Inotuzumab Ozogamicin and Post-Induction Chemotherapy in Treating Patients With High-Risk B-ALL, Mixed Phenotype Acute Leukemia, and B-LLy

Titre officiel

A Phase 3 Randomized Trial of Inotuzumab Ozogamicin (NSC#: 772518) for Newly Diagnosed High-Risk B-ALL; Risk-Adapted Post-Induction Therapy for High-Risk B-ALL, Mixed Phenotype Acute Leukemia, and Disseminated B-LLy

Sommaire:

Cet essai de phase III étudie si l’ajout d’inotuzumab ozogamicine à la chimiothérapie post-induction chez les patients atteints de leucémie lymphoblastique aiguë à cellules B (LLA-B) présentant un risque élevé améliore les résultats. Cet essai étudie également les résultats des patients atteints de leucémie aiguë à phénotype mixte (LAPM) et de lymphome lymphoblastique à cellules B (LLB-B) avec un traitement contre la LLA sans inotuzumab ozogamicine. L’inotuzumab ozogamicine est un anticorps monoclonal, appelé inotuzumab, lié à un type de chimiothérapie appelé calichéamicine. L’inotuzumab se fixe de manière ciblée sur les cellules cancéreuses et délivre de la calichéamicine pour les tuer. D’autres médicaments utilisés dans le schéma chimiothérapeutique, comme le cyclophosphamide, la cytarabine, la dexaméthasone, la doxorubicine, la daunorubicine, le méthotrexate, la leucovorine, la mercaptopurine, la prednisone, la thioguanine, la vincristine et la pégaspargase, agissent de différentes manières pour arrêter la croissance des cellules cancéreuses, soit en tuant les cellules, soit en les empêchant de se diviser ou de se propager. Cet essai étudiera également les résultats des patients atteints de leucémie aiguë à phénotype mixte (LAPM) et de lymphome lymphoblastique à cellules B disséminées (LLB-B) lorsqu’ils sont traités par une chimiothérapie contre la LLA présentant un risque élevé. L’objectif général de cette étude est de comprendre si l’ajout de l’inotuzumab ozogamicine à la chimiothérapie standard maintient ou améliore les résultats dans la leucémie lymphoblastique aiguë à cellules B présentant un risque élevé (LLA-B-RÉ). La première partie de l’étude comprend les deux premières phases du traitement : l’induction et la consolidation. Cette partie permettra de recueillir des renseignements sur la leucémie, ainsi que sur les effets du traitement initial, afin de classer les patients dans des groupes de traitement après la consolidation. Dans la deuxième partie de cette étude, les patients recevront le reste des cycles de chimiothérapie (entretien intermédiaire I, intensification retardée, entretien intermédiaire II, entretien), certains patients étant répartis de façon aléatoire pour recevoir de l’inotuzumab. Cette étude vise également à déterminer si le fait de traiter les hommes et les femmes avec la même durée de chimiothérapie permet de maintenir les résultats chez les hommes qui ont déjà été traités pendant une année supplémentaire par rapport aux femmes, ainsi qu’à évaluer les meilleurs moyens d’aider les patients à respecter les schémas chimiothérapiques par voie orale. Enfin, cette étude sera la première à suivre les résultats de sujets atteints de leucémie lymphoblastique à cellules B disséminées (LLB-B) ou de leucémie aiguë à phénotype mixte (LAPM) lorsqu’ils sont traités par une chimiothérapie contre la LLA-B.

Description de l'essai

Primary Outcome:

  • Improvement in 5-year disease-free survival (DFS) after adding 2 blocks of inotuzumab ozogamicin (InO) to Berlin-Frankfurt-Munster (mBFM) chemotherapy in children and young adults with High-Risk (HR) B-ALL

Secondary Outcome:

  • 5-year DFS for favourable risk subset of NCI HR B-ALL (HR favourable) when treated with mBFM chemotherapy with a single high-dose methotrexate (HD MTX) Interim Maintenance (IM) phase and treatment duration of 2 years from the start of IM regardless of sex
  • Incidence of adverse events for the integration of inotuzumab ozogamicin into the mBFM chemotherapy backbone in HR B-ALL
  • 5-year event-free survival (EFS) for patients with mixed phenotype acute leukemia (MPAL) receiving mBFM HR B-ALL therapy that includes a second IM phase with Capizzi escalating intravenous MTX without leucovorin rescue plus pegaspargase (C-MTX)
  • 5-year EFS for patients with disseminated (Murphy stage III-IV) B-cell lymphoblastic lymphoma (B-LLy) receiving mBFM HR B-ALL therapy that includes a second IM phase with C-MTX

PRIMARY OBJECTIVE:

  • To determine in a randomized manner if the addition of 2 blocks of inotuzumab ozogamicin to modified Berlin-Frankfurt-Munster (mBFM) chemotherapy will improve 5-year disease-free survival (DFS) in children and young adults with high-risk B-cell acute lymphoblastic leukemia (HR B-ALL).

