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

Condition(s) targeted: Acute Lymphoblastic Leukemia; Lymphoma, Non-Hodgkin's; Leukemia, T-Cell; Leukemia, B-Cell

Intervention: 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 (Drug)

Phase: Phase 2

Status: Not yet recruiting

Sponsored by: St. Jude Children's Research Hospital

Official(s) and/or principal investigator(s):
Sima Jeha, MD, Principal Investigator, Affiliation: St. Jude Children's Research Hospital

Overall contact:
Sima Jeha, MD, Phone: 866-278-5833, Email: referralinfo@stjude.org

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 not been approved by the FDA for any indication (it is not yet

commercially available), and this drug 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.

Official title: A Phase II Study Incorporating Panobinostat, Bortezomib and Liposomal Vincristine Into Re-Induction Therapy for Relapsed Pediatric T-Cell Acute Lymphoblastic Leukemia or Lymphoma

Study design: Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome: Complete Remission (CR) Rate

Secondary outcome:

Block A Minimal Residual Disease (MRD)

Block B Minimal Residual Disease (MRD)

Block C Minimal Residual Disease (MRD)

Proportion of relevant toxicities

Detailed description: This is a study of re-induction therapy that will comprise of three blocks of multi-agent chemotherapy. CR will be evaluated following each block of therapy. All patients will be candidates for hematopoietic stem cell transplant (HSCT) once they achieve negative minimal residual disease (MRD). If patients cannot proceed to HSCT following Block A, they will continue therapy on Block B and Block C until ready for HSCT. Three Block Induction: Block A: approximately 5 weeks

- Dexamethasone 10 mg/m^2/day orally (PO) Days 1-8, 15-22 (Total 16 days)

- Panobinostat 24 mg/m^2/dose PO Day 2,4,6

- Liposomal vincristine (VSLI) 2. 25 mg/m^2 no cap intravenously (IV) on Days 7, 14, 21,

28

- Mitoxantrone 10 mg/m^2 IV Day 7,14 (In the absence of peripheral blasts, Day 14

Mitoxantrone will be given if WBC ≥1000 and ANC ≥300)

- Peg-asparaginase 2500 units/m^2 on Days 9,23

- Bortezomib 1. 3 mg/m^2 IV Days 16, 19, 23, 26

- Intrathecal Triples (IT) (intrathecal methotrexate/hydrocortisone/cytarabine) (ITMHA)

Days 1, 7, 14, 21, 28. Additional ITs on Days 10 and 17 for patients with central nervous system (CNS) 2, 3 or traumatic tap with blasts Block B: approximately 5 weeks

- High-dose methotrexate 8 g/m^2 IV over 24 hours (will not be given to patients with

prior cranial irradiation) Day 1

- 6-mercaptopurine 50 mg/m^2 PO days 1-14

- ITMHA Day 1

- High-dose cytarabine 3 g/m^2 IV every 12 hours (Q12H) Days 15 and 16

Block C: approximately 3 weeks

- Nelarabine 650 mg/m^2/day IV Days 1-5 (Clofarabine 40 mg/m^2/day IV Days 1-5 will be

given instead of nelarabine for patients with B-lymphoblastic leukemia and lymphoma in stratum II)

- Cyclophosphamide 300 mg/m^2 IV Days 1-5

- Etoposide 100 mg/m^2/day IV Days 1-5

Response evaluation is performed after the end of each treatment block. All patients should proceed to hematopoietic stem cell transplantation (HSCT) after achieving negative minimal residual disease (MRD) when a suitable donor is identified. Patients could continue on Block B and Block C if not ready for HSCT. If after completion of Block C, MRD is persistently positive, the plan will be discussed with the principal investigator and co-principal investigator and the transplant team. Enrollment on ongoing natural killer (NK) cell studies will be considered. For patients who require a second transplant, HAP3R (another clinical trial at St. Jude Children's Research Hospital) may be an option. Donor will be selected according to institutional practices and transplant regimens will be used according to institutional HSCT protocols and guidelines.

Minimum age: N/A. Maximum age: 21 Years. Gender(s): Both.

Criteria:

Inclusion Criteria:

- 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.

- If age is 2 to 6 years, then maximum serum creatinine (mg/dL) is 0. 8 for males

or females.

- If age is 6 to 10 years, then maximum serum creatinine (mg/dL) is 1 for males or

females.

- If age is 10 to <13 years, then maximum serum creatinine (mg/dL) is 1. 2 for

males or females.

- If age is 13 to 16 years, then maximum serum creatinine (mg/dl) is 1. 5 for males

or 1. 4 for females.

- If age is > 16 years, then maximum serum creatinine (mg/dl) is 1. 7 for males or

1. 4 for females.

- Adequate hepatic function defined as:

- Direct bilirubin ≤ 1. 4 mg/dL (if total bilirubin > 1. 4 mg/dL) AND

- AST and ALT < 5 x ULN for age.

- Adequate cardiac function defined as shortening fraction of ≥ 27% or ejection

fraction ≥ 45%.

- Lymphoma participants without bone marrow involvement must have:

- Absolute neutrophil count (ANC) >1,000/mm3, AND

- Platelet count ≥50,000/mm^3 (without transfusion support)

- NOTE: These criteria are waived for participants with leukemia or lymphoma

participants with bone marrow involvement.

- Written, informed consent and assent following Institutional Review Board, NCI, FDA

and OHRP guidelines. Exclusion Criteria:

- 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.

- Inability or unwillingness or research participant or legal guardian/representative

to give written informed consent.

Sima Jeha, MD, Phone: 866-278-5833, Email: referralinfo@stjude.org

St. Jude Children's Research Hospital, Memphis, Tennessee 38105, United States

St. Jude Children's Research Hospital

Clinical Trials Open at St. Jude

Starting date: August 2015
Last updated: August 5, 2015