Tipifarnib in Treating Older Patients With Acute Myeloid Leukemia

Sponsor
National Cancer Institute (NCI) (NIH)
Overall Status
Completed
CT.gov ID
NCT01361464
Collaborator
(none)
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Study Details

Study Description

Brief Summary

This phase II trial is studying how well tipifarnib works in treating older patients with acute myeloid leukemia. Tipifarnib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

Detailed Description

PRIMARY OBJECTIVES:
  1. To determine the complete remission (CR) rate in acute myeloid leukemia (AML) patients prospectively selected for tipifarnib (ZARNESTRA) treatment on the basis of a 2-gene signature (RASGRP1:APTX ratio) in bone marrow aspirates.
SECONDARY OBJECTIVES:
  1. To determine the median overall and 1-year survival of patients treated with this regimen

  2. To determine the median relapse-free survival of patients treated with this regimen.

  3. To determine the safety of this regimen in these patients IV. To determine the immunophenotypic expression of RASGRP1 on baseline bone marrow blasts and assess correlation with PCR-based detection.

OUTLINE: This is a multicenter study.

Patients receive tipifarnib orally twice daily on days 1-21. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

Bone marrow aspirate and/or biopsy are collected at baseline and on day 28 of course 1 and 2 for RasGRP1 protein expression analysis by qRT-PCR.

After completion of study therapy, patients are followed up every 30 days.

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:
Phase 2 Trial of R115777 in Previously Untreated Older Adults With AML and Baseline Presence of a Specific 2-Gene Expression Signature Ratio
Study Start Date :
May 1, 2011
Actual Primary Completion Date :
Nov 1, 2014
Actual Study Completion Date :
Nov 1, 2014

Arms and Interventions

Arm Intervention/Treatment
Experimental: Treatment (tipifarnib)

Patients receive tipifarnib orally twice daily on days 1-21. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

Drug: Tipifarnib
Given PO
Other Names:
  • R115777
  • Zarnestra
  • Other: Laboratory Biomarker Analysis
    Correlative studies

    Outcome Measures

    Primary Outcome Measures

    1. Complete Remission (CR) Rate [From first treatment through follow up period, an expected average of 12 months]

      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

    1. Median Overall Survival (OS) [From first treatment through follow up period, an expected average of 12 months]

      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).

    2. Median 1-Year Survival Rate [1 year]

      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.

    3. Number of Participants With Relapse Free Survival [7 months]

      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.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    65 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:
    • Previously untreated acute myeloid leukemia (AML) (de novo or secondary)

    • No diagnosis of acute promyelocytic leukemia (APL)

    • Deemed unsuitable for or refuses standard induction chemotherapy

    • RASGRP1:APTX ratio >= 5, through bone marrow screening

    • No patients with known leukemic involvement of the central nervous system

    • ECOG performance status =< 2

    • No WBC >= 30,000/uL (hydroxyurea permitted up to 24 hours prior to initiation of therapy)

    • 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 (unless the increase is unequivocally due to hemolysis or Gilbert syndrome)

    • ALT and AST less than 2.5 times ULN (NCI CTC Grade 1)

    • 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

    • No symptomatic neuropathy of grade 2 or worse

    • No uncompensated disseminated intravascular coagulation (DIC) or uncontrolled bleeding

    • No history of allergic reactions attributed to compounds of similar chemical or biologic composition to tipifarnib (R115777), such as the imidazole drugs, including clotrimazole, ketoconazole, miconazole, econazole, fenticonazole, isoconazole, sulconazole, ticonazole, or terconazole

    • No 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 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 CD4 cell count >= 400/mm^3 are eligible

    • No other concurrent cytotoxic or biologic antileukemic therapy

    • No patients who are receiving any other investigational agents

    • Use of enzyme-inducing anticonvulsants (e.g., phenytoin, fosphenytoin, phenobarbital, primidone, carbamazepine, oxcarbazepine) while taking tipifarnib (R115777) is contraindicated

    • If clinically indicated, subjects may use non-enzyme-inducing anticonvulsants during treatment with R115777