SECONDARY OBJECTIVES:

  • To describe the 5-year DFS for a favourable risk subset of National Cancer Institute (NCI) HR B-ALL (HR-Fav) when treated with mBFM chemotherapy with a single high-dose methotrexate (HD-MTX) interim maintenance (IM) phase and treatment duration of 2 years from the start of IM regardless of sex.
  • To determine the toxicity and tolerability of inotuzumab ozogamicin integrated into the mBFM chemotherapy backbone in HR B-ALL.
  • To describe the 5-year event-free survival (EFS) for patients with mixed phenotype acute leukemia (MPAL) receiving mBFM HR B-ALL therapy that includes a second IM phase with Capizzi escalating intravenous (IV) methotrexate (MTX) without leucovorin rescue plus pegaspargase (C-MTX).
  • To describe the 5-year EFS for patients with disseminated (Murphy stage III-IV) B-cell lymphoblastic lymphoma (B-LLy) receiving mBFM HR B-ALL therapy that includes a second IM phase with C-MTX.

EXPLORATORY OBJECTIVES:

  • To describe the therapy administered, disease response, and survival outcomes of patients with MPAL who come off protocol therapy due to poor disease response to ALL therapy either during Induction, at end of induction (EOI), or at end of consolidation (EOC).
  • To define the prevalence and significance of minimal marrow disease (MMD) at diagnosis and bone marrow minimal residual disease (MRD) at EOI in disseminated B-LLy.
  • To determine the impact of proposed adherence-enhancing interventions, IP (intervention package as used in ACCL1033) versus (vs.) iIP (intensified intervention package) vs. pIP (patient/parent-established intervention package), on adherence to oral 6 mercaptopurine in children and young adults with ALL.

OUTLINE: All patients receive the same Induction and Consolidation chemotherapy. Patients with HR-Fav B-ALL are assigned to Arm I. Patients with HR B-ALL are randomized to Arm II or III. Patients with MPAL are assigned to Arm IV, and patients with B-LLy are assigned to Arm V. All patients with B-ALL receive Induction and Consolidation therapy:

INDUCTION: Patients receive cytarabine intrathecally (IT) on day 1 and central nervous system (CNS)2 patients also receive cytarabine IT on days 4, 5 or 6 and 11 or 12. Patients also receive vincristine intravenously (IV) over 1 minute on days 1, 8, 15, and 22, daunorubicin IV over 1-15 minutes days 1, 8, 15, and 22, pegaspargase intramuscularly (IM) or IV over 1-2 hours on day 4, and methotrexate IT on days 8 and 29 (and on days 15 and 22 for CNS3 patients). Patients < 10 years old receive dexamethasone orally (PO) twice daily (BID) or IV on days 1-14; patients >= 10 years old receive prednis(ol)one PO BID or IV on days 1-28. Treatment continues for 5 weeks in the absence of disease progression or unacceptable toxicity.

CONSOLIDATION: Patients receive cyclophosphamide IV over 30-60 minutes on days 1 and 29, cytarabine IV over 1-30 minutes or subcutaneously (SC) on days 1-4, 8-11, 29-32, and 36-39, mercaptopurine PO once daily (QD) on days 1-14 and 29-42, and methotrexate IT on days 1, 8, 15, and 22 (CNS3 patients receive methotrexate IT on days 1 and 8). Patients also receive vincristine IV over 1 minute on days 15, 22, 43, and 50, and pegaspargase IV over 1-2 hours or IM on days 15 and 43. Treatment continues for 8 weeks in the absence of disease progression or unacceptable toxicity. Additionally, patients with testicular disease at diagnosis that does not resolve by the end of induction will undergo radiation therapy over 12 once daily fractions.

POST-CONSOLIDATION THERAPY: After Consolidation, based on clinical features and response, patients with B-ALL are designated as HR-Fav or HR B-ALL. Patients with HR-Fav B-ALL are assigned to Arm I. Patients with HR B-ALL are randomized to Arm II or III. Patients with MPAL and B-LLy are assigned to therapy arms (Arms IV and V) that are identical to Arm II. Patients that are < 10 years, have CNS1, no testicular leukemia, with favourable cytogenetics (ETV6 RUNX1 fusion or double trisomies [4 and 10]), =< 24 hours of steroids in the two weeks prior to diagnosis, and EOI MRD < 0.01% are assigned to Arm I. Patients with HR B-ALL who are CD22 positive at diagnosis, are randomized to either Arm II or III.

