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

National Cancer Institute (NCI)

Status and phase: Completed; Phase 2

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

Treatments: Drug: idarubicin; Other: laboratory biomarker analysis; Drug: etoposide; Drug: bortezomib; Drug: cytarabine

Study type: Interventional

Funder types: NIH

Identifiers

NCT00666588

CDR0000594224 (Registry Identifier)

NCI-2009-00323 (Other Identifier)

U10CA098543 (U.S. NIH Grant/Contract)

COG-AAML07P1 (Other Identifier)

Details and patient eligibility

About

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

Full description

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.

Enrollment: 52 patients

Sex: All

Ages: 1 to 21 years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

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.

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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52 participants in 4 patient groups

Bortezomib 1.3mg/m2-assess efficacy-low anthracycline exposure

Experimental group

Description:

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.

Treatment:

Drug: cytarabine

Other: laboratory biomarker analysis

Drug: bortezomib

Drug: idarubicin

Bortezomib 1.0mg/m2-assess feasibility high anthracycline exp

Experimental group

Description:

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.

Treatment:

Drug: cytarabine

Other: laboratory biomarker analysis

Drug: bortezomib

Drug: etoposide

Bortezomib 1.3 mg/m2-assess feasibility high anthracycline exp

Experimental group

Description:

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).

Treatment:

Drug: cytarabine

Other: laboratory biomarker analysis

Drug: bortezomib

Drug: etoposide

Bortezomib 1.3 mg/m2-assess efficacy high anthracycline exp

Experimental group

Description:

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

Treatment:

Drug: cytarabine

Other: laboratory biomarker analysis

Drug: bortezomib

Drug: etoposide