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.
Completed
Phase 2
| Drug | Synonyms | Arms |
|---|---|---|
| Temozolomide | Temodar, Temodal, Temcad, TMZ | Participant Group 1 (methylated MGMT promoter) |
| Vorinostat | Zolinza | Participant Group 1 (methylated MGMT promoter) |
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.
| Name | Type | Description | Interventions |
|---|---|---|---|
| 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). |
|
| 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). |
|
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.
| Maximum Eligible Age: | N/A |
| Minimum Eligible Age: | 18 Years |
| Eligible Gender: | All |
| Healthy Volunteers: | No |
| Measure: | Complete Remission (CR) |
| Time Frame: | up to 10 weeks |
| Safety Issue: | |
| Description: | 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 |
| Measure: | Morphologic Leukemia-free State (MLFS) |
| Time Frame: | up to 10 weeks |
| Safety Issue: | |
| Description: | The rate of morphologic leukemia-free state (MLFS) is reported as the percentage without dispersion of participants in Groups 1 and 2 that achieve MLFS. The outcome is reported as the percentage without dispersion of participants in Groups 1 and 2 that demonstrated MLFS. This assessment is independent of absolute neutrophil count (ANC) or platelets (PLT) recovery status. MLFS is defined below. MLFS = < 5% blasts in bone marrow aspirate containing marrow spicules > 200 nucleated cells no blasts with Auer rods no persistence of extramedullary disease |
| Measure: | Complete Remission With Incomplete Blood Count Recovery (CRp) |
| Time Frame: | up to 10 weeks |
| Safety Issue: | |
| Description: | The rate of complete remission with incomplete blood count recovery (CRp) for Groups 1 and 2 was assessed as the rate of morphologic leukemia-free state (MLFS) but with EITHER residual neutropenia (ANC < 1,000/µL) OR residual thrombocytopenia (PLT < 100,000/µL). MLFS is defined as follows. MLFS = < 5% blasts in bone marrow aspirate containing marrow spicules > 200 nucleated cells no blasts with Auer rods no persistence of extramedullary disease |
| Measure: | Cytogenetic Response (CyR) |
| Time Frame: | up to 10 weeks |
| Safety Issue: | |
| Description: | Cytogenetic response (CyR) is defined as complete remission (CR), PLUS a documented decrease or absence of cytogenetic abnormalities, when analyzed microscopically for 20 cellular metaphases (actively dividing cells). The outcome is reported as the percentage without dispersion of participants in Groups 1 and 2 that demonstrated CyR. CR is defined as all of the following. CR = < 5% blasts in bone marrow aspirate containing marrow spicules; > 200 nucleated cells no blasts with Auer rods; no persistence of extramedullary disease absolute neutrophil count (ANC) ≥ 1,000/µL platelets (PLT) ≥ 100,000/µL |
| Measure: | Partial Remission (PR) |
| Time Frame: | up to 10 weeks |
| Safety Issue: | |
| Description: | Partial remission (PR) is reported as the percentage without dispersion of participants in Groups 1 and 2 that demonstrated PR. PR is defined as all of the following. PR = 5% to 25% blasts (must be ≥ 50% reduction of blasts) in bone marrow aspirate containing marrow spicules; > 200 nucleated cells no blasts with Auer rods no persistence of extramedullary disease absolute neutrophil count (ANC) ≥ 1,000/µL platelets (PLT) ≥ 100,000/µL |
| Measure: | Treatment Failure (TF) |
| Time Frame: | up to 10 weeks |
| Safety Issue: | |
| Description: | Treatment failure (TF) is defined as failing to achieve either a complete remission (CR) or partial remission (PR) after induction chemotherapy. The outcome is reported as the percentage without dispersion of participants in Groups 1 and 2 that experienced TF. CR and PR are defined as the following. CR = < 5% blasts in bone marrow aspirate containing marrow spicules; > 200 nucleated cells no blasts with Auer rods; no persistence of extramedullary disease absolute neutrophil count (ANC) ≥ 1,000/µL platelets (PLT) ≥ 100,000/µL PR = 5% to 25% blasts (must be ≥ 50% reduction of blasts) in bone marrow aspirate containing marrow spicules; > 200 nucleated cells no blasts with Auer rods no persistence of extramedullary disease absolute neutrophil count (ANC) ≥ 1,000/µL platelets (PLT) ≥ 100,000/µL |
| Measure: | Disease-free Survival (DFS) at 2 Years |
| Time Frame: | 2 years |
| Safety Issue: | |
| Description: | Disease-Free Survival (DFS) is defined as survival after complete response (CR) without disease progression. DFS is reported as the percentage without dispersion of participants in Groups 1 and 2 that experienced CR and were alive without progression (ie, without disease) 2 years after induction chemotherapy. CR is defined as all of the following. CR = < 5% blasts in bone marrow aspirate containing marrow spicules; > 200 nucleated cells no blasts with Auer rods; no persistence of extramedullary disease absolute neutrophil count (ANC) ≥ 1,000/µL platelets (PLT) ≥ 100,000/µL |
| Measure: | Relapse-Free Survival (RFS) at 2 Years |
| Time Frame: | 2 years |
| Safety Issue: | |
| Description: | Relapse-free survival (RFS) is defined as survival after complete response (CR) or (PR) without further disease progression. RFS is reported as the percentage without dispersion of participants in Groups 1 and 2 that experienced CR or PR, and were alive without progression 2 years after induction chemotherapy. CR and PR are defined as the following. CR = < 5% blasts in bone marrow aspirate containing marrow spicules; > 200 nucleated cells no blasts with Auer rods; no persistence of extramedullary disease absolute neutrophil count (ANC) ≥ 1,000/µL platelets (PLT) ≥ 100,000/µL PR = 5% to 25% blasts (must be ≥ 50% reduction of blasts) in bone marrow aspirate containing marrow spicules; > 200 nucleated cells no blasts with Auer rods no persistence of extramedullary disease absolute neutrophil count (ANC) ≥ 1,000/µL platelets (PLT) ≥ 100,000/µL |
| Measure: | Overall Survival (OS) at 2 Years |
| Time Frame: | 2 years |
| Safety Issue: | |
| Description: | Overall Survival (OS) is defined as survival regardless of clinical status. OS is reported as the percentage without dispersion of participants in Groups 1 and 2 that remained alive 2 years after induction chemotherapy. |
| Phase: | Phase 2 |
| Primary Purpose: | Interventional |
| Overall Status: | Completed |
| Lead Sponsor: | Steven E. Coutre |
August 9, 2018
