Chemoradiotherapy With Targeted Immunotherapy in Pediatric Lymphoma

Study Overview
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Brief Summary
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The addition of targeted immunotherapy will be safe and well tolerated and facilitate the reduction of anthracycline exposure while preserving lymphoma disease control in children, adolescents and young adults (CAYA) with mature B-cell non-Hodgkin lymphoma (MB-NHL) and classical Hodgkin lymphoma (cHL).

Detailed Description
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The primary objective is 1) to determine feasibility and safety, as defined by dose limiting toxicities (DLTs), of adding polatuzumab vedotin (Pv) in combination with rituximab (RTX) containing French-American-British (FAB) chemoimmunotherapy, with reduced dose anthracycline, in CAYA with intermediate and high risk newly diagnosed MB-NHL; 2) To define the feasibility and safety, as defined by DLTs, of the addition of nivolumab to the backbone of reduced toxicity chemoimmunotherapy with brentuximab vedotin (Bv), vinblastine, dacarbazine and rituximab, with reduced dose anthracycline, in CAYA with newly diagnosed intermediate and high risk cHL.

Official Title
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Reducing the Burden of Oncologic Chemoradiotherapy And Radiation Exposure From Diagnostic Imaging by Utilizing Targeted Immunotherapy in Children, Adolescents and Young Adults With Lymphoma

Conditions
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Non-hodgkin Lymphoma, Hodgkin Lymphoma

Intervention / Treatment
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* Drug: DOC Group B
* Drug: Pv-COMRAD 1 and 2 Group B
* Drug: Pv-R-CYM 1 and 2 Group B
* Drug: DOC Group C
* Drug: MAD CPR 1 and 2
* Drug: Pv-R CYVE 1 and 2
* Drug: Pv-R CYVE-MTX 1 and 2
* Drug: MAD CP
* Drug: Pv-Cytarabine/etoposide
* Drug: AD CP
* Drug: Bv-AVD-R 1 and 2: COHORT IIa
* Drug: Bv-NVD-R, Cycle 1-2
* Drug: Bv-NVD-R, Cycle 1-4 SER
* Drug: Bv-AVD-R
* Drug: Bv-NVD-R, Cycle 1-4 RER
* Drug: Bv-NAVD-R, Cycle 1-2
* Radiation: Involved Site Radiation Therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Newly diagnosed patients with histologically or cytologically proven newly diagnosed MB-NHL or cHL according to WHO Classification who meet the following criteria are eligible: COHORT I: Burkitt lymphoma (ICD-O 9687/3) Burkitt-like lymphoma with 11q aberration (ICD-O 9687/3) Diffuse large B-cell lymphoma, NOS (ICD-O 9680/3) High grade B-cell lymphoma (ICD-O 9680/3) COHORT Ia: stage III with LDH ≥ 2 ULN OR stage IV (5-24% bone marrow lymphoma infiltration) (GROUP B)61 COHORT Ib: any CNS involvement and/or BM involvement (≥ 25% lymphoma cells) (GROUP C)61 OR patients with less than 20% tumor size reduction post chemotherapy with cyclophosphamide, dexamethasone, vincristine (DOC Reduction for Cohort Ia). COHORT II Classical Hodgkin lymphoma (ICD-O 9650/3, 9663/3, 9651/3, 9652/3, 9653/3) COHORT IIa: stage I-IIA with bulky ± E, I-IIB no bulky ± E, IIIA ± E (INTERMEDIATE RISK) COHORT IIb: stage IIB with bulky ± E, IIIA with bulky ± E, IIIB, IV (HIGH RISK) Adequate organ function Exclusion Criteria: Primary mediastinal B-cell lymphoma (PMBL) T-cell/histiocyte-rich large B-cell lymphoma Gray zone lymphoma Follicular lymphoma Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) Posttransplant lymphoproliferative lymphoma (PTLD)

