Recurrent Pediatric ALL, Relapsed Pediatric ALL, Acute Lymphoblastic Leukemia, Refractory Pediatric ALL
Conditions
Keywords
Acute Lymphoblastic Leukemia, Pediatrics, Relapsed, Recurrence, ABT-751, Therapeutic Advances in Childhood Leukemia, Investigational, Childhood, ALL, Relapsed ALL, Refractory ALL, Relapsed pediatric ALL, Refractory pediatric ALL, TACL
Brief summary
This is a phase I/II study of an investigational drug called ABT-751, produced by Abbott Laboratories, given in combination with chemotherapy drugs used to treat acute lymphoblastic leukemia (ALL) that has come back (recurred). The phase I portion of this study is being done to find the highest dose of ABT-751 that can be given safely in combination with other chemotherapy drugs. A safe dose is one that does not result in unacceptable side effects. After a safe dose for ABT-751 given with chemotherapy has been found, the study will add additional patients to find out if ABT-751 (given at the maximal safe dose) when given with additional chemotherapy is an effective therapy for the treatment of children with relapsed ALL. It is expected that approximately 15-35 children and young adults will take part in this study.
Detailed description
All patients will receive the 2 courses of chemotherapy unless medical complications prevent the administration of some of the drugs. Treatment for the first 2 courses of therapy will last about 2 months. Treatment on this study will consist of a combination of 8 anti-cancer medications. The 8 anticancer medicines are ABT-751, dexamethasone, PEG-asparaginase, doxorubicin, cytarabine (Ara-C), methotrexate (MTX), cyclophosphamide, and 6-thioguanine. All the drugs except ABT-751 are well known anti-cancer drugs and have been used extensively in the treatment of cancer. During the Phase I portion of this study, when you enroll, you will be given an assigned dose of ABT-751. The dose of ABT-751 will be based on doses given in previous studies done with adults and children. At each dose level of ABT-751, between 3 and 6 children will receive ABT-751 in combination with chemotherapy. If the side effects are not too severe, the next group of children will receive a higher dose. The dose will continue to be increased until we find the dose that causes serious side effects. Your dose of ABT-751 will not be increased. If you have bad side effects, your dose may be decreased. The dose used during the Phase 2 part of this study will be determined by the outcome of the Phase I study. The highest dose used in Phase I that was tolerated without serious side effects will be the one used in Phase 2.
Interventions
DRUGABT-751
Treatment Course 1: Oral capsule to be given daily for 21 days at assigned dose. Treatment Course 2: ABT-751 will be taken once daily, by mouth, at the assigned dose on days 15-35. Treatment Course 3: ABT-751 will be taken once daily, by mouth, at the assigned dose on days 1-21 followed by 1 week of rest.
DRUGDexamethasone
In Treatment Course 1 only: * 10 mg/m2/day divided BID. * Take dexamethasone by mouth days 1-14.
DRUGPEG-asparaginase
In Treatment Course 1: * 2500 IU's/m2/day. * Intramuscular injection (IM) on days 4, 11 and 18. In Treatment Course 2: * 2500 IU's/m2/day. * Intramuscular injection (IM) on day 15.
DRUGDoxorubicin
In Treatment Course 1 only: • 60 mg/m2/day IV over 15 minutes on day 1.
DRUGCytarabine
* Given Intrathecally on day 1 of course 1 at the dose defined by age below. * 30 mg for patients age 1-1.99 * 50 mg for patients age 2-2.99 * 70 mg for patients \>3 years of age * Omit IT Ara-C on Day 1 if patient received IT therapy prior to study enrollment as part of diagnostic lumbar puncture procedure. In Treatment Course 2: • 75 mg/m2/day IV on days 2 through 5 and days 9 through 12.
DRUGMethotrexate
In Treatment Course 1: • Given Intrathecally on day 15 at the dose defined by age below. * 8 mg for patients age 1-1.99 * 10 mg for patients age 2-2.99 * 12 mg for patients 3-8.99 years of age * 15 mg for patients \>9 years of age In Treatment Course 2: • Given Intrathecally on day 1, 8, 15 and 22 at the dose defined by age below. * 8 mg for patients age 1-1.99 * 10 mg for patients age 2-2.99 * 12 mg for patients 3-8.99 years of age * 15 mg for patients \>9 years of age In Treatment Course 3: Intrathecally on day 1 at the age-defined dose
DRUGCyclophosphamide
Course 2 only: • 1000mg/m2/day IV over 30 minutes to be given on day 1.
DRUG6-thioguanine
Treatment Course 2 only: • 60 mg/m2/day to be given orally on days 1 through 14.
