Principal Investigator: Phillip Barnette
Keywords: Pediatrics , Oncology , Acute Myeloid Leukemia , AML Department: Pediatric Administration
IRB Number: 00050937
Specialty: Oncology
Sub Specialties:
Recruitment Status: Recruiting

Contact Information

Jennifer Craig

Brief Summary

Primary Objectives

1.To compare event free survival (EFS) and overall survival (OS) in patients with de novo acute myeloid leukemia (AML) without high allelic ratio FLT3/ITD+ mutations who are randomized to standard therapy versus bortezomib/standard combination therapy.

2. To determine the feasibility of combining bortezomib with standard chemotherapy in patients with de novo AML.

3. To compare the OS and EFS of high risk patients treated with intensive Induction II with historical controls from AAML03P1 and AAML0531.

4. To determine the feasibility of administering sorafenib with standard chemotherapy and in a one year maintenance phase in patients with de novo high allelic ratio FLT3/ITD+ AML.

Secondary Objectives

1.To assess the anti-leukemic activity of sorafenib in patients with de novo high allelic ratio FLT3/ITD+ AML.

2. To compare the percentage of patients converting from positive MRD to negative MRD after Intensive Induction II with historical controls from AAML03P1 and AAML0531.

3. To compare OS, disease free survival (DFS), cumulative incidence of relapse, and treatment related mortality from end of Intensification I between patients allocated to best allogenic donor stem cell transplant (SCT) and comparable patients on AAML0531 who did not receive allogenic donor SCT.

4. To compare OS, DFS, cumulative incidence of relapse, treatment related mortality, and severe toxicity between patients allocated to matched family donor SCT on AAML1031 and AAML0531.

5. To assess the health-related quality of life (HRQOL) of patients treated with chemotherapy and stem cell transplant (SCT) for AML.

6. To evaluate bortezomib pharmacokinetics (PK) in patients receiving the combination regimen.

7. To obtain sorafenib and metabolite steady state pharmacokinetics and pharmacokinetic-pharmacodynamic data in subjects with FLT3/ITD receiving sorafenib.

8. To compare the changes in shortening fraction/ejection fraction over time between patients treated with and without dexrazoxane.

9. To refine the use of minimal residual disease (MRD) detection with 4-color flow cytometry.

10. To evaluate the prognostic significance of molecular MRD and its contribution to risk identification with MDF-based MRD in patients with translocations amenable to quantitative RT-PCR (e.g., t(8;21), inv(16), t(9;11), WT1 expression).

11. To determine the leukemic involvement of the hematopoietic early progenitor cell and its role in defining response to therapy.

12. To define the leukemic stem cell population in patients with AML.

13. To determine the prevalence and prognostic significance of molecular abnormalities of WT1, RUNX1, MLL-PTD, TET2, c-CBL, KIT and other novel AML associated genes in pediatric AML.

14. Correlate the expression of CD74 antigen as well as PSMB5 gene expression and mutation with response to bortezomib.

15. To evaluate the changes in protein expression and unfolded protein response (UPR) in patients with AML.

16. Determine the expression level of wild type FLT3, and correlate with outcome and in vitro sensitivity to FLT3 inhibition.

17. To collect biology specimens at diagnosis, treatment time points, and relapse for future biology studies.

18.  To create a pediatric-specific algorithm to predict the occurrence of Grade 2-4 acute graft-versus-host disease (GVHD) prior to its clinical manifestations using a combination of pre-transplant clinical variables and serum GVHD biomarker concentrations in the first weeks after SCT.