ARM I: HR-FAV B-ALL (Patients that are < 10 years, have CNS1 status, no testicular leukemia, with favourable cytogenetics (ETV6 RUNX1 fusion or double trisomies [4 and 10]), =< 24 hours of steroids in the two weeks prior to diagnosis, and EOI MRD < 0.01%)

INTERIM MAINTENANCE: Patients receive vincristine IV over 1 minute on days 1, 15, 29, and 43, high dose methotrexate IV over 24 hours on days 1, 15, 29, and 43, leucovorin PO or IV on days 3-4, 17-18, 31-32, and 45-46, mercaptopurine PO QD on days 1-14, 15-28, 29-42, and 43-56, and methotrexate IT on days 1 and 29. Treatment continues for 9 weeks in the absence of disease progression or unacceptable toxicity.

DELAYED INTENSIFICATION (PART I): Patients receive methotrexate IT on day 1, dexamethasone PO BID or IV on days 1-7 and 15-21, vincristine IV over 1 minute on days 1, 8, and 15, doxorubicin IV over 1-15 minutes or up to 1 hour on days 1, 8, and 15, and pegaspargase IV over 1-2 hours or IM on day 4. Treatment (Parts I and II of Delayed Intensification) continues for 8 weeks in the absence of disease progression or unacceptable toxicity.

DELAYED INTENSIFICATION (PART II): Patients receive cyclophosphamide IV over 30-60 minutes on day 29, thioguanine PO on days 29-42, cytarabine IV over 1-30 minutes or SC on days 29-32 and 36-39, methotrexate IT on days 29 and 36, vincristine IV over 1 minute on days 43 and 50, and pegaspargase IV over 1-2 hours or IM on day 43. Treatment (Parts I and II of Delayed Intensification) continues for 8 weeks in the absence of disease progression or unacceptable toxicity.

MAINTENANCE: Patients receive methotrexate IT on days 1 and 29 for cycles 1-4, and day 1 for subsequent cycles. Patients also receive vincristine IV over 1 minute on day 1, prednisolone PO BID or IV on days 1-5, mercaptopurine PO QD on days 1-84, and methotrexate PO on days 8, 15, 22, (29 excluded in cycles 1-4), 36, 43, 50, 57, 64, 71, and 78. Cycles repeat every 12 weeks for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients with HR B-ALL and leukemic blasts positive for CD22 at diagnosis are randomized to Arm II or Arm III.

ARM II: HR B-ALL (CONTROL) INTERIM MAINTENANCE I: Patients receive vincristine IV over 1 minute on days 1, 15, 29 and 43, high dose methotrexate IV over 24 hours on days 1, 15, 29 and 43, leucovorin PO or IV on days 3-4, 17-18, 31-32, 45-46, mercaptopurine PO QD on days 1-14, 15-28, 29-42, and 43-56, and methotrexate IT on days 1 and 29. Treatment continues for 9 weeks in the absence of disease progression or unacceptable toxicity.

DELAYED INTENSIFICATION (PART I): Patients receive methotrexate IT on day 1, dexamethasone PO BID or IV on days 1-7 and 15-21, vincristine IV over 1 minute on days 1, 8, and 15, doxorubicin IV over 1-15 minutes or up to 1 hour on days 1, 8, and 15, and pegaspargase IV over 1-2 hours or IM on day 4. Treatment (Parts I and II of Delayed Intensification) continues for 8 weeks in the absence of disease progression or unacceptable toxicity.

DELAYED INTENSIFICATION (PART II): Patients receive cyclophosphamide IV over 30-60 minutes on day 29, thioguanine PO on days 29-42, cytarabine IV over 1-30 minutes or SC on days 29-32 and 36-39, methotrexate IT on days 29 and 36, vincristine IV over 1 minute on days 43 and 50, and pegaspargase IV over 1-2 hours or IM on day 43. Treatment (Parts I and II of Delayed Intensification) continues for 8 weeks in the absence of disease progression or unacceptable toxicity.