Sponsors
Abbott
Therapeutic Advances in Childhood Leukemia Consortium
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 21 Years
Healthy volunteers
No
Inclusion criteria
1. Age Patients must be \< 21 years of age when enrolled onto this study. T2005-001 Protocol version 6/27/2007 17 2. Diagnosis Patients must have relapsed or refractory ALL with a M3 marrow (marrow blasts \>25%) without clinical evidence of testicular disease or laboratory evidence of CNS disease defined as CSF WBC \> 5 cells/microliter and blasts. (See Appendix I for method of evaluating traumatic lumbar punctures.) Patients in early first relapse (defined as a patient who relapses less than 36 months from their initial remission \[CR1\]) are eligible for the phase I portion of the trial. 3. Performance Level Karnofsky \> 60% for patients \> 10 years of age and Lansky \> 60% for patients \< 10 years of age. 4. Prior Therapy Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study. 1. Prior anthracycline exposure: Patients must have less than 300mg/m2 lifetime exposure of anthracycline chemotherapy. (See Appendix III for calculation criteria) 2. Stem Cell Transplant (SCT): Patients are eligible 6 months after allogeneic stem cell transplant as long as patients are not actively being treated for graft-versus-host-disease (GvHD). 3. During the phase I portion of the trial, there is no limit on the number of prior treatment regimens. 4. During the phase II portion of the trial, patients must have had two or more prior therapeutic attempts defined as: * Persistent initial disease after two induction attempts, or * Relapse after one-reinduction attempt (2nd relapse), or * Persistent disease after first relapse and initial re-induction attempt (Patients in any first relapse are not eligible for the phase II portion of the study) 5. During the phase II portion of the trial, patients must have no more than 3 prior therapeutic attempts and it must be at least 6 months since the last treatment with a VPLD induction/re-induction regimen. 5. Reproductive Function 1. Female patients of childbearing potential must have a negative urine or serum pregnancy test confirmed prior to enrollment and within 48 hours of starting therapy. 2. Female patients with infants must agree not to breastfeed their infants while on this study. 3. Male and female patients of child-bearing potential must agree to use an effective method of contraception approved by the investigator during the study and for 3 months following completion of therapy.
Exclusion criteria
1. Drug Allergies Patients will be excluded if they have allergies to the following drugs: * Asparaginase products * Sulfa containing medications 2. Renal Function Patients will be excluded if their serum creatinine is \> the upper limit of normal (ULN) for age at the institution's laboratory. 3. Liver/Pancreatic Function 1. Direct bilirubin \> 1.5x the institutional ULN for age. A total bilirubin result that is less than 1.5 times the institutional ULN for age may be used for eligibility if a direct bilirubin result is not available. 2. SGPT (ALT) \> 4 x institutional ULN 3. Grade 3 or greater pancreatitis as defined by the CTCAE v3.0 4. Amylase or Lipase \> 2 x institutional ULN 4. Cardiac Function Patients will be excluded if their shortening fraction by echocardiogram is less than 30%. 5. Infection Patients will be excluded if they have an active, uncontrolled infection. 1. Patients with grade 2 or greater motor or sensory neuropathy per CTC 3.0 criteria. 2. Patients with grade 2 or greater Ileus (neuroconstipation) per CTC 3.0 criteria. 3. Patients currently being treated with coumadin. 4. Patients currently being treated with colchicines. 5. Patients planning on receiving other investigational agents while on this study. (An investigational agent is defined as any drug not currently approved for use in humans.) 6. Patients planning on receiving other anti-cancer therapies while on this study. 7. Patients who, in the opinion of the investigator, may not be able to comply with the safety monitoring requirements of the study. 8. Patients who, based on BSA and current dose level, require a daily dose of ABT-751 that is less than 25mg per day. 9. Patients who have started protocol therapy prior to enrollment. Patient may still enroll if IT Ara-C or IT MTX were given within 48 hours of study enrollment as part of the diagnostic lumbar procedure. These patients will not participate in the CSF PK portion of the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients That Experienced Dose Limiting Toxicity From ABT-751 | Each dose level is evaluated | ABT-751 was given daily for 21 days for a period of 28 day course in combination with dexamethasone, PEG-asparaginase, and doxorubicin. The occurrence of a dose limiting toxicity (DLT) was evaluated at the end of the 28 day course. DLT will be defined as any of the following events that are deemed by the investigator as probably or definitely attributable to ABT-751. Toxicity grade follows the CTCAE criteria, version 3.0. A copy of the CTCAE can be downloaded from the CTEP home page (http://ctep.cancer.gov). * Grade 3 or 4 Ileus * Grade 3 or 4 Constipation * Grade 3 or 4 Gastrointestinal obstruction, any location * Grade 3 or 4 Sensory Neuropathy * Grade 3 or 4 Motor Neuropathy * Grade 3 or 4 Neuropathic pain lasting longer than 24 hours despite medical intervention * Grade 3 or 4 Hypoxia in the absence of anemia or infection * Grade 4 Alanine aminotransferase (ALT) which does not return to |
