Clinical Trials /

A Study to Compare Blinatumomab Alone to Blinatumomab With Nivolumab in Patients Diagnosed With First Relapse B-Cell Acute Lymphoblastic Leukemia (B-ALL)

NCT04546399

Description:

This phase II trial studies the effect of nivolumab in combination with blinatumomab compared to blinatumomab alone in treating patients with B-cell acute lymphoblastic leukemia (B-ALL) that has come back (relapsed). Down syndrome patients with relapsed B-ALL are included in this study. Blinatumomab is an antibody, which is a protein that identifies and targets specific molecules in the body. Blinatumomab searches for and attaches itself to the cancer cell. Once attached, an immune response occurs which may kill the cancer cell. Nivolumab is a medicine that may boost a patient's immune system. Giving nivolumab in combination with blinatumomab may cause the cancer to stop growing for a period of time, and for some patients, it may lessen the symptoms, such as pain, that are caused by the cancer.

Related Conditions:
  • B-Cell Acute Lymphoblastic Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A Study to Compare Blinatumomab Alone to Blinatumomab With Nivolumab in Patients Diagnosed With First Relapse B-Cell Acute Lymphoblastic Leukemia (B-ALL)
  • Official Title: A Phase 2 Study of Blinatumomab (NSC# 765986) in Combination With Nivolumab (NSC # 748726), a Checkpoint Inhibitor of PD-1, in B-ALL Patients Aged ≥ 1 to < 31 Years Old With First Relapse

Clinical Trial IDs

  • ORG STUDY ID: NCI-2020-06813
  • SECONDARY ID: NCI-2020-06813
  • SECONDARY ID: AALL1821
  • SECONDARY ID: AALL1821
  • SECONDARY ID: U10CA180886
  • NCT ID: NCT04546399

