg/m2 in Cohort 1, 2, 3, 4 and Cohort 0 (in the event of excessive DLT in Treatment Cohort 1). For Retreatment Etoposide will be administered on Days 1-4 at the dose of 100mg/m2 in Cohort 1, 2, 3, 4 and Cohort 0 (in the event of excessive DLT in Retreatment Cohort 1).

Treatment Cohort 3

Etoposide (Days 1-5) 100 mg/m2; Mitoxantrone (Days 1-3) 8 mg/m2; Clofarabine (Days 2-6) 30 mg/m2

Group Type: EXPERIMENTAL

Clofarabine

Intervention Type: DRUG

For Treatment Clofarabine will be administered on Days 2-6 at the dose of 20mg/m2 in Cohort 1, 25mg/m2 in Cohort 2 and 30mg/m2 in Cohort 3 and 4 and 10mg/m2 in Cohort 0 (In the event of excessive DLT in Treatment Cohort 1). For Retreatment Clofarabine will be administered on Days 1-4 at the dose of 20mg/m2 in Cohort 1, 25mg/m2 in Cohort 2 and 30mg/m2 in Cohort 3 and 4 and 10mg/m2 in Cohort 0 (In the event of excessive DLT in Retreatment Cohort 1).

Mitoxantrone

Intervention Type: DRUG

For Treatment Mitoxantrone will be administered on Days 1-3 at the dose of 8mg/m2 in Cohort 1, 2, 3 and on Days 1-5 for Cohort 4 and on Days 1-3 8mg/m2 in Cohort 0 (In the event of excessive DLT in Treatment Cohort 1). For Retreatment Mitoxantrone will be administered on Days 1-2 (2 doses) at the dose of 8mg/m2 in Cohort 1, 2 and 3 and on Days 1-4 (4 doses) at the dose of 8mg/m2 in Cohort 4, and on Days 1-2 (2 doses) at the dose of 8mg/m2 in Cohort 0 (In the event of excessive DLT in Retreatment Cohort 1).

Etoposide

Intervention Type: DRUG

For Treatment Etoposide will be administered on Days 1-5 at the dose of 100mg/m2 in Cohort 1, 2, 3, 4 and Cohort 0 (in the event of excessive DLT in Treatment Cohort 1). For Retreatment Etoposide will be administered on Days 1-4 at the dose of 100mg/m2 in Cohort 1, 2, 3, 4 and Cohort 0 (in the event of excessive DLT in Retreatment Cohort 1).

Treatment Cohort 4

Etoposide (Days 1-5) 100 mg/m2; Mitoxantrone (Days 1-5) 8 mg/m2; Clofarabine (Days 2-6) 30 mg/m2

Group Type: EXPERIMENTAL

Clofarabine

Intervention Type: DRUG

For Treatment Clofarabine will be administered on Days 2-6 at the dose of 20mg/m2 in Cohort 1, 25mg/m2 in Cohort 2 and 30mg/m2 in Cohort 3 and 4 and 10mg/m2 in Cohort 0 (In the event of excessive DLT in Treatment Cohort 1). For Retreatment Clofarabine will be administered on Days 1-4 at the dose of 20mg/m2 in Cohort 1, 25mg/m2 in Cohort 2 and 30mg/m2 in Cohort 3 and 4 and 10mg/m2 in Cohort 0 (In the event of excessive DLT in Retreatment Cohort 1).

Mitoxantrone

Intervention Type: DRUG

For Treatment Mitoxantrone will be administered on Days 1-3 at the dose of 8mg/m2 in Cohort 1, 2, 3 and on Days 1-5 for Cohort 4 and on Days 1-3 8mg/m2 in Cohort 0 (In the event of excessive DLT in Treatment Cohort 1). For Retreatment Mitoxantrone will be administered on Days 1-2 (2 doses) at the dose of 8mg/m2 in Cohort 1, 2 and 3 and on Days 1-4 (4 doses) at the dose of 8mg/m2 in Cohort 4, and on Days 1-2 (2 doses) at the dose of 8mg/m2 in Cohort 0 (In the event of excessive DLT in Retreatment Cohort 1).

Etoposide

Intervention Type: DRUG

For Treatment Etoposide will be administered on Days 1-5 at the dose of 100mg/m2 in Cohort 1, 2, 3, 4 and Cohort 0 (in the event of excessive DLT in Treatment Cohort 1). For Retreatment Etoposide will be administered on Days 1-4 at the dose of 100mg/m2 in Cohort 1, 2, 3, 4 and Cohort 0 (in the event of excessive DLT in Retreatment Cohort 1).

Treatment Cohort 0

Etoposide (Days 1-5) 100 mg/m2; Mitoxantrone (Days 1-3) 8 mg/m2; Clofarabine (Days 2-6) 10 mg/m2 (In the event of a DLT in Treatment Cohort 1)

Group Type: EXPERIMENTAL

Clofarabine

Intervention Type: DRUG

For Treatment Clofarabine will be administered on Days 2-6 at the dose of 20mg/m2 in Cohort 1, 25mg/m2 in Cohort 2 and 30mg/m2 in Cohort 3 and 4 and 10mg/m2 in Cohort 0 (In the event of excessive DLT in Treatment Cohort 1). For Retreatment Clofarabine will be administered on Days 1-4 at the dose of 20mg/m2 in Cohort 1, 25mg/m2 in Cohort 2 and 30mg/m2 in Cohort 3 and 4 and 10mg/m2 in Cohort 0 (In the event of excessive DLT in Retreatment Cohort 1).