INTERIM MAINTENANCE II: Patients receive vincristine IV over 1 minute on days 1, 11, 21, 31 and 41, methotrexate IV over 2-15 minutes or 10-15 minutes on days 1, 11, 21, 31, and 41, methotrexate IT on days 1 and 31, and pegaspargase IV over 1-2 hours or IM on days 2 and 22. Treatment continues for 8 weeks in the absence of disease progression or unacceptable toxicity.

ARM III: HR B-ALL (EXPERIMENTAL) INOTUZUMAB OZOGAMICIN (InO) BLOCK 1: Patients receive inotuzumab ozogamicin IV over 60 minutes on days 1, 8, and 15 and methotrexate IT on day 1. Treatment continues for 4 weeks in the absence of disease progression or unacceptable toxicity.

INTERIM MAINTENANCE I: Patients receive vincristine IV over 1 minute on days 1, 15, 29 and 43, high dose methotrexate IV over 24 hours on days 1, 15, 29, and 43, leucovorin PO or IV on days 3-4, 17-18, 31-32, and 45-46, mercaptopurine PO on days 1-14, 15-28, 29-42, and 43-56, and methotrexate IT on days 1 and 29. Treatment continues for 9 weeks in the absence of disease progression or unacceptable toxicity.

InO BLOCK 2: Patients receive inotuzumab ozogamicin IV over 60 minutes on days 1, 8, and 15. Treatment continues for 4 weeks in the absence of disease progression or unacceptable toxicity.

DELAYED INTENSIFICATION (PART I): Patients receive methotrexate IT on day 1, dexamethasone PO BID or IV on days 1-7 and 15-21, vincristine IV over 1 minute on days 1, 8, and 15, doxorubicin IV over 1-15 minutes or up to 1 hour on days 1, 8, and 15, and pegaspargase IV over 1-2 hours or IM on day 4. Treatment (Parts I and II of Delayed Intensification) continues for 8 weeks in the absence of disease progression or unacceptable toxicity.

DELAYED INTENSIFICATION (PART II): Patients receive cyclophosphamide IV over 30-60 minutes on day 29, thioguanine PO on days 29-42, cytarabine IV over 1-30 minutes or SC on days 29-32 and 36-39, methotrexate IT on days 29 and 36, vincristine IV over 1 minute on days 43 and 50, and pegaspargase IV over 1-2 hours or IM on day 43. Treatment (Parts I and II of Delayed Intensification) continues for 8 weeks in the absence of disease progression or unacceptable toxicity.

INTERIM MAINTENANCE II: Patients receive vincristine IV over 1 minute on days 1, 11, 21, 31, and 41, methotrexate IV on days 1, 11, 21, 31, and 41, methotrexate IT on days 1 and 31, and pegaspargase IV over 1-2 hours or IM on days 2 and 22. Treatment continues for 8 weeks in the absence of disease progression or unacceptable toxicity.

ARMS II AND III: HR B-ALL MAINTENANCE: Patients receive vincristine IV over 1 minute on day 1, prednisolone PO BID or IV on days 1-5, mercaptopurine PO on days 1-84, methotrexate PO on days 8, 15, 22, 29 (excluded in cycles 1 and 2), 36, 43, 50, 57, 64, 71 and 78, and methotrexate IT on days 1 (and 29 of cycles 1-2 for patients who do not receive cranial radiation). Cycles repeat every 12 weeks for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients with CNS3 disease undergo cranial radiation therapy over 10 fractions during the first 4 weeks.

ARM IV: MPAL INDUCTION: Patients receive cytarabine IT on day 1 and CNS2 patients also receive cytarabine IT on days 4, 5 or 6 and 11 or 12. Patients also receive vincristine IV over 1 minute on days 1, 8, 15, and 22, daunorubicin IV over 1-15 minutes days 1, 8, 15, and 22, pegaspargase IM or IV over 1-2 hours on day 4, and methotrexate IT on days 8 and 29 (and on days 15 and 22 for CNS3 patients). Patients < 10 years old receive dexamethasone PO BID or IV on days 1-14; patients >= 10 years old receive prednisolone PO BID or IV on days 1-28. Treatment continues for 5 weeks in the absence of disease progression or unacceptable toxicity.

CONSOLIDATION: Patients receive cyclophosphamide IV over 30-60 minutes on days 1 and 29, cytarabine IV over 1-30 minutes or SC on days 1-4, 8-11, 29-32, and 36-39, mercaptopurine PO on days 1-14 and 29-42, methotrexate IT on days 1, 8, 15, and 22 (excluded on days 15 and 22 for CNS3 patients), vincristine IV over 1 minute on days 15, 22, 43, and 50, and pegaspargase IV over 1-2 hours or IM on days 15 and 43. Treatment continues for 8 weeks in the absence of disease progression or unacceptable toxicity. Patients with testicular disease at diagnosis that does not resolve by the end of induction will and continued evidence of testicular disease at end of induction undergo testicular radiation over 12 once-daily fractions.