Conditions

  • Down Syndrome
  • Recurrent B Acute Lymphoblastic Leukemia

Interventions

DrugSynonymsArms
BlinatumomabAnti-CD19 x Anti-CD3 Bispecific Monoclonal Antibody, Anti-CD19/Anti-CD3 Recombinant Bispecific Monoclonal Antibody MT103, Blincyto, MEDI-538, MT-103Arm G (dexamethasone, blinatumomab, nivolumab,MTX) DS patients
Cyclophosphamide(-)-Cyclophosphamide, 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate, Carloxan, Ciclofosfamida, Ciclofosfamide, Cicloxal, Clafen, Claphene, CP monohydrate, CTX, CYCLO-cell, Cycloblastin, Cycloblastine, Cyclophospham, Cyclophosphamid monohydrate, Cyclophosphamide Monohydrate, Cyclophosphamidum, Cyclophosphan, Cyclophosphane, Cyclophosphanum, Cyclostin, Cyclostine, Cytophosphan, Cytophosphane, Cytoxan, Fosfaseron, Genoxal, Genuxal, Ledoxina, Mitoxan, Neosar, Revimmune, Syklofosfamid, WR- 138719Group 3, Arm E (dexamethasone, blinatumomab, MTX)
Cytarabine.beta.-Cytosine arabinoside, 1-.beta.-D-Arabinofuranosyl-4-amino-2(1H)pyrimidinone, 1-.beta.-D-Arabinofuranosylcytosine, 1-Beta-D-arabinofuranosyl-4-amino-2(1H)pyrimidinone, 1-Beta-D-arabinofuranosylcytosine, 1.beta.-D-Arabinofuranosylcytosine, 2(1H)-Pyrimidinone, 4-Amino-1-beta-D-arabinofuranosyl-, 2(1H)-Pyrimidinone, 4-amino-1.beta.-D-arabinofuranosyl-, Alexan, Ara-C, ARA-cell, Arabine, Arabinofuranosylcytosine, Arabinosylcytosine, Aracytidine, Aracytin, Aracytine, Beta-Cytosine Arabinoside, CHX-3311, Cytarabinum, Cytarbel, Cytosar, Cytosine Arabinoside, Cytosine-.beta.-arabinoside, Cytosine-beta-arabinoside, Erpalfa, Starasid, Tarabine PFS, U 19920, U-19920, Udicil, WR-28453Arm G (dexamethasone, blinatumomab, nivolumab,MTX) DS patients
DexamethasoneAacidexam, Adexone, Aknichthol Dexa, Alba-Dex, Alin, Alin Depot, Alin Oftalmico, Amplidermis, Anemul mono, Auricularum, Auxiloson, Baycadron, Baycuten, Baycuten N, Cortidexason, Cortisumman, Decacort, Decadrol, Decadron, Decadron DP, Decalix, Decameth, Decasone R.p., Dectancyl, Dekacort, Deltafluorene, Deronil, Desamethasone, Desameton, Dexa-Mamallet, Dexa-Rhinosan, Dexa-Scheroson, Dexa-sine, Dexacortal, Dexacortin, Dexafarma, Dexafluorene, Dexalocal, Dexamecortin, Dexameth, Dexamethasone Intensol, Dexamethasonum, Dexamonozon, Dexapos, Dexinoral, Dexone, Dinormon, Dxevo, Fluorodelta, Fortecortin, Gammacorten, Hexadecadrol, Hexadrol, Lokalison-F, Loverine, Methylfluorprednisolone, Millicorten, Mymethasone, Orgadrone, Spersadex, TaperDex, Visumetazone, ZoDexArm G (dexamethasone, blinatumomab, nivolumab,MTX) DS patients
EtoposideDemethyl Epipodophyllotoxin Ethylidine Glucoside, EPEG, Lastet, Toposar, Vepesid, VP 16, VP 16-213, VP-16, VP-16-213, VP16Group 3, Arm E (dexamethasone, blinatumomab, MTX)
Hydrocortisone Sodium Succinate(11beta)-21-(3-Carboxy-1-oxopropyl)-11,17-dihydroxypregn-4-ene-3,20-dione, Monosodium Salt, A-Hydrocort, Buccalsone, Corlan, Cortisol Sodium Succinate, Cortop, Efcortelan, Emergent-EZ, Flebocortid, Hidroc Clora, Hycorace, Hydro-Adreson, Hydrocort, Hydrocortisone 21-Sodium Succinate, Hydrocortisone Na Succinate, Kinogen, Nordicort, Nositrol, Sinsurrene, Sodium hydrocortisone succinate, Solu-Cortef, Solu-GlycArm G (dexamethasone, blinatumomab, nivolumab,MTX) DS patients
Leucovorin CalciumAdinepar, Calcifolin, Calcium (6S)-Folinate, Calcium Folinate, Calcium Leucovorin, Calfolex, Calinat, Cehafolin, Citofolin, Citrec, Citrovorum Factor, Cromatonbic Folinico, Dalisol, Disintox, Divical, Ecofol, Emovis, Factor, Citrovorum, Flynoken A, Folaren, Folaxin, FOLI-cell, Foliben, Folidan, Folidar, Folinac, Folinate Calcium, folinic acid, Folinic Acid Calcium Salt Pentahydrate, Folinoral, Folinvit, Foliplus, Folix, Imo, Lederfolat, Lederfolin, Leucosar, leucovorin, Rescufolin, Rescuvolin, Tonofolin, WellcovorinArm G (dexamethasone, blinatumomab, nivolumab,MTX) DS patients
Mercaptopurine3H-Purine-6-thiol, 6 MP, 6 Thiohypoxanthine, 6 Thiopurine, 6-Mercaptopurine, 6-Mercaptopurine Monohydrate, 6-MP, 6-Purinethiol, 6-Thiopurine, 6-Thioxopurine, 6H-Purine-6-thione, 1,7-dihydro- (9CI), 7-Mercapto-1,3,4,6-tetrazaindene, Alti-Mercaptopurine, Azathiopurine, Bw 57-323H, Flocofil, Ismipur, Leukerin, Leupurin, Mercaleukim, Mercaleukin, Mercaptina, Mercaptopurinum, Mercapurin, Mern, NCI-C04886, Puri-Nethol, Purimethol, Purine, 6-mercapto-, Purine-6-thiol (8CI), Purine-6-thiol, monohydrate, Purinethiol, Purinethol, U-4748, WR-2785Group 3, Arm E (dexamethasone, blinatumomab, MTX)
MethotrexateAbitrexate, Alpha-Methopterin, Amethopterin, Brimexate, CL 14377, CL-14377, Emtexate, Emthexat, Emthexate, Farmitrexat, Fauldexato, Folex, Folex PFS, Lantarel, Ledertrexate, Lumexon, Maxtrex, Medsatrexate, Metex, Methoblastin, Methotrexate LPF, Methotrexate Methylaminopterin, Methotrexatum, Metotrexato, Metrotex, Mexate, Mexate-AQ, MTX, Novatrex, Rheumatrex, Texate, Tremetex, Trexeron, Trixilem, WR-19039Arm G (dexamethasone, blinatumomab, nivolumab,MTX) DS patients
NivolumabBMS-936558, MDX-1106, NIVO, ONO-4538, OpdivoArm G (dexamethasone, blinatumomab, nivolumab,MTX) DS patients
PegaspargaseL-Asparaginase with Polyethylene Glycol, Oncaspar, Oncaspar-IV, PEG-Asparaginase, PEG-L-Asparaginase, PEG-L-Asparaginase (Enzon - Kyowa Hakko), PEGLA, Polyethylene Glycol L-Asparaginase, Polyethylene Glycol-L-AsparaginaseGroup 3, Arm E (dexamethasone, blinatumomab, MTX)
Thioguanine2-Amino 6MP, 2-Amino-1,7-dihydro-6H-purine-6-thione, 2-Amino-6-mercaptopurine, 2-Amino-6-purinethiol, 2-Aminopurin-6-thiol, 2-Aminopurine-6(1H)-thione, 2-Aminopurine-6-thiol, 2-Aminopurine-6-thiol Hemihydrate, 2-Mercapto-6-aminopurine, 6-Amino-2-mercaptopurine, 6-Mercapto-2-aminopurine, 6-Mercaptoguanine, 6-TG, 6H-Purine-6-thione, 2-amino-1,7-dihydro- (9CI), BW 5071, Lanvis, Tabloid, Thioguanine Hemihydrate, Thioguanine Hydrate, Tioguanin, Tioguanine, Wellcome U3B, WR-1141, X 27Group 3, Arm E (dexamethasone, blinatumomab, MTX)
Vincristine SulfateKyocristine, Leurocristine Sulfate, Leurocristine, sulfate, Oncovin, Vincasar, Vincosid, Vincrex, Vincristine, sulfateGroup 3, Arm E (dexamethasone, blinatumomab, MTX)

