Clofarabine and Cytarabine in Treating Older Patients With AML or High-Risk MDS

Phase 1

Completed

• Conditions: Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Myelodysplastic Syndrome With Isolated Del(5q); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Myeloid Leukemia
• Interventions: Drug: clofarabine; Drug: cytarabine

• Registration Number: NCT00839982
• Lead Sponsor: Fred Hutchinson Cancer Center

Brief Summary

This phase I/II trial studied the side effects and best dose of clofarabine when given together with cytarabine and to see how well they work in treating older patients with acute myeloid leukemia (AML) or high-risk myelodysplastic syndromes (MDS) that have relapsed or not responded to treatment.

Detailed Description

PRIMARY OBJECTIVES:

I. To estimate the maximum tolerated dose (MTD) of oral clofarabine when given with LDAC (cytarabine) in patients age \>= 60 with previously treated AML or high risk MDS.

SECONDARY OBJECTIVES:

I. To determine the response rate, disease-free survival (DFS), and overall survival (OS) after therapy with oral clofarabine and LDAC for previously treated AML or high-risk MDS.

OUTLINE: This is a phase I, dose-escalation study of clofarabine followed by a phase II study.

Patients receive clofarabine orally (PO) once daily (QD) on days 1-5 and low-dose cytarabine subcutaneously (SC) twice daily (BID) on days 1-10 or SC QD on days 1-14. Treatment repeats every 21-28 days for up to 4 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years and then annually for 3 years.

Study Timeline

• Study Start: 2008-11
• Study First Submitted: 2009-02-07
• Study First Submitted QC: 2009-02-07
• Study First Posted: 2009-02-10
• Primary Completion: 2012-12
• Study Completion: 2012-12
• Results First Submitted: 2017-03-07
• Status Verified: 2017-07
• Results First Submitted QC: 2017-07-06
• Last Update Submitted: 2017-07-06
• Results First Posted: 2017-07-11
• Last Update Posted: 2017-07-11

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 35

Inclusion Criteria

• Diagnosis of 1st relapse or refractory AML; or patients with high risk MDS (10-19% blasts) who have received previous therapy 1st remission must have been < 1 year
• Must not have received previous ara-C (cytarabine) or clofarabine
• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2
• Not candidates for standard 7 + 3 regimen (Ara-C and an anthracycline), high dose Ara-C, or hematopoietic stem-cell transplantation
• Serum creatinine =< 1.0 mg/dL; if serum creatinine > 1.0 mg/dL, then the estimated glomerular filtration rate (GFR) must be > 50 L/min/1.73 m^2 as calculated by the Modification of Diet in Renal Disease equation
• Serum bilirubin =< 1.5 x upper limit of normal (ULN)
• Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 x ULN
• Alkaline phosphatase =< 2.5 x ULN
• 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 should use an effective contraceptive method during the study and for a minimum of 6 months after study treatment

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Exclusion Criteria

• Current concomitant chemotherapy, radiation therapy, or immunotherapy other than as specified in the protocol

• Patients with acute promyelocytic leukemia (APL)

• 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 (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

• 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 including the following:

  • Patients with treated non-melanoma skin cancer, in situ carcinoma, or cervical intraepithelial neoplasia, regardless of the disease-free duration, are eligible for this 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 (PSA) values are also eligible for this study if hormonal therapy has been initiated, or a radical prostatectomy or definitive radiotherapy has been performed

• Have currently active gastrointestinal disease, or prior surgery that may affect the ability of the patient to absorb oral clofarabine

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (chemotherapy)	cytarabine	Patients receive clofarabine PO QD on days 1-5 and low-dose cytarabine SC BID on days 1-10 or SC QD on days 1-14. Treatment repeats every 21-28 days for up to 4 courses in the absence of disease progression or unacceptable toxicity.
Treatment (chemotherapy)	clofarabine	Patients receive clofarabine PO QD on days 1-5 and low-dose cytarabine SC BID on days 1-10 or SC QD on days 1-14. Treatment repeats every 21-28 days for up to 4 courses in the absence of disease progression or unacceptable toxicity.

Primary Outcome Measures

Name	Time	Method
Number of Patients With Dose Limiting Toxicity	Outcomes by day 30	Dose limiting toxicity (DLT) consists of grade 3-4 non-hematologic toxicity at least possibly related to study drug. Exceptions include neutropenic fever; drug-related fever; alopecia; anorexia; inadequately treated nausea, vomiting and/or diarrhea; and grade 3/4 increase in ALT, AST, or bilirubin recovering to \< grade 2 by 7 days. Prolonged grade 2 myelosuppression lasting longer than 49 days in patients who don't proceed to additional cytotoxic therapy is considered a DLT. The MTD or recommended phase II dose is the highest dose level at which no more than 1 patient out of 6 experiences DLT.
Maximum Tolerated Dose	up to 5 years	We identified 20 mg/d for 5 d as the maximum tolerated dose (MTD) of oral clofarabine.

Secondary Outcome Measures

Name	Time	Method
Treatment Response	Up to 5 years	CR = no evidence of leukemia with complete blood count recovery (ANC \>1,000 and PLTS \>100k) CRi = no evidence of leukemia but with incomplete blood count recovery
Disease Free Survival	Up to 5 years	Median disease-free survival
Overall Survival	Up to 5 years	Median overall survival

Trial Locations

Locations (1)

Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium; 🇺🇸 Seattle, Washington, United States