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Moffitt Cancer Center Tampa Florida United States 33612
    2 Emory University/Winship Cancer Institute Atlanta Georgia United States 30322
    3 Blood and Marrow Transplant Group of Georgia Atlanta Georgia United States 30342
    4 Johns Hopkins University/Sidney Kimmel Comprehensive Cancer Center Baltimore Maryland United States 21287
    5 Memorial Sloan-Kettering Cancer Center New York New York United States 10065
    6 Weill Medical College of Cornell University New York New York United States 10065
    7 University of North Carolina Chapel Hill North Carolina United States 27599

    Sponsors and Collaborators

    • National Cancer Institute (NCI)

    Investigators

    • Principal Investigator: Jeffrey Lancet, Moffitt Cancer Center

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    National Cancer Institute (NCI)
    ClinicalTrials.gov Identifier:
    NCT01361464
    Other Study ID Numbers:
    • NCI-2011-02589
    • NCI-2011-02589
    • 16572
    • CDR0000699713
    • 8977
    • 8977
    • P30CA076292
    • N01CM00071
    • U01CA070095
    • N01CM00100
    • NCT01364038
    First Posted:
    May 26, 2011
    Last Update Posted:
    Apr 8, 2015
    Last Verified:
    Feb 1, 2015

    Study Results

    Participant Flow

    Recruitment Details The Southeast Phase II Consortium (SEP2C) enrolled participants at 3 cancer centers in the United States. The study opened to accrual on 5/24/2011 and closed to accrual 07/25/2012. Further development of Tipifarnib in acute myeloid leukemia (AML) was terminated after the study failed to meet the primary endpoint.
    Pre-assignment Detail
    Arm/Group Title R115777 Therapy
    Arm/Group Description 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.
    Period Title: Overall Study
    STARTED 21
    COMPLETED 18
    NOT COMPLETED 3

    Baseline Characteristics

    Arm/Group Title R115777 Therapy
    Arm/Group Description 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.
    Overall Participants 21
    Age (Count of Participants)
    <=18 years
    0
    0%
    Between 18 and 65 years
    0
    0%
    >=65 years
    21
    100%
    Age (years) [Median (Full Range) ]
    Median (Full Range) [years]
    75
    Sex: Female, Male (Count of Participants)
    Female
    10
    47.6%
    Male
    11
    52.4%
    Region of Enrollment (participants) [Number]
    United States
    21
    100%

    Outcome Measures

    1. Primary Outcome
    Title Complete Remission (CR) Rate
    Description 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.
    Time Frame From first treatment through follow up period, an expected average of 12 months

    Outcome Measure Data

    Analysis Population Description
    All evaluable participants
    Arm/Group Title R115777 Therapy
    Arm/Group Description 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.
    Measure Participants 18
    Number [percentage of participants]
    11
    52.4%
    2. Secondary Outcome
    Title Median Overall Survival (OS)
    Description 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).
    Time Frame From first treatment through follow up period, an expected average of 12 months

    Outcome Measure Data

    Analysis Population Description
    All evaluable participants
    Arm/Group Title R115777 Therapy
    Arm/Group Description 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.
    Measure Participants 18
    Median (95% Confidence Interval) [months]
    6.6
    3. Secondary Outcome
    Title Median 1-Year Survival Rate
    Description 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.
    Time Frame 1 year

    Outcome Measure Data

    Analysis Population Description
    Evaluable participants at planned study completion date
    Arm/Group Title R115777 Therapy
    Arm/Group Description 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.
    Measure Participants 0
    4. Secondary Outcome
    Title Number of Participants With Relapse Free Survival
    Description 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.
    Time Frame 7 months

    Outcome Measure Data

    Analysis Population Description
    All evaluable participants
    Arm/Group Title R115777 Therapy
    Arm/Group Description 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.
    Measure Participants 18
    Number [participants]
    2
    9.5%