Purpose

This phase II trial studies the effect of nivolumab in combination with blinatumomab compared to blinatumomab alone in treating patients with B-cell acute lymphoblastic leukemia (B-ALL) that has come back (relapsed). Down syndrome patients with relapsed B-ALL are included in this study. Blinatumomab is an antibody, which is a protein that identifies and targets specific molecules in the body. Blinatumomab searches for and attaches itself to the cancer cell. Once attached, an immune response occurs which may kill the cancer cell. Nivolumab is a medicine that may boost a patient's immune system. Giving nivolumab in combination with blinatumomab may cause the cancer to stop growing for a period of time, and for some patients, it may lessen the symptoms, such as pain, that are caused by the cancer.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To compare rate of minimal residual disease (MRD) negative second remission (Rem-2) after
      up to two cycles of reinduction with blinatumomab versus (vs.) blinatumomab/nivolumab in
      Group 1 patients aged >= 1 to < 31 years old with first relapse of CD19+ B-ALL.

      II. To compare event-free survival (EFS) PI (EFS post-induction) between consolidation with
      blinatumomab vs. blinatumomab/nivolumab in Group 3 patients aged >= 1 to <31 years old with
      first relapse of CD19+ B ALL.

      SECONDARY OBJECTIVES:

      I. To evaluate the safety and tolerability of blinatumomab/nivolumab in patients aged >= 1 to
      < 31 years old with first relapse of CD19+ B ALL.

      II. To compare EFS post-induction between blinatumomab vs. blinatumomab/nivolumab in Group 2
      patients aged >= 1 to < 31 years old with first relapse of CD19+ B ALL.

      EXPLORATORY OBJECTIVES:

      I. In Group 1 patients, compare EFS between blinatumomab monotherapy and
      blinatumomab/nivolumab arms as compared to similar patients treated on the predecessor trial
      AALL1331.

      II. In Group 1 patients, compare toxicity as defined by grade 3 or greater adverse events
      during the first cycle of blinatumomab or blinatumomab/nivolumab to similar patients treated
      with block 1 of cytotoxic chemotherapy on the predecessor trial AALL1331.

      III. In Group 2 patients with MRD >= 0.1% after vincristine sulfate, dexamethasone, pegylated
      asparaginase, and doxorubicin hydrochloride (VXLD), compare MRD negative second remission
      (Rem-2) rate after the first cycle of immunotherapy between blinatumomab monotherapy and
      blinatumomab/nivolumab arms.

      IV. In patients with Down syndrome (DS) with first relapse of B-ALL, describe the safety,
      tolerability and efficacy (as defined by MRD negative second remission, Rem-2) after up to
      two cycles of blinatumomab/nivolumab.

      OUTLINE: Patients >= 18 years old with marrow +/- extramedullary (EM) relapse of any duration
      after initial diagnosis, or patients < 18 years old with marrow +/- EM relapse < 24 months
      after initial diagnosis are assigned to Group 1. Patients < 18 years old with marrow +/- EM
      relapse >= 24 months from initial diagnosis, or all isolated extramedullary (IEM) relapses >=
      1 to < 31 years old are assigned to Groups 2-3 re-induction. Patients with DS are assigned to
      Arm G. NOTE: Patients in Group 1 and DS patients with white blood cells (WBC) >= 30,000/uL,
      CNS 2/3 disease, or testicular disease must first receive 1 of 3 pre-immunotherapy
      treatments.

      PRE-IMMUNOTHERAPY TREATMENT FOR PATIENTS WITH WBC >= 30,000/uL: Patients receive methotrexate
      (MTX) intrathecally (IT) or cytarabine IT or intrathecal triple therapy (ITT) consisting of
      MTX, hydrocortisone sodium succinate, and cytarabine IT at the time of diagnostic lumbar
      puncture (LP) or on day 1 (if intrathecal therapy is given with relapse diagnostic LP < 7
      days prior to the start of protocol therapy). Patients also receive dexamethasone
      intravenously (IV) or orally (PO) twice daily (BID) on days 1-5, vincristine sulfate IV push
      over 1 minute or via infusion on day 1. Patients with DS also receive leucovorin calcium PO
      or IV every 6 hours (q6h) for 2 doses on day 2 or at 24 and 30 hours after each MTX or ITT
      dose. Patients should proceed to the next cycle when CNS 1 and no testicular disease is
      present, no sooner than Day 8 and no later than Day 15.

      PRE-IMMUNOTHERAPY TREATMENT FOR CNS 2/3 DISEASE: Patients receive MTX IT or cytarabine IT
      twice weekly (Q2W) for 5-7 doses or Intrathecal Triple Therapy (ITT) IT Q2W for 3-4 doses
      until patient is CNS 1. Patients with DS also receive leucovorin calcium PO or IV q6h for 2
      doses at 24 and 30 hours after each MTX or ITT dose. Patients should proceed to the next
      cycle when CNS 1 and no testicular disease is present, no sooner than Day 15 and no later
      than Day 24.

