Acute Lymphoblastic Leukemia
Conditions
Brief summary
Both of bortezomib and vorinostat have identified Phase II doses for pediatric and adult patients of which no grade 4 dose limiting toxicities have been observed in prior studies. The pre-clinical synergy of these 2 agents when used in combination along with the lack of over-riding toxicities and different mechanisms of action provide strong rationale for a clinical trial investigating bortezomib and vorinostat in combination. This trial will use the identified Phase II dose which is at or below the maximum tolerated dose for both agents which have very acceptable toxicity profiles and such should prove feasible and tolerable in this relapsed/refractory ALL population.
Detailed description
This is a phase II study of bortezomib 1.3 mg/m\^2 by intravenous pyelogram (IVP) on days 1, 4, 8, and 11, vorinostat 180 mg/m\^2 by mouth (PO) per day (not to exceed 400 mg per day) days 1-14, and dexamethasone 6 mg/m\^2 PO days 4-15 for the treatment of relapsed/refractory acute lymphoblastic leukemia (ALL). No more than 3 treatment courses may be given.
Interventions
DRUGBortezomib
1.3 mg/m\^2 by intravenous pyelogram (IVP) over 3-5 seconds on days 1, 4, 8 and 11.
DRUGVorinostat
180 mg/m\^2 (max dose 400mg) by mouth (PO) divided twice a day (BID) on days 1-14
DRUGDexamethasone
6 mg/m\^2 by mouth (PO) divided twice a day (BID) on days 4-15.
DRUGMethotrexate
Intrathecal Methotrexate at age based dose on day 1 (repeat on day 15 or 16 for CNS positive patients only)
DRUGImatinib mesylate
For Ph+ acute lymphoblastic leukemia (ALL) patients only: Imatinib Mesylate is allowable at 340 mg/m2 PO once a day (rounded to the nearest 100 mg) for age ≤18 years and 400 mg for \>18 years on Days 1-16.
Sponsors
Millennium Pharmaceuticals, Inc.
Masonic Cancer Center, University of Minnesota
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
2 Years to 30 Years
Healthy volunteers
No
Inclusion criteria
* Diagnosis of lymphoblastic lymphoma or acute lymphoblastic leukemia (ALL) with ≥ 5% blasts in the bone marrow (M2/M3) with or without extramedullary disease that meets one of the following criteria: * Refractory Disease/Induction Failure: Failure to achieve initial remission after 2 attempts of standard induction therapy * Relapsed Disease: Patients in relapse #1 or higher for whom standard curative therapies or therapies to prolong survival do not exist. Patients who are Philadelphia chromosome-positive (Ph + ALL) are eligible provided they are not imatinib resistant or intolerant. Patients with CNS positive disease will be eligible. * Age 2 to 30 years * Karnofsky ≥ 50% for patients 16 years and older and Lansky status ≥ 50 for patients under 16 years of age. * Patients must have a life expectancy ≥ 8 weeks as determined by the enrolling investigator. * Have acceptable organ function as defined within 7 days of starting treatment: * Renal: creatinine clearance ≥ 70ml/min/1.73m\^2 or serum creatinine based on age/gender as follows: Maximum serum creatinine (mg/dl) 0.8 for 2 years to \<6 years; 1.0 for 6 years to \<10 years; 1.2 for 10 years to \<13 years; 1.5 male and 1.4 female for 13 years to \<16 years; 1.7 male and 1.4 female for ≥ 16 years * Hepatic: ALT \< 5 x upper limit of normal (ULN) and total bilirubin ≤ 1.5x upper limit of normal (ULN) for age. * Cardiac: left ventricular ejection fraction ≥ 40% by echocardiogram/multi gated acquisition scan (ECHO/MUGA). Normal QTc on electrocardiogram (EKG) (not to exceed upper limit of normal - men: 430 milliseconds (ms); women: 450 ms; children up to 15 years: 440 ms). * Prior Therapy: * Patients must have recovered from the non-hematologic toxic effects of all prior therapy before entry onto this trial. Recovery is defined as a Common Toxicity Criteria for Adverse Events (CTCAE) version 4.0 toxicity grade \<2, unless otherwise specified in the Inclusion and
Exclusion criteria
. Cytotoxic therapy: Patients must have had their last dose of chemotherapy at least two weeks prior to study entry. * Hematopoietic growth factors: At least 7 days since the completion of therapy with a growth factor and at least 14 days since pegfilgrastim (Neulasta®) administration. * Biologic (anti-neoplastic) therapy: At least 7 days since the completion of therapy with a biologic agent. For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur. The duration of this interval must be discussed with the study chair. * Monoclonal antibodies: At least 3 half-lives of the antibody after the last administration of a monoclonal antibody. * Hematopoietic Stem Cell Transplant (HSCT): Patients who have experienced their relapse after a HSCT are eligible, provided they have no evidence of Graft-versus-Host Disease (GVHD). * Women of child bearing potential must agree to use adequate contraception (diaphragm, birth control pills, injections, intrauterine device \[IUD\], surgical sterilization, subcutaneous implants, or abstinence, etc.) for the duration of treatment and for 2 months after the last dose of chemotherapy. Sexually active men must agree to use barrier contraceptive for the duration of treatment and for 2 months after the last dose of chemotherapy. * Voluntary written consent before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject/guardian at any time without prejudice to future medical care.