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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01550224
Recruitment Status : Completed
First Posted : March 9, 2012
Results First Posted : July 16, 2018
Last Update Posted : August 9, 2018
Sponsor:
Collaborator:
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
Steven E. Coutre, Stanford University

Study Type Interventional
Study Design Allocation: Non-Randomized;   Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Acute Myeloid Leukemia With 11q23-abnormality in Relapse
Interventions Drug: Temozolomide
Drug: Vorinostat
Enrollment 23
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Participant Group 1 (Methylated MGMT Promoter) Participant Group 2 (Non-methylated MGMT Promoter)
Hide Arm/Group Description

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).

Temozolomide: An alkylating agent administered for induction per standard of care at 200 mg/m²/day for 7days. Group 2 participants also receive at protracted, pre-induction treatment with 100 mg/m²/day for 14 days.

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.

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).

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

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.

Period Title: Overall Study
Started 3 20
Completed 3 20
Not Completed 0 0
Arm/Group Title Participant Group 1 (Methylated MGMT Promoter) Participant Group 2 (Non-methylated MGMT Promoter) Total
Hide Arm/Group Description

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).

Temozolomide: An alkylating agent administered for induction per standard of care at 200 mg/m²/day for 7days. Group 2 participants also receive at protracted, pre-induction treatment with 100 mg/m²/day for 14 days.

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.

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).

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

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.

Total of all reporting groups
Overall Number of Baseline Participants 3 20 23
Hide Baseline Analysis Population Description
[Not Specified]
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 3 participants 20 participants 23 participants
<=18 years
0
   0.0%
0
   0.0%
0
   0.0%
Between 18 and 65 years
0
   0.0%
0
   0.0%
0
   0.0%
>=65 years
3
 100.0%
20
 100.0%
23
 100.0%
Age, Continuous  
Median (Full Range)
Unit of measure:  Years
Number Analyzed 3 participants 20 participants 23 participants
76.3
(71 to 85)
83
(72.4 to 89.3)
82.7
(71 to 89.3)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 3 participants 20 participants 23 participants
Female
2
  66.7%
5
  25.0%
7
  30.4%
Male
1
  33.3%
15
  75.0%
16
  69.6%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 3 participants 20 participants 23 participants
Hispanic or Latino
0
   0.0%
1
   5.0%
1
   4.3%
Not Hispanic or Latino
3
 100.0%
17
  85.0%
20
  87.0%
Unknown or Not Reported
0
   0.0%
2
  10.0%
2
   8.7%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 3 participants 20 participants 23 participants
American Indian or Alaska Native
0
   0.0%
0
   0.0%
0
   0.0%
Asian
1
  33.3%
1
   5.0%
2
   8.7%
Native Hawaiian or Other Pacific Islander
0
   0.0%
0
   0.0%
0
   0.0%
Black or African American
0
   0.0%
0
   0.0%
0
   0.0%
White
1
  33.3%
15
  75.0%
16
  69.6%
More than one race
0
   0.0%
0
   0.0%
0
   0.0%
Unknown or Not Reported
1
  33.3%
4
  20.0%
5
  21.7%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 3 participants 20 participants 23 participants
3 20 23
1.Primary Outcome
Title Complete Remission (CR)
Hide 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

Time Frame up to 10 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Participant Group 1 (Methylated MGMT Promoter) Participant Group 2 (Non-methylated MGMT Promoter)
Hide Arm/Group Description:

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).

Temozolomide: An alkylating agent administered for induction per standard of care at 200 mg/m²/day for 7days. Group 2 participants also receive at protracted, pre-induction treatment with 100 mg/m²/day for 14 days.

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.

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).

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

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.

Overall Number of Participants Analyzed 3 20
Measure Type: Count of Participants
Unit of Measure: Participants
0
   0.0%
0
   0.0%
2.Secondary Outcome
Title Morphologic Leukemia-free State (MLFS)
Hide 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

Time Frame up to 10 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Participant Group 1 (Methylated MGMT Promoter) Participant Group 2 (Non-methylated MGMT Promoter)
Hide Arm/Group Description:

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).

Temozolomide: An alkylating agent administered for induction per standard of care at 200 mg/m²/day for 7days. Group 2 participants also receive at protracted, pre-induction treatment with 100 mg/m²/day for 14 days.

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.

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).

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

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.