Ages Eligible for Study
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Minimum Age: 3 Years
Maximum Age: 39 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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1a<br>Mature B-cell Non-hodgkin Lymphoma [MB NHL], GROUP B will receive reduction therapy with dexamethasone, vincristine and cyclophosphamide (DOC), then undergo disease assessment. If tumor reduction ≥ 20%, will get induction 1 and 2 with polatuzumab vedotin, cyclophosphamide, vincristine, methotrexate, rituximab, doxorubicin (Pv-COM3RA25D) 1 and 2, then Consolidation 1 with rituximab, cytarabine, methotrexate (R-CYM) . Patients will undergo disease assessment post Consolidation 1. If no residual disease, they proceed to receive Consolidation 2 with Pv-R-CYM (R-CYM 2). Cohort Ia patients with < 20% tumor reduction post DOC will be assigned to Cohort Ib starting at Induction 1. Cohort Ia patients with residual disease post Consolidation 1 will be assigned to Cohort Ib starting at Consolidation 1 polatuzumab vedotin, rituximab, high dose cytarabine, cytarabine, high dose methotrexate, etoposide (Pv-R-CYVE 1). | Drug: DOC Group B<br>* Cyclophosphamide 300 mg x1; dexamethasone x 7; vincristine x1<br>* Other names: Reduction Phase;Drug: Pv-COMRAD 1 and 2 Group B<br>* polatuzumab vedotin x1; dexamethasone x 5; vincristine x1, cyclophosphamide x 3; doxorubicin x1; methotrexate x; rituximab 2x; ITT x1<br>* Other names: Induction 1 and 2;Drug: Pv-R-CYM 1 and 2 Group B<br>* polatuzumab vedotin x 1; methotrexate x 1; rituximab x 1; cytarabine x 5;<br>* Other names: Consolidation 1 and 2;|
| Experimental: Cohort 1b<br>MB NHL, GROUP C will receive reduction therapy with DOC. Patients with < 20% tumor reduction will be off protocol. Patients with ≥ 20% tumor reduction get Induction 1 and 2 with cyclophosphamide, doxorubicin, dexamethasone, high dose methotrexate, polatuzumab vedotin, and triple intrathecal chemotherapy (M8A30D CPR) 1 and 2, then Consolidation 1 with Pv-R-CYVE 1. If no residual disease, they get Consolidation 2 (Pv-R-CYVE 2), followed by Maintenance (M) 1 with M8A30D CP, M 2 with Pv-cytarabine/etoposide, M 3 with cyclophosphamide, doxorubicin, dexamethasone and polatuzumab vedotin (A30D CP), and M 4 with Pv-cytarabine/etoposide. Cohort Ib patients with CNS disease will receive additional intrathecal chemotherapy and high dose methotrexate during Consolidation. | Drug: DOC Group C<br>* cyclophosphamide x 1, dexamethasone x 5; vincristine x1; IT triples x 3<br>* Other names: Reduction with IT;Drug: MAD CPR 1 and 2<br>* methotrexate x 1; dexamethasone x 5; polatuzumab Vedotin x 1, cyclophosphamide x 3; doxorubicin x 1; rituximab x2; IT triples x 2 in induction 1, IT triples x 2 in induction 2<br>* Other names: Induction 1 and 2 Group C;Drug: Pv-R CYVE 1 and 2<br>* Polatuzumab Vedotin x 1; Rituximab x 1; Cytarabine x 5; Etoposide x4;<br>* Other names: Consolidation 1 and 2 Group C CNS Negative;Drug: Pv-R CYVE-MTX 1 and 2<br>* Polatuzumab Vedotin x 1; Rituximab x 1; Cytarabine x 5; Etoposide x4; high dose cytarabine x4; high dose methotrexate x 1 (only consolidation 1); IT triples x 2 (only 1 in consolidation 2)<br>* Other names: Consolidation 1 and 2 Group C CNS Positive;Drug: MAD CP<br>* dexamethasone x1; polatuzumab vedotin x 1; cyclophosphamide x 2; doxorubicin x 1; high dose methotrexate x 1; IT triples x 1<br>* Other names: Maintenance 1 Group C;Drug: Pv-Cytarabine/etoposide<br>* polatuzumab vedotin x 1; cytarabine x 5; etoposide x 3;<br>* Other names: Maintenance 2, 4 Group C;Drug: AD CP<br>* polatuzumab vedotin x 1; cyclophosphamide x2; doxorubicin x 2;<br>* Other names: Maintenance 3 Group C;Radiation: Involved Site Radiation Therapy<br>* 21 Gy in 14 fractions of 1.50 Gy per day. The treatment will be given 5 days per week. All fields shall be treated once each day. The total elapsed treatment time will be 2.8 weeks (14 sessions) for each field.<br>* Other names: Cohort II ONLY;|