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects Who Achieved Complete Remission of Their Disease | Day 30 | Complete Remission (CR): A CR requires that the following be recorded concurrently: an absolute neutrophil count (segs and bands) \> 1000/μL, no circulating blasts, platelets \> 100,000/μL; adequate bone marrow cellularity with trilineage hematopoiesis, and \< 5% marrow leukemia blast cells. All previous extramedullary manifestations of disease must be absent. If patients continue on with treatment, there can be no evidence of recurrence of ALL for at least 4 weeks. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects Experiencing Drug Related Adverse Events | Day 1 of Treatment to 30 Days Post Treatment | To characterize the toxicities of bortezomib, vorinostat and dexamethasone when used in combination. Toxicity will be graded using the NCI's Common Terminology Criteria for Adverse Events (CTCAE 4.0). |
| Number of Subjects With Activated Caspases and Other Regulators of Apoptosis | From Day 1 to 30 Days After Last Dose | Activation of caspases and other regulators of apoptosis in treated blast cells will be determined by Western analysis (correlative lab analysis). |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Chemotherapy bortezomib, vorinostat and dexamethasone combination, as well as intrathecal methotrexate and imatinib mesylate.
Bortezomib: 1.3 mg/m\^2 by intravenous pyelogram (IVP) over 3-5 seconds on days 1, 4, 8 and 11.
Vorinostat: 180 mg/m\^2 (max dose 400mg) by mouth (PO) divided twice a day (BID) on days 1-14
Dexamethasone: 6 mg/m\^2 by mouth (PO) divided twice a day (BID) on days 4-15.
Methotrexate: Intrathecal Methotrexate at age based dose on day 1 (repeat on day 15 or 16 for CNS positive patients only)
Imatinib mesylate: For Ph+ acute lymphoblastic leukemia (ALL) patients only:
Imatinib Mesylate is allowable at 340 mg/m2 PO once a day (rounded to the nearest 100 mg) for age ≤18 years and 400 mg for \>18 years on Days 1-16. | 2 |
| Total | 2 |
Baseline characteristics
| Characteristic | Chemotherapy |
|---|---|
| Age, Categorical <=18 years | 2 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants |
| Region of Enrollment United States | 2 participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 2 / 2 |
| serious Total, serious adverse events | 1 / 2 |
Outcome results
Primary
Number of Subjects Who Achieved Complete Remission of Their Disease
Complete Remission (CR): A CR requires that the following be recorded concurrently: an absolute neutrophil count (segs and bands) \> 1000/μL, no circulating blasts, platelets \> 100,000/μL; adequate bone marrow cellularity with trilineage hematopoiesis, and \< 5% marrow leukemia blast cells. All previous extramedullary manifestations of disease must be absent. If patients continue on with treatment, there can be no evidence of recurrence of ALL for at least 4 weeks.
Time frame: Day 30
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ALL Treated Patients | Number of Subjects Who Achieved Complete Remission of Their Disease | 0 participants |
Secondary
Number of Subjects Experiencing Drug Related Adverse Events
To characterize the toxicities of bortezomib, vorinostat and dexamethasone when used in combination. Toxicity will be graded using the NCI's Common Terminology Criteria for Adverse Events (CTCAE 4.0).
Time frame: Day 1 of Treatment to 30 Days Post Treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ALL Treated Patients | Number of Subjects Experiencing Drug Related Adverse Events | 1 participants |
Secondary
Number of Subjects With Activated Caspases and Other Regulators of Apoptosis
Activation of caspases and other regulators of apoptosis in treated blast cells will be determined by Western analysis (correlative lab analysis).
Time frame: From Day 1 to 30 Days After Last Dose
Population: The trial was terminated early with only 2 patients so caspase samples were not sent for analysis.