Re-Induction Therapy for Relapsed Pediatric T-Cell Acute Lymphoblastic Leukemia or Lymphoma

NCT02518750 | Terminated Phase 2 Results FDA Drug

• 2 other identifiers: TSALVNCI-2015-00935
• Study Type: interventional
• Target: 3
• Locations: 1 country
• Sites: 1

Brief Summary

This is a phase-II study to evaluate the efficacy of a salvage regimen in children with relapsed T-cell ALL or lymphoma. Peg-asparaginase, mitoxantrone, intrathecal triples (IT) (intrathecal methotrexate/hydrocortisone/cytarabine) (ITMHA) and dexamethasone are commonly used drugs to treat relapsed or refractory acute lymphocytic leukemia or lymphoma (ALL). In this study, the investigators want to know if adding three drugs called panobinostat, bortezomib and liposomal vincristine (VSLI) to this regimen will result in remission (no signs or symptoms of leukemia or lymphoma).

• Panobinostat has been approved by the FDA for treating adults with multiple myeloma, but it has not been approved for use in children and has not been given together with the other drugs used in this study. It has not been widely studied in children.
• VSLI has been approved by the FDA for adults with relapsed or refractory ALL, but has not yet been approved for treating children with leukemia or lymphoma.
• Bortezomib has been approved by the FDA for treating adults with a cancer called multiple myeloma and adults with relapsed mantle cell lymphoma; it has not been approved for treating children. PRIMARY OBJECTIVE:
• To estimate the complete remission (CR) rate for patients with T-cell lymphoblastic leukemia and lymphoma in first relapse. SECONDARY OBJECTIVES:
• To evaluate minimal residual disease (MRD) levels at end of each block of therapy.
• To describe the toxicities of vincristine sulfate liposome injection (VSLI) when used in combination with chemotherapy and bortezomib.

Conditions

Acute Lymphoblastic Leukemia; Lymphoma, Non-Hodgkin's; Leukemia, T-Cell; Leukemia, B-Cell

Keywords

Hematopoietic Stem Cell Transplantation; Salvage Regimen; Re-Induction Therapy; Multi-agent chemotherapy

Outcome Measures

Primary Outcomes (1)

• Complete Remission (CR) Rate

  All participants who start re-induction Block A therapy are considered evaluable. Any patient who at any time point achieves CR and goes to transplant is considered as a success; or any patient who successfully reaches the end of block C and achieves/remains in CR is considered a success; all other cases are considered as failure.

  At the end of each remission re-induction block C (approximately 13 weeks after start of therapy)

Secondary Outcomes (4)

• Block A Minimal Residual Disease (MRD)

  At the end of Block A therapy (approximately 5 weeks after start of therapy)

• Block B Minimal Residual Disease (MRD)

  At the end of Block B therapy (approximately 10 weeks after start of therapy)

• Block C Minimal Residual Disease (MRD)

  At the end of Block C therapy (approximately 13 weeks after start of therapy)

• Proportion of Relevant Toxicities

  At the completion of therapy (up to approximately 5 months after the start of therapy)

Study Arms (1)

Study Participants

EXPERIMENTAL

Participants with ALL will receive the following interventions in three treatment blocks: * Block A: Dexamethasone, panobinostat, liposomal vincristine, mitoxantrone, peg-asparaginase, bortezomib, intrathecal triples. * Block B: High-dose methotrexate, 6-mercaptopurine, intrathecal triples, high-dose cytarabine. * Block C: Nelarabine or clofarabine, cyclophosphamide, etoposide.

Drug: Dexamethasone; Drug: Panobinostat; Drug: Liposomal vincristine; Drug: Mitoxantrone; Drug: Peg-asparaginase; Drug: Bortezomib; Drug: Intrathecal Triples; Drug: High-dose methotrexate; Drug: 6-Mercaptopurine; Drug: High-dose cytarabine; Drug: Nelarabine; Drug: Cyclophosphamide; Drug: Etoposide; Drug: Clofarabine

Interventions

Dexamethasone DRUG

Given orally (PO).

Also known as: Decadron®

Study Participants

Panobinostat DRUG

Given PO.

