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

NCT02419755 | Terminated Phase 2 Results DMC

• 2 other identifiers: RELMLLNCI-2015-00602
• Study Type: interventional
• Target: 12
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Mixed Lineage Acute Leukemia; Acute Myeloid Leukemia; Acute Lymphoid Leukemia

Keywords

Infant leukemia; ALL; AML; Biphenotypic leukemia; Pediatric

Outcome Measures

Primary Outcomes (1)

• Overall Response Rate in All Participants

  For the purpose of the statistical analysis of the primary objective, response is assessed at the end of first treatment block at maximum tolerated dose of vorinostat (i.e., Induction Ia or Ib for myeloid and Induction for lymphoid and mixed lineage). Any eligible patient who starts first treatment block is considered evaluable. Response of CR, CRi, PR, or PRi is considered a success; otherwise a failure, which will include the cases of No-response, as well as off- treatment or off-study before response can be assessed, except cases found ineligible after enrollment. A patient found ineligible after enrollment will be taken off study and replaced by enrolling an additional MLLr patient. The rate (probability) of response will be estimated by the sample proportion of patients who responded (CR, CRi, PR, PRi) to Induction, along with the 99% confidence interval and lower confidence bound. Three interim analyses will be performed to monitor the possible lack of efficacy.

  End of first treatment block (up to 2 months)

Secondary Outcomes (7)

• Number of Participants With 3 Year Event Free Survival (EFS)

  Three years after the last enrollment

• Number of Participants With 5- Year Event Free Survival

  Five years after the last enrollment

• Number of Participant With 10-year Event Free Survival

  Ten years after the last enrollment

• Number of Participants With 3-year Overall Survival (OS)

  Three years after the last enrollment

• Number of Participants With 5-year Overall Survival

  Five years after the last enrollment

Other Outcomes (2)

• Frequency of Identified Genomic Lesions

  Once at enrollment

• Minimal Residual Disease (MRD)

  Various time points until completion of therapy (up to 18 months)

Study Arms (2)

Stratum 1: Myeloid Malignancies

EXPERIMENTAL

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

Drug: Bortezomib; Drug: Vorinostat; Drug: Mitoxantrone; Drug: Cytarabine; Drug: Methotrexate; Drug: Hydrocortisone

Stratum 2: ALL and MLM

EXPERIMENTAL

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.

Drug: Bortezomib; Drug: Vorinostat; Drug: Mitoxantrone; Drug: Cytarabine; Drug: Methotrexate; Drug: Hydrocortisone; Drug: Peg-L-Asparaginase; Drug: Erwinia L-Asparaginase; Drug: Dexamethasone; Drug: Mercaptopurine; Drug: Doxorubicin

Interventions

Bortezomib DRUG

Bortezomib will be given as a 1 mg/mL solution intravenous (IV) push over 3 to 5 seconds. For subcutaneous (SQ) administration, bortezomib will be mixed at 2.5 mg/ml.

Also known as: Velcade, PS-341, MLN341, LDP-341

Stratum 1: Myeloid Malignancies; Stratum 2: ALL and MLM

Vorinostat DRUG

Vorinostat should be taken orally (PO) with food.

Also known as: Zolinza, Suberoylanilide Hydroxamic Acid, SAHA

Stratum 1: Myeloid Malignancies; Stratum 2: ALL and MLM

Mitoxantrone DRUG

Given by intravenous (IV) injection.

Also known as: Novantrone

Stratum 1: Myeloid Malignancies; Stratum 2: ALL and MLM

Cytarabine DRUG

Given by intravenous (IV) injection.

Also known as: Ara-C, Cytosar

Stratum 1: Myeloid Malignancies; Stratum 2: ALL and MLM

Methotrexate DRUG

Methotrexate will be given intrathecally (IT) along with hydrocortisone and cytarabine.

