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A PHASE III TRIAL TO EVALUATE THE EFFICACY OF THE ADDITION OF INOTUZUMAB OZOGAMICIN (A CONJUGATED ANTI-CD22MONOCLONAL ANTIBODY) TO FRONTLINE THERAPY IN YOUNG ADULTS (AGES 18-39 YEARS) WITH NEWLY DIAGNOSED PRECURSOR B-CELL ALL

Enrolling

Trial ID:NCT03150693

View complete trial on ClinicalTrials.gov

Protocol #:17-717

DiseasesLymphoid Leukemia

Phase:III

Principal Investigator:DeAngelo, Daniel, J

Site Investigator(s):Hock, Hanno, R.

Trial Description:
PRIMARY OBJECTIVES:
I. To confirm tolerability of the combination regimen with the addition of inotuzumab ozogamicin to the pediatric-inspired regimen of cancer and leukemia group B (CALGB) 10403.
II. To determine whether the addition of inotuzumab ozogamicin significantly improves the event-free survival (EFS) in patients who achieve an induction response achieved with the pediatric-inspired regimen of CALGB 10403, without censoring for transplant. (Phase III)

SECONDARY OBJECTIVES:
I. To determine the impact of inotuzumab ozogamicin on disease-free (DFS) and overall survival (OS) in patients who achieve an induction response.
II. To determine whether the addition of inotuzumab ozogamicin significantly improves the event-free survival (EFS) in patients who achieve an induction response achieved with the pediatric-inspired regimen of CALGB 10403, with censoring for transplant.
III. To determine the impact of inotuzumab ozogamicin on minimal residual disease (MRD) and correlate this with the EFS, DFS and OS.
IV. To determine the prognosis based on patients’ low-density array (LDA) gene signature in terms of EFS, DFS, and OS after treatment with or without inotuzumab ozogamicin when added to the C10403 backbone regimen.
V. To evaluate the toxicity and tolerability of the addition of inotuzumab ozogamicin to the pediatric-inspired regimen of CALGB 10403.

TERTIARY OBJECTIVES:
I. To assess both the correlation of MRD post-induction and at sequential timepoints with LDA signature.
II. To evaluate the influence of MRD status (detectable versus [vs.] not and as a continuous measure) in relation to EFS both in the univariate setting as well as adjusting for other clinical features including initial white blood cell (WBC), ethnicity, gender and age at diagnosis.
III. To evaluate the impact of inotuzumab ozogamicin (inotuzumab) on the kinetics of MRD during treatment with inotuzumab in patients randomized to the experimental treatment arm.
IV. To perform genomic analyses to identify and evaluate the incidence and clinical significance of recurring novel fusion genes including those associated with the BCR-ABL1-like signature and to correlate with MRD status, complete response (CR) rate, EFS and OS.
V. To assess whether rs4958351 is correlated with L-asp allergic reaction in the adolescent and young adult (AYA) population.
VI. To assess the incidence of inherited genetic variants in the GR1A1, CEP72, CPA2, TPMT, NUDT15, GRIN3A, GRIK1, and other genes (which can be found using a whole genome association study [GWAS]), are correlated with increased rates of target toxicities including peripheral neuropathy, hepatotoxicity, pancreatitis, myelosuppression, neurotoxicity, thrombosis, and osteonecrosis, and correlate with treatment discontinuation and other clinical response parameters including CR rate, EFS, and OS.
VII. To evaluate asparaginase pharmacokinetics in adolescents and young adults, and investigate its correlation with toxicities and treatment outcomes.
VIII. To investigate the effect of anti-polyethylene glycol (PEG) and anti-agouti signaling protein (ASP) antibodies (PEG-ASP) on ASP enzyme activity.
IX. To measure adherence to oral 6 mercaptopurine (MP) and methotrexate in AYAs with acute lymphoblastic leukemia (ALL) and to examine sociodemographic and behavioral determinants of adherence.
X. To determine the impact of adherence on risk of relapse among AYAs with ALL.

OUTLINE:
COURSE I (REMISSION INDUCTION THERAPY): All patients receive allopurinol orally (PO) once daily until peripheral blasts and extramedullary disease are reduced and cytarabine intrathecally (IT) over 1 minute on day 1. Patients also receive daunorubicin hydrochloride intravenously (IV) and vincristine sulfate IV on days 1, 8, 15 and 22, dexamethasone PO or IV twice daily (BID) on days 1-7 and 15-21, pegylated recombinant L-asparaginase erwinia chrysanthemi IV on day 4, 5, or 6, and methotrexate IT over 1 minute on days 8 and 29. Patients with central nervous system (CNS) 3 disease receive methotrexate IT over 1 minute also on days 15 and 22. All patients then undergo bone marrow aspirate and biopsy on day 29.

Patients with response to remission induction therapy are randomized to 1 of 2 arms. Patients with no response are omitted from the study.

ARM I:
COURSE II (REMISSION CONSOLIDATION CHEMOTHERAPY): Patients receive cyclophosphamide IV on days 1 and 29, cytarabine IV or SC on days 1-4, 8-11, 29-32, and 36-39, mercaptopurine PO on days 1-14 and 29-42, and vincristine sulfate IV on days 15, 22, 43, and 50. Patients also receive pegylated recombinant L- asparaginase erwinia chrysanthemi IV on days 15 and 43, and methotrexate IT on days 1, 8, 15, and 22. Patients with CNS3 receive methotrexate IT only on days 1 and 8. CD20 positive (+) patients receive rituximab IV on days 1, 8, 29, and 36. Patients with evidence of testicular disease at diagnosis also receive radiation therapy (RT). Patients then undergo bone marrow aspirate and biopsy on day 56.