      PRE-IMMUNOTHERAPY TREATMENT FOR TESTICULAR DISEASE: Patients receive MTX IT, cytarabine IT,
      or ITT IT on days 1 and 15 (day 1 may be omitted if intrathecal therapy is given with relapse
      diagnostic LP < 7 days prior to the start of protocol therapy). Patients with DS also receive
      leucovorin calcium PO or IV q6h for 2 doses on days 2 and 16 or at 24 and 30 hours after each
      IT MTX or ITT dose. Males with testicular disease at relapse undergo radiation once daily
      (QD) for a total of 12 fractions over 12 days. Patients should proceed to the next cycle when
      CNS 1 and no testicular disease is present, no sooner than Day 15 and no later than Day 22.

      GROUP 1: Patients are randomized to Arm A or Arm B.

      ARM A: Patients receive dexamethasone PO or IV on days 1 and 8 of cycle 1, blinatumomab via
      continuous IV infusion on days 1-28 of cycles 1-2, MTX IT, cytarabine IT, or ITT IT on days 1
      and 15 of cycle 1 (MTX on day 1 may be omitted if intrathecal therapy is given with relapse
      diagnostic LP < 7 days prior to the start of protocol therapy), and MTX IT on days 1 and 15
      of cycle 2. Treatment repeats every 36 days for 2 cycles in the absence of disease
      progression or unacceptable toxicity. NOTE: Patients with MRD < 0.01% after cycle 1 may stop
      study treatment or may choose to continue to cycle 2. Patients with MRD >= 0.01% after cycle
      1 proceed to cycle 2.

      ARM B: Patients receive dexamethasone, blinatumomab, and MTX, cytarabine, or ITT as in Arm A.
      Patients also receive nivolumab IV over 30 minutes on days 11 and 25 of cycle 1 and days 1
      and 15 of cycle 2. Treatment repeats every 36 days for 2 cycles in the absence of disease
      progression or unacceptable toxicity. NOTE: Patients with MRD < 0.01% after cycle 1 may stop
      study treatment or may choose to continue to cycle 2. Patients with MRD >= 0.01% after cycle
      1 proceed to cycle 2.

      GROUPS 2-3 REINDUCTION: Patients receive vincristine sulfate IV push over 1 minute or via
      infusion on days 1, 8, 15, and 22, dexamethasone PO or IV on days 1-14, doxorubicin
      hydrochloride IV over 1-15 minutes on day 1, MTX IT on days 1, 8, and 29 (day 1 may be
      omitted if intrathecal therapy is given with relapse diagnostic LP < 7 days prior to the
      start of protocol therapy) (days 8 and 29 for CNS 1/2 patients at relapse only), pegaspargase
      intramuscularly (IM) or IV over 1-2 hours on days 2 and 16, cytarabine IT on days 4 and 11
      (CNS 2 patients at relapse only), then Q2W until 3 consecutive samples are clear of blasts,
      and ITT IT on days 8, 15, 22, and 29 (CNS 3 patients at relapse only). Treatment continues in
      the absence of disease progression or unacceptable toxicity.

      GROUP 2: The following patients are randomized to Arm C or Arm D: 1) >= 1 to < 31 years old,
      IEM relapse < 18 months from diagnosis, regardless of MRD after Re-Induction. 2) < 18 years
      old with marrow relapse >= 24 to < 36 months from diagnosis regardless of MRD after
      Re-Induction, 3) >= 1 to < 31 years old, IEM relapse >= 18 months, and MRD >= 0.1% after
      Re-Induction, 4) < 18 years old with marrow relapse >= 36 months, and MRD >= 0.1% after
      Re-Induction.

      ARM C: Patients receive dexamethasone PO or IV on day 1 of cycle 1, blinatumomab via
      continuous IV infusion on days 1-28 of cycles 1 and 2, and MTX IT on days 1 and 15 of cycles
      1 and 2 (day 1 may be omitted from cycle 1 if intrathecal MTX is given < 7 days prior to the
      start of cycle 1 ). Treatment repeats every 36 days for 2 cycles in the absence of disease
      progression or unacceptable toxicity. NOTE: Patients with MRD < 0.01% after cycle 1 may stop
      study treatment or may choose to continue to cycle 2. Patients with MRD >= 0.01% after cycle
      1 proceed to cycle 2.

      ARM D: Patients receive dexamethasone, blinatumomab, and MTX as in Arm C. Patients also
      receive nivolumab IV over 30 minutes on days 11 and 25 of cycle 1 and days 1 and 15 of cycle
      2. Treatment repeats every 36 days for 2 cycles in the absence of disease progression or
      unacceptable toxicity. NOTE: Patients with MRD < 0.01% after cycle 1 may stop study treatment
      or may choose to continue to cycle 2. Patients with MRD >= 0.01% after cycle 1 proceed to
      cycle 2.

      GROUP 3: The following patients are randomized to Arm E or Arm F: 1) >= 1 to < 31 years old
      with IEM relapse >= 18 months from diagnosis and MRD < 0.1% after Re-Induction, 2) < 18 years
      old with marrow relapse >= 36 months from diagnosis and MRD < 0.1% after Re-Induction.

      ARM E:

      IMMUNOTHERAPY CYCLES 1-2: Patients receive dexamethasone PO or IV on day 1 of cycle 1 only,
      blinatumomab IV via continuous infusion on days 1-28, and MTX IT on days 1 and 15 (day 1 may
      be omitted from cycle 1 if intrathecal therapy is given < 7 days prior to the start of this
      cycle).Immunotherapy Cycles 1-2 alternate with Continuation Cycles 1-2.

