Therapy for Pediatric Relapsed or Refractory Acute Lymphoblastic Leukemia

Phase 2

Completed

• Conditions: Acute Lymphoblastic Leukemia; Lymphoma, Lymphoblastic
• Interventions: Drug: Etoposide, cytarabine, vincristine, dexamethasone; Drug: methotrexate, teniposide, PEG-asparaginase; Drug: mitoxantrone, cyclophosphamide, mercaptopurine, vinblastine; Drug: L-asparaginase, erwinia asparaginase; Procedure: chemotherapy, intrathecal chemotherapy, steroid therapy; Procedure: Hematopoietic Stem Cell Transplant; Procedure: Natural Killer (NK) Cell Transplant

• Registration Number: NCT00186875
• Lead Sponsor: St. Jude Children's Research Hospital

Brief Summary

The main purpose of this study is to find out how well participants with relapsed or refractory ALL respond to treatment with an etoposide- and teniposide-based induction chemotherapy regimen and what the side effects are.

Primary Objectives:

* To estimate the response rate for patients with refractory or relapsed ALL.

* To estimate the survival rate of patients with refractory or relapsed ALL treated with risk-directed therapy.

Detailed Description

In this study, subjects will be divided into high-risk and standard-risk subgroups according to the length of their first remission, the type of early cancer cell (T or B-cell) and the site or sites of disease relapse. The remission induction phase (the beginning phase of therapy) will consist of three blocks of therapy. Block A features daily IV low-dose etoposide in combination with cytarabine given by continuous IV, weekly vincristine, and daily dexamethasone. In block B, a combination of weekly PEG-asparaginase, vincristine, and daily dexamethasone will be given. Block C will be a combination of high-dose methotrexate, high-dose cytarabine, and teniposide.

There will be two phases of consolidation (treatment phase after induction therapy). Additional therapy will be given between the two consolidation phases. Continuation will consist of eight weekly cycles of chemotherapy. Periodic intrathecal therapy (medicine given into the spinal fluid) will be given throughout the treatment. Participants who do not achieve remission (absence of leukemia) after consolidation will be offered enrollment on St. Jude NKEHM protocol (NK cell transplant). Hematopoietic stem cell transplant (HSCT) is planned for participants with high risk disease. HSCT will be done according to current institutional practice. The duration of chemotherapy will be one year for patients with extramedullary (outside the bone marrow) relapse and two years for all others.

Exploratory objectives include:

* To determine the prevalence of MRD in children undergoing treatment for relapsed ALL and to compare the results to those obtained in children with newly diagnosed ALL.

* To compare the level of MRD in bone marrow and peripheral blood concomitantly in children undergoing treatment for relapsed ALL.

* To characterize the gene expression profile of leukemia cells at the time of diagnosis and relapse to improve our understanding of mechanisms of relapse and of the development of drug resistance.

* To study whether pre-existing or emerging development of serum antibodies to asparaginase is related to hypersensitivity reaction to asparaginase in patient with relapsed ALL.

Detailed Description of Treatment Plan:

All patients will receive the same remission induction. All high-risk patients will be offered HSCT which will be performed after a suitable donor is identified and preferably after MRD becomes negative. If they do not have a donor or they refuse HSCT, they will continue to receive chemotherapy. Standard-risk patients continue chemotherapy if MRD is negative after induction, but will be offered HSCT if MRD is \>0.01% after Block C of Induction. Those who do not achieve morphological CR after induction will be treated according to the contingency plan.

Block A (14 days)

Dexamethasone 5 mg/m2/day, days 1-14

Vincristine 1.5 mg/m2 (max 2 mg), days 1 and 8

Etoposide 25 mg/m2, days 1-14

Cytarabine 25 mg/m2, days 1-14

All patients will proceed to Block B if the clinical condition permits.

CNS prophylaxis (IT MHA)

CNS-1: At the time of relapse and day 14.

CNS-2 and 3: At the time of relapse, day 8 and 14.

Leucovorin: 5 mg/m2 (5 mg max dose) PO, 24 and 30 hours after each IT MHA.

Block B (15 days)

All patients will proceed to Block B immediately after Block A if they are clinically well.

