Bortezomib and Vorinostat in Younger Patients With Refractory or Relapsed MLL Rearranged Hematologic Malignancies

St. Jude Children's Research Hospital

Status and phase

Terminated

Phase 2

Conditions

Acute Lymphoid Leukemia

Mixed Lineage Acute Leukemia

Acute Myeloid Leukemia

Treatments

Drug: Dexamethasone

Drug: Peg-L-Asparaginase

Drug: Erwinia L-Asparaginase

Drug: Doxorubicin

Drug: Mercaptopurine

Drug: Cytarabine

Drug: Bortezomib

Drug: Vorinostat

Drug: Methotrexate

Drug: Mitoxantrone

Drug: Hydrocortisone

Study type

Interventional

Funder types

Other

Identifiers

NCT02419755

RELMLL

NCI-2015-00602 (Registry Identifier)

Details and patient eligibility

About

This study will test the safety and effectiveness of adding bortezomib and vorinostat to other chemotherapy drugs commonly used to treat relapsed or refractory leukemia. Both drugs have been approved by the Food and Drug Administration (FDA) to treat other cancers in adults, but they have not yet been approved tor treatment younger patients with leukemia.

PRIMARY OBJECTIVE

To estimate the overall response rate of patients with MLL rearranged (MLLr) hematologic malignancies receiving bortezomib and vorinostat in combination with a chemotherapy backbone.

SECONDARY OBJECTIVES

Estimate event-free and overall-survival.
Describe toxicities experienced by participants during treatment.

OTHER PRESPECIFIED OBJECTIVES

To identify all genomic lesions by comprehensive whole genome, exome and transcriptome sequencing on all patients.
To compare minimal residual disease (MRD) results by three modalities: flow cytometry, polymerase chain reaction (PCR) and deep sequencing.

Full description

All participants will undergo diagnostic lumbar puncture and intrathecal (IT) chemotherapy [Cytarabine, methotrexate, hydrocortisone (ITMHA)] prior to cycle 1. Throughout all phases of therapy, dexrazoxane will be given as supportive care for all participants prior to receiving mitoxantrone or doxorubicin.

STRATUM 1: MYELOID MALIGNANCIES:

Induction:

Cytarabine, Days 1-5
Bortezomib, Days 1, 4, 8, 11, 15, 18
Vorinostat, Days 1-4, 8-11, 15-18
ITMHA.for those with CNS1, Day 1
ITMHA for those with CNS 2/3, Days 1, 4, 8, 11*, 15*, 18* and 22* (* Twice weekly until two negative CSF; CNS3 patients must receive at least 6 doses)
Participants with cumulative anthracycline <460 mg/m2 also receive Mitoxantrone on Day 1
Responders may receive up to 6 courses. ITMHA will be limited to day 1 for subsequent courses

Maintenance (bridge) therapy (1 cycle before stem cell transplant if needed)::

Bortezomib, Days 1, 4, 8, 11, 15, 18
Vorinostat, Days 1-4, 8-11, 15-18
ITMHA, Day 1

STRATUM 2: Acute Lymphoid Leukemia (ALL) and Mixed Lineage Malignancies (MLL):

Induction:

Mitoxantrone, Day 1
PEG-L-Asparaginase (or Erwinia L-asparaginase), Day 3
Dexamethasone, Days 1-4, 8-11, 15-18
Bortezomib, Days 1, 4, 8, 11, 15, 18
Vorinostat, Days 1-4, 8-11, 15-18
ITMHA for those with CNS1, Days 1, 8, 15, and 22
ITMHA for those with CNS2/3, Days 1, 4, 8, 11, 15, and 22
Participants with >460 mg/m2 cumulative anthracyclines will not receive mitoxantrone

Consolidation:

Methotrexate, Days 1 and 15
Bortezomib, Days 8, 11, 22, 25
Vorinostat, Days 8-11, and 22-25
ITMHA, Days 1 and 15

Interim Maintenance:

Mercaptopurine, Days 1-42
Doxorubicin, Days 1 and 29
PEG-L-asparaginase (or Erwinia L-asparaginase), Days 1, 15, and 29
Dexamethasone, Days 8-11, 22-25, and 36-39
Bortezomib Days 8,11,22,25,36,39
Vorinostat, Days 8-11, 22-25, and 36-39
ITMHA, Day 1

Reinduction:

Mitoxantrone, Day 1
PEG-L-asparaginase (or Erwinia L-asparaginase), Day 3
Dexamethasone, Days 1-4, 8-11, 15-18
Bortezomib Days 1, 4, 8, 11, 15, 18
Vorinostat Days 1-4, 8-11, 15-18
IT MHA Day 1

Maintenance (12 cycles):

Mercaptopurine, Days 1-28
Methotrexate, Days 8, 15, and 22
Dexamethasone, Days 1-4
Bortezomib, Days 1 and 4
Vorinostat, Days 1-4
ITMHA, Day 1

Bridge Therapy (1 cycle before stem cell transplant if needed):

Bortezomib, Days 1, 4, 8, 11, 15, 18
Vorinostat, Days 1-4, 8-11, 15-18
Dexamethasone, Days 1-4, 8-11, 15-18
ITMHA, Day 1

