Chemoimmunotherapy and Allogeneic Stem Cell Transplant for NK T-cell Leukemia/Lymphoma

Study Overview
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Brief Summary
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Patients are in 2 cohorts: Cohort 1: dexamethasone, methotrexate, ifosfamide, pegaspargase, and etoposide (modified SMILE) chemotherapy regimen alone and pembrolizumab in children, adolescents, and young adults with advanced stage NK lymphoma and leukemia Cohort 2: combining pralatrexate (PRX) (Cycles 1, 2, 4, 6) and brentuximab vedotin (BV) (Cycles 3, 5) to cyclophosphamide, doxorubicin, and prednisone in children, adolescent, and young adults with advanced peripheral T-cell lymphoma (non-anaplastic large cell lymphoma or non-NK lymphoma/leukemia) . Both groups proceed to allogeneic stem cell transplant with disease response.

Official Title
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Pilot Study Using Induction Chemo-immunotherapy Followed by Consolidation With Reduced Toxicity Conditioning and Allogenic Stem Cell Transplant in Advanced Stage Mature Non-anaplastic T-Cell or NK Lymphoma/Leukemia in Children, Adolescents and Young Adults; A NK/T-Cell Lymphoma/Leukemia Consortium Study

Conditions
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NK-Cell Lymphoma, NK-Cell Leukemia, Peripheral T Cell Lymphoma

Intervention / Treatment
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* Drug: Methotrexate
* Drug: pralatraxate,
* Drug: Ifosfamide
* Drug: Dexamethasone
* Drug: Etoposide
* Drug: calaspargase pegol
* Drug: cyclophosphamide
* Drug: Doxorubicin
* Drug: Prednisone
* Drug: Brentuximab Vedotin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must weigh at least 10 kilograms at the time of the study enrollment. Diagnosis Newly diagnosed patients with histologically proven mature T- and NK- cell neoplasms: COHORT 1 Aggressive NK cell leukemia (ICD-O code 9948/3) Extranodal NK/T-cell lymphoma, nasal type (ICD-O code 9719/3) COHORT 2 Enteropathy-associated T-cell lymphoma (ICD-O code 9717/3) Hepatosplenic T-cell lymphoma (ICD-O code 9716/3) Peripheral T-cell lymphoma, non-otherwise specified (ICD-O code 9702/3) Angioimmunoblastic T-cell lymphoma (ICD-O code 9705/3) Other mature T- and NK-cell neoplasm histologies will considered after case-by-case discussion with Study Chairs and executive Vice-Chair Patients with lymphoma must have stage III or IV disease (See Appendix III for Staging). Organ Function Requirements Adequate liver function defined as: Total bilirubin ≤ 1.5 x upper limit of normal (ULN) for age. ALT (SGPT) < 3 x ULN for age. Adequate cardiac function defined as: Shortening fraction of ≥ 27% by echocardiogram, or Ejection fraction of ≥ 50% by radionuclide angiogram. Adequate pulmonary function defined as: • Patients with a history of pulmonary dysfunction must have no evidence of dyspnea at rest, no exercise intolerance due to pulmonary insufficiency, and a pulse oximetry > 92% while breathing room air unless current dysfunction is due to the lymphoma, in which case the patient is eligible. Exclusion Criteria: Alk+ or Alk- Anaplastic Large Cell Lymphoma (ALCL) Patients with active CNS disease. Patients with stage I or stage II disease (See Appendix III for Staging). Patients who have received any prior cytotoxic chemotherapy for the current diagnosis of NHL. Previous steroid treatment and/or radiation treatment are not allowed unless they are used for emergency management. Patients who have received emergency irradiation and/or steroid therapy will be eligible only if started on protocol therapy not more than one week from the start of radiotherapy or steroids. Female patients who are pregnant. Pregnancy tests must be obtained in girls who are post menarchal. Lactating females, unless they have agreed not to breastfeed their infants. Patients with Down syndrome. Patients taking CYP3A4 substrates with narrow therapeutic indices. Patients (COHORT 2 ONLY) chronically receiving medications known to be metabolized by CYP3A4 and with narrow therapeutic indices (See Appendix V). The topical use of these medications (if applicable) is allowed. Patients taking CYP3A4 inhibitors. Patients (COHORT 2 ONLY) chronically receiving drugs that are known potent CYP3A4 inhibitors within 7 days prior to study enrollment (See Appendix V). The topical use of these medications (if applicable) is allowed. Patients taking CYP3A4 inducers. Patients (COHORT 2 ONLY) chronically receiving drugs that are known potent CYP3A4 inducers within 12 days prior to study enrollment (See Appendix V).

