Bortezomib and Combination Chemotherapy in Treating Younger Patients With Recurrent, Refractory, or Secondary Acute Myeloid Leukemia

Study Overview
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Brief Summary
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This phase II trial is studying the side effects and best dose of bortezomib and to see how well it works when given together with combination chemotherapy in treating younger patients with recurrent, refractory, or secondary acute myeloid leukemia (AML). Bortezomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as idarubicin, cytarabine, and etoposide, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) together with bortezomib may kill more cancer cells

Detailed Description
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PRIMARY OBJECTIVES: I. To determine the toxicities and tolerability of bortezomib in combination with standard-relapse AML therapy (idarubicin/cytarabine or etoposide/high-dose cytarabine) in pediatric and young adult patients with relapsed or primary-refractory or secondary AML. II. To estimate the complete response rate to the Arm A and Arm B regimens. SECONDARY OBJECTIVES: I. To determine whether bortezomib inhibits proteasome activity, NF-kB activity and induces apoptosis pathway proteins in leukemia myeloblasts. II. To determine the feasibility of measuring AML stem cells in relapsed and recovering bone marrow. OUTLINE: This is a multicenter, dose-escalation study of bortezomib. Patients are stratified according to anthracycline*-equivalent cumulative exposure (≤ 400 mg/m² vs > 400 mg/m²). Patients are assigned to 1 of 2 groups. GROUP I (efficacy phase, patients with ≤ 400 mg/m² anthracycline-equivalent cumulative exposure - Closed as of 08/01/10): Patients receive idarubicin IV over 15 minutes on days 1-3, low-dose cytarabine IV continuously over days 1-7, and bortezomib IV on days 1, 4, and 8. GROUP II (dose-finding phase (closed as of 10/10) and efficacy phase, patients with > 400 mg/m² anthracycline*-equivalent cumulative exposure): Patients receive etoposide IV over 1 hour on days 1-5, high-dose cytarabine IV over 1 hour twice daily on days 1-5, and bortezomib IV on days 1, 4, and 8. NOTE: * Anthracycline restriction no longer required for group 2 as of 10/02/10. All patients receive intrathecal cytarabine prior to courses 1 and 2. In both arms, treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity. After completion of study therapy, patients are followed periodically for at least 5 years.

Official Title
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A Phase II Pilot Study of Bortezomib (PS-341, Velcade) Combined With Reinduction Chemotherapy in Children and Young Adults With Recurrent, Refractory or Secondary Acute Myeloid Leukemia

Conditions
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Adult Acute Monoblastic Leukemia (M5a), Adult Acute Monocytic Leukemia (M5b), Adult Acute Myeloblastic Leukemia With Maturation (M2), Adult Acute Myeloblastic Leukemia Without Maturation (M1), Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities, Adult Acute Myeloid Leukemia With Del(5q), Adult Acute Myeloid Leukemia With t(15;17)(q22;q12), Adult Acute Myeloid Leukemia With t(16;16)(p13;q22), Adult Acute Myelomonocytic Leukemia (M4), Childhood Acute Basophilic Leukemia, Childhood Acute Eosinophilic Leukemia, Childhood Acute Erythroleukemia (M6), Childhood Acute Megakaryocytic Leukemia (M7), Childhood Acute Minimally Differentiated Myeloid Leukemia (M0), Childhood Acute Monoblastic Leukemia (M5a), Childhood Acute Monocytic Leukemia (M5b), Childhood Acute Myeloblastic Leukemia With Maturation (M2), Childhood Acute Myeloblastic Leukemia Without Maturation (M1), Childhood Acute Myelomonocytic Leukemia (M4), Recurrent Adult Acute Myeloid Leukemia, Recurrent Childhood Acute Myeloid Leukemia, Secondary Acute Myeloid Leukemia

Intervention / Treatment
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* Drug: idarubicin
