Idarubicin, Cytarabine, and Tipifarnib in Treating Patients With Newly Diagnosed Myelodysplastic Syndromes or Acute Myeloid Leukemia

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT00096122
• Collaborator: (none)
• Enrollment: 95
• Location: 1
• Arm: 1
• Duration (Months): 65
• Patients Per Site Per Month: 1.5

Study Details

Study Description

Brief Summary

This phase I/II trial is studying the side effects and best dose of tipifarnib when given with idarubicin and cytarabine and to see how well it works in treating patients with newly diagnosed myelodysplastic syndromes or acute myeloid leukemia. Drugs used in chemotherapy, such as idarubicin and cytarabine, work in different ways to stop cancer cells from dividing so they stop growing or die. Tipifarnib (Zarnestra) may stop the growth of cancer cells by blocking the enzymes necessary for their growth. Giving idarubicin and cytarabine with tipifarnib may kill more cancer cells.

Condition or Disease	Intervention/Treatment	Phase
Adult Acute Basophilic Leukemia; Adult Acute Eosinophilic Leukemia; Adult Acute Megakaryoblastic Leukemia (M7); Adult Acute Minimally Differentiated Myeloid Leukemia (M0); Adult Acute Monoblastic Leukemia (M5a); Adult Acute Monocytic Leukemia (M5b); Adult Acute Myeloblastic Leukemia With Maturation (M2); Adult Acute Myeloblastic Leukemia Without Maturation (M1); Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Acute Myelomonocytic Leukemia (M4); Adult Erythroleukemia (M6a); Adult Pure Erythroid Leukemia (M6b); Childhood Myelodysplastic Syndromes; Chronic Myelomonocytic Leukemia; de Novo Myelodysplastic Syndromes; Refractory Anemia With Excess Blasts; Refractory Anemia With Excess Blasts in Transformation; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes; Untreated Adult Acute Myeloid Leukemia	Drug: cytarabine; Drug: idarubicin; Drug: tipifarnib	Phase 1/Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. To determine the tolerability of the combination of R115777 (Zarnestra™) and Idarubicin plus cytarabine by defining the DLT and MTD. (Phase I) II. To determine the efficacy of the combination of Idarubicin, cytarabine and ZARNESTRA in patients with high-risk MDS and AML. (Phase II)

OUTLINE: This is a dose-escalation study of tipifarnib. Patients are stratified according to age (< 50 versus ≥ 50) and, in patients ≥ 50 years of age, cytogenetics (diploid versus unfavorable).

INDUCTION THERAPY:

PHASE I: Patients receive cytarabine IV continuously on days 1-3 (or 1-4), idarubicin intravenous (IV) over 1 hour on days 1-3, and oral tipifarnib twice daily on days 1-21. Treatment repeats every 21 days for up to 2 courses in the absence of disease progression or unacceptable toxicity.

Cohorts of 6 patients receive escalating doses of tipifarnib until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 6 patients experience dose-limiting toxicity.

PHASE II: Patients receive cytarabine, idarubicin, and tipifarnib as in phase I at the MTD.

Patients in both phases who respond to induction therapy proceed to consolidation maintenance therapy.

CONSOLIDATION MAINTENANCE THERAPY: Patients receive consolidation therapy comprising cytarabine IV continuously on days 1-3, idarubicin IV over 1 hour on days 1-2, and tipifarnib twice daily on days 1-14. Treatment repeats every 4-6 weeks for 5 courses in the absence of unacceptable toxicity.

Patients then begin maintenance therapy comprising oral tipifarnib twice daily on day 1-21. Treatment repeats every 4-6 weeks for 6 courses in the absence of unacceptable toxicity.

Study Design

• Study Type: Interventional
• Actual Enrollment: 95 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: PHASE I-II STUDY OF IDARUBICIN, CYTARABINE AND R115777 (TIPIFARNIB, ZARNESTRA; 702818; IND 58359), A FARNESYLTRANSFERASE INHIBITOR, IN PATIENTS WITH HIGH-RISK MYELODYSPLASTIC SYNDROMES AND ACUTE MYELOID LEUKEMIAS
• Study Start Date: Sep 1, 2004
• Actual Primary Completion Date: Sep 1, 2006
• Actual Study Completion Date: Feb 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm I See Detailed Description	Drug: cytarabine; Given IV; Other Names: ARA-C arabinofuranosylcytosine arabinosylcytosine Cytosar-U cytosine arabinoside ; Drug: idarubicin; Given IV; Other Names: 4-demethoxydaunorubicin 4-DMDR DMDR IDA ; Drug: tipifarnib; Given orally; Other Names: R115777 Zarnestra