Also known as: ITMHA, Intrathecal Triples

Stratum 1: Myeloid Malignancies; Stratum 2: ALL and MLM

Hydrocortisone DRUG

Hydrocortisone will be given intrathecally (IT) along with methotrexate and cytarabine.

Also known as: ITMHA, Intrathecal Triples

Stratum 1: Myeloid Malignancies; Stratum 2: ALL and MLM

Peg-L-Asparaginase DRUG

Given by intravenous (IV) or intramuscular (IM) injection.

Also known as: Pegaspargase, Oncaspar

Stratum 2: ALL and MLM

Erwinia L-Asparaginase DRUG

To be used in case of allergy or intolerance to PEG-Asparaginase. Given by intravenous (IV) or intramuscular (IM) injection.

Also known as: Erwinase

Stratum 2: ALL and MLM

Dexamethasone DRUG

Given orally (PO) or intravenously (IV).

Also known as: Decadron

Stratum 2: ALL and MLM

Mercaptopurine DRUG

Given orally (PO).

Also known as: 6-MP, Purinethol

Stratum 2: ALL and MLM

Doxorubicin DRUG

Given intravenously (IV).

Also known as: Adriamycin®

Stratum 2: ALL and MLM

Eligibility Criteria

• Age: Up to 21 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• St. Jude Children's Research Hospital: lead

Study Sites (1)

St. Jude Children's Research Hospital

Memphis, Tennessee, 38105, United States

Location

Related Links

• St. Jude Children's Research Hospital
• Clinical Trials Open at St. Jude

MeSH Terms

Conditions

Leukemia, Biphenotypic, Acute; Leukemia, Myeloid, Acute; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Interventions

Bortezomib; Vorinostat; Mitoxantrone; Cytarabine; Methotrexate; Hydrocortisone; pegaspargase; asparaginase erwinia chrysanthemi recombinant; Asparaginase; Dexamethasone; Calcium Dobesilate; Mercaptopurine; Doxorubicin

Condition Hierarchy (Ancestors)

Leukemia, Lymphoid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Leukemia, Myeloid

Intervention Hierarchy (Ancestors)

Boronic Acids; Acids, Noncarboxylic; Acids; Inorganic Chemicals; Boron Compounds; Organic Chemicals; Pyrazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Anilides; Amides; Aniline Compounds; Amines; Hydroxamic Acids; Hydroxylamines; Hydroxy Acids; Carboxylic Acids; Anthraquinones; Anthrones; Anthracenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Quinones; Polycyclic Compounds; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Arabinonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Aminopterin; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Pregnenediones; Pregnenes; Pregnanes; Steroids; Fused-Ring Compounds; 11-Hydroxycorticosteroids; Hydroxycorticosteroids; Adrenal Cortex Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; 17-Hydroxycorticosteroids; Amidohydrolases; Hydrolases; Enzymes; Enzymes and Coenzymes; Pregnadienetriols; Pregnadienes; Steroids, Fluorinated; Benzenesulfonates; Benzene Derivatives; Arylsulfonates; Arylsulfonic Acids; Sulfonic Acids; Sulfur Acids; Sulfur Compounds; Sulfhydryl Compounds; Purines; Daunorubicin; Anthracyclines; Naphthacenes; Aminoglycosides; Glycosides; Carbohydrates

Limitations and Caveats

The study was terminated early, because accrual goals were no longer feasible based on restrictions imposed by the Data Safety Monitoring Board (DSMB).

Results Point of Contact

• Title: Tanja A. Gruber, MD, PhD
• Organization: St. Jude Children's Research Hospital

tanja.gruber@stjude.org

901-595-2252

Study Officials

• Tanja A. Gruber, MD, PhD

  St. Jude Children's Research Hospital

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 14, 2015
• First Posted: April 17, 2015
• Study Start: April 14, 2015
• Primary Completion: December 31, 2016
• Study Completion: December 31, 2016
• Last Updated: March 7, 2018
• Results First Posted: February 1, 2018

Record last verified: 2017-11

Locations

US (1)