* Drug: cytarabine
* Drug: bortezomib
* Drug: etoposide
* Other: laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of acute myeloid leukemia (AML) according to WHO classification At least 5% blasts in the bone marrow With or without extramedullary disease To be eligible for the dose-finding phase (closed as of 10/10) : Relapsed patients must meet the following criteria: Must have had a prior diagnosis of AML, but may NOT have inv(16) or t(8;21) cytogenetics May be in first or any subsequent relapse If in first relapse, remission duration must be less than one year Refractory patients must meet the following criteria: Must have had a prior diagnosis of AML May have received one or more attempt at remission induction Patients with treatment-related AML may be previously treated or untreated for secondary AML To be eligible for the efficacy phase: Relapsed patients must meet the following criteria: Must have had a prior diagnosis of AML, with no restriction on prior cytogenetics Must be in first relapse Must not have received prior reinduction therapy Refractory patients must meet the following criteria: Must have had a prior diagnosis of AML Must not have received more than one attempt at remission induction (which may consist of up to two therapy courses) Patients with treatment-related AML must be previously untreated for secondary AML No juvenile myelomonocytic leukemia or acute promyelocytic leukemia (APL; FAB M3) Patients with the following CNS status are eligible only in the absence of neurologic symptoms suggestive of CNS leukemia, such as cranial nerve palsy: CNS 1, defined as absence of blasts in cerebral spinal fluid (CSF) on cytospin preparation, regardless of the number of WBCs CNS 2, defined as presence of < 5/μL WBCs in CSF and cytospin positive for blasts, or > 5/uL WBCs but negative by Steinherz/Bleyer algorithm: CNS 2a: < 10/μL RBCs; < 5/μL WBCs and cytospin positive for blasts CNS 2b: ≥ 10/μL RBCs; < 5/μL WBCs and cytospin positive for blasts CNS 2c: ≥ 10/μL RBCs; ≥ 5/μL WBCs and cytospin positive for blasts but negative by Steinherz/Bleyer algorithm Patients with CNS3 disease (presence of ≥ 5/μL WBCs in CSF and cytospin positive for blasts [in the absence of a traumatic lumbar puncture] and/or clinical signs of CNS leukemia) are not eligible CNS toxicity ≤ grade 2 Lansky (patients ≤ 16 years of age) or Karnofsky (patients > 16 years of age) performance status (PS) 50-100% ECOG PS 0-2 No Down syndrome No Fanconi anemia, Kostmann syndrome, Shwachman syndrome, or any other known bone marrow failure syndrome No evidence of active graft-vs-host disease Creatinine clearance or radioisotope glomerular filtration rate ≥ 70 mL/min OR serum creatinine based on age/gender as follows: 0.4 mg/dL for patients 1 month to < 6 months of age 0.5 mg/dL for patients 6 months to < 1 year of age 0.6 mg/dL for patients 1 to < 2 years of age 0.8 mg/dL for patients 2 to < 6 years of age 1 mg/dL for patients 6 to < 10 years of age 1.2 mg/dL for patients 10 to < 13 years of age 1.5 mg/dL (male) or 1.4 mg/dL (female) for patients 13 to < 16 years of age 1.7 mg/dL (male) or 1.4 mg/dL (female) for patients ≥ 16 years of age Total bilirubin ≤ 1.5 times upper limit of normal (ULN) for age ALT < 3.0 times ULN for age (unless elevation due to leukemia involvement) Shortening fraction ≥ 27% by ECHO OR LVEF ≥ 50% by gated radionuclide Normal respiratory rate and pulse oximetry > 94% on room air FEV_1 ≥ 80% of predicted FVC and DLCO > 50% (corrected for hemoglobin) Patients who are unable to perform pulmonary function tests (PFTs) (e.g., because of young age) will be excluded provided they have a medical history of significant prior pulmonary events or chronic pulmonary disease (e.g., pneumonia requiring mechanical ventilation support, pulmonary GVHD, pneumonectomy, or pulmonary toxin exposure) Children with histories of resolved bronchiolitis, resolved viral pneumonias and well-controlled