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

NCT01550224 | Completed Phase 2 Results DMC FDA Drug

• 3 other identifiers: IRB-22794NCT01550224HEMAML0017
• Study Type: interventional
• Target: 23
• Locations: 1 country
• Sites: 1

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.

Conditions

Acute Myeloid Leukemia With 11q23-abnormality in Relapse

Outcome Measures

Primary Outcomes (1)

• Complete Remission (CR)

  This study evaluates the clinical efficacy of temozolomide + vorinostat as administered to Groups 1 and 2, assessed as the rate of complete remission \[CR, aka morphologic complete remission (mCR)\], defined as the morphologic leukemia-free state (MLFS), WITH absolute neutrophil count (ANC) ≥ 1,000/µL AND platelets (PLT) ≥ 100,000/µL. The outcome is reported as the percentage without dispersion of participants in Groups 1 and 2 that demonstrated CR. CR is defined as all of the following. MLFS = \< 5% blasts in bone marrow aspirate containing marrow spicules \> 200 nucleated cells no blasts with Auer rods no persistence of extramedullary disease ANC = ≥ 1,000/µL PLT = ≥ 100,000/µL

  up to 10 weeks

Secondary Outcomes (8)

• Morphologic Leukemia-free State (MLFS)

  up to 10 weeks

• Complete Remission With Incomplete Blood Count Recovery (CRp)

  up to 10 weeks

• Cytogenetic Response (CyR)

  up to 10 weeks

• Partial Remission (PR)

  up to 10 weeks

• Treatment Failure (TF)

  up to 10 weeks

Study Arms (2)

Participant Group 1 (methylated MGMT promoter)

ACTIVE COMPARATOR

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).

Drug: Temozolomide; Drug: Vorinostat

Participant Group 2 (non-methylated MGMT promoter)

ACTIVE COMPARATOR

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).

Drug: Temozolomide; Drug: Vorinostat

Interventions

Temozolomide DRUG

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

Also known as: Temodar, Temodal, Temcad, TMZ

Participant Group 1 (methylated MGMT promoter); Participant Group 2 (non-methylated MGMT promoter)

Vorinostat 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.

Also known as: Zolinza

Participant Group 1 (methylated MGMT promoter); Participant Group 2 (non-methylated MGMT promoter)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Steven E. Coutre: lead
• Merck Sharp & Dohme LLC: collaborator

Study Sites (1)

Stanford University Medical Center

Stanford, California, 94305, United States

Location

MeSH Terms

Interventions

Temozolomide; Vorinostat

Intervention Hierarchy (Ancestors)

Dacarbazine; Triazenes; Organic Chemicals; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Anilides; Amides; Aniline Compounds; Amines; Hydroxamic Acids; Hydroxylamines; Hydroxy Acids; Carboxylic Acids

Results Point of Contact

• Title: Steven Edward Coutre, MD; Professor of Medicine (Hematology)
• Organization: Stanford University Medical Center

coutre@stanford.edu

650-725-4040

Study Officials

• Steven E Coutre, MD

  Stanford University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor of Medicine (Hematology)

Study Record Dates

• First Submitted: March 7, 2012
• First Posted: March 9, 2012
• Study Start: May 1, 2013
• Primary Completion: November 17, 2014
• Study Completion: November 17, 2014
• Last Updated: August 9, 2018
• Results First Posted: July 16, 2018

Record last verified: 2018-07

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)