Overall Number of Participants Analyzed 3 20
Measure Type: Count of Participants
Unit of Measure: Participants
0
   0.0%
1
   5.0%
3.Secondary Outcome
Title Complete Remission With Incomplete Blood Count Recovery (CRp)
Hide 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

Time Frame up to 10 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Participant Group 1 (Methylated MGMT Promoter) Participant Group 2 (Non-methylated MGMT Promoter)
Hide Arm/Group Description:

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).

Temozolomide: An alkylating agent administered for induction per standard of care at 200 mg/m²/day for 7days. Group 2 participants also receive at protracted, pre-induction treatment with 100 mg/m²/day for 14 days.

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.

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).

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

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.

Overall Number of Participants Analyzed 3 20
Measure Type: Count of Participants
Unit of Measure: Participants
0
   0.0%
1
   5.0%
4.Secondary Outcome
Title Cytogenetic Response (CyR)
Hide 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

Time Frame up to 10 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Participant Group 1 (Methylated MGMT Promoter) Participant Group 2 (Non-methylated MGMT Promoter)
Hide Arm/Group Description:

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).

Temozolomide: An alkylating agent administered for induction per standard of care at 200 mg/m²/day for 7days. Group 2 participants also receive at protracted, pre-induction treatment with 100 mg/m²/day for 14 days.

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.

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).

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

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.

Overall Number of Participants Analyzed 3 20
Measure Type: Count of Participants
Unit of Measure: Participants
0
   0.0%
0
   0.0%
5.Secondary Outcome
Title Partial Remission (PR)
Hide 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

Time Frame up to 10 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Participant Group 1 (Methylated MGMT Promoter) Participant Group 2 (Non-methylated MGMT Promoter)
Hide Arm/Group Description:

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).

Temozolomide: An alkylating agent administered for induction per standard of care at 200 mg/m²/day for 7days. Group 2 participants also receive at protracted, pre-induction treatment with 100 mg/m²/day for 14 days.

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.

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).

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

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.

Overall Number of Participants Analyzed 3 20
Measure Type: Count of Participants
Unit of Measure: Participants
0
   0.0%
0
   0.0%
6.Secondary Outcome
Title Treatment Failure (TF)
Hide 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

Time Frame up to 10 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Participant Group 1 (Methylated MGMT Promoter) Participant Group 2 (Non-methylated MGMT Promoter)
Hide Arm/Group Description:

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).

Temozolomide: An alkylating agent administered for induction per standard of care at 200 mg/m²/day for 7days. Group 2 participants also receive at protracted, pre-induction treatment with 100 mg/m²/day for 14 days.

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.

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).

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

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.

Overall Number of Participants Analyzed 3 20
Measure Type: Count of Participants
Unit of Measure: Participants
3
 100.0%
20
 100.0%
7.Secondary Outcome
Title Disease-free Survival (DFS) at 2 Years
Hide 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

Time Frame 2 years
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Participant Group 1 (Methylated MGMT Promoter) Participant Group 2 (Non-methylated MGMT Promoter)
Hide Arm/Group Description:

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).

Temozolomide: An alkylating agent administered for induction per standard of care at 200 mg/m²/day for 7days. Group 2 participants also receive at protracted, pre-induction treatment with 100 mg/m²/day for 14 days.

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.

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).

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

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.

Overall Number of Participants Analyzed 3 20
Measure Type: Count of Participants
Unit of Measure: Participants
0
   0.0%
0
   0.0%
8.Secondary Outcome
Title Relapse-Free Survival (RFS) at 2 Years
Hide 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

Time Frame 2 years
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Participant Group 1 (Methylated MGMT Promoter) Participant Group 2 (Non-methylated MGMT Promoter)
Hide Arm/Group Description:

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).

Temozolomide: An alkylating agent administered for induction per standard of care at 200 mg/m²/day for 7days. Group 2 participants also receive at protracted, pre-induction treatment with 100 mg/m²/day for 14 days.

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.

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).

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

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.

Overall Number of Participants Analyzed 3 20
Measure Type: Count of Participants
Unit of Measure: Participants
0
   0.0%
0
   0.0%
9.Secondary Outcome
Title Overall Survival (OS) at 2 Years
Hide 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.
Time Frame 2 years
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Participant Group 1 (Methylated MGMT Promoter) Participant Group 2 (Non-methylated MGMT Promoter)
Hide Arm/Group Description:

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).