| Number of Patients That Achieved Complete Response to ABT-751 | Day 29 of Course 1 | Complete response (CR) is the occurrence of all of the following on approximately Day 29: less than 5% leukemic blasts in the bone marrow aspirate with no evidence of leukemic blasts in the CSF or peripheral blood and recovery of peripheral blood counts of an Absolute neutrophil count (ANC) \> 750/μL and Platelet count \> 75,000 μL. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Occurrence of Toxic Death | From the first dose of study therapy until 30 days after last therapy dose. Last dose protocol therapy is on day 21. | The occurrence of toxic death at anytime that is definitely, probably or possibly related to the treatment. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Dose Level 1 Starting dose for study is 80 mg/m2/day of ABT-751 | 5 |
| Dose Level 0 De-escalation dose due to DLTs: 65 mg/m2/day of ABT-751 | 4 |
| Total | 9 |
Baseline characteristics
| Characteristic | Dose Level 1 | Dose Level 0 | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 4 Participants | 3 Participants | 7 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants | 1 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 2 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 2 Participants | 1 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 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 | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 4 Participants | 3 Participants | 7 Participants |
| Sex: Female, Male Female | 2 Participants | 2 Participants | 4 Participants |
| Sex: Female, Male Male | 3 Participants | 2 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 4 / 5 | 0 / 4 |
| other Total, other adverse events | 5 / 5 | 4 / 4 |
| serious Total, serious adverse events | 5 / 5 | 4 / 4 |
Outcome results
Primary
Number of Patients That Achieved Complete Response to ABT-751
Complete response (CR) is the occurrence of all of the following on approximately Day 29: less than 5% leukemic blasts in the bone marrow aspirate with no evidence of leukemic blasts in the CSF or peripheral blood and recovery of peripheral blood counts of an Absolute neutrophil count (ANC) \> 750/μL and Platelet count \> 75,000 μL.
Time frame: Day 29 of Course 1
Population: Number of patients that completed at least 1 course of treatment and was evaluable for response assessment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Dose Level 1 | Number of Patients That Achieved Complete Response to ABT-751 | # of patients not achieving complete response | 4 Participants |
| Dose Level 1 | Number of Patients That Achieved Complete Response to ABT-751 | # of patients who achieved complete response | 1 Participants |
| Dose Level 0 | Number of Patients That Achieved Complete Response to ABT-751 | # of patients not achieving complete response | 1 Participants |
| Dose Level 0 | Number of Patients That Achieved Complete Response to ABT-751 | # of patients who achieved complete response | 3 Participants |
Primary
Number of Patients That Experienced Dose Limiting Toxicity From ABT-751
ABT-751 was given daily for 21 days for a period of 28 day course in combination with dexamethasone, PEG-asparaginase, and doxorubicin. The occurrence of a dose limiting toxicity (DLT) was evaluated at the end of the 28 day course. DLT will be defined as any of the following events that are deemed by the investigator as probably or definitely attributable to ABT-751. Toxicity grade follows the CTCAE criteria, version 3.0. A copy of the CTCAE can be downloaded from the CTEP home page (http://ctep.cancer.gov). * Grade 3 or 4 Ileus * Grade 3 or 4 Constipation * Grade 3 or 4 Gastrointestinal obstruction, any location * Grade 3 or 4 Sensory Neuropathy * Grade 3 or 4 Motor Neuropathy * Grade 3 or 4 Neuropathic pain lasting longer than 24 hours despite medical intervention * Grade 3 or 4 Hypoxia in the absence of anemia or infection * Grade 4 Alanine aminotransferase (ALT) which does not return to
Time frame: Each dose level is evaluated
Population: Number of participants that completed at least 1 course of treatment and are evaluable for toxicities.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Dose Level 1 | Number of Patients That Experienced Dose Limiting Toxicity From ABT-751 | # of patients with DLT | 2 Participants |
| Dose Level 1 | Number of Patients That Experienced Dose Limiting Toxicity From ABT-751 | # of patients without DLT | 3 Participants |
| Dose Level 0 | Number of Patients That Experienced Dose Limiting Toxicity From ABT-751 | # of patients with DLT | 0 Participants |
| Dose Level 0 | Number of Patients That Experienced Dose Limiting Toxicity From ABT-751 | # of patients without DLT | 4 Participants |
Secondary
Number of Patients With Occurrence of Toxic Death
The occurrence of toxic death at anytime that is definitely, probably or possibly related to the treatment.
Time frame: From the first dose of study therapy until 30 days after last therapy dose. Last dose protocol therapy is on day 21.
Population: Number of patients that completed at least 1 course of treatment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Dose Level 1 | Number of Patients With Occurrence of Toxic Death | # of patients that experienced toxic death | 0 Participants |
| Dose Level 1 | Number of Patients With Occurrence of Toxic Death | # of patients that did not experience toxic death | 5 Participants |
| Dose Level 0 | Number of Patients With Occurrence of Toxic Death | # of patients that experienced toxic death | 0 Participants |
| Dose Level 0 | Number of Patients With Occurrence of Toxic Death | # of patients that did not experience toxic death | 4 Participants |