Detailed Description

Disease recurrence and treatment related toxicities still account for approximately 40% of deaths in pediatric patients with de novo Acute Myeloid Leukemia (AML) despite substantial progress made with various treatment modalities. Thus, the incorporation of new approaches to standard AML therapy that will further improve the overall outcome of patients with de novo AML by testing clinically relevant hypotheses that enhance better understanding of AML blast biology, more accurate patient risk stratification, and more effective supportive care practices is a high priority. Bortezomib, a proteasome inhibitor has been shown to selectively deplete the leukemic stem cells that are a source of resistance for AML. Despite limited pediatric data, adult and in vitro studies demonstrate that bortezomib can be safely combined with standard AML chemotherapy (without high dose cytarabine arabinoside), augmenting their anti-leukemic effects. Fms-like tyrosine kinase 3 (FLT3) which is an AML oncogene that plays a significant role in AML pathogenesis is a target of the multi-target tyrosine kinase inhibitor, sorafenib. Sorafenib has shown encouraging results with its use as a single agent in adults with relapsed FLT3 positive internal tandem duplication (FLT3/ITD+) AML. Despite limited pediatric experience of sorafenib in combination with AML chemotherapy, it has been safely combined with AML chemotherapy in younger adults with AML. This clinical trial seeks to determine the role of bortezomib in upfront therapy for pediatric AML, and to determine the safety of sorafenib in the treatment of patients with high allelic ratio FLT3/ITD+ (HR FLT3/ITD+) AML. AAML1031 will utilize a 4 course chemotherapy backbone. Patients with low risk disease will receive cytarabine/daunorubicin/etoposide (ADE 10+3+5), cytarabine/daunorubicin/etoposide (ADE 8+3+5), cytarabine/etoposide (AE), and cytarabine/mitoxantrone (ARAC/Mitox). Patients with high risk disease will receive 3 courses of chemotherapy: cytarabine/daunorubicin/etoposide (ADE 10+3+5), cytarabine/mitoxantrone (ARAC/Mitox), and cytarabine/etoposide (AE), prior to best allogenic donor stem cell transplant (SCT). High risk patients without an appropriate allogenic donor will receive high dose cytarabine/L-asparaginase (HD ARAC/LASP) as a fourth chemotherapy course. Patients with HR FLT3/ITD+ will receive 3 courses of chemotherapy, cytarabine/daunorubicin/etoposide (ADE 10+3+5), cytarabine/daunorubicin/etoposide (ADE 8+3+5), cytarabine/etoposide (AE) in combination with sorafenib, followed by best allogenic donor SCT. Patients with HR FLT3/ITD+ who do not have an appropriate allogenic donor will receive sorafenib with ARAC/Mitox as a fourth course of chemotherapy. Bortezomib evaluation will involve random allocation to treatment with standard pediatric AML therapy only (Arm A), or standard AML therapy with bortezomib (Arm B). Sorafenib evaluation will occur in 2 Parts. Part 1 will determine a tolerable dose of sorafenib in combination with standard AML chemotherapy in an initial group of patients with HR FLT3/ITD+ mutations (Cohort 1-Arm C). Once sorafenib dose determination is concluded, patients with HR FLT3/ITD+ will be allocated to sorafenib plus standard chemotherapy for additional feasibility and efficacy determination (Cohort 2-Arm C). Risk stratification of patients in AAML1031 will utilize cytogenetics, molecular markers and multidimensional flow cytometry to allocate patients into high risk (HR) and low risk (LR) groups. This study will assess health related quality of life (HRQOL) and parental stress at multiple time points during and after therapy, for longitudinal assessment of QOL and parental stress. AAML1031 will also incorporate correlative studies aimed at contributing to the enhancement of future AML treatment parameters and assessment. These correlative studies include evaluation of the in vitro levels of wild type FLT3 in response to sorafenib, analyzing chromosomal abnormalities, complex karyotypes; molecular abnormalities of WT1, RUNX1, MLL- PTD and other novel AML associated genes, and leukemic involvement of early progenitor cells.

Inclusion Criteria

Age: Patients must be less than 30 years of age at the time of study enrollment.

Diagnosis: Patients must be newly diagnosed with de novo acute myelogenous leukemia.

Patients with previously untreated primary AML who meet the customary criteria for AML with ≥ 20% bone marrow blasts as set out in the 2008 WHO Myeloid Neoplasm Classification are eligible.

Attempts to obtain bone marrow either by aspirate or biopsy must be made unless clinically prohibitive. In cases where it is clinically prohibitive, peripheral blood with an excess of 20% blasts and in which adequate flow cytometric and cytogenetics/FISH testing is feasible can be substituted for the marrow exam at diagnosis.

Patients with < 20% bone marrow blasts are eligible if they have:

A karyotypic abnormality characteristic of de novo AML (t(8;21)(q22;q22), inv(16)(p13q22) or t(16;16)(p13;q22) or 11q23 abnormalities),

The unequivocal presence of megakaryoblasts, or

Biopsy proven isolated myeloid sarcoma (myeloblastoma; chloroma, including leukemia cutis).

Patients with any performance status are eligible for enrollment.

Prior therapy with hydroxyurea, all-trans retinoic acid (ATRA), corticosteroids (any route), and IT cytarabine given at diagnosis is allowed. Hydroxyurea and ATRA must be discontinued prior to initiation of protocol therapy. Patients who have previously received any other chemotherapy, radiation therapy or any other
antileukemic therapy are not eligible for this protocol.


Exclusion Criteria

1) Excluded Constitutional Conditions:

Patients with any of the following constitutional conditions are not eligible:

a. Fanconi anemia

b.  Shwachman syndrome

c.  any other known bone marrow failure syndrome

d.  patients with constitutional trisomy 21 or with constitutional mosaicism of trisomy 21

Note:  enrollment may occur pending results of clinically indicated studies to exclude these conditions.

2)  Other excluded conditions

Patients with any of the following oncologic diagnoses are not eligible:

a.  Any concurrent malignancy

b.  Juvenile myelomonocytic leukemia (JMML)

c.  Philadelphia chromosome positive AML

d.  Biphenotypic or bilineal acute leukemia

e.  Acute promyelocytic leukemia

f.  Acute myeloid leukemia arising from myelodysplasia

g.  Therapy-related myeloid neoplasms

Note:  Enrollment may occur pending results of clinically indicated studies to exclude these conditions.

3) Pregnancy and Breast Feeding: Female patients who are pregnant are ineligible since fetal toxicities and teratogenic effects have been noted for several of the study drugs. Lactating females are not eligible unless they have agreed not to breastfeed their infants. Female patients of childbearing potential are not eligible unless a negative pregnancy test result has been obtained. Sexually active patients of reproductive potential are not eligible unless they have agreed to use an effective contraceptive method for the duration of their study participation.