Dexamethasone 6 mg/m2, Days 1-14

Vincristine 1.5 mg/m2, days 1 and 8

PEG-Asparaginase 2500 units/m2, days 1, 8 and 15

CNS prophylaxis (IT MHA): CNS-2 or 3 only, if necessary.

* CNS-1: no IT MHA

* CNS-2 and 3: day 8 (minimum 4 doses and maximum 8 doses during induction)

Leucovorin: 5 mg/m2 (5 mg max) PO 24 and 30 hours after each IT MHA

Block C (1 day)

All patients who received Block B will proceed to Block C when WBC \>1,000/microL, ANC \>300/microL and platelets \>50,000 microL after recovery from Block B.

Methotrexate 8 gm/m2, day 1

Cytarabine 1 g/m2 at least 24 h after ITHMA, day 1

Teniposide 165 mg/m2, day 1

CNS prophylaxis (IT MHA):

* CNS-1: at the time of BMA after Block C

* CNS-2 and 3: day 1 and 8 (These two doses of IT MHA may be omitted if the patient had negative CSF for blasts in the 3 preceding CSF exam) and at the time of BMA after Block C (regardless of the previous CSF status).

Leucovorin: 5 mg/m2 (5 mg maximum dose) PO 24 and 30 hours after each IT MHA

Consolidation I

This is a 4-week phase. It will be started if WBC \>1000/microL, ANC \>500/microL and platelets \>50,000 /microL

Week 1: Dex day 1, 2, 3, PEG, VCR, Mito day 4

Week 2: Dex day 1, 2, 3, PEG, VCR, day 4

Week 3: Dex day 1, 2, 3, PEG, VCR, Mito day 4

Week 4: Dex day 1, 2, 3, PEG, VCR, day 4

Dexamethasone 8 mg/m2/day, day 1-3

PEG-Asparaginase 2500 units/m2 IM, day 4 each week

Vincristine 2 mg/m2 (max 2 mg), day 4 each week

Mitoxantrone 12 mg/m2, day 4 week 1 and 3

Interim Continuation

Week 1\*†:

etoposide 300 mg/m2 IV, 1 dose on day 1

Cyclophosphamide 300 mg/m2 IV, 1 dose on day 1

Week 2\*:

Methotrexate 40 mg/m2 IV, 1 dose on day 1

6-mercaptopurine# 75 mg/m2 PO, Days 1 to 7

Week 3\*:

teniposide 150 mg/m2 IV, 1 dose on day 1

Cytarabine 300 mg/m2 IV, 1 dose on day 1

Week 4\*:

Dexamethasone§ 12 mg/m2/day PO, TID Days 1 to 5

Vinblastine 6 mg/m2 IV (max 10 mg), 1 dose on day 1

Consolidation II

Week 1\*†:

etoposide 300 mg/m2 IV, 1 dose on day 1

Cyclophosphamide 300 mg/m2 IV, 1 dose on day 1

Week 2\*:

Methotrexate 40 mg/m2 IV, 1 dose on day 1

6-mercaptopurine# 75 mg/m2 PO, Days 1 to 7

Week 3\*:

teniposide 150 mg/m2 IV, 1 dose on day 1

Cytarabine 300 mg/m2 IV, 1 dose on day 1

Week 4\*:

Dexamethasone§ 12 mg/m2/day PO, TID, Days 1 to 5

Vinblastine 6 mg/m2 IV (max 10 mg), 1 dose on day 1

Continuation

Week 1\*†¶:

etoposide 300 mg/m2 IV, 1 dose on day 1

Cyclophosphamide 300 mg/m2 IV, 1 dose on day 1

Week 2\*:

Methotrexate 40 mg/m2 IV, 1 dose on day 1

6-mercaptopurine# 75 mg/m2 PO, QHS, Days 1 to 7

Week 3\*:

teniposide 150 mg/m2 IV, 1 dose on day 1

Cytarabine 300 mg/m2 IV, 1 dose on day 1

Week 4:

Dexamethasone§ 12 mg/m2/day PO, TID, Days 1 to 5

Vincristine§ 2 mg/m2 IV(maximum 2mg), 1 dose on day 1

Week 5\*‡:

etoposide 300 mg/m2 IV, 1 dose on day 1

Cyclophosphamide 300 mg/m2 IV, 1 dose on day 1

Week 6\*:

