Growth Factor Signature (GFS) Pilot Study (MK0000-098)(COMPLETED)

A Multicenter Phase Ib Trial to Determine Whether a Gene Expression Signature Changes in Response to Treatment With Bcr-Abl Inhibitors in Patients With Blast Phase Philadelphia Chromosome Positive Chronic Myelogenous Leukemia or Philadelphia Chromosome Positive Acute Lymphocytic Leukemia

This study will evaluate a gene expression signature (Growth Factor Signature [GFS]) as a biomarker for response/resistance to BRC-ABL oncogene inhibitors.

Study Overview

• Status: Terminated
• Conditions: Blast Phase Philadelphia Chromosomes Positive (Ph+) Chronic Myelogenous Leukemia (CML); Philadelphia Chromosome Positive (Ph+) Acute Lymphocytic Leukemia (ALL)
• Intervention / Treatment: Other: Comparator: Biomarker evaluation

• Study Type: Interventional
• Enrollment (Actual): 9
• Phase: Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Participant must have a histologically or cytopathologically confirmed blast phase Ph+ CML or Ph+ ALL.
• Participant is 18 years of age on the day of signing informed consent
• Participant must have performance status 0-3 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale

• Participant has at least 30 percent blasts in peripheral blood; or at least 30 percent lymphoblasts in peripheral blood or bone marrow

  • For Part II:
• Participant has progressed while taking imatinib or is unable to tolerate imatinib, being defined as discontinuing imatinib treatment as a result of nonhematologic toxic effects of any grade
• If female, participant is either post-menopausal, free from menses for >2 years, surgically sterilized or willing to use 2 adequate barrier methods of contraception to prevent pregnancy or agrees to abstain from heterosexual activity throughout the study, starting with Visit 1
• Female participants of childbearing potential must have a negative serum or urine pregnancy test (beta hCG) at screening
• If male, participant is surgically sterilized, agrees to use an adequate method of contraception, or agrees to abstain from heterosexual activity for the duration of the study
• Participant or the patrticipant's legal representative has voluntarily agreed to participate by giving written informed consent
• Participant must be available for periodic blood sampling, study related assessments, and management at the treating institution for the duration of the study

Exclusion Criteria:

• Participant is currently participating in or has participated in a study with an investigational compound or device within 30 days or 5 half-lives, whichever is longer, of the start of treatment
• Participant has known human immunodeficiency virus (HIV) infection or HIV-related malignancy
• Participant is a female who is pregnant or breastfeeding, or is expecting to conceive within the projected duration of the study
• Participant has a known allergy or hypersensitivity to imatinib, dasatinib or nilotinib
• Participant has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not in the best interest of the participant to participate
• Participant has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
• There is any concern by the investigator regarding the safe participation of the participant in the study or for any other reason, the investigator considers the participant inappropriate for participation in the study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Ph+ CML or Ph+ ALL; GFS biomarker evaluation

Other: Comparator: Biomarker evaluation; Patients on standard of care treatment will have blood drawn to evaluate biomarker changes in response to treatment with BCR-ABL inhibitors over a ~3.5 month period. Part I will enroll patients who are beginning treatment with imatinib (recommended dose 400 mg every day [qd]), dasatinib (recommended dose 70 mg twice a day [bid]), or nilotinib (recommended dose 400 mg bid). Part II will enroll patients who are changing from imatinib therapy to either dasatinib or nilotinib. A decision to initiate Part II will be made based on analysis of the results of Part I.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Growth Factor Signature (GFS) Variability at Baseline	The GFS was measured by microarray analysis using the entire 101 gene signature. The GFS is quantified as the change in gene expression between two separate samples collected from the same patient. The signature has 101 genes in two oppositely regulated arms, which are pre-specified. The expression of genes in the UP arm goes up with increasing pathway activity, and the expression of genes in the DOWN arm goes down with increasing pathway activity. The GFS variability was represented by the GFS change between two baseline samples (Mean GFS Fold Ratio [Screening to Day 1 Predose]).	Screening to Day 1 Predose
Growth Factor Signature (GFS) Change From Baseline Measured by Time Weighted Average (TWA) for Days 1 to 22	The GFS was measured by microarray analysis using the entire 101 gene signature. The TWA is the area under the curve (AUC) divided by the time interval (for this study it was the AUC of gene-expression divided by Days 1 to 22). Participants with blast phase Ph+ CML or Ph+ ALL were measured for change in the GFS post-treatment when treated with imatinib, dasatinib, or nilotinib, using Microarray. Change was represented as the GFS Fold Ratio of TWA for Days 1 to 22 to Baseline.	Baseline to 22 Days After Initiation of Therapy

Collaborators and Investigators

• Sponsor: Merck Sharp & Dohme LLC

Study record dates

Study Major Dates

• Study Start: June 1, 2009
• Primary Completion (Actual): April 1, 2010
• Study Completion (Actual): June 1, 2010

Study Registration Dates

• First Submitted: March 5, 2009
• First Submitted That Met QC Criteria: March 11, 2009
• First Posted (Estimate): March 12, 2009

Study Record Updates

• Last Update Posted (Estimate): September 30, 2015
• Last Update Submitted That Met QC Criteria: September 28, 2015
• Last Verified: September 1, 2015

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Bone Marrow Diseases; Hematologic Diseases; Myeloproliferative Disorders; Neoplastic Processes; Cell Transformation, Neoplastic; Carcinogenesis; Chromosome Aberrations; Translocation, Genetic; Leukemia; Leukemia, Myeloid; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Blast Crisis; Philadelphia Chromosome
• Other Study ID Numbers: 0000-098; 2009_558