Acute Myeloid Leukemia With 11q23-abnormality in RelapsePhase 2NCT01550224

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

A Phase 2 study testing Temozolomide and Vorinostat in people with Acute Myeloid Leukemia With 11q23-abnormality in Relapse, run by Steven E. Coutre at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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Trial summary

Who is it for?: Ages 18 years and older
Conditions the study is for: Acute Myeloid Leukemia With 11q23-abnormality in Relapse
What is being tested?: Temozolomide and Vorinostat
Type of treatment: Pill or oral medicine
Could I receive a placebo?: No, everyone receives an active treatment
How many people: 23 participants
Where: 1 siteUnited States
Study dates: 1 May 2013to 17 Nov 2014
Phase: Phase 2
Are there results?: Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 18 years and older
All sexes
No healthy volunteers
Adult, Older adult

Who may be able to join

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)

Show all 19Show fewer

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

Who cannot join

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.

Show all 14Show fewer

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.

Trial locations and contacts

1 site in 1 country.

United States1 site

Stanford University Medical Center
Stanford, California, 94305

Other trials in United States

About this study

Official title: Temozolomide Plus Vorinostat in Patients With Relapse/Refractory Acute Myeloid Leukemia (AML)

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.

Read the 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
Being tested: Temozolomide, Vorinostat

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

TemozolomideDrug
Also called Temodar, Temodal, Temcad, TMZ
An alkylating agent administered for induction per standard of care at 200 mg/m²/day for 7days.
VorinostatDrug
Also called Zolinza
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.

Study groups in NCT01550224
Study group	Role	What they receive
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). Receives: 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). Receives: Drug: Temozolomide; Drug: Vorinostat

What is being measured

The primary outcome is the main question the study is designed to answer.

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
Measured: up to 10 weeks

Secondary outcomes (8)

Morphologic Leukemia-free State (MLFS)
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
Measured: up to 10 weeks
Complete Remission With Incomplete Blood Count Recovery (CRp)
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
Measured: up to 10 weeks
Cytogenetic Response (CyR)
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
Measured: up to 10 weeks
Partial Remission (PR)
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
Measured: up to 10 weeks
Treatment Failure (TF)
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
Measured: up to 10 weeks
Disease-free Survival (DFS) at 2 Years
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
Measured: 2 years
Relapse-Free Survival (RFS) at 2 Years
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
Measured: 2 years
Overall Survival (OS) at 2 Years
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.
Measured: 2 years

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

1 May 201317 Nov 2014

First posted9 Mar 2012 (estimated)
Study start1 May 2013
Primary completion17 Nov 2014
Study completion17 Nov 2014

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
Other trials for Acute Myeloid Leukemia With 11q23-abnormality in RelapseStudies of the same condition, open and under way.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 2
Primary purpose: Treatment
Allocation: Non-randomised
Intervention model: Single group
Masking: None (open label)
Enrolment: 23 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT01550224
Sponsor's protocol ID: IRB-22794
Other IDs: NCT01550224, HEMAML0017
Status last verified: Jul 2018
First submitted: 7 Mar 2012
Last updated: 9 Aug 2018
Results posted: Yes, on ClinicalTrials.gov
Data monitoring committee: Yes
FDA-regulated drug: Yes
FDA-regulated device: No
Individual data sharing: No

Study at a glance

From the registry record, last updated by the sponsor on 9 Aug 2018. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: Temozolomide Plus Vorinostat in Patients With Relapse/Refractory Acute Myeloid Leukemia (AML)
ClinicalTrials.gov ID: NCT01550224
Acronym / sponsor ID: IRB-22794
Conditions: Acute Myeloid Leukemia With 11q23-abnormality in Relapse
Phase: Phase 2
Study type: Interventional
Recruitment status: Completed
Enrolment: 23 participants (actual)
Lead sponsor: Steven E. CoutreUniversity, hospital or other
Collaborators: Merck Sharp & Dohme LLC
Study start: 1 May 2013 (actual)
Primary completion: 17 Nov 2014 (actual)
Study completion: 17 Nov 2014 (actual)
First posted: 9 Mar 2012 (estimated)
Results: Posted 16 Jul 2018

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

Detailed description

Study design

Primary purpose: Treatment
Allocation: Non-randomised
Intervention model: Single group
Masking: None (open label)
Number of arms: 2

Arm	Type	Receives
Participant Group 1 (methylated MGMT promoter)	Active comparator	Drug: Temozolomide, Drug: VorinostatParticipants 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	Drug: Temozolomide, Drug: VorinostatParticipants 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).

Who may qualify

Ages: 18 years and older
Sex: All
Healthy volunteers: Not accepted
Age groups: Adult, Older adult

Key inclusion criteria (19 listed)

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

Key exclusion criteria (14 listed)

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)

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
TemozolomideAlso: Temodar, Temodal, Temcad, TMZAn alkylating agent administered for induction per standard of care at 200 mg/m²/day for 7days.	Drug	Participant Group 1 (methylated MGMT promoter), Participant Group 2 (non-methylated MGMT promoter)
VorinostatAlso: ZolinzaA 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.	Drug	Participant Group 1 (methylated MGMT promoter), Participant Group 2 (non-methylated MGMT promoter)

Primary outcome

Complete Remission (CR)
Time frame: up to 10 weeks
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

8 secondary outcomes

Morphologic Leukemia-free State (MLFS)
Time frame: up to 10 weeks
Complete Remission With Incomplete Blood Count Recovery (CRp)
Time frame: up to 10 weeks
Cytogenetic Response (CyR)
Time frame: up to 10 weeks
Partial Remission (PR)
Time frame: up to 10 weeks
Treatment Failure (TF)
Time frame: up to 10 weeks
Disease-free Survival (DFS) at 2 Years
Time frame: 2 years
Relapse-Free Survival (RFS) at 2 Years
Time frame: 2 years
Overall Survival (OS) at 2 Years
Time frame: 2 years

Results and safety

Results posted to the registry on 16 Jul 2018, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

Group	Started	Completed
Participant Group 1 (Methylated MGMT Promoter)	3	3
Participant Group 2 (Non-methylated MGMT Promoter)	20	20

Primary outcome: Complete Remission (CR)

Time frame: up to 10 weeks. Count of participants. Unit: Participants

Measure	Participant Group 1 (Methylated MGMT Promoter) n = 3	Participant Group 2 (Non-methylated MGMT Promoter) n = 20
Value	0	0

8 secondary outcomes are reported in the full results.

Adverse events

Time frame: 2 years. Other adverse events reported at 0% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
Participant Group 1 (Methylated MGMT Promoter)	0 of 3 (0%)	3 of 3 (100%)	3 of 3
Participant Group 2 (Non-methylated MGMT Promoter)	11 of 20 (55%)	20 of 20 (100%)	20 of 20

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 9 Aug 2018.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
Individual participant dataSharing planned: No

Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

Steven E Coutre, MD principal investigator

Stanford University

1 site in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Temozolomide and Vorinostat in people with Acute Myeloid Leukemia With 11q23-abnormality in Relapse, run by Steven E. Coutre at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 19 inclusion and 14 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 9 Aug 2018. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 16 Jul 2018). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Complete Remission (CR) (time frame: up to 10 weeks). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01550224.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 9 Aug 2018.