T2009-003, A Pilot Study of Decitabine and Vorinostat with Chemotherapy for Relapsed ALL

Summary

This is a pilot study whose primary objectives are to characterize the toxicities and explore the pharmacodynamic effects of decitabine and vorinostat (SaHa) when used in combination prior to and concurrently with chemotherapy in aLL patients who are refractory to primary treatment or who are in 2nd or greater relapse. The secondary objective is to obtain preliminary data on classical and MRD response rate with this treatment, and in this sense this study could be viewed as the first stage of a two-stage Phase ii design. 16 patients will be enrolled. it is anticipated that enrollment will take 2.5 years.

Based on the encouraging results from the aLLR3 trial, the chemotherapy agents to be used in this study will include a four drug combination of vincristine, dexamethasone, mitoxantrone and PeG asparaginase along with CnS therapy of intrathecal methotrexate.

only 1 course of treatment will be permitted. Treatment on this study consists of approximately 5 weeks of re-induction chemotherapy. The subject will receive decitabine and vorinostat for two 5 day pulses during this trial. Decitabine will be given by through the vein on days 1-5 and days 15-19. Vorinostat will be given by mouth on days 2-7 and days 16-21. This schedule is believed to allow for the greatest effect of decitabine and vorinostat on the leukemia cells. The other standard chemotherapy will start on day 8 and continue until day 35.

Primary endpoints
* Dose-limiting toxicity (DLT), as defined in section 4.3.
* Toxicity, graded using the nCi's Common Terminology Criteria for adverse events (CTCae 4.0).

Secondary endpoints
* achievement of a complete clinical response (CR) (i.e., [Less Than]5% blasts in the bone marrow on day 35 with recovery of both anC and platelets).
* achievement of MRD response (i.e., [Less Than]10-5 blasts via MRD assay on day 35 with recovery of both anC and platelets.)
* Change in global and gene-specific promoter Dna methylation in bone marrow samples taken pretreatment (day 1) and post-treatment with decitabine/vorinostat (day 8).
* Change in global and gene-specific histone acetylation in these same bone marrow samples.
* Change in expression of epigenetically modified genes in the same bone marrow samples.
* Change in chemosensitivity to standard chemotherapy agents of leukemic blasts obtained pre-treatment (day 1) and post-treatment with decitabine/vorinostat (day 8), as reflected by the pre-post difference in iC50 values for each chemotherapy agent.

Participant Eligibility


* Age- Patients must be >=1 and <= 21 years of age when originally diagnosed with ALL.

* Diagnosis- a. Patients must have a diagnosis of acute lymphoblastic leukemia (ALL) with >= 25% blasts in the bone marrow (M3), with or without extramedullary disease. b. Patients may have CNS 1, 2 or 3 disease.

* Performance Level- Karnofsky > 50% for patients > 16 years of age and Lansky > 50% for patients <= 16 years of age. (See Appendix I for Performance Scales)

* Prior Therapy- Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study.

* Renal and Hepatic Function- a. Patient[Single Quote]s serum creatinine must be <= 1.5 x institutional upper limit of normal (ULN) according to age.

* Cardiac Function- Patient must have a shortening fraction >= 27% by Echo or an ejection fraction >= 50% by MUGA.

* Reproductive Function-
a. Female patients of childbearing potential must have a negative urine or serum pregnancy test confirmed prior to enrollment.
b. Female patients with infants must agree not to breastfeed their infants while on this study.
c. Male and female patients of child-bearing potential must agree to use an effective method of contraception approved by the investigator during the study.
d. Patient will receive antifungal prophylaxis with either an echinocandin (e.g. caspofungin or micafungin) or amphotericin class.