Tipifarnib in Treating Older Patients With Acute Myeloid Leukemia

Study Overview
=================
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: I. 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: I. To determine the median overall and 1-year survival of patients treated with this regimen II. To determine the median relapse-free survival of patients treated with this regimen. III. 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.

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

Conditions
-----------------
Adult Erythroleukemia, Adult Acute Myeloid Leukemia With Inv(16)(p13.1q22); CBFB-MYH11, Adult Acute Myeloid Leukemia With Maturation, Adult Acute Myeloid Leukemia With Minimal Differentiation, Adult Acute Myeloid Leukemia With t(16;16)(p13.1;q22); CBFB-MYH11, Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); RUNX1-RUNX1T1, Adult Acute Myeloid Leukemia With t(9;11)(p22;q23); MLLT3-MLL, Adult Acute Myeloid Leukemia Without Maturation, Adult Acute Myelomonocytic Leukemia, Adult Pure Erythroid Leukemia, Alkylating Agent-Related Acute Myeloid Leukemia, Secondary Acute Myeloid Leukemia, Untreated Adult Acute Myeloid Leukemia, Adult Acute Megakaryoblastic Leukemia, Adult Acute Monoblastic Leukemia, Adult Acute Monocytic Leukemia

Intervention / Treatment
-----------------
* Drug: Tipifarnib
* Other: Laboratory Biomarker Analysis


Participation Criteria
=================
Eligibility 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 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

Ages Eligible for Study
-----------------
Minimum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (tipifarnib)<br>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<br>* Given PO<br>* Other names: Zarnestra;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

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

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median Overall Survival (OS) | 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). | From first treatment through follow up period, an expected average of 12 months | 
| Median 1-Year Survival Rate | 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. | 1 year | 
| Number of Participants With Relapse Free Survival | 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. | 7 months |