Acute Myeloid Leukemia
Conditions
Brief summary
This research is being done because treatment options are very limited and usually unsuccessful for Acute Myeloid Leukemia (AML) in older individuals, or younger people with disease that has relapsed and/or proven resistant to standard therapy. Subjects are invited to participate in this study that will examine the use of three drugs called Sorafenib (Nexavar), Vorinostat (Zolinza) and Bortezomib (Velcade) for treating acute myeloid leukemia.
Interventions
DRUGsorafenib, vorinostat and bortezomib
Escalating dose cohorts of sorafenib, vorinostat and bortezomib. The first cohort will receive sorafenib from day 1 to 14, vorinostat will be given on days 1-4 and 8-12, and bortezomib will be given on days 1 and 8. This will be followed by 7 days of rest. Therefore each cycle will be 21 days.
Sponsors
Millennium Pharmaceuticals, Inc.
Bayer
Merck Sharp & Dohme LLC
Hamid Sayar
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* A confirmed baseline diagnosis of AML by the revised guidelines of the International Working Group for AML including newly diagnosed, relapsed or refractory disease. * Poor-risk or complex cytogenetics profile, or deletion of chromosome 5, or deletion of chromosome 7, or positive FLT3-ITD mutation. * The patient must have discontinued all previous therapies for acute leukemia for at least 14 days and recovered from the acute non-hematologic side effects of the therapy. * Hydroxyurea to control peripheral blood blast count must be discontinued within 24 hours prior to the initiation of treatment. * Patients must have an ECOG (Zubrod) performance status of 0-2 * Patients must have adequate hepatic and renal function according to the protocol within one week prior to treatment. * Female patients must be postmenopausal, surgically sterile or agree to use effective methods of contraception throughout the study. * Male patients, even if surgically sterilized, must agree to practice effective contraception throughout the study. * Patients must be able to swallow and tolerate oral medications.
Exclusion criteria
* Known central nervous system (CNS) leukemia. * Diagnosis of acute promyelocytic leukemia (APL). * Grade \>/= 2 peripheral neuropathy. * Serious illness including, significant ongoing or active infection, New York Heart Association (NYHA) Grade III or IV congestive heart failure, unstable angina or new onset angina or myocardial infarction within the past 6 months, cardiac ventricular arrhythmias requiring anti-arrhythmic therapy, thrombotic or embolic events such as a cerebrovascular accident including transient ischemic attacks within past 3 months. Serious medical or psychiatric illness/social situations that in the opinion of the investigator would limit compliance with study requirements. * Diagnosed or treated for another malignancy within 3 years of enrollment, with the exception of complete resection of basal cell carcinoma or squamous cell carcinoma of the skin, an in situ malignancy, or low-risk prostate cancer after curative therapy. * Active corneal erosions or history of abnormal corneal sensitivity test. * Known or suspected history of severe hypersensitivity reaction to tyrosine kinase inhibitors, histone deacetylase inhibitors, proteosome inhibitors, boron, or mannitol. * Female patients who are lactating or have a positive serum pregnancy test within 72 hours of initiation of treatment, or a positive urine pregnancy test on Day 1 before first dose of study drug. * Concurrent use of other histone deacetylase inhibitors (e.g. valproic acid) are prohibited except for HDAC inhibitors or HDAC-inhibitor like agents used for non-cancer treatment (e.g. epilepsy), where a 14 day washout is allowed. * Radiation therapy within 3 weeks before randomization. * Patients with known HIV, or known active hepatitis B or C infections.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Dose Limiting Toxicity | up to 9 months | The number of patients who had a DLT during the dose finding/confirming portion (Phase I) of the trial for the safety of the combination of sorafenib, vorinostat, and bortezomib. |
| Phase II - Percentage of Patients With a Partial Response or Greater | up to 9 months | Evaluate the overall response rate of patients receiving therapy. Patients are considered as having a response if their overall response is Partial Response or better. The percentage of patients achieving this and the exact 95% confidence interval will be calculated. Responses will be defined using the response criteria determined by the International Working Group for AML. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase II - Time to Relapse | Up to one year | Will be examined using Kaplan-Meier estimates. Time from date of confirmed complete remission to date of relapse. The observations of patients who died or remained alive and relapse free were censored at date of death or last disease evaluation, respectively. |
| Phase II - Treatment-Related Adverse Events Grade 3 or Higher | Up to one year | Number of unique patients who had a treatment-related (possible, probable or definite) adverse events that were graded 3 or higher. |
Countries
United States
Participant flow
Recruitment details
This protocol was based on enrolling up to 44 patients with 2 to 30 patients in phase I and 14 patients in phase II. The study enrolled 37 patients with 17 in phase I and 20 in phase II.
