Zarnestra in Newly Diagnosed Acute Myelogenous Leukemia (AML)With 2 Gene Expression Signature Ratio

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
H. Lee Moffitt Cancer Center and Research Institute
ClinicalTrials.gov Identifier:
NCT01361464
First received: May 24, 2011
Last updated: April 4, 2014
Last verified: April 2014
  Purpose

The purpose of this study is to determine the ability of a new test to predict whether patients will benefit from treatment with R115777 (ZARNESTRA, also called Tipifarnib). R115777 is an orally dosed, medication that inhibits the activity of the Farnesyl Transferase protein. Scientific experiments have suggested that R115777 can inhibit the function of proteins that play a role in the development of leukemia, and clinical studies of R115777 in humans has demonstrated that it can induce complete remissions (CR) in approximately 8-20% of patients with AML. R115777 is an investigational or experimental anticancer agent that has not yet been approved by the Food and Drug Administration for use in Acute Myelogenous Leukemia (AML).


Condition Intervention Phase
Acute Myelogenous Leukemia
Drug: R115777
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase 2 Trial of R115777 in Previously Untreated Older Adults With AML and Baseline Presence of a Specific 2-Gene Expression Signature Ratio

Resource links provided by NLM:


Further study details as provided by H. Lee Moffitt Cancer Center and Research Institute:

Primary Outcome Measures:
  • Complete Remission (CR) Rate [ Time Frame: From first treatment through follow up period, an expected average of 12 months ] [ Designated as safety issue: No ]
    Complete Remission (CR) rate in Acute Myelogenous Leukemia (AML) patients prospectively selected for R115777R115777 (ZARNESTRA) treatment on the basis of a 2-gene signature (RASGRP1:APTX ratio) in bone marrow aspirates. AML Complete Remission: Bone marrow aspiration - Less than 5% leukemic blasts, Auer rods not detected; Peripheral blood counts - Absolute neutrophil count >/= 1,000/mm^3, Platelet count >/= 100,000/mm^3, Leukemic blasts not present; Blood-product transfusion independence; Absence of extramedullary leukemia.


Secondary Outcome Measures:
  • Median Overall Survival (OS) [ Time Frame: From first treatment through follow up period, an expected average of 12 months ] [ Designated as safety issue: No ]
    Overall survival is calculated from the first day of R115777 treatment and lasts until the date of death recorded on the case report form (CRF).

  • Median 1-Year Survival Rate [ Time Frame: 1 year ] [ Designated as safety issue: No ]
    Prior to the early discontinuation of the study (for not meeting the primary endpoint of at least 3 CR/CRi after 2 cycles), investigators had planned to calculate one year survival from Kaplan Meier estimates.

  • Number of Participants With Relapse Free Survival [ Time Frame: 7 months ] [ Designated as safety issue: No ]
    Relapse-free survival is calculated from the date of documentation of complete remission/morphologic complete remission with incomplete blood count recovery (CR/CRi) until disease relapse or death from any cause.


Enrollment: 21
Study Start Date: May 2011
Estimated Study Completion Date: December 2014
Primary Completion Date: December 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: R115777 Therapy
Each participant will begin R115777 treatment with an orally dosed regimen of 300 mg twice a day (BID) for the first 21 consecutive days of a 28-day cycle.
Drug: R115777
All screened participants with an RASGRP1:APTX ratio ≥ 5 will be eligible for a R115777 treatment course of a maximum of 6 cycles. Treatment will be administered on an outpatient basis.
Other Names:
  • Zarnestra™
  • NSC # 702818
  • Tipifarnib

Detailed Description:

This study will test the ability of a newly developed screening test, the RASGRP1:aprataxin (APTX) ratio, to identify patients who are more likely to benefit from R115777 therapy. RASGRP1 and APTX are genes that are expressed in leukemia cells. This test is performed on a sample of bone marrow tissue, and determines the ratio of RASGRP1 and APTX expression in the bone marrow. Ratios that are C5 are will be considered as a positive result, and these patients will be eligible for treatment with R115777. The ratio of C5 is expected to be found in about 30% of patients. This screening test is still considered an experimental procedure.

