Sorafenib and Low Dose Cytarabine in Older Patients With Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndrome

Sponsor

NCIC Clinical Trials Group (Other)

Overall Status

Completed

CT.gov ID

NCT00516828

Collaborator

Bayer (Industry)

Enrollment

Locations

Arm

65.6

Actual Duration (Months)

5.3

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

RATIONALE: Sorafenib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth or by blocking blood flow to the cancer. Drugs used in chemotherapy, such as cytarabine, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving sorafenib together with cytarabine may kill more cancer cells.

PURPOSE: This phase I/II trial is studying the side effects and best dose of giving sorafenib together with cytarabine and to see how well it works in treating older patients with acute myeloid leukemia or high-risk myelodysplastic syndrome.

Condition or Disease	Intervention/Treatment	Phase
Leukemia Myelodysplastic Syndromes	Drug: cytarabine	Phase 1/Phase 2

Detailed Description

OBJECTIVES:

To determine the recommended dose of sorafenib tosylate and cytarabine when given in combination to elderly patients with acute myeloid leukemia or high-risk myelodysplastic syndromes who are not suitable for intensive chemotherapy. (Phase I)
To determine the safety, tolerability, toxicity profile, and dose-limiting toxicities in patients treated with this regimen. (Phase I)
To estimate the efficacy (as measured by complete response rate) in patients treated with this regimen. (Phase II)
To describe the toxic effects and overall response rate (complete and partial) in patients treated with this regimen. (Phase II)
To evaluate potential correlates of response in translational research studies including FLT-3 internal tandem duplications and point mutations in blasts. (Phase II)

OUTLINE: This is a multicenter study.

Phase I: Patients receive oral sorafenib tosylate twice daily on days 2-28 and cytarabine subcutaneously twice daily on days 1-10 at the dose level assigned at registration. Doses of both drugs will be escalated and the recommended doses for the combination will be determined. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients who respond to treatment will receive 2 cycles after response criteria are met.
Phase II: Patients receive sorafenib tosylate and cytarabine as in phase I at the recommended doses for the combination determined in phase I.

Bone marrow (or blood) samples are collected at baseline and at the end of each course of study treatment. Baseline samples are analyzed for mutational status of FLT-3 (i.e., internal tandem duplication [ITD] and point mutations).

After completion of study treatment, patients are followed at 4 weeks and then every 3 months thereafter until progression and toxicities resolve.

Study Design

Study Type:

Interventional

Actual Enrollment :

21 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase I/II Study of Sorafenib (BAY 43-9006) in Combination With Low Dose ARA-C (CYTARABINE) in Elderly Patients With AML or High-Risk MDS

Actual Study Start Date :

Jul 24, 2007

Actual Primary Completion Date :

Mar 18, 2010

Actual Study Completion Date :

Jan 10, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Sorafenib and Cytarabine Cytarabine: subcutaneously twice daily from day 1 - 10. Sorafenib: Days 2-28; at the dose level assigned at registration. Sorafenib will be given orally twice daily.	Drug: cytarabine subcutaneously twice daily from Day 1 to 10

Arm

Intervention/Treatment

Experimental: Sorafenib and Cytarabine

Cytarabine: subcutaneously twice daily from day 1 - 10. Sorafenib: Days 2-28; at the dose level assigned at registration. Sorafenib will be given orally twice daily.

Drug: cytarabine

subcutaneously twice daily from Day 1 to 10

Outcome Measures

Primary Outcome Measures

Recommended phase II dose of sorafenib tosylate when given in combination with cytarabine (Phase I) [29 months]
Dose-limiting toxicity (Phase I) [29 months]
Complete remission (Phase II) [29 months]

Secondary Outcome Measures

Overall response rate (complete and partial response) (Phase II) [29 months]
Time to progression (Phase II) [29 months]
Overall survival (Phase II) [29 months]
FLT-3 ITD endpoint mutation response correlation. [29 months]
Toxicity (Phase II) [29 months]

Eligibility Criteria

Criteria

Ages Eligible for Study:

60 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

DISEASE CHARACTERISTICS:

Diagnosis of 1 of the following:
Acute myeloid leukemia (AML) by FAB criteria (By morphology and routine histochemistry and confirmed, when possible, by flow cytometric analysis of surface immunophenotype; co-expression of lymphoid markers permitted)
High-risk myelodysplastic syndromes defined as IPSS category of intermediate-2 or greater
Must be considered unsuitable for intensive chemotherapy regimens
No documented CNS involvement

PATIENT CHARACTERISTICS:

ECOG performance status 0-2
AST and ALT ≤ 2 times upper limit of normal (ULN)
Bilirubin normal
Creatinine ≤ 1.2 times ULN OR creatinine clearance ≥ 50 mL/min
Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective contraception
No history of other malignancies, except adequately treated nonmelanoma skin cancer, curatively treated in situ carcinoma of the cervix, or other solid tumors curatively treated with no evidence of disease for ≥ 5 years
No upper gastrointestinal or other conditions that would preclude compliance with or administration of oral medication
No serious illness or medical condition that would not permit the patient to be managed according to the protocol, including any of the following:
History of significant neurologic or psychiatric disorder that would impair the ability to obtain consent
Active, uncontrolled, serious infections
Active peptic ulcer disease
Evidence of bleeding diathesis
No myocardial infarction within the past 6 months
No congestive heart failure
No unstable angina
No active cardiomyopathy or unstable ventricular arrhythmia
No poorly controlled hypertension (e.g., systolic BP ≥ 150 mm Hg or diastolic BP ≥ 95 mm Hg)
No known hypersensitivity to the study drugs or their components
No preexisting hypothyroidism prior to enrollment unless patient is euthyroid on medication
No neuropathy ≥ grade 2

PRIOR CONCURRENT THERAPY:

At least 2 days since prior hydroxyurea
No other prior chemotherapy
No concurrent therapeutic doses (≥ 2 mg/day) of anticoagulants (e.g., warfarin)
Doses of up to 2 mg/day given for prophylaxis of thrombosis are accepted provided INR is ≤ 1.5
No other concurrent experimental drugs or anticancer therapy

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	QEII Health Sciences Center	Halifax	Nova Scotia	Canada	B3H 1V7
2	Juravinski Cancer Centre at Hamilton Health Sciences	Hamilton	Ontario	Canada	L8V 5C2
3	Univ. Health Network-Princess Margaret Hospital	Toronto	Ontario	Canada	M5G 2M9
4	McGill University - Dept. Oncology	Montreal	Quebec	Canada	H2W 1S6

Sponsors and Collaborators

NCIC Clinical Trials Group
Bayer

Investigators

Study Chair: Brian Leber, MD, FRCPC, McMaster Children's Hospital at Hamilton Health Sciences
Study Chair: David A. MacDonald, MD, Nova Scotia Cancer Centre