Methotrexate 40 mg/m2 IV, 1 dose on day 1

6-mercaptopurine# 75 mg/m2 PO, QHS, Days 1 to 7

Week 7\*:

teniposide 150 mg/m2 IV, 1 dose on day 1

Cytarabine 300 mg/m2 IV, 1 dose on day 1

Week 8\*:

Dexamethasone§ 12 mg/m2/day PO, TID, Days 1 to 5

Vinblastine 6 mg/m2 IV(max 10 mg), 1 dose on day 1

Plan for Stem Cell Transplant

Patients who have positive MRD (high-risk or standard-risk) at the end of induction or all high-risk patients regardless of MRD are eligible for HSCT

* All high-risk patients are eligible for HSCT. HSCT will be performed as soon as MRD becomes negative after induction. If MRD becomes negative (\<0.01%) and a donor has not been found, the patient will continue chemotherapy phases (Consolidation I, Interim Continuation, etc) until a suitable donor is found.

* Those who have persistent positive MRD (\>0.01%) after Block C are also eligible for HSCT

All standard-risk patients will continue chemotherapy if MRD is negative (\<0.01%) after induction.

* If MRD is positive (\>0.01%) after Block C of induction, they become eligible for HSCT.

* Standard-risk patients who have no response or progressive disease after Block A and who have positive MRD (\>0.01%) after Block B will be candidates for HSCT. They will be re-evaluated after Block C. If MRD after Block C is positive, follow the plan above. If MRD is negative after Block C, the management will be discussed with Transplant Service

Contingency Plan

Patients who do not achieve morphological CR (M1 marrow) after Induction

If CR (M1 marrow) is not achieved after Induction, patients will proceed to Consolidation I. If they do not achieve CR after Consolidation I, they will be offered enrollment on the St. Jude NKHEM protocol or offered alternative therapy. If they do not achieve CR after NKHEM, they will come off treatment.

Patients who achieve CR but have positive MRD (\>0.01%) after Block C of induction: Become eligible for HSCT. Up to two more courses of chemotherapy (course 1 and 2) will be given to attempt reducing MRD. They will receive HSCT as soon as MRD becomes negative (MRD may be repeated every 2-4 weeks as indicated).

Standard-risk patients who have positive MRD (\>0.01%) after Block B will proceed to Block C. Patients in this category will become candidates for HSCT, but if MRD becomes negative after Block C, the management will be discussed with Transplant Service. Chemotherapy may be administered to reduce MRD prior to HSCT. Patients will be transplanted as soon as the MRD becomes negative.

Patients (high-risk or standard-risk) who achieved CR, but have positive MRD (\>0.01%) after Block C of Induction will become eligible for HSCT. Up to two more courses of chemotherapy (course 1 and 2) will be given to attempt reducing MRD. They will receive HSCT as soon as MRD becomes negative. If MRD remains positive after course 2, then, they will proceed to HSCT after discussion with Transplant Service.

Course 1

Give chemotherapy according to the plan for Consolidation I. Start it immediately regardless of CBC. BMA will be performed when WBC \>1000/microL, ANC \>300/microL and platelets \>50,000/microL. If MRD is negative, they will receive HSCT.

Course 2

This course will be given if MRD is positive after Course 1. Patients will be offered enrollment on St. Jude NKHEM protocol.

If they are still MRD positive after Course 2, patients may receive Interim Continuation, Consolidation II, and then Continuation until MRD becomes negative or while awaiting HSCT.