    Adverse Events

    Time Frame 19 months
    Adverse Event Reporting Description
    Arm/Group Title R115777 Therapy
    Arm/Group Description 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.
    All Cause Mortality
    R115777 Therapy
    Affected / at Risk (%) # Events
    Total / (NaN)
    Serious Adverse Events
    R115777 Therapy
    Affected / at Risk (%) # Events
    Total 7/21 (33.3%)
    Blood and lymphatic system disorders
    Febrile neutropenia 4/21 (19%) 5
    Cardiac disorders
    Sinus tachycardia 1/21 (4.8%) 1
    Gastrointestinal disorders
    Nausea 1/21 (4.8%) 2
    Vomiting 1/21 (4.8%) 2
    General disorders
    Chills 1/21 (4.8%) 1
    Fatigue 1/21 (4.8%) 1
    Fever 1/21 (4.8%) 1
    General disorders and administration site conditions - Other 1/21 (4.8%) 1
    Infections and infestations
    Infections and infestations - Other 1/21 (4.8%) 1
    Lung infection 2/21 (9.5%) 3
    Upper respiratory infection 1/21 (4.8%) 1
    Injury, poisoning and procedural complications
    Fall 1/21 (4.8%) 1
    Investigations
    Neutrophil count decreased 1/21 (4.8%) 1
    Musculoskeletal and connective tissue disorders
    Generalized muscle weakness 1/21 (4.8%) 2
    Other (Not Including Serious) Adverse Events
    R115777 Therapy
    Affected / at Risk (%) # Events
    Total 17/21 (81%)
    Blood and lymphatic system disorders
    Febrile neutropenia 8/21 (38.1%) 11
    Anemia 4/21 (19%) 5
    Gastrointestinal disorders
    Nausea 7/21 (33.3%) 10
    Diarrhea 6/21 (28.6%) 9
    Vomiting 6/21 (28.6%) 8
    Constipation 3/21 (14.3%) 3
    Mucositis - oral 2/21 (9.5%) 2
    General disorders
    Fatigue 8/21 (38.1%) 10
    General disorders and administration site conditions - Other 3/21 (14.3%) 3
    Chills 2/21 (9.5%) 3
    Edema - face 2/21 (9.5%) 3
    Fever 2/21 (9.5%) 2
    Non-cardiac chest pain 2/21 (9.5%) 3
    Pain 2/21 (9.5%) 4
    Infections and infestations
    Lung infection 4/21 (19%) 4
    Sepsis 3/21 (14.3%) 3
    Injury, poisoning and procedural complications
    Fall 3/21 (14.3%) 3
    Bruising 2/21 (9.5%) 3
    Investigations
    White blood cell decreased 7/21 (33.3%) 9
    Platelet count decreased 5/21 (23.8%) 10
    Neutrophil count decreased 2/21 (9.5%) 2
    Metabolism and nutrition disorders
    Anorexia 7/21 (33.3%) 8
    Hypokalemia 2/21 (9.5%) 4
    Musculoskeletal and connective tissue disorders
    Back pain 2/21 (9.5%) 3
    Pain in extremity 2/21 (9.5%) 3
    Nervous system disorders
    Dizziness 4/21 (19%) 6
    Headache 2/21 (9.5%) 2
    Syncope 2/21 (9.5%) 2
    Psychiatric disorders
    Confusion 3/21 (14.3%) 4
    Insomnia 3/21 (14.3%) 5
    Delirium 2/21 (9.5%) 2
    Renal and urinary disorders
    Urinary frequency 3/21 (14.3%) 4
    Urinary incontinence 2/21 (9.5%) 2
    Respiratory, thoracic and mediastinal disorders
    Dyspnea 6/21 (28.6%) 6
    Epistaxis 2/21 (9.5%) 2
    Wheezing 2/21 (9.5%) 2
    Skin and subcutaneous tissue disorders
    Rash maculo-papular 5/21 (23.8%) 7
    Pruritus 4/21 (19%) 6

    Limitations/Caveats

    Due to trial not meeting primary endpoint of at least 3 CR/CRi after 2 cycles, accrual was suspended. 1 year survival was not calculated, not relevant in the setting of a median survival of 6.6 months and with study not meeting its primary endpoint.

    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.

    Results Point of Contact

    Name/Title Jeffrey Lancet, M.D.
    Organization H. Lee Moffitt Cancer Center and Research Institute
    Phone 813-745-6841
    Email jeffrey.lancet@moffitt.org
    Responsible Party:
    National Cancer Institute (NCI)
    ClinicalTrials.gov Identifier:
    NCT01361464
    Other Study ID Numbers:
    • NCI-2011-02589
    • NCI-2011-02589
    • 16572
    • CDR0000699713
    • 8977
    • 8977
    • P30CA076292
    • N01CM00071
    • U01CA070095
    • N01CM00100
    • NCT01364038
    First Posted:
    May 26, 2011
    Last Update Posted:
    Apr 8, 2015
    Last Verified:
    Feb 1, 2015