Also known as: LBH589

Study Participants

Liposomal vincristine DRUG

For intravenous (IV) use only.

Also known as: Vincristine sulfate liposome injection, VSLI, Marqibo®

Study Participants

Mitoxantrone DRUG

Given IV.

Also known as: Novantrone®

Study Participants

Peg-asparaginase DRUG

Given IV or intramuscularly (IM). In case of allergy or intolerance to Peg-asparaginase, Erwinia L-asparaginase (Erwinase®) will be used. Erwinia L-asparaginase is given by either IV or IM injection.

Also known as: Peg-L-asparaginase, Pegaspargase, Oncaspar®

Study Participants

Bortezomib DRUG

Given by IV push over 3 to 5 seconds. For IV use only.

Also known as: Velcade, MLN341, LDP-341

Study Participants

Intrathecal Triples DRUG

Given IT as ITMHA.

Also known as: ITMHA, Methotrexate/Hydrocortisone/Cytarabine

Study Participants

High-dose methotrexate DRUG

Given intrathecally (IT) or IV.

Also known as: HDMTX

Study Participants

6-Mercaptopurine DRUG

Given PO at consistent time each day.

Also known as: 6-MP, Purinethol®

Study Participants

High-dose cytarabine DRUG

Given IT or IV.

Also known as: Ara-C, Cytosar-U®

Study Participants

Nelarabine DRUG

Given IV

Also known as: Arranon®, Compound 506U78

Study Participants

Cyclophosphamide DRUG

Given IV.

Also known as: Cytoxan®

Study Participants

Etoposide DRUG

Given IV. In case of etoposide reactions, IV etoposide phosphate (Etopophos®) will be used.

Also known as: VP-16, Vepesid®

Study Participants

Clofarabine DRUG

Given IV. Clofarabine will be given instead of nelarabine for patients with B-lymphoblastic leukemia and lymphoma in stratum II.

Also known as: Clolar™, Clofarex

Study Participants

Eligibility Criteria

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

You may qualify if:

• Participants must have relapsed or refractory acute lymphoblastic leukemia or lymphoma (ALL):
• Stratum I: T-cell lymphoblastic leukemia or lymphoma in first relapse or refractory to one or two courses of frontline induction therapy.
• Stratum II: B-cell or T-cell lymphoblastic leukemia or lymphoma in second or third relapse or refractory to 2 or 3 induction or re-induction attempts. Patients with Ph+ ALL must be refractory or relapsed after treatment with regimen that included a tyrosine kinase inhibitor (TKI).
• Relapse in ALL is defined as the reappearance (in a patient who has previously achieved remission) of leukemic blasts in the bone marrow.
• Should flow cytometric analyses suggest relapse (by the reappearance of a similar immunophenotype to the original leukemia) in the presence of \<5% blasts morphologically, a repeat bone marrow test is recommended to confirm relapse.
• Molecular or genetic relapse is characterized by the reappearance of a cytogenetic or molecular abnormality.
• Age is ≤ 21 years (participant has not yet reached 22nd birthday).
• Able to swallow capsules.
• Karnofsky or Lansky performance score is ≥ 60%. The Lansky performance score should be used for participants \< 16 years and the Karnofsky performance score for participants ≥ 16 years.
• Prior therapy:
• There is no waiting period for participants who relapse while receiving therapy if they are free from side effects attributable to such therapy.
• Emergent radiation therapy, one dose of intrathecal chemotherapy and up to 7 days of steroids or hydroxyurea are permitted before start of treatment in participants who relapse after completion of frontline therapy. Other circumstances must be cleared by PI or medical designee.
• At least 90 days have elapsed since bone marrow transplant and participant is off immune suppression for ≥ 2 weeks, if applicable.
• Adequate renal function defined as glomerular filtration rate ≥ 60 cc/min/1.73m\^2 or serum creatinine based on age as follows:
• If age is 1 to 2 years, then maximum serum creatinine (mg/dL) is 0.6 for males or females.