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Complete Response [21 Day Cycle]

   Complete Response (CR) is required bone marrow blasts ≤5% and recovery of normal hematopoiesis with an absolute neutrophil count (ANC) of 1*10^9/L or more and platelet count of 100*10^9/L or more; and a complete response without platelets (CRp) is the same criteria as CR but with platelet counts from 20*10^9/L to less than 100*10^9/L.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 15 Years to 70 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Diagnosis of 1) AML (WHO classification definition of > 20% blasts), or 2) high risk MDS (defined as the presence of > 10% blasts)

• Patients must be chemo-naïve, i.e. not have received any prior chemotherapy (except hydrea) for AML or MDS; they could have received transfusions, hematopoietic growth factors or vitamins; temporary measures such as pheresis or hydrea (0.5 to 5g daily for up to 3 days) are allowed

• ECOG PS of 0-1 at screening

• Creatinine =< 2 mg/dl

• Total bilirubin =< 2 mg/dL, unless increase is due to hemolysis

• Transaminases (SGPT) =< 2.5 x ULN

• Ability to take oral medication

• Ability to understand and provide signed informed consent

Exclusion Criteria:

• Subjects with APL

• Presence of active systemic infection

• Any coexisting medical condition that in the judgment of the treating physician is likely to interfere with study procedures or results

• Nursing women, women of childbearing potential with positive urine pregnancy test, or women of childbearing potential who are not willing to maintain adequate contraception (such as birth control pills, IUD, diaphragm, abstinence, or condoms by their partner) over the entire course of the study

• Known allergy to imidazole drugs (such as clotrimazole, ketoconazole, miconazole, econazole, fenticonazole, isoconazole, sulconazole, tioconazole, terconazole)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	M D Anderson Cancer Center	Houston	Texas	United States	77030

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Jorge Cortes, M.D. Anderson Cancer Center

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT00096122
• Other Study ID Numbers: NCI-2012-02862; 2003-0563; 6625; N01CM62202
• First Posted: Nov 9, 2004
• Last Update Posted: May 26, 2014
• Last Verified: Jun 1, 2013

• Additional relevant MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Preleukemia; Neoplasm Metastasis; Leukemia, Myelomonocytic, Acute; Leukemia, Myelomonocytic, Chronic; Leukemia, Myelomonocytic, Juvenile; Leukemia, Monocytic, Acute; Leukemia, Megakaryoblastic, Acute; Leukemia, Erythroblastic, Acute; Leukemia, Basophilic, Acute; Leukemia, Eosinophilic, Acute; Anemia; Myelodysplastic Syndromes; Anemia, Refractory; Anemia, Refractory, with Excess of Blasts; Hypereosinophilic Syndrome; Syndrome; Cytarabine; Idarubicin; Tipifarnib

Study Results

Participant Flow

Recruitment Details	Recruitment Period: 9/16/2004 to 9/22/2006. All patients registered at The University of Texas M.D. Anderson Cancer Center.
Pre-assignment Detail	One participant enrolled was excluded from the study.

Arm/Group Title	Idarubicin, Cytarabine + Tipifarnib
Arm/Group Description	Cytarabine 1.5 g/m^2 and Idarubicin 12 mg/m^2 intravenous (IV) continuously on days 1-3 (or 1-4), with Oral Tipifarnib 200/300 twice daily on days 1-21, repeats every 21 days.
Period Title: Overall Study
STARTED	95
COMPLETED	95
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Idarubicin, Cytarabine + Tipifarnib
Arm/Group Description	Cytarabine 1.5 g/m^2 and Idarubicin 12 mg/m^2 intravenous (IV) continuously on days 1-3 (or 1-4), with Oral Tipifarnib 200/300 twice daily on days 1-21, repeats every 21 days.
Overall Participants	95
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	50
Sex: Female, Male (Count of Participants)
Female	53 55.8%
Male	42 44.2%
Region of Enrollment (participants) [Number]
United States	95 100%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Complete Response
Description	Complete Response (CR) is required bone marrow blasts ≤5% and recovery of normal hematopoiesis with an absolute neutrophil count (ANC) of 1*10^9/L or more and platelet count of 100*10^9/L or more; and a complete response without platelets (CRp) is the same criteria as CR but with platelet counts from 20*10^9/L to less than 100*10^9/L.
Time Frame	21 Day Cycle

Outcome Measure Data

Analysis Population Description

Analysis was per protocol.