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 31 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Cohort 1 and 2 will be based on initial diagnosis.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br>Patients with aggressive NK cell leukemia or stage III or IV extranodal NK/T-cell lymphoma, nasal type. Chemotherapy Regimen: mSMILE: Methotrexate Day 1, Ifosfamide Days 2-4, Dexamethasone Days 2-4, Etoposide Days 2-4, calaspargase pegol Day 8. For patients in CR and no available allogeneic SCT can receive up to 2 additional cycles of mSMILE. Pembrolizumab: For patients in PR/MR/NR/PD after 2 cycles of mSMILE. Allogeneic Stem Cell Transplant if donor available and not in PD. | Drug: Methotrexate<br>* Patients will receive methotrexate as part of chemoimmunotherapy regemin followed by allogeneic stem cell transplant.<br>Drug: Ifosfamide<br>* Patients will receive Ifsofamide as part of chemoimmunotherapy regimen followed by allogeneic stem cell transplant.<br>Drug: Dexamethasone<br>* Patients will receive dexamethasone as part of chemoimmunotherapy regimen followed by allogeneic stem cell transplant.<br>Drug: Etoposide<br>* Patients will receive etoposide as part of chemoimmunotherapy regimen followed by allogeneic stem cell transplant.<br>Drug: calaspargase pegol<br>* Patients will receive pegaspargase as part of chemoimmunotherapy regimen followed by allogeneic stem cell transplant.<br>|
| Experimental: Cohort 2<br>Patients with stage III or IV peripheral T-cell lymphoma-NOS, angioimmunoblastic T-cell lymphoma, hepatosplenic T-cell lymphoma, or enteropathy-associated T-cell lymphoma (other histologies will be considered after case-by-case discussion with Study Chairs and Executive Vice-Chairs). Chemotherapy Regimen: Cycle 1 & 2: Pralatrexate Days 1, 8, and 15, cyclophosphamide Day 1, DOXOrubicin Day 1, predniSONE days 1-5 Cycle 3 & 5: Brentuximab vedotin Day 1, cyclophosphamide Day 1, DOXOrubicin Day 1, predniSONE days 1-5 Cycle 4 & 6: Pralatrexate Days 1, 8, and 15, cyclophosphamide Day 1, DOXOrubicin Day 1, predniSONE days 1-5 Allogeneic Stem Cell Transplant if donor available and not in PD. | Drug: pralatraxate,<br>* Patients will receive pralaxtraxate as part of chemoimmunotherapy regimen followed by allogeneic stem cell transplant.<br>Drug: cyclophosphamide<br>* Patients will receive cyclophosphamide as part of chemoimmunotherapy regimen followed by allogeneic stem cell transplant.<br>Drug: Doxorubicin<br>* Patients will receive doxorubicin as part of chemoimmunotherapy regimen followed by allogeneic stem cell transplant.<br>Drug: Prednisone<br>* Patients will receive prednisone as part of chemoimmunotherapy regimen followed by allogeneic stem cell transplant.<br>Drug: Brentuximab Vedotin<br>* Patients will receive brentuximab vedotin as part of chemoimmunotherapy regimen followed by allogeneic stem cell transplant.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| overall response rate | to assess overall response rate following chemoimmunotherapy induction therapy | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| event free survival | to determine the event free survival after induction chemoimmunotherapy and allogeneic stem cell transplantation | 2 year |