You may not qualify if:

• Prior histone deacytylases (HDAC), DAC, HSP90 inhibitors or valproic acid for treatment of cancer.
• Patients who will need valproic acid for any medical condition during the study or within 5 days prior to first panobinostat treatment.
• Impaired cardiac function or clinically significant cardiac diseases, history of arrhythmia (including ventricular fibrillation or torsade de pointes), bradycardia \<50 bpm, screening ECG with prolonged QTc or uncontrolled hypertension.
• Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of panobinostat.
• Patients with diarrhea \> CTCAE grade 2.
• Other concurrent severe and/or uncontrolled medical conditions (e.g., uncontrolled diabetes or active or uncontrolled infection) including abnormal laboratory values, that could cause unacceptable safety risks or compromise compliance with the protocol.
• Patients using medications that have a relative risk of prolonging the QT interval or inducing torsade de pointes if treatment cannot be discontinued or switched to a different medication prior to starting treatment.
• Patients who have received targeted agents within 2 weeks or within 5 half-lives of the agent and active metabolites (whichever is longer) and who have not recovered from side effects of those therapies.
• Patients who have undergone major surgery ≤ 4 weeks prior to starting treatment or who have not recovered from side effects of such therapy.
• Patients with known positivity for human immunodeficiency virus (HIV) or hepatitis B/C.
• Inability to swallow capsules.
• Active, uncontrolled infection or severe concurrent medical disease, including but not limited to congestive heart failure, cardiac arrhythmias, or psychiatric illness.
• Isolated extramedullary relapse (leukemia) or isolated CNS lymphoma.
• Pregnant or lactating (female participant of childbearing potential must have negative serum or urine pregnancy test required within 7 days prior to start of treatment). Male or female of reproductive potential has agreed to use effective contraception method for duration of study treatment.
• Down syndrome.

Sponsors & Collaborators

• St. Jude Children's Research Hospital: lead
• Novartis Pharmaceuticals: collaborator
• Spectrum Pharmaceuticals, Inc: collaborator

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

Precursor Cell Lymphoblastic Leukemia-Lymphoma; Lymphoma, Non-Hodgkin; Leukemia, T-Cell; Leukemia, B-Cell

Interventions

Dexamethasone; Calcium Dobesilate; Panobinostat; Vincristine; Mitoxantrone; pegaspargase; Bortezomib; Methotrexate; Mercaptopurine; Cytarabine; nelarabine; Cyclophosphamide; Etoposide; Clofarabine

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; Lymphoma

Intervention Hierarchy (Ancestors)

Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Steroids, Fluorinated; Benzenesulfonates; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Arylsulfonates; Arylsulfonic Acids; Sulfonic Acids; Sulfur Acids; Sulfur Compounds; Hydroxamic Acids; Hydroxylamines; Amines; Hydroxy Acids; Carboxylic Acids; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Vinca Alkaloids; Secologanin Tryptamine Alkaloids; Indole Alkaloids; Alkaloids; Indolizidines; Indolizines; Anthraquinones; Anthrones; Anthracenes; Polycyclic Aromatic Hydrocarbons; Quinones; Boronic Acids; Acids, Noncarboxylic; Acids; Inorganic Chemicals; Boron Compounds; Pyrazines; Heterocyclic Compounds, 1-Ring; Aminopterin; Pterins; Pteridines; Sulfhydryl Compounds; Purines; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Arabinonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Phosphoramides; Organophosphorus Compounds; Podophyllotoxin; Tetrahydronaphthalenes; Naphthalenes; Glucosides; Glycosides; Carbohydrates; Adenine Nucleotides; Purine Nucleotides; Nucleotides; Ribonucleotides

Limitations and Caveats

Given the very small enrollment number, no statistical analyses was performed.

Results Point of Contact

• Title: Sima Jeha, MD
• Organization: St. Jude Children's Research Hospital

sima.jeha@stjude.org

901-595-3901

Study Officials

• Sima Jeha, MD

  St. Jude Children's Research Hospital

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 16, 2015
• First Posted: August 10, 2015
• Study Start: November 23, 2016
• Primary Completion: March 11, 2018
• Study Completion: March 11, 2018
• Last Updated: April 3, 2019
• Results First Posted: April 3, 2019

Record last verified: 2018-06

Locations

US (1)