| Experimental: Cohort 2a<br>Classical Hodgkin lymphoma, INTERMEDIATE RISK will receive 2 cycles of brentuximab vedotin (Bv), doxorubicin, vinblastine, dactinomycin, and rituximab (Bv-AVD-R 1 and 2). Response assessment with FDG-PET scan after 2 cycles of Bv-AVD-R. Rapid early responders (RER) will continue therapy with 2 cycles of Bv, vinblastine, dactinomycin, nivolumab, and rituximab (Bv-NVD-R 1 and 2). RERs will not receive radiation therapy. Patients deemed to be Slow Early Responders (SER) after 2 cycles of Bv-AVD-R will continue therapy with 4 cycles of Bv-NVD-R (Bv-NVD-R 1, 2, 3, and 4). Radiation therapy will be given at completion of therapy only for SER patients NOT achieving complete remission at the end of chemoimmunotherapy. | Drug: Bv-AVD-R 1 and 2: COHORT IIa<br>* brentuximab vedotin x 2; doxorubicin x 2; vinblastine x 2; dacarbazine 2x; rituximab x 2<br>* Other names: Intermediate Risk cohort IIa;Drug: Bv-NVD-R, Cycle 1-2<br>* brentuximab vedotin x 2; nivolumab x 2; vinblastine x2; dacarbazine x 2; rituximab x 2;<br>* Other names: Cohort IIa Rapid Early Responders;Drug: Bv-NVD-R, Cycle 1-4 SER<br>* brentuximab vedotin x 2; nivolumab x 2; vinblastine x 2; rituximab x 2;<br>* Other names: Cohort IIa Slow Early Responders;|
| Experimental: Cohort 2b<br>COHORT IIb (Classical Hodgkin lymphoma, HIGH RISK) Cohort IIb patients will receive 2 cycles of brentuximab vedotin (Bv), doxorubicin, vinblastine, dactinomycin, and rituximab (Bv-AVD-R 1 and 2). Response assessment will be performed with FDG-PET scan after 2 cycles of Bv-AVD-R. Rapid early responders (RER) will continue therapy with 4 cycles of Bv, vinblastine, dactinomycin, nivolumab, and rituximab (Bv-NVD-R 1, 2, 3, and 4). RERs will not receive radiation therapy. Patients deemed to be Slow Early Responders (SER) after 2 cycles of Bv-AVD-R will receive 2 cycles of Bv, nivolumab, doxorubicin, vinblastine, dactinomycin, and rituximab (Bv-NAVD-R 1 and 2), followed by 4 cycles of Bv, vinblastine, dactinomycin, nivolumab, and rituximab (Bv-NVD-R 1, 2, 3, and 4). Radiation therapy will be given at completion of therapy only for SER patients NOT achieving complete remission at the end of chemoimmunotherapy. | Drug: Bv-AVD-R<br>* Brentuximab vedotin x2; doxorubicin x2; vinblastine x 2; dacarbazine x 2; rituximab x2;<br>* Other names: High-Risk cohort IIb;Drug: Bv-NVD-R, Cycle 1-4 RER<br>* brentuximab vedotin x 2; nivolumab x 2; vinblastine x 2; dacarbazine x 2; rituximab x 2;<br>* Other names: cohort IIb Rapid Early Responders;Drug: Bv-NAVD-R, Cycle 1-2<br>* brentuximab vedotin x 2; nivolumab x 2; doxorubicin x 2; vinblastine x 2; dacarbazine x 2; rituximab x 2;<br>* Other names: cohort IIb Slow Early Responders;Radiation: Involved Site Radiation Therapy<br>* 21 Gy in 14 fractions of 1.50 Gy per day. The treatment will be given 5 days per week. All fields shall be treated once each day. The total elapsed treatment time will be 2.8 weeks (14 sessions) for each field.<br>* Other names: Cohort II ONLY;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Grade 3 and 4 Adverse Events related to polatuzumab vedotin | to evaluate the DLTs of polatuzumab vedotin (Pv) in combination with rituximab (RTX) containing French-American-British (FAB) chemoimmunotherapy, with reduced dose anthracycline to MB-NHL | 1 year | 
| Grade 3 and 4 Adverse events related to nivolumab | To evaluate the DLTs of nivolumab to the backbone of reduced toxicity chemoimmunotherapy with brentuximab vedotin (Bv), vinblastine, dacarbazine and rituximab, with reduced dose anthracycline in intermediate and high risk cHL | 1 year |