Temozolomide Plus Vorinostat in Relapse/Refractory Acute Myeloid Leukemia (AML)

NCT ID: NCT01550224

Last Updated: 2018-08-09

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 23 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-05-01
• Study Completion Date: 2014-11-17

Brief Summary

The purpose of the study is to first determine if temozolomide plus vorinostat in combination can control relapsed or refractory acute myeloid leukemia (AML) and determine if this combination can be safely taken. The study will look at the side effects of the Temozolomide plus Vorinostat in combination and whether the treatment schedule is tolerated.

Detailed Description

The primary endpoint of the study is to determine the clinical efficacy as determined by the rate of morphological complete remission, of 2 different treatment regimens of temozolomide and vorinostat administered to 2 distinct groups of participants patients with AML and poor prognostic features. Participants will be allocated to treatment on the basis of O6-methylguanine DNA methyltransferase (MGMT) promoter methylation status.

Conditions

Acute Myeloid Leukemia With 11q23-abnormality in Relapse

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Participant Group 1 (methylated MGMT promoter)

Participants with methylated O6-methylguanine DNA methyltransferase (MGMT) promoter, ie, expected to have no expression of MGMT protein, will be assigned into Group 1, and will receive vorinostat 500 mg orally 3 times daily for 3 days, followed by conventional doses of temozolomide (200 mg/m2 for 7 days).

Group Type: ACTIVE_COMPARATOR

Temozolomide

Intervention Type: DRUG

An alkylating agent administered for induction per standard of care at 200 mg/m²/day for 7days.

Vorinostat

Intervention Type: DRUG

A synthetic hydroxamic acid derivative with antineoplastic activity administered for both groups at 500 mg orally 3 times daily for 3 days prior to Temozolomide 200 mg/m²/day.

Participant Group 2 (non-methylated MGMT promoter)

Participants with non-methylated O6-methylguanine DNA methyltransferase (MGMT) promoter, ie, expected to have expression MGMT protein, will be assigned to into Group 2, and will initially receive daily, low doses (protracted dose schedule) of temozolomide (100 mg/m2) for 14 days in an attempt to inactivate MGMT activity. Following the protracted dose schedule, participants will receive vorinostat 500 mg orally 3 times daily for 3 days, followed by conventional doses of temozolomide (200 mg/m2 for 7 days).

Group Type: ACTIVE_COMPARATOR

Temozolomide

Intervention Type: DRUG

An alkylating agent administered for induction per standard of care at 200 mg/m²/day for 7days.

Vorinostat

Intervention Type: DRUG

A synthetic hydroxamic acid derivative with antineoplastic activity administered for both groups at 500 mg orally 3 times daily for 3 days prior to Temozolomide 200 mg/m²/day.

Interventions

Temozolomide

An alkylating agent administered for induction per standard of care at 200 mg/m²/day for 7days.

Intervention Type: DRUG

Vorinostat

A synthetic hydroxamic acid derivative with antineoplastic activity administered for both groups at 500 mg orally 3 times daily for 3 days prior to Temozolomide 200 mg/m²/day.

Intervention Type: DRUG

Other Intervention Names

Temodar; Temodal; Temcad; TMZ; Zolinza

Eligibility Criteria

Inclusion Criteria

• Histologically- or cytologically-confirmed acute myeloid leukemia (AML)
• Relapsed or refractory (AML), after at least 1 prior induction regimen
• Age ≥ 18 years
• Life expectancy > 2 months.
• Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 2
• Calculated creatinine clearance ≤ 2.0 mg/dL (OR ≥ 30 mL/min for patients with serum creatinine levels > 2.0 mg/dL)
• Serum total bilirubin ≤ 1.5 X upper limit of normal (ULN)
• Aspartate aminotransferase (AST) ≤ 2.5 X ULN
• Alanine aminotransferase (ALT) ≤ 2.5 X ULN
• Alkaline phosphatase (liver fraction) ≤ 2.5 X ULN
• If male, must agree to use an adequate method of contraception for the duration of the study and 1 month following coming off study or of study completion
• If female of childbearing potential, must a negative serum pregnancy test within 72 hours prior to receiving the first dose of vorinostat.
• If female, must be one of the following:

• Post-menopausal (free from menses for ≥ 2 years),
• Surgically-sterilized
• Willing to use 2 adequate barrier methods of contraception
• Agree to abstain from heterosexual activity throughout the study, starting with Visit 1
• Available at the treating institution for study assessments and procedures for the duration of the study
• Written informed consent

Exclusion Criteria

• Received chemotherapy; radiotherapy; or biological therapy within 30 days (42 days for nitrosoureas or mitomycin C) prior to initial dosing with study drug(s), or has not recovered from adverse events due to agents administered more than 30 days earlier, except for hydroxyurea-related adverse events.
• Currently participating or within 30 days of initial dosing with study drug(s), has participated in a study with an investigational compound or device
• Receiving any other investigational agents or concomitant radiotherapy, chemotherapy, or immunotherapy.
• Received a histone deacetylase (HDAC) inhibitor [eg, romidepsin (Depsipeptide), NSC-630176, MS 275, LAQ-824, belinostat (PXD-101), LBH589, MGCD0103, CRA024781, etc] within the past 30 days. Patients who have received valproic acid or other compounds with HDAC inhibitor-like activity, as anti-tumor therapy should not enroll in this study. Patients who have received such compounds for other indications, eg, valproic acid for epilepsy, may enroll after a 30-day washout period.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to temozolomide; vorinostat; dacarbazine (DTIC-Dome, DIC, imidazole carboxamide)
• History of gastrointestinal disease or significant bowel resection that could interfere with drug absorption or inability to swallow tablets.
• Uncontrolled intercurrent illness (as defined by the investigators) including, but not limited to, ongoing or active infection (HIV, Hepatitis B or Hepatitis C), symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• Prior allogeneic stem cell transplantation within 2 months of trial enrollment or prior radiation up to more than 25% of bone marrow.
• Currently active 2nd malignancy, other than nonmelanoma skin cancer and carcinoma in situ of the cervix (completed therapy for a prior malignancy, and disease-free from prior malignancies for >5 years or are considered by their physician to be at less than 30% risk of relapse is not considered to be an "currently active" malignancy)
• Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
• Pregnant or breast feeding
• Expecting to conceive or father children within the projected duration of the study.
• Uncontrolled intercurrent illness or circumstances that could limit compliance with the study, including, but not limited to the following: active infection, acute or chronic graft versus host disease, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric conditions.
• History or current evidence of any condition, therapy, or lab abnormality that might confound the results of the study, interfere with the patient's participation for the full duration of the study, or is not in the best interest of the patient to participate.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Merck Sharp & Dohme LLC

INDUSTRY

Sponsor Role: collaborator

Steven E. Coutre

OTHER

Sponsor Role: lead

Responsible Party

Steven E. Coutre

Professor of Medicine (Hematology)

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Steven E Coutre, MD

Role: PRINCIPAL_INVESTIGATOR

Stanford University

Locations

Stanford University Medical Center

Stanford, California, United States

Countries

United States

Other Identifiers

NCT01550224

Identifier Type: OTHER

Identifier Source: secondary_id

HEMAML0017

Identifier Type: OTHER

Identifier Source: secondary_id

IRB-22794

Identifier Type: -

Identifier Source: org_study_id