  Eligibility

Ages Eligible for Study:   65 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Age ≥ 65 with previously untreated AML (de novo or secondary)
  • Deemed unsuitable for or refuses standard induction chemotherapy
  • RASGRP1:APTX ratio ≥5, through bone marrow screening
  • Eastern Cooperative Oncology Group (ECOG) performance status ≤2
  • Patients must have normal organ function as defined below:
  • Serum creatinine less than 1.5 times the upper limit of the normal range (ULN) National Cancer Institute (NCI) Common Toxicity Criteria (CTC) Grade 1
  • Total bilirubin less than 1.5 times ULN (CTC Grade 1), unless the increase is unequivocally due to hemolysis or Gilbert's Syndrome
  • Alanine transaminase (ALT) and aspartate transaminase (AST) less than 2.5 times ULN (CTC Grade 1)
  • Ability to understand and the willingness to sign a written informed consent document
  • The effects of R115777 (ZARNESTRA) on the developing human fetus are unknown. For this reason and because farnesyl transferase inhibitor (FTI) agents as well as other therapeutic agents used in this trial are known to be teratogenic, men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation.

Exclusion Criteria:

  • Diagnosis of acute promyelocytic leukemia (APL)
  • Patients who are receiving any other investigational agents
  • Patients with known leukemic involvement of the central nervous system
  • Patients with white blood cells (WBC) ≥ 30,000/uL (hydroxyurea permitted up to 24 hours prior to initiation of therapy)
  • Symptomatic neuropathy of grade 2 or worse
  • Uncompensated disseminated intravascular coagulation (DIC) or uncontrolled bleeding
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to R115777, such as the imidazole drugs, including clotrimazole, ketoconazole, miconazole, econazole, fenticonazole, isoconazole, sulconazole, tioconazole or terconazole
  • Use of enzyme-inducing anticonvulsants (e.g., phenytoin, fosphenytoin, phenobarbital, primidone, carbamazepine, oxcarbazepine) while taking R115777 is contraindicated. If clinically indicated, subjects may use nonenzyme-inducing anticonvulsants during treatment with R115777.
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
  • Known human immunodeficiency virus (HIV) positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with R115777. In addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy. Known HIV-positive patients NOT on antiretroviral therapy AND with a cluster of differentiation 4 (CD4) cell count ≥ 400/mm³ are eligible.
  Contacts and Locations
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Please refer to this study by its ClinicalTrials.gov identifier: NCT01361464

Locations
United States, Florida
H. Lee Moffitt Cancer Center and Research Institute
Tampa, Florida, United States, 33612
United States, Georgia
Emory - Winship Cancer Institute
Atlanta, Georgia, United States, 30322
United States, Illinois
University of Chicago Medical Center
Chicago, Illinois, United States, 60637
United States, Maryland
Johns Hopkins Sidney Kimmel Comprehensive Cancer Center
Baltimore, Maryland, United States, 21231
University of Maryland Medical Center
Baltimore, Maryland, United States, 21201
United States, New Jersey
Cancer Institute of New Jersey
New Brunswick, New Jersey, United States, 08901
United States, New York
Cornell - Weill Medical College of Cornell University
New York, New York, United States, 10065
United States, North Carolina
UNC-Lineberger Comprehensive Cancer Center
Chapel Hill, North Carolina, United States, 27599
United States, Tennessee
Vanderbilt-Ingram Cancer Center
Nashville, Tennessee, United States, 37232
Sponsors and Collaborators
H. Lee Moffitt Cancer Center and Research Institute
Investigators
Principal Investigator: Jeffrey Lancet, M.D. H. Lee Moffitt Cancer Center and Research Institute
  More Information

Additional Information:
No publications provided

Responsible Party: H. Lee Moffitt Cancer Center and Research Institute
ClinicalTrials.gov Identifier: NCT01361464     History of Changes
Other Study ID Numbers: NCI # 8977, MCC-16572
Study First Received: May 24, 2011
Results First Received: November 15, 2013
Last Updated: April 4, 2014
Health Authority: United States: Food and Drug Administration
United States: Institutional Review Board

Keywords provided by H. Lee Moffitt Cancer Center and Research Institute:
AML

Additional relevant MeSH terms:
Leukemia
Leukemia, Myeloid, Acute
Leukemia, Myeloid
Neoplasms by Histologic Type
Neoplasms
Tipifarnib
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions

ClinicalTrials.gov processed this record on July 22, 2014