Temozolomide: An alkylating agent administered for induction per standard of care at 200 mg/m²/day for 7days. Group 2 participants also receive at protracted, pre-induction treatment with 100 mg/m²/day for 14 days.

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.

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).

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

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.

Overall Number of Participants Analyzed 3 20
Measure Type: Count of Participants
Unit of Measure: Participants
0
   0.0%
0
   0.0%
Time Frame 2 years
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Participant Group 1 (Methylated MGMT Promoter) Participant Group 2 (Non-methylated MGMT Promoter)
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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).

Temozolomide: An alkylating agent administered for induction per standard of care at 200 mg/m²/day for 7days. Group 2 participants also receive at protracted, pre-induction treatment with 100 mg/m²/day for 14 days.

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.

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).

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

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.

All-Cause Mortality
Participant Group 1 (Methylated MGMT Promoter) Participant Group 2 (Non-methylated MGMT Promoter)
Affected / at Risk (%) Affected / at Risk (%)
Total   3/3 (100.00%)      20/20 (100.00%)    
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Participant Group 1 (Methylated MGMT Promoter) Participant Group 2 (Non-methylated MGMT Promoter)
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   0/3 (0.00%)      11/20 (55.00%)    
Blood and lymphatic system disorders     
Febrile neutropenia  1  0/3 (0.00%)  0 2/20 (10.00%)  3
Infections and infestations     
Infection - E coli bacteremia  1  0/3 (0.00%)  0 1/20 (5.00%)  1
Infection - neutropenic fever  1  0/3 (0.00%)  0 4/20 (20.00%)  4
Infection - pneumonia  1  0/3 (0.00%)  0 3/20 (15.00%)  3
Infection - Sepsis  1  0/3 (0.00%)  0 2/20 (10.00%)  2
Investigations     
Thrombocytopenia (platelet count decreased)  1  0/3 (0.00%)  0 1/20 (5.00%)  1
Respiratory, thoracic and mediastinal disorders     
Pulmonary/Upper Respiratory - Hemoptysis (coughing up blood)  1  0/3 (0.00%)  0 1/20 (5.00%)  1
Vascular disorders     
Hemorrhage (bleeding), subdural hematoma  1  0/3 (0.00%)  0 1/20 (5.00%)  1
1
Term from vocabulary, CTCAE (4.0)
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Participant Group 1 (Methylated MGMT Promoter) Participant Group 2 (Non-methylated MGMT Promoter)
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   3/3 (100.00%)      20/20 (100.00%)    
Blood and lymphatic system disorders     
Anemia (reduced level of red blood cells)  1  0/3 (0.00%)  0 1/20 (5.00%)  1
Leukopenia (reduced level of white blood cells)  1  0/3 (0.00%)  0 1/20 (5.00%)  1
Low hemoglobin  1  0/3 (0.00%)  0 1/20 (5.00%)  1
Neutropenia (reduced level of neutrophils)  1  0/3 (0.00%)  0 1/20 (5.00%)  1
Neutropenic fever  1  1/3 (33.33%)  1 0/20 (0.00%)  0
Pancytopenia (reduced level of many or all blood cells)  1  0/3 (0.00%)  0 1/20 (5.00%)  1
Thrombocytopenia (reduced level of platlets)  1  0/3 (0.00%)  0 5/20 (25.00%)  5
Cardiac disorders     
Arrhythmia (irregular heart beat)  1  0/3 (0.00%)  0 2/20 (10.00%)  2
