ABT-751 With Chemotherapy for Relapsed Pediatric ALL

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.

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.

Eligibility Criteria:
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.