      CONTINUATION CYCLES 1-2: Patients receive dexamethasone PO on days 1-5, vincristine sulfate
      IV push over 1 minute or via infusion on day 1, mercaptopurine PO on days 1-42, MTX PO on
      days 8, 15, 29, and 36, cyclophosphamide IV over 15-30 minutes on days 43 and 50, etoposide
      IV over 90-120 minutes on days 43 and 50, thioguanine PO once daily (QD) on days 43-49, and
      cytarabine IV over 1-30 minutes or subcutaneously (SC) on days 44-47 and 51-54. CNS 1/2
      patients at relapse also receive MTX IT on days 1 and 43 and PO q6h for 4 doses on day 22,
      and leucovorin calcium PO q6h for 2 doses on day 24. CNS 3 patients at relapse also receive
      ITT IT on days 1 and 43, intermediate dose MTX IV over 36 hours on day 22, and leucovorin
      calcium IV or PO q6h on days 24 and 25. Treatment repeats every 8 weeks for 2 cycles in the
      absence of disease progression or unacceptable toxicity.

      IMMUNOTHERAPY CYCLE 3: Patients receive blinatumomab IV via continuous infusion on days 1-28,
      and MTX IT on days 1 and 15.

      MAINTENANCE: Patients receive dexamethasone PO BID on days 1-5, 29-33, and 57-61, vincristine
      sulfate IV push over 1 minute or via infusion on days 1, 29, and 57, mercaptopurine PO on
      days 1-84, MTX IT on day 1 (CNS 1/2 patients at relapse only), ITT IT on day 1 (CNS 3
      patients at relapse only), and MTX PO on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78.
      Treatment repeats every 12 weeks for 2 years from the start of Re-Induction therapy in the
      absence of disease progression or unacceptable toxicity.

      MAINTENANCE CHEMORADIATION (FOR CNS 3 PATIENTS ONLY): Beginning between the first and second
      cycles of maintenance therapy, patients receive dexamethasone PO BID on days 1-7 and 15-21,
      vincristine sulfate IV push over 1 minute or via infusion on days 1, 8, and 15, and
      pegaspargase IM or IV over 1-2 hours on day 1. Patients with CNS 3 and isolated CNS relapse
      undergo cranial radiation in the form of 3-dimensional (D)-conformal radiation therapy (CRT)
      over 5 days per week for a total of 10 treatments.

      ARM F:

      IMMUNOTHERAPY CYCLES 1-2: Patients receive dexamethasone PO or IV on day 1 of cycle 1 only,
      blinatumomab IV via continuous infusion on days 1-28, nivolumab IV over 30 minutes on days
      11-25 of cycle 1 and on days 1 and 15 of cycles 2 and 3, and MTX IT on days 1 and 15 (day 1
      may be omitted from cycle 1 if intrathecal therapy is given with < 7 days prior to the start
      of this cycle). Immunotherapy Cycles 1-2 alternate with Continuation Cycles 1-2.

      CONTINUATION CYCLES 1-2: Patients receive dexamethasone PO on days 1-5, vincristine sulfate
      IV push over 1 minute or via infusion on day 1, mercaptopurine PO on days 1-42, MTX PO on
      days 8, 15, 29, and 36, cyclophosphamide IV over 15-30 minutes on days 43 and 50, etoposide
      IV over 90-120 minutes on days 43 and 50, thioguanine PO QD on days 43-49, and cytarabine IV
      over 1-30 minutes or SC on days 44-47 and 51-54. CNS 1/2 patients at relapse also receive MTX
      IT on days 1 and 43 and PO q6h for 4 doses on day 22, and leucovorin calcium PO q6h for 2
      doses on day 24. CNS 3 patients at relapse also receive ITT IT on days 1 and 43, intermediate
      dose MTX IV over 36 hours on day 22, and leucovorin calcium IV or PO q6h on days 24 and 25.

      IMMUNOTHERAPY CYCLE 3: Patients receive blinatumomab IV via continuous infusion on days 1-28,
      nivolumab IV over 30 minutes on days 1 and 15 and MTX IT on days 1 and 15.

      MAINTENANCE: Patients receive dexamethasone PO BID on days 1-5, 29-33, and 57-61, vincristine
      sulfate IV push over 1 minute or via infusion on days 1, 29, and 57, mercaptopurine PO on
      days 1-84, MTX IT on day 1 (CNS 1/2 patients at relapse only), ITT IT on day 1 (CNS 3
      patients at relapse only), and MTX PO on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78.
      Treatment repeats every 12 weeks for 2 years from the start of Re-Induction therapy in the
      absence of disease progression or unacceptable toxicity.

      MAINTENANCE CHEMORADIATION (FOR CNS 3 PATIENTS): Beginning between the first and second
      cycles of maintenance therapy, patients receive dexamethasone PO BID on days 1-7 and 15-21,
      vincristine sulfate IV push over 1 minute or via infusion on days 1, 8, and 15, and
      pegaspargase IM or IV over 1-2 hours on day 1. Patients with CNS 3 and isolated CNS relapse
      undergo cranial radiation in the form of 3D-CRT over 5 days per week for a total of 10
      treatments in the absence of disease progression or unacceptable toxicity.