Mitoxantrone

Intervention Type: DRUG

For Treatment Mitoxantrone will be administered on Days 1-3 at the dose of 8mg/m2 in Cohort 1, 2, 3 and on Days 1-5 for Cohort 4 and on Days 1-3 8mg/m2 in Cohort 0 (In the event of excessive DLT in Treatment Cohort 1). For Retreatment Mitoxantrone will be administered on Days 1-2 (2 doses) at the dose of 8mg/m2 in Cohort 1, 2 and 3 and on Days 1-4 (4 doses) at the dose of 8mg/m2 in Cohort 4, and on Days 1-2 (2 doses) at the dose of 8mg/m2 in Cohort 0 (In the event of excessive DLT in Retreatment Cohort 1).

Etoposide

Intervention Type: DRUG

For Treatment Etoposide will be administered on Days 1-5 at the dose of 100mg/m2 in Cohort 1, 2, 3, 4 and Cohort 0 (in the event of excessive DLT in Treatment Cohort 1). For Retreatment Etoposide will be administered on Days 1-4 at the dose of 100mg/m2 in Cohort 1, 2, 3, 4 and Cohort 0 (in the event of excessive DLT in Retreatment Cohort 1).

Interventions

Clofarabine

For Treatment Clofarabine will be administered on Days 2-6 at the dose of 20mg/m2 in Cohort 1, 25mg/m2 in Cohort 2 and 30mg/m2 in Cohort 3 and 4 and 10mg/m2 in Cohort 0 (In the event of excessive DLT in Treatment Cohort 1). For Retreatment Clofarabine will be administered on Days 1-4 at the dose of 20mg/m2 in Cohort 1, 25mg/m2 in Cohort 2 and 30mg/m2 in Cohort 3 and 4 and 10mg/m2 in Cohort 0 (In the event of excessive DLT in Retreatment Cohort 1).

Intervention Type: DRUG

Mitoxantrone

For Treatment Mitoxantrone will be administered on Days 1-3 at the dose of 8mg/m2 in Cohort 1, 2, 3 and on Days 1-5 for Cohort 4 and on Days 1-3 8mg/m2 in Cohort 0 (In the event of excessive DLT in Treatment Cohort 1). For Retreatment Mitoxantrone will be administered on Days 1-2 (2 doses) at the dose of 8mg/m2 in Cohort 1, 2 and 3 and on Days 1-4 (4 doses) at the dose of 8mg/m2 in Cohort 4, and on Days 1-2 (2 doses) at the dose of 8mg/m2 in Cohort 0 (In the event of excessive DLT in Retreatment Cohort 1).

Intervention Type: DRUG

Etoposide

For Treatment Etoposide will be administered on Days 1-5 at the dose of 100mg/m2 in Cohort 1, 2, 3, 4 and Cohort 0 (in the event of excessive DLT in Treatment Cohort 1). For Retreatment Etoposide will be administered on Days 1-4 at the dose of 100mg/m2 in Cohort 1, 2, 3, 4 and Cohort 0 (in the event of excessive DLT in Retreatment Cohort 1).

Intervention Type: DRUG

Other Intervention Names

Clolar; Mitoxantrone hydrochloride; Etoposide Phosphate

Eligibility Criteria

Inclusion Criteria

• Adequate renal and hepatic function.
• Capable of understanding the investigational nature, potential risks and benefits of the study and able to provide valid informed consent.
• 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.
• LVEF must be ≥ 50% within 2 weeks.

Exclusion Criteria

• Current concomitant chemotherapy, radiation therapy, or immunotherapy other than as specified in the protocol.
• Use of investigational agents within 30 days or any anticancer therapy within 2 weeks before study entry with the exception of hydroxyurea. The patient must have recovered from all acute toxicities from any previous therapy.
• 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.
• 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.
• Have had a diagnosis of another malignancy, unless the patient has been disease free for at least 3 years following the completion of curative intent therapy with the following exceptions: patients with treated non-melanoma skin cancer, in situ carcinoma or cervical intraepithelial neoplasia, regardless of the disease-free duration, are eligible for the study if definitive treatment for the condition has been completed. Patients with organ-confined prostate cancer with no evidence of recurrent or progressive disease based on prostate-specific antigen values are also eligible for this study if hormonal therapy has been initiated or a radical prostatectomy has been performed. Additionally, patients with prostate cancer treated with radiation therapy are also eligible for the study.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 70 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Milton S. Hershey Medical Center

OTHER

Sponsor Role: lead

Responsible Party

David F. Claxton, MD

Professor of Medicine

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

David F. Claxton, MD

Role: PRINCIPAL_INVESTIGATOR

Penn State College of Medicine

Locations

Penn State Hershey Cancer Institute

Hershey, Pennsylvania, United States

Countries

United States

Other Identifiers

PSHCI 08-096

Identifier Type: -

Identifier Source: org_study_id