Enrollment

12 patients

Sex

All

Ages

Under 21 years old

Volunteers

No Healthy Volunteers

Inclusion criteria

Age: Patient is ≤ 21 years of age (i.e., eligible until 22nd birthday).
Diagnosis: Participant has a hematologic malignancy that is positive for MLLr as determined by fluorescent in situ hybridization (FISH) or RT-PCR, and disease meets at least one of the following criteria:
- Relapsed after or is refractory to chemotherapy
- Relapsed after hematopoietic stem cell transplantation (HSCT)
- Relapsed or refractory secondary leukemia (Relapse is defined as reappearance of leukemia cells after the attainment of complete remission and refractory is defined as ≥5% blasts at the end of induction. Patients that achieved MRD negative status followed by reappearance of blasts at less than 5% are eligible.)
Patients must have had verification of the malignancy at relapse, including immunophenotyping, to confirm diagnosis.
Performance Level: Karnofsky ≥50% for patients >16 years of age and Lansky ≥50 for patients ≤16 years of age (See Appendix III). Patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.
Prior therapy:
- Patients who relapse while receiving standard ALL maintenance chemotherapy consisting of daily 6MP, weekly methotrexate, monthly vincristine, and monthly steroid pulse will not be required to have a waiting period before entry onto this study.
- Patients who relapse on therapy other than standard ALL maintenance therapy must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study.
- Cytotoxic therapy: At least 14 days since the completion of cytotoxic therapy with the exception of hydroxyurea, low dose cytarabine, and intrathecal chemotherapy which is permitted up to 24 hours prior to the start of protocol therapy. For patients with aggressive disease that is in the peripheral blood and rising, this 14 day washout period may be omitted.
- Biologic (anti-neoplastic) agent: At least 7 days since the completion of therapy with a biologic agent or donor lymphocyte infusions (DLI). For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur.
- Stem cell transplant or rescue: ≥2 months must have elapsed since the time of transplant. Patients with active graft-vs-host disease (GVHD) are not eligible.
Organ function requirements: All patients must have:
- Adequate renal function defined as: Creatinine clearance or radioisotope GFR ≥70 mL/min/1.73 m^2, OR adequate serum creatinine based on age/gender.
- Adequate liver function defined as: Total bilirubin ≤ ULN for age, or if total bilirubin is > ULN, direct bilirubin is ≤ 1.4 mg/dL, AND SGPT (ALT) ≤4 x ULN for age, unless elevation due to leukemic infiltration
- Adequate cardiac function defined as: Shortening fraction of ≥27% by echocardiogram OR Ejection fraction of ≥50% by gated radionuclide study
- Central nervous system (CNS) function defined as: Patients with seizure disorder may be enrolled if on allowed anti-convulsants and well controlled. Benzodiazepines and gabapentin are acceptable. CNS toxicity ≤ Grade 2.
- Adequate pulmonary function defined as FVC>50% predicted OR, if unable to perform pulmonary function testing, must maintain pulse oximetry oxygen saturation >92% on room air.

Exclusion criteria

Patients requiring anticonvulsants known to activate the cytochrome p450 system, in particular anticonvulsants such as phenytoin, carbamazepine, and phenobarbital, are not eligible. Benzodiazepines and gabapentin are acceptable. Please see Appendix I for a list of drugs known to be potent inducers/inhibitors of the cytochrome p450 system and Appendix II for a list of anticonvulsants based on CYP3A4/5 enzyme induction.
ALL patients who cannot receive any asparaginase products (E. Coli, PEG-asparaginase, or Erwinia asparaginase) on this study (eg, due to prior severe pancreatitis, stroke or other toxicity) are not eligible. Patients with clinically significant prior allergies to PEG-asparaginase are eligible if Erwinia L-asparaginase can be substituted.
Pregnancy and breast feeding: patients who are pregnant or breast-feeding are not eligible for this study as there is as yet no available information regarding human fetal or teratogenic toxicities. Negative pregnancy tests must be obtained in girls who are post-menarchal. Males or females of reproductive potential may not participate unless they have agreed to use an effective birth control method.
Investigational drugs: Patients who are currently receiving another investigational drug are not eligible.
Anti-cancer agents: Patients who are currently receiving other anti-cancer agents with the exception of those delineated in the eligibility criteria.
Infection: Patients who have an uncontrolled infection are not eligible. Infections controlled on concurrent anti-microbial agents are acceptable, and anti-microbial prophylaxis per institutional guidelines are acceptable.
Known human immunodeficiency virus (HIV) infection (pre-study testing not required).
Any significant concurrent disease, illness, or psychiatric disorder that would compromise patient safety or compliance, study participation, follow up, or interpretation of study research.
Patients with Fanconi anemia, Kostmann syndrome, Shwachman syndrome, or other inherited bone marrow failure syndromes are not eligible.
Patients who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study are not eligible.

Trial design

Primary purpose

Treatment

Allocation

Non-Randomized

Interventional model

Parallel Assignment

Masking

None (Open label)

12 participants in 2 patient groups

Stratum 1: Myeloid Malignancies

Experimental group

Description:

Participants receive cytarabine, bortezomib, vorinostat, methotrexate, hydrocortisone, mitoxantrone as described in the Detailed Study Description.

Treatment:

Drug: Hydrocortisone

Drug: Mitoxantrone

Drug: Methotrexate

Drug: Vorinostat

Drug: Bortezomib

Drug: Cytarabine

Stratum 2: ALL and MLM

Experimental group

Description:

Participants in Stratum 2 \[Acute Lymphoid Leukemia (ALL) and Mixed Lineage Malignancies (MLM)\] receive mitoxantrone, PEG-L-Asparaginase (or Erwinia L-asparaginase), dexamethasone, bortezomib, vorinostat, cytarabine, methotrexate, hydrocortisone, mercaptopurine, and doxorubicin as described in the Detailed Study Description.

Treatment:

Drug: Hydrocortisone

Drug: Mitoxantrone

Drug: Methotrexate

Drug: Vorinostat

Drug: Bortezomib

Drug: Cytarabine

Drug: Mercaptopurine

Drug: Doxorubicin

Drug: Erwinia L-Asparaginase

Drug: Peg-L-Asparaginase

Drug: Dexamethasone