      ARM G (DS PATIENTS): Patients receive dexamethasone PO or IV on days 1 and 8 of cycle 1 only,
      blinatumomab IV via continuous infusion on days 1-28, nivolumab IV over 30 minutes on days 11
      and 25 of cycle 1 and days 1 and 15 of cycle 2, and MTX IT, cytarabine IT, or ITT IT on days
      1 and 15 of cycle 1 (MTX on day 1 may be omitted if intrathecal therapy is given with relapse
      diagnostic LP < 7 days prior to the start of protocol therapy), MTX IT on days 1 and 15 of
      cycle 2, and leucovorin calcium IV or PO q6h for 2 doses on days 2 and 16.

      Patients with MRD < 0.01% are eligible to come off protocol therapy to receive Consolidation
      therapy at the end of Cycle 1, or may choose to proceed to Arm G, Cycle 2.

      After completion of study treatment, patients are followed up every 3 months for 1 year.
    

Trial Arms

NameTypeDescriptionInterventions
Arm G (dexamethasone, blinatumomab, nivolumab,MTX) DS patientsExperimentalDS Patients receive dexamethasone PO or IV on days 1 and 8 of cycle 1 only, blinatumomab IV via continuous infusion on days 1-28, nivolumab IV over 30 minutes on days 11 and 25 of cycle 1 and days 1 and 15 of cycle 2, and methotrexate IT, cytarabine IT, or ITT IT on days 1 and 15 of cycle 1 (methotrexate on day 1 may be omitted if intrathecal therapy is given < 7 days prior to the start of protocol therapy), methotrexate IT on days 1 and 15 of cycle 2, and leucovorin calcium IV or PO q6h for 2 doses on days 2 and 16. Treatment repeats every 36 days for 2 cycles in the absence of disease progression or unacceptable toxicity.
  • Blinatumomab
  • Cytarabine
  • Dexamethasone
  • Hydrocortisone Sodium Succinate
  • Leucovorin Calcium
  • Methotrexate
  • Nivolumab
Group 1, Arm A (dexamethasone, blinatumomab, MTX)ExperimentalPatients receive dexamethasone PO or IV on days 1 and 8 of cycle 1, blinatumomab via continuous IV infusion on days 1-28 of cycles 1-2, MTX IT, cytarabine IT, or ITT IT on days 1 and 15 of cycle 1 (MTX on day 1 may be omitted if intrathecal therapy is given with relapse diagnostic LP < 7 days prior to the start of protocol therapy), and MTX IT on days 1 and 15 of cycle 2. Treatment repeats every 36 days for 2 cycles in the absence of disease progression or unacceptable toxicity. NOTE: Patients with MRD < 0.01% after cycle 1 may stop study treatment or may choose to continue to cycle 2. Patients with MRD >= 0.01% after cycle 1 proceed to cycle 2.
  • Blinatumomab
  • Cytarabine
  • Dexamethasone
  • Hydrocortisone Sodium Succinate
  • Methotrexate
Group 1, Arm B (dexamethasone, blinatumomab, MTX)ExperimentalPatients receive dexamethasone, blinatumomab, and MTX, cytarabine, or ITT as in Arm A. Patients also receive nivolumab IV over 30 minutes on days 11 and 25 of cycle 1 and days 1 and 15 of cycle 2. Treatment repeats every 36 days for 2 cycles in the absence of disease progression or unacceptable toxicity. NOTE: Patients with MRD < 0.01% after cycle 1 may stop study treatment or may choose to continue to cycle 2. Patients with MRD >= 0.01% after cycle 1 proceed to cycle 2.
  • Blinatumomab
  • Cytarabine
  • Dexamethasone
  • Hydrocortisone Sodium Succinate
  • Methotrexate
  • Nivolumab
Group 2, Arm C (dexamethasone, blinatumomab, MTX)ExperimentalPatients receive dexamethasone PO or IV on day 1 of cycle 1, blinatumomab via continuous IV infusion on days 1-28 of cycles 1 and 2, and methotrexate IT on days 1 and 15 of cycles 1 and 2 (day 1 may be omitted from cycle 1 if intrathecal therapy is given < 7 days prior to the start of this cycle). Treatment repeats every 36 days for 2 cycles in the absence of disease progression or unacceptable toxicity. NOTE: Patients with MRD < 0.01% after cycle 1 may stop study treatment or may choose to continue to cycle 2. Patients with MRD >= 0.01% after cycle 1 proceed to cycle 2.
  • Blinatumomab
  • Dexamethasone
  • Methotrexate
Group 2, Arm D (dexamethasone, nivolumab, blinatumomab, MTX)ExperimentalPatients receive dexamethasone, blinatumomab, and MTX as in Arm C. Patients also receive nivolumab IV over 30 minutes on days 11 and 25 of cycle 1 and days 1 and 15 of cycle 2. Treatment repeats every 36 days for 2 cycles in the absence of disease progression or unacceptable toxicity. NOTE: Patients with MRD < 0.01% after cycle 1 may stop study treatment or may choose to continue to cycle 2. Patients with MRD >= 0.01% after cycle 1 proceed to cycle 2.
  • Blinatumomab
  • Dexamethasone
  • Methotrexate
  • Nivolumab
Group 3, Arm E (dexamethasone, blinatumomab, MTX)ExperimentalSee Outline section
  • Blinatumomab
  • Cyclophosphamide
  • Cytarabine
  • Dexamethasone
  • Etoposide
  • Hydrocortisone Sodium Succinate
  • Leucovorin Calcium
  • Mercaptopurine
  • Methotrexate
  • Pegaspargase
  • Thioguanine
  • Vincristine Sulfate
Group 3, Arm F (dexamethasone, blinatumomab, nivolumab)ExperimentalSee Outline section
  • Blinatumomab
  • Cyclophosphamide
  • Cytarabine
  • Dexamethasone
  • Etoposide
  • Hydrocortisone Sodium Succinate
  • Leucovorin Calcium
  • Mercaptopurine
  • Methotrexate
  • Nivolumab
  • Pegaspargase
  • Thioguanine
  • Vincristine Sulfate