Arm/Group Title	Idarubicin, Cytarabine + Tipifarnib
Arm/Group Description	Cytarabine 1.5 g/m^2 and Idarubicin 12 mg/m^2 intravenous (IV) continuously on days 1-3 (or 1-4), with Oral Tipifarnib 200/300 twice daily on days 1-21, repeats every 21 days.
Measure Participants	95
CR	61 64.2%
CRp	9 9.5%

Adverse Events

Time Frame	5 years 4 months
Arm/Group Title	Idarubicin, Cytarabine + Tipifarnib
Arm/Group Description	Cytarabine 1.5 g/m^2 and Idarubicin 12 mg/m^2 intravenous (IV) continuously on days 1-3 (or 1-4), with Oral Tipifarnib 200/300 twice daily on days 1-21, repeats every 21 days.
All Cause Mortality
	Idarubicin, Cytarabine + Tipifarnib
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Idarubicin, Cytarabine + Tipifarnib
	Affected / at Risk (%)	# Events
Total	46/95 (48.4%)
Blood and lymphatic system disorders
Thrombocytopenia	1/95 (1.1%)	1
Cardiac disorders
Decreased left ventricular ejection fraction (LVEF)	1/95 (1.1%)	1
Gastrointestinal disorders
Enteritis	1/95 (1.1%)	1
Typhilitis	1/95 (1.1%)	1
Ileus	1/95 (1.1%)	1
Esophagitis	1/95 (1.1%)	1
Colitis	2/95 (2.1%)	2
Nausea	1/95 (1.1%)	1
Vomiting	1/95 (1.1%)	1
Diarrhea	2/95 (2.1%)	2
General disorders
Death	5/95 (5.3%)	5
Edema	1/95 (1.1%)	1
Pain	1/95 (1.1%)	1
Hepatobiliary disorders
Hyperbilirubinemia	6/95 (6.3%)	6
Infections and infestations
Infection	12/95 (12.6%)	14
Febrile neutropenia	14/95 (14.7%)	21
Metabolism and nutrition disorders
Hypokalemia	2/95 (2.1%)	2
Nervous system disorders
Cognitive disturbance	1/95 (1.1%)	1
Seizure	1/95 (1.1%)	1
Confusion	1/95 (1.1%)	1
Renal and urinary disorders
Renal Failure	1/95 (1.1%)	1
Respiratory, thoracic and mediastinal disorders
Bilateral pleural effusions	1/95 (1.1%)	1
Respiratory Failure	1/95 (1.1%)	1
Vascular disorders
Hemorrhage	5/95 (5.3%)	5
Other (Not Including Serious) Adverse Events
	Idarubicin, Cytarabine + Tipifarnib
	Affected / at Risk (%)	# Events
Total	95/95 (100%)
Cardiac disorders
Hypotension	12/95 (12.6%)	12
Gastrointestinal disorders
Diarrhea	66/95 (69.5%)	66
Nausea/Vomiting	54/95 (56.8%)	54
Mucositis	23/95 (24.2%)	23
Constipation	11/95 (11.6%)	11
Anorexia	8/95 (8.4%)	8
General disorders
Pain	27/95 (28.4%)	27
Fatigue	20/95 (21.1%)	20
Edema	11/95 (11.6%)	11
Hepatobiliary disorders
Hyperbilirubinemia	25/95 (26.3%)	25
Metabolism and nutrition disorders
Hypokalemia	12/95 (12.6%)	12
Hypoalbuminemia	10/95 (10.5%)	10
Hyperglycemia	10/95 (10.5%)	10
Hypophosphatemia	8/95 (8.4%)	8
Hypocalcemia	6/95 (6.3%)	6
Nervous system disorders
Mood alteration	12/95 (12.6%)	12
Renal and urinary disorders
Elevated creatinine	7/95 (7.4%)	7
Respiratory, thoracic and mediastinal disorders
Dyspnea	9/95 (9.5%)	9
Skin and subcutaneous tissue disorders
Rash/Puritis	51/95 (53.7%)	51

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.