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



Status:Terminated
Conditions:Blood Cancer, Lymphoma, Lymphoma
Therapuetic Areas:Oncology
Healthy:No
Age Range:Any - 21
Updated:4/5/2019
Start Date:November 23, 2016
End Date:March 11, 2018

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

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.

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.

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.
We found this trial at
1
site
262 Danny Thomas Pl
Memphis, Tennessee 38105
(901) 495-3300
Principal Investigator: Sima Jeha, MD
Phone: 866-278-5833
St. Jude Children's Research Hospital St. Jude is unlike any other pediatric treatment and research...
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