Eligibility Criteria

        Inclusion Criteria:

          -  Patients must be >= 1 and < 31 years at time of enrollment

          -  Patients must have first relapse of CD19+ B-ALL (relapse blasts must express CD19) in
             one of the following categories:

               -  Isolated bone marrow relapse

               -  Isolated central nervous system (CNS) (excluding known optic nerve/retinal and
                  CNS chloromas) and/or testicular relapse

               -  Combined bone marrow with extramedullary relapse in the CNS (excluding known
                  optic nerve/retinal and CNS chloromas) and/or testes

          -  Patients with Down syndrome (DS) are eligible in the following categories:

               -  Isolated bone marrow relapse

               -  Combined bone marrow with CNS (excluding known optic nerve/retinal and CNS
                  chloromas) and/or testicular relapse

          -  Patients must have a performance status corresponding to Eastern Cooperative Oncology
             Group (ECOG) scores of 0, 1 or 2. Use Karnofsky for patients > 16 years of age and
             Lansky for patients =< 16 years of age

          -  Patients must have fully recovered from the acute toxic effects of all prior
             chemotherapy, immunotherapy, or radiotherapy prior to entering this study

               -  Patients with prior blinatumomab or CD19+ chimeric antigen receptor therapy in
                  the upfront setting will be eligible, provided relapsed lymphoblasts retain CD19
                  expression

               -  Radiation therapy (RT): >= 3 months must have elapsed if prior RT. This includes
                  any patient requiring urgent radiation to any sites of extramedullary disease
                  prior to enrollment (e.g. retinal/optic nerve involvement)

               -  Hematopoietic stem cell transplant (HSCT): Patients must not have had a prior
                  hematopoietic stem cell transplant

               -  A single intrathecal chemotherapy at the time of relapse will be allowed. If < 7
                  days have elapsed between this intrathecal therapy (IT) and the start of protocol
                  therapy, then the day 1 intrathecal chemotherapy (i.e. methotrexate, cytarabine,
                  or triple intrathecal) may be omitted

               -  In the 28 days prior to enrollment, up to five days of post-relapse,
                  pre-enrollment therapy (steroid and/or hydroxyurea only) is permissible

                    -  Group 1 and Down syndrome patients who received pre-enrollment therapy and
                       have a white blood count (WBC) >= 30,000/ul at the time of enrollment must
                       receive protocol specified cytoreductive therapy with vincristine and
                       dexamethasone, and no "washout" is required

                    -  Group 1 and Down syndrome patients who received pre-enrollment therapy and
                       have a WBC < 30,000/ul at the time of enrollment must be given a 24 hour
                       "washout" before starting immunotherapy

               -  Note: There is no waiting period or "washout" for patients who relapse while
                  receiving upfront therapy

          -  Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70
             mL/min/1.73 m^2 OR a serum creatinine based on age/gender as follows (within 5
             calendar days prior to enrollment):

               -  Age: Maximum serum creatinine (mg/dL)

                    -  1 to < 2 years: 0.6 (male), 0.6 (female)

                    -  2 to < 6 years: 0.8 (male), 0.8 (female)

                    -  6 to < 10 years: 1 (male), 1 (female)

                    -  10 to < 13 years: 1.2 (male), 1.2 (female)

                    -  13 to < 16 years: 1.5 (male), 1.4 (female)

                    -  >= 16 years: 1.7 (male), 1.4 (female)

          -  Shortening fraction of >= 27% by echocardiogram, or ejection fraction of >= 50% by
             echocardiogram, cardiac magnetic resonance imaging (MRI) or radionuclide angiogram

          -  No evidence of dyspnea at rest, no exercise intolerance, and a pulse oximetry > 94% if
             there is clinical indication for determination.

          -  All patients and/or their parents or legal guardians must sign a written informed
             consent

          -  All institutional, Food and Drug Administration (FDA), and National Cancer Institute
             (NCI) requirements for human studies must be met

        Exclusion Criteria:

          -  Patients with B-lymphoblastic lymphoma (B-LLy)

          -  Patients with Burkitt leukemia/lymphoma or mature B-cell leukemia

          -  Patients with Philadelphia chromosome positive (Ph+) B-ALL

          -  Patients with mixed phenotype acute leukemia (MPAL)

          -  Patients with known Charcot-Marie-Tooth disease

          -  Patients with known MYC translocation associated with mature (Burkitt) B-cell ALL,
             regardless of blast immunophenotype

          -  Patients with active, uncontrolled infection defined as:

               -  Positive bacterial blood culture within 48 hours of study enrollment

               -  Receiving IV or PO antibiotics for an infection with continued signs or symptoms.
                  Note: Patients may be receiving IV or oral antibiotics to complete a course of
                  therapy for a prior documented infection as long as cultures have been negative
                  for at least 48 hours and signs or symptoms of active infection have resolved.
                  For patients with clostridium (C.) difficile diarrhea, at least 72 hours of
                  antibacterial therapy must have elapsed and stools must have normalized to
                  baseline.