ARM V: B-LLY INDUCTION: Patients receive cytarabine IT on day 1 and CNS2 patients also receive cytarabine IT on days 4, 5 or 6 and 11 or 12. Patients also receive vincristine IV over 1 minute on days 1, 8, 15, and 22, daunorubicin IV over 1-15 minutes days 1, 8, 15, and 22, pegaspargase IM or IV over 1-2 hours on day 4, and methotrexate IT on days 8 and 29 (and on days 15 and 22 for CNS3 patients). Patients < 10 years old receive dexamethasone PO BID or IV on days 1-14; patients >= 10 years old receive prednisolone PO BID or IV on days 1-28. Treatment continues for 5 weeks in the absence of disease progression or unacceptable toxicity.

CONSOLIDATION: Patients receive cyclophosphamide IV over 30-60 minutes on days 1 and 29, cytarabine IV over 1-30 minutes or SC on days 1-4, 8-11, 29-32, and 36-39, mercaptopurine PO on days 1-14 and 29-42, methotrexate IT on days 1, 8, 15, and 22 (excluded on days 15 and 22 CNS3 patients), vincristine IV over 1 minute on days 15, 22, 43, and 50, and pegaspargase IV over 1-2 hours or IM on days 15 and 43. Treatment continues for 8 weeks in the absence of disease progression or unacceptable toxicity. Patients with testicular disease at diagnosis that does not resolve by the end of induction will and continued evidence of testicular disease at end of induction undergo testicular radiation therapy over 12 once-daily fractions.

ARM IV AND V: MPAL AND B-LLY (Post-Consolidation Therapy) INTERIM MAINTENANCE I: Patients receive vincristine IV over 1 minute on days 1, 15, 29, and 43, high dose methotrexate IV over 24 hours on days 1, 15, 29, and 43, leucovorin PO or IV on days 3-4, 17-18, 31-32, and 45-46, methotrexate IT on days 1 and 29 and mercaptopurine PO QD on days 1-14, 15-28, 29-42, and 43-56. Treatment continues for 9 weeks in the absence of disease progression or unacceptable toxicity.

DELAYED INTENSIFICATION (PART I): Patients receive methotrexate IT on day 1, dexamethasone PO BID or IV on days 1-7 and 15-21, vincristine IV over 1 minute on days 1, 8, and 15, doxorubicin IV over 1-15 minutes or up to 1 hour on days 1, 8, and 15, and pegaspargase IV over 1-2 hours or IM on day 4. Treatment (Parts I and II of Delayed Intensification) continues for 8 weeks in the absence of disease progression or unacceptable toxicity.

DELAYED INTENSIFICATION (PART II): Patients receive cyclophosphamide IV over 30-60 minutes on day 29, thioguanine PO on days 29-42, cytarabine IV over 1-30 minutes or SC on days 29-32 and 36-39, methotrexate IT on days 29 and 36, vincristine IV over 1 minute on days 43 and 50, and pegaspargase IV over 1-2 hours or IM on day 43. Treatment (Parts I and II of Delayed Intensification) continues for 8 weeks in the absence of disease progression or unacceptable toxicity.

INTERIM MAINTENANCE II: Patients receive vincristine IV over 1 minute on days 1, 11, 21, 31, and 41, methotrexate IV or infusion over 2-15 minutes or 10-15 minutes on days 1, 11, 21, 31, and 41, methotrexate IT on days 1 and 31, and pegaspargase IV over 1-2 hours or IM on days 2 and 22. Treatment continues for 8 weeks in the absence of disease progression or unacceptable toxicity.

MAINTENANCE: Patients receive vincristine IV over 1 minute on days 1, prednisolone PO BID or IV on days 1-5, mercaptopurine PO on days 1-84, methotrexate PO on days 8, 15, 22, 29 (excluded in cycles 1 and 2), 36, 43, 50, 57, 64, 71, and 78, and methotrexate IT on days 1 (and 29 of cycles 1-2 for patients who do not receive cranial radiation). Cycles repeat every 12 weeks for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients with CNS3 disease at diagnosis undergo cranial radiation therapy for 10 fractions over 4 weeks. After completion of study treatment, patients are followed up at 4 weeks, then every 3 months for 2 years, every 4-6 months for the third year, then every 6-12 months for years 4-5.

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