COURSE III (INTERIM MAINTENANCE CHEMOTHERAPY): Patients receive vincristine sulfate IV on days 1, 11, 21, 31, and 41, methotrexate IV and IT on days 1, 11, 21, 31, and 41, and pegylated recombinant L- asparaginase erwinia chrysanthemi IV on days 2 and 22. CD20+ patients receive rituximab IV on days 1 and 11.

COURSE IV (DELAYED INTENSIFICATION): Patients receive vincristine sulfate IV on days 1, 8, 15, 43, and 50, dexamethasone PO or IV BID on days 1-7 and 15-21, doxorubicin IV on days 1, 8, and 15, and pegylated recombinant L- asparaginase erwinia chrysanthemi IV on day 4, 5, or 6 and day 43. Patients also receive cyclophosphamide IV on day 29, cytarabine IV or SC on days 29-32 and 36-39, thioguanine PO on days 29-42 and methotrexate IT on days 1, 29, and 36. CD20+ patients receive rituximab IV on days 1 and 8. Patients then undergo bone marrow aspirate and biopsy on day 50.

COURSE V (MAINTENANCE THERAPY): Patients receive vincristine sulfate IV on days 1, 29, and 57, dexamethasone PO or IV BID on days 1-5, 29-33, and 57-61, and mercaptopurine PO on days 1-84. Patients also receive methotrexate IT or PO on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78. Treatment repeats every 12 weeks for up to 3 years in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive inotuzumab ozogamicin IV on days 1, 8, and 15 and undergo bone marrow aspirate and biopsy on day 28. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity. Patients also receive remission consolidated chemotherapy, interim maintenance chemotherapy, delayed intensification, and maintenance therapy as in Arm I.

After completion of study treatment, patients are followed up every month for the first year, every 2 months for the second year, every 3 months for the third year, and every 6 months for the fourth through tenth year.

Eligibilty Requirements:
REGISTRATION ELIGIBILITY CRITERIA (STEP 1)

Newly diagnosed patients with CD-22 positive B-cell acute lymphoblastic leukemia (World Health Organization [WHO] criteria) are eligible; patients with Burkitt type ALL are NOT eligible

Patients who have BCR-ABL fusion transcript determined by fluorescence in situ hybridization (FISH) or real time-polymerase chain reaction (RT-PCR) or t(9;22)(q34;q11) by cytogenetics are not eligible and should be considered for enrollment on studies that incorporate imatinib during induction; please note: patients must also be assessed for CD20 positivity and other markers; positivity for CD22 and CD20 is defined as baseline expression of the CD22 or CD20 antigen in more than 20% of leukemic cells using local multiparameter flow-cytometric immunophenotyping with the use of CD45 expression as a marker to gate the ALL blast population, according to recommendations from the European LeukemiaNet

No prior therapy for ALL except for limited treatment (=< 7 days) with corticosteroids or hydroxyurea and a single dose of intrathecal cytarabine; however, patients who are being treated with chronic steroids for other reasons (for example, to treat asthma, autoimmune disorders, lupus, etc.) are eligible

No prior therapy for acute leukemia except emergency therapy (corticosteroids or hydroxyurea) for blast cell crisis, superior vena cava syndrome, or renal failure due to leukemic infiltration of the kidneys; when indicated, leukapheresis or exchange transfusion is recommended to reduce the WBC

Single-dose intrathecal cytarabine is allowed prior to registration or prior to initiation of systematic therapy for patient convenience; systemic chemotherapy must begin within 72 hours of this intrathecal therapy

Not pregnant and not nursing; for women of childbearing potential only, a negative urine or serum pregnancy test done =< 8 days prior to registration is required

Eastern Cooperative Oncology Group (ECOG) performance status 0-2

Patients with down syndrome are excluded from this study

Aspartate aminotransferase (AST), alanine aminotransferase (ALT) =< 3 x upper limit of normal (ULN), unless suspected leukemic involvement of the liver

Direct bilirubin =< 3 x upper limit of normal (ULN), unless suspected leukemic involvement of the liver

Calculated (calc.) creatinine clearance >= 50 mL/min by Cockcroft-Gault

RANDOMIZATION ELIGIBILITY CRITERIA (STEP 2)

Completion of remission induction therapy

Patients with M2 marrow or better are eligible; patients with M3 or M4 marrow (greater than 25% lymphoblasts) will not be eligible to be randomized * Rating: M0, M1; Blast Cells (%): 0-5.0 * Rating: M2; Blast Cells (%): 5.1-25.0 * Rating: M3; Blast Cells (%): > 25-50 * Rating: M4; Blast Cells (%): > 50.0 * The term “blast cell” includes any cell that cannot be classified as a more mature normal element, and includes “leukemic cells,” pathologic lymphocytes, and stem cells

Absolute neutrophil count (ANC) >= 750/mm^3

Platelet count >= 75,000/mm^3

Total bilirubin =< 1.5 x upper limit of normal (ULN), except for patients with known Gilbert’s syndrome

AST =< 8 x upper limit of normal (ULN)