Tipifarnib in Treating Older Patients With Acute Myeloid Leukemia
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:
- 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:
-
To determine the median overall and 1-year survival of patients treated with this regimen
-
To determine the median relapse-free survival of patients treated with this regimen.
-
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
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:
Other: Laboratory Biomarker Analysis
Correlative studies
|
Outcome Measures
Primary Outcome Measures
- 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
- 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).
- 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.
- 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
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
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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.- NCI-2011-02589
- NCI-2011-02589
- 16572
- CDR0000699713
- 8977
- 8977
- P30CA076292
- N01CM00071
- U01CA070095
- N01CM00100
- NCT01364038
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
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%
|
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
|
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 |
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
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 |
jeffrey.lancet@moffitt.org |
- NCI-2011-02589
- NCI-2011-02589
- 16572
- CDR0000699713
- 8977
- 8977
- P30CA076292
- N01CM00071
- U01CA070095
- N01CM00100
- NCT01364038