asthma are eligible, even if they are unable to perform PFTs Patients with seizure disorder may be enrolled if on a non-enzyme-inducing anticonvulsant and if seizures are well-controlled No uncontrolled infection No known allergy to idarubicin, cytarabine, etoposide, boron, mannitol or bortezomib Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception Concurrent radiotherapy allowed for patients who present with a chloroma that is producing or threatens to produce an irreversible neurologic deficit Recovered from all prior chemotherapy, immunotherapy, or radiotherapy More than 2 weeks since prior cytotoxic chemotherapy (4 weeks for nitrosoureas), except for hydroxyurea, which is allowed up to 24 hours prior to first dose of study drug, and intrathecal chemotherapy, which is allowed immediately up to administration of study drug Prior steroid allowed as clinically indicated for patients with asthma Hydrocortisone and methylprednisolone allowed as premedication in patients with a history of severe allergic reactions At least 7 days since prior biologic agents, such as steroids, retinoids, or donor lymphocyte infusion without conditioning At least 2 weeks since prior local palliative radiotherapy (small port) At least 8 weeks since prior craniospinal radiotherapy or ≥ 50% radiation of pelvis At least 6 weeks since prior other bone marrow radiation At least 1 day since prior green tea containing products, any products containing vitamin C, flavanoids or other antioxidants (e.g., vitamins, herbal supplements), and foods with high vitamin C content No prior radiotherapy to > 25% of lung volume No prior total-body irradiation as part of a hematopoietic stem cell conditioning regimen At least 2 months since prior stem cell transplantation No concurrent graft-vs-host disease prophylactic medication No prior bortezomib or other proteasome inhibitors No other concurrent investigational drugs More than 4 days since prior growth factors that support platelet or white cell number or function No concurrent enzyme-inducing anticonvulsant medications known to be potent inducers of the cytochrome P450 system, including phenytoin, carbamazepine, and phenobarbital Concurrent benzodiazepines and gabapentin allowed No concurrent grapefruit juice with bortezomib No other concurrent cancer chemotherapy or immunomodulating agents No concurrent corticosteroids as anti-emetic therapy Concurrent corticosteroids therapy allowed as treatment or prophylaxis for anaphylactic reactions, symptoms of cytarabine syndrome, and as treatment for presumptive bortezomib-induced pulmonary toxicity.

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Bortezomib 1.3mg/m2-assess efficacy-low anthracycline exposure<br>Bortezomib 1.3mg/m2 to assess efficacy in low prior anthracycline exposure. Patients receive idarubicin IV (12 mg/m2/day) over 15 minutes on days 1-3, low-dose cytarabine IV (100 mg/m2/day) continuously over days 1-7, and bortezomib IV (1.3 mg/m2) on days 1, 4, and 8. All patients receive intrathecal cytarabine (30 mg - age 1-1.99 years, 50 mg - age 2-2.99 years, 70 mg - age ≥ 3 years) prior to courses 1 and 2. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity (closed as of 08/01/10). Dosage modification based on age < 3 years old. | Drug: idarubicin<br>* Given IV<br>* Other names: IDA;Drug: cytarabine<br>* Given IV or IT<br>* Other names: cytosine arabinoside;Drug: bortezomib<br>* Given IV<br>* Other names: VELCADE;Other: laboratory biomarker analysis<br>* Correlative studies<br>|
| Experimental: Bortezomib 1.0mg/m2-assess feasibility high anthracycline exp<br>Bortezomib 1.0 mg/m2 to assess feasibility in high prior anthracycline exposure. Patients receive etoposide IV (150 mg/m2/dose) over 1 hour on days 1-5, high-dose cytarabine IV (1000 mg/m2/dose) over 1 hour twice daily on days 1-5, and bortezomib IV (1.0 mg/m2) on days 1, 4, and 8. All patients receive intrathecal cytarabine (30 mg - age 1-1.99 years, 50 mg - age 2-2.99 years, 70 mg - age ≥ 3 years) prior to courses 1 and 2. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity. | Drug: cytarabine<br>* Given IV or IT<br>* Other names: cytosine arabinoside;Drug: bortezomib<br>* Given IV<br>* Other names: VELCADE;Drug: etoposide<br>* Given IV<br>* Other names: VP-16-213;Other: laboratory biomarker analysis<br>* Correlative studies<br>|