Hypotension (low blood pressure)  1  0/3 (0.00%)  0 1/20 (5.00%)  1
Tachycardia  1  0/3 (0.00%)  0 1/20 (5.00%)  1
Gastrointestinal disorders     
Abdominal or epigastric discomfort  1  0/3 (0.00%)  0 2/20 (10.00%)  2
Constipation  1  0/3 (0.00%)  0 1/20 (5.00%)  1
Cough  1  0/3 (0.00%)  0 5/20 (25.00%)  5
Diarrhea  1  1/3 (33.33%)  1 9/20 (45.00%)  9
Dysphagia (difficulty swallowing)  1  0/3 (0.00%)  0 1/20 (5.00%)  1
Loss of appetite  1  2/3 (66.67%)  2 1/20 (5.00%)  1
Melena (blood in stool)  1  0/3 (0.00%)  0 1/20 (5.00%)  1
Nausea  1  2/3 (66.67%)  2 8/20 (40.00%)  8
Rectal abscess  1  0/3 (0.00%)  0 1/20 (5.00%)  1
Vomiting  1  2/3 (66.67%)  2 7/20 (35.00%)  7
General disorders     
Back pain  1  0/3 (0.00%)  0 1/20 (5.00%)  1
Dysgeusia (altered sense of taste)  1  0/3 (0.00%)  0 2/20 (10.00%)  2
Elevated serum lactase  1  0/3 (0.00%)  0 1/20 (5.00%)  1
Fatigue  1  2/3 (66.67%)  2 10/20 (50.00%)  10
Limb edema (swelling in extremities)  1  0/3 (0.00%)  0 3/20 (15.00%)  3
Maceration  1  0/3 (0.00%)  0 1/20 (5.00%)  1
Night sweat  1  0/3 (0.00%)  0 1/20 (5.00%)  1
Skin infection (boil)  1  0/3 (0.00%)  0 1/20 (5.00%)  1
Weakness  1  0/3 (0.00%)  0 1/20 (5.00%)  1
Weight loss  1  0/3 (0.00%)  0 2/20 (10.00%)  2
Nervous system disorders     
Altered mental status (confusion)  1  0/3 (0.00%)  0 2/20 (10.00%)  2
Insomnia (inability to sleep)  1  0/3 (0.00%)  0 1/20 (5.00%)  1
Lethargic  1  0/3 (0.00%)  0 2/20 (10.00%)  2
Metabolic encephalopathy  1 [1]  0/3 (0.00%)  0 1/20 (5.00%)  1
Vertigo (dizziness or syncope)  1  0/3 (0.00%)  0 4/20 (20.00%)  4
Renal and urinary disorders     
Difficulty urinating  1  0/3 (0.00%)  0 1/20 (5.00%)  1
Hematuria (blood in urine)  1  0/3 (0.00%)  0 1/20 (5.00%)  1
Respiratory, thoracic and mediastinal disorders     
Acute respiratory distress  1  0/3 (0.00%)  0 2/20 (10.00%)  2
Chest pain  1  0/3 (0.00%)  0 2/20 (10.00%)  2
Chills  1  0/3 (0.00%)  0 1/20 (5.00%)  1
Difficulty of breathing  1  0/3 (0.00%)  0 1/20 (5.00%)  1
Dyspnea (shortness of breath)  1  1/3 (33.33%)  1 4/20 (20.00%)  4
Epistaxis (nosebleed)  1  1/3 (33.33%)  1 1/20 (5.00%)  1
Fever  1  2/3 (66.67%)  2 2/20 (10.00%)  2
Pleural effusion  1  0/3 (0.00%)  0 1/20 (5.00%)  1
Pneumonia  1  1/3 (33.33%)  1 2/20 (10.00%)  2
Respiratory failure  1  0/3 (0.00%)  0 1/20 (5.00%)  1
Sore throat  1  0/3 (0.00%)  0 1/20 (5.00%)  1
Upper respiratory infection  1  0/3 (0.00%)  0 0/20 (0.00%)  0
Skin and subcutaneous tissue disorders     
Petechiae (skin spots)  1  0/3 (0.00%)  0 5/20 (25.00%)  5
Pruritus (itching)  1  0/3 (0.00%)  0 1/20 (5.00%)  1
Rash  1  0/3 (0.00%)  0 1/20 (5.00%)  1
1
Term from vocabulary, CTCAE (4.0)
Indicates events were collected by systematic assessment
[1]
altered blood chemistry affecting the brain
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
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Name/Title: Steven Edward Coutre, MD; Professor of Medicine (Hematology)
Organization: Stanford University Medical Center
Phone: 650-725-4040
EMail: coutre@stanford.edu
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Responsible Party: Steven E. Coutre, Stanford University
ClinicalTrials.gov Identifier: NCT01550224    
Other Study ID Numbers: IRB-22794
HEMAML0017 ( Other Identifier: OnCore )
First Submitted: March 7, 2012
First Posted: March 9, 2012
Results First Submitted: June 15, 2018
Results First Posted: July 16, 2018
Last Update Posted: August 9, 2018