Study Timeline

• Study Start: 2003-11
• Study First Submitted: 2005-09-01
• Study First Submitted QC: 2005-09-12
• Study First Posted: 2005-09-16
• Results First Submitted: 2013-10-25
• Results First Submitted QC: 2013-10-25
• Results First Posted: 2013-12-16
• Primary Completion: 2016-08
• Study Completion: 2016-08
• Status Verified: 2017-06
• Last Update Submitted: 2017-07-26
• Last Update Posted: 2017-07-28

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 47

Inclusion Criteria

Not provided

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Exclusion Criteria

Not provided

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment	methotrexate, teniposide, PEG-asparaginase	Participants receive chemotherapy, intrathecal chemotherapy, steroid therapy, hematopoietic stem cell transplant, and natural killer cell transplant as outlined in the Interventions section, including etoposide, cytarabine, vincristine, dexamethasone, methotrexate, teniposide, PEG-asparaginase, mitoxantrone, cyclophosphamide, mercaptopurine, vinblastine, L-asparaginase, erwinia asparaginase.
Treatment	mitoxantrone, cyclophosphamide, mercaptopurine, vinblastine	Participants receive chemotherapy, intrathecal chemotherapy, steroid therapy, hematopoietic stem cell transplant, and natural killer cell transplant as outlined in the Interventions section, including etoposide, cytarabine, vincristine, dexamethasone, methotrexate, teniposide, PEG-asparaginase, mitoxantrone, cyclophosphamide, mercaptopurine, vinblastine, L-asparaginase, erwinia asparaginase.
Treatment	chemotherapy, intrathecal chemotherapy, steroid therapy	Participants receive chemotherapy, intrathecal chemotherapy, steroid therapy, hematopoietic stem cell transplant, and natural killer cell transplant as outlined in the Interventions section, including etoposide, cytarabine, vincristine, dexamethasone, methotrexate, teniposide, PEG-asparaginase, mitoxantrone, cyclophosphamide, mercaptopurine, vinblastine, L-asparaginase, erwinia asparaginase.
Treatment	Etoposide, cytarabine, vincristine, dexamethasone	Participants receive chemotherapy, intrathecal chemotherapy, steroid therapy, hematopoietic stem cell transplant, and natural killer cell transplant as outlined in the Interventions section, including etoposide, cytarabine, vincristine, dexamethasone, methotrexate, teniposide, PEG-asparaginase, mitoxantrone, cyclophosphamide, mercaptopurine, vinblastine, L-asparaginase, erwinia asparaginase.
Treatment	L-asparaginase, erwinia asparaginase	Participants receive chemotherapy, intrathecal chemotherapy, steroid therapy, hematopoietic stem cell transplant, and natural killer cell transplant as outlined in the Interventions section, including etoposide, cytarabine, vincristine, dexamethasone, methotrexate, teniposide, PEG-asparaginase, mitoxantrone, cyclophosphamide, mercaptopurine, vinblastine, L-asparaginase, erwinia asparaginase.
Treatment	Hematopoietic Stem Cell Transplant	Participants receive chemotherapy, intrathecal chemotherapy, steroid therapy, hematopoietic stem cell transplant, and natural killer cell transplant as outlined in the Interventions section, including etoposide, cytarabine, vincristine, dexamethasone, methotrexate, teniposide, PEG-asparaginase, mitoxantrone, cyclophosphamide, mercaptopurine, vinblastine, L-asparaginase, erwinia asparaginase.
Treatment	Natural Killer (NK) Cell Transplant	Participants receive chemotherapy, intrathecal chemotherapy, steroid therapy, hematopoietic stem cell transplant, and natural killer cell transplant as outlined in the Interventions section, including etoposide, cytarabine, vincristine, dexamethasone, methotrexate, teniposide, PEG-asparaginase, mitoxantrone, cyclophosphamide, mercaptopurine, vinblastine, L-asparaginase, erwinia asparaginase.

Primary Outcome Measures

Name	Time	Method
Response Rate	End of re-induction Block C (approximately 1 month after the start of therapy)	The "response rate" is defined as the proportion of participants who attain morphological complete remission after the re-induction Block C, inclusive of all patients who begin re-induction. Morphological complete remission was defined as \<5% blasts in bone marrow by morphology.
Overall Survival (OS)	2 years after last patient completes therapy (approximately 4 years after enrollment)	OS is measured from the start of on-study to the date of death or to the last date of follow-up. Measurement is determined by Kaplan-Meyer estimate. The probability of survival at 5 years after diagnosis is given.

Trial Locations

Locations (2)

Rady Children's Hospital and Health Center; 🇺🇸 San Diego, California, United States

St. Jude Children's Research Hospital; 🇺🇸 Memphis, Tennessee, United States