Participants by arm
| Arm | Count |
|---|---|
| Phase I Dose Escalating escalating dose cohorts of sorafenib, vorinostat and bortezomib. All cohorts will receive sorafenib from day 1 to 14 and vorinostat from day 1 to 4 and day 8 to 12. Bortezomib will be given on days 1 and 8 for all cohorts, with cohorts 4 and 5 also receiving bortezomib on days 4 and 11 for cycles 1 through 4. This will be followed by 7 days of rest. Therefore each cycle will be 21 days. | 17 |
| Phase II at MTD patients received sorafenib at 400 mg bid from day 1 to 14 and vorinostat 200 mg bid from day 1 to 14. Bortezomib will be given at 1.3 mg/m2 on days 1, 4, 8 and 11 for cycles 1-4, and then on days 1 and 8 for cycle 5 and beyond. Bortezomib will be given on days 1 and 8 beyond 4 cycles to reduce the risk of neurotoxicity. | 20 |
| Total | 37 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 8 |
| Overall Study | Death | 2 | 0 |
| Overall Study | Disease Progression | 8 | 6 |
| Overall Study | Lack of Efficacy | 1 | 1 |
| Overall Study | No treatment, per protocol | 0 | 1 |
| Overall Study | Physician Decision | 3 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 3 |
Baseline characteristics
| Characteristic | Phase I Dose Escalating | Phase II at MTD | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 3 Participants | 8 Participants | 11 Participants |
| Age, Categorical Between 18 and 65 years | 14 Participants | 12 Participants | 26 Participants |
| Age, Continuous | 51.6 years STANDARD_DEVIATION 14.2 | 58.2 years STANDARD_DEVIATION 14.8 | 55.2 years STANDARD_DEVIATION 14.7 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 17 Participants | 18 Participants | 35 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 14 Participants | 19 Participants | 33 Participants |
| Sex: Female, Male Female | 7 Participants | 10 Participants | 17 Participants |
| Sex: Female, Male Male | 10 Participants | 10 Participants | 20 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 16 / 17 | 18 / 20 |
| serious Total, serious adverse events | 7 / 17 | 11 / 20 |
Outcome results
Primary
Number of Patients With Dose Limiting Toxicity
The number of patients who had a DLT during the dose finding/confirming portion (Phase I) of the trial for the safety of the combination of sorafenib, vorinostat, and bortezomib.
Time frame: up to 9 months
Population: All Phase I patients receiving at least one dose of study drug and having at least one evaluable post-baseline visit
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase I Dose Escalating | Number of Patients With Dose Limiting Toxicity | 0 Participants |
Primary
Phase II - Percentage of Patients With a Partial Response or Greater
Evaluate the overall response rate of patients receiving therapy. Patients are considered as having a response if their overall response is Partial Response or better. The percentage of patients achieving this and the exact 95% confidence interval will be calculated. Responses will be defined using the response criteria determined by the International Working Group for AML.
Time frame: up to 9 months
Population: All Phase II patients who received at least one dose of study drug and had at least one evaluable post-baseline visit
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I Dose Escalating | Phase II - Percentage of Patients With a Partial Response or Greater | 40.0 percentage of participants |
Secondary
Phase II - Time to Relapse
Will be examined using Kaplan-Meier estimates. Time from date of confirmed complete remission to date of relapse. The observations of patients who died or remained alive and relapse free were censored at date of death or last disease evaluation, respectively.
Time frame: Up to one year
Population: All Phase II patients who received at least one dose of study drug, had at least one evaluable post-baseline visit, and achieved complete remission
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase I Dose Escalating | Phase II - Time to Relapse | 32 days |
Secondary
Phase II - Treatment-Related Adverse Events Grade 3 or Higher
Number of unique patients who had a treatment-related (possible, probable or definite) adverse events that were graded 3 or higher.
Time frame: Up to one year
Population: All Phase II patients who received treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase I Dose Escalating | Phase II - Treatment-Related Adverse Events Grade 3 or Higher | 4 Participants |