| Experimental: Bortezomib 1.3 mg/m2-assess feasibility high anthracycline exp<br>Bortezomib 1.3 mg/m2 to assess feasibility in high prior anthracycline exposure. Patients receive etoposide IV (150 mg/m2/dose) over 1 hour on days 1-5, high-dose cytarabine IV (1000 mg/m2/dose) over 1 hour twice daily on days 1-5, and bortezomib IV (1.3 mg/m2) on days 1, 4, and 8. All patients receive intrathecal cytarabine (30 mg - age 1-1.99 years, 50 mg - age 2-2.99 years, 70 mg - age ≥ 3 years) prior to courses 1 and 2. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity (dose-finding phase closed as of 10/10). | Drug: cytarabine<br>* Given IV or IT<br>* Other names: cytosine arabinoside;Drug: bortezomib<br>* Given IV<br>* Other names: VELCADE;Drug: etoposide<br>* Given IV<br>* Other names: VP-16-213;Other: laboratory biomarker analysis<br>* Correlative studies<br>|
| Experimental: Bortezomib 1.3 mg/m2-assess efficacy high anthracycline exp<br>Bortezomib 1.3 mg/m2 to assess efficacy in high prior anthracycline exposure. Patients receive etoposide IV (150 mg/m2/dose) over 1 hour on days 1-5, high-dose cytarabine IV (1000 mg/m2/dose) over 1 hour twice daily on days 1-5, and bortezomib IV (1.3 mg/m2) on days 1, 4, and 8. All patients receive intrathecal cytarabine (30 mg - age 1-1.99 years, 50 mg - age 2-2.99 years, 70 mg - age ≥ 3 years) prior to courses 1 and 2. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity | Drug: cytarabine<br>* Given IV or IT<br>* Other names: cytosine arabinoside;Drug: bortezomib<br>* Given IV<br>* Other names: VELCADE;Drug: etoposide<br>* Given IV<br>* Other names: VP-16-213;Other: laboratory biomarker analysis<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose Limiting Toxicity | Number of participants with dose limiting toxicity. | During Course 1 | 
| Overall Response (Complete Remission [CR] and CR With Partial Recovery [CRp]) During Course 1 | Overall response (complete remission [CR] and CR with partial recovery [CRp]) during course 1. | After course 1 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| NF-kB Activity by Enzyme-linked Immunosorbent Assay (ELISA) | NF-kB activity will be measured as a continuous variable (ng NF-kB/Mg protein). Differences in NF-κB activity between time points will be assessed using summary statistics such as mean, standard deviation, and range. We may perform exploratory analyses to determine if single time point measurements, or the difference between time points, correlate with treatment response. | At baseline, prior to and up to 24 hours after bortezomib treatment | 
| Proteasome Inhibition Activity | Mean and standard deviation of β1 and β5- Results are ratios (proteasome subunit/β-actin based on loading of 15 µg total protein, normalized to CEM). | At baseline | 
| Protein Expression Assessed by Western Blot | Relative expression of apoptotic and cell cycle proteins will be characterized using descriptive statistics. If differences are noted between pre and post-treatment protein expression, pairwise comparisons will be made using paired t-test or an equivalent nonparametric test if the data are non-normally distributed. The normality assumption will be assessed on the log-transformed data prior to paired t-test evaluation. | At baseline, prior to and up to 24 hours after bortezomib treatment | 
| Feasibility of Stem Cell Quantitation: Percentage of Leukemia Initiation Cells (LIC) Depletion | Descriptive statistics to assess mean +/- standard deviation for the percentage leukemia initiation cells (LIC) depletion. | At baseline and after completion of course 1 |