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

Sponsor:	NCIC Clinical Trials Group
Information provided by (Responsible Party):	NCIC Clinical Trials Group
ClinicalTrials.gov Identifier:	NCT00516828

Purpose

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	Intervention	Phase
Leukemia Myelodysplastic Syndromes	Drug: cytarabine	Phase I Phase II

Study Type:	Interventional
Study Design:	Allocation: Non-Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Single Group Assignment Masking: 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

Resource links provided by NLM:

MedlinePlus related topics: Acute Myeloid Leukemia Cancer Leukemia Myelodysplastic Syndromes

Drug Information available for: Cytarabine hydrochloride Sorafenib Sorafenib tosylate Cytarabine

U.S. FDA Resources

Further study details as provided by NCIC Clinical Trials Group:

Primary Outcome Measures:

Recommended phase II dose of sorafenib tosylate when given in combination with cytarabine (Phase I) [ Time Frame: 29 months ] [ Designated as safety issue: Yes ]
Dose-limiting toxicity (Phase I) [ Time Frame: 29 months ] [ Designated as safety issue: Yes ]
Complete remission (Phase II) [ Time Frame: 29 months ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

Overall response rate (complete and partial response) (Phase II) [ Time Frame: 29 months ] [ Designated as safety issue: No ]
Time to progression (Phase II) [ Time Frame: 29 months ] [ Designated as safety issue: No ]
Overall survival (Phase II) [ Time Frame: 29 months ] [ Designated as safety issue: No ]
FLT-3 ITD endpoint mutation response correlation. [ Time Frame: 29 months ] [ Designated as safety issue: No ]
Toxicity (Phase II) [ Time Frame: 29 months ] [ Designated as safety issue: Yes ]

Enrollment:	21
Study Start Date:	July 2007
Estimated Study Completion Date:	October 2011
Primary Completion Date:	March 2010 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
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

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.

Eligibility

Ages Eligible for Study:	60 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

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

Please refer to this study by its ClinicalTrials.gov identifier: NCT00516828

Locations

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

Sponsors and Collaborators

NCIC Clinical Trials Group

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

More Information

Additional Information:

Clinical trial summary from the National Cancer Institute's PDQ® database This link exits the ClinicalTrials.gov site

No publications provided

Responsible Party:	NCIC Clinical Trials Group
ClinicalTrials.gov Identifier:	NCT00516828 History of Changes
Other Study ID Numbers:	I186, CAN-NCIC-IND186, CDR0000560975
Study First Received:	August 14, 2007
Last Updated:	September 28, 2011
Health Authority:	Canada: Health Canada

Keywords provided by NCIC Clinical Trials Group:

adult acute myeloid leukemia with 11q23 (MLL) abnormalities
adult acute myeloid leukemia with inv(16)(p13;q22)
adult acute myeloid leukemia with t(15;17)(q22;q12)
adult acute myeloid leukemia with t(16;16)(p13;q22)
adult acute myeloid leukemia with t(8;21)(q22;q22)

untreated adult acute myeloid leukemia
secondary acute myeloid leukemia
de novo myelodysplastic syndromes
secondary myelodysplastic syndromes

Additional relevant MeSH terms:

Leukemia
Leukemia, Myeloid, Acute
Leukemia, Myeloid
Myelodysplastic Syndromes
Preleukemia
Neoplasms by Histologic Type
Neoplasms
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Cytarabine
Sorafenib
Antimetabolites, Antineoplastic

Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses
Antiviral Agents
Anti-Infective Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Protein Kinase Inhibitors
Enzyme Inhibitors

ClinicalTrials.gov processed this record on February 13, 2012