               -  Fever above 38.2 degrees Celsius (C) within 48 hours of study enrollment with
                  clinical signs of infection. Fever without clinical signs of infection that is
                  attributed to tumor burden is allowed as long as blood cultures are negative for
                  > 48 hours

               -  A positive fungal culture within 30 days of study enrollment or active therapy
                  for presumed invasive fungal infection

               -  Active viral or protozoal infection requiring IV treatment

          -  Patients known to have one of the following concomitant genetic syndromes: Bloom
             syndrome, ataxia-telangiectasia, Fanconi anemia, Kostmann syndrome, Shwachman syndrome
             or any other known bone marrow failure syndrome are not eligible. Of note, patients
             with known human immunodeficiency virus (HIV) infection on effective anti-retroviral
             therapy with undetectable viral load for at least the last 6 months prior to
             enrollment are eligible. Similarly, hepatitis B and hepatitis C positive patients who
             have been treated and have no viral detectable burden are also eligible

          -  Patients with significant central nervous system pathology that would preclude
             treatment with blinatumomab, including history of severe neurologic disorder or
             autoimmune disease with CNS involvement

               -  Note: Patients with a history of seizures that are well controlled on stable
                  doses of anti-epileptic drugs are eligible Patients with a history of
                  cerebrovascular ischemia/hemorrhage with residual deficits are not eligible.
                  Patients with a history of cerebrovascular ischemia/hemorrhage remain eligible
                  provided all neurologic deficits have resolved

          -  Patients with an active known/suspected autoimmune disease are not eligible. However,
             patients with type I diabetes mellitus, hypothyroidism only requiring hormone
             replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring
             systemic treatment, or conditions not expected to recur in the absence of an external
             trigger are permitted to enroll

          -  Group 1 and DS patients with known non-hematopoietic, non-CNS/testicular
             extramedullary disease (i.e., chloromatous disease) are not eligible

               -  Note: Group 2 and 3 patients with known non-hematopoietic, non-CNS/testicular
                  extramedullary disease (i.e., chloromatous disease) are eligible provided that
                  this is NOT the only site of relapsed disease

          -  Female patients of childbearing potential are not eligible unless a negative pregnancy
             test result has been obtained within 7 days prior to enrollment. Patients who are
             sexually active and of reproductive potential are not eligible unless they agree to
             use an effective contraceptive method for the duration of this study. Men with female
             partners of childbearing potential should use effective contraception during the
             duration of their treatment. The effect of blinatumomab on fertility has not been
             evaluated. Blinatumomab is not recommended for pregnant women or women of childbearing
             potential (WOCBP) not using contraception. Females of reproductive potential must use
             effective contraception during treatment and for at least 48 hours after the last dose
             of blinatumomab. Studies in animal models have shown that nivolumab can adversely
             impair pregnancy. Thus, nivolumab is expected to cause fetal harm during pregnancy.
             WOCBP receiving nivolumab must continue contraception for a period of at least 5
             months after the last dose of nivolumab. It is unknown whether nivolumab is present in
             breast milk, thus breastfeeding should be discontinued while a patient is receiving
             nivolumab. Men receiving nivolumab and who are sexually active with WOCBP must
             continue contraception for 7 months after the last dose of nivolumab

          -  Lactating females are not eligible unless they agree not to breastfeed their infants.
             It is unknown whether blinatumomab or its metabolites are excreted in human breast
             milk. Women are not permitted to breastfeed while receiving blinatumomab and for the
             last 48 hours after the last blinatumomab dose. Due to the potential for serious
             adverse reactions in the breastfed infant, women are not permitted to breastfeed
             during treatment and for 5 months after the last nivolumab dose
      
Maximum Eligible Age:30 Years
Minimum Eligible Age:1 Year
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Minimal residual disease (MRD) negative second remission (Rem-2) rate with blinatumomab vs with blinatumomab + nivolumab (Group 1)
Time Frame:Up to 2 cycles of therapy (each cycle = 36 days)
Safety Issue:
Description:MRD negative Rem-2 be defined as Rem-2 (i.e., achievement of MRD < 1% blasts by flow cytometry and resolution of extramedullary disease (for CNS disease, requires CNS 1) ) and bone marrow with MRD < 0.01% by flow cytometry. MRD negative Rem-2 rate between Arm A vs Arm B will be compared using a one-sided Z test of proportions with Type I error of 0.10. Interim analysis will be conducted to monitor for futility. The futility boundary will be based on testing the alternative hypothesis at the 0.067 level.

Secondary Outcome Measures

Measure:Dose-limiting toxicity
Time Frame:Up to 1 cycle of therapy (each cycle = 36 days)
Safety Issue:
Description:Will be assessed using the Common Terminology Criteria for Adverse Events version 5.0.
Measure:Event-free survival post-induction (Group 2)
Time Frame:From date of randomization to date of treatment failure, relapse, disease progression, SMN or death due to any cause, assessed up to 5 years after completion of enrollment
Safety Issue:
Description:Comparison of EFS post-induction between Arm C versus Arm D will be based on a one-sided two-sample logrank test with type I error of 0.15, to be conducted 2 years after completion of enrollment of Group 2. Interim based on testing the alternative hypothesis at the 0.092 level.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

Last Updated

April 21, 2021