Clinical Trials /

Low-Intensity Chemotherapy and Venetoclax in Treating Patients With Relapsed or Refractory B- or T-Cell Acute Lymphoblastic Leukemia

NCT03808610

Description:

This phase I/II trial studies the side effects and best dose of venetoclax and how well it works in combination with low-intensity chemotherapy in patients with B- or T-cell acute lymphoblastic leukemia that has not responded to treatment or that has come back. Venetoclax may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, including vincristine, cyclophosphamide, dexamethasone, rituximab, methotrexate, and cytarabine, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving venetoclax with low-intensity chemotherapy may work better in treating patient with B- or T-cell acute lymphoblastic leukemia.

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

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Low-Intensity Chemotherapy and Venetoclax in Treating Patients With Relapsed or Refractory B- or T-Cell Acute Lymphoblastic Leukemia
  • Official Title: Phase I/II Study of the Combination of Low-Intensity Chemotherapy and Venetoclax (ABT-199) in Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia (ALL)

Clinical Trial IDs

  • ORG STUDY ID: 2016-0629
  • SECONDARY ID: NCI-2018-03360
  • SECONDARY ID: 2016-0629
  • SECONDARY ID: P30CA016672
  • NCT ID: NCT03808610

Conditions

  • Recurrent B Acute Lymphoblastic Leukemia
  • Recurrent T Acute Lymphoblastic Leukemia
  • Refractory B Acute Lymphoblastic Leukemia
  • Refractory T Acute Lymphoblastic Leukemia

Interventions

DrugSynonymsArms
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, Cyclophosphamidum, Cyclophosphan, Cyclophosphane, Cyclophosphanum, Cyclostin, Cyclostine, Cytophosphan, Cytophosphane, Cytoxan, Fosfaseron, Genoxal, Genuxal, Ledoxina, Mitoxan, Neosar, Revimmune, Syklofosfamid, WR- 138719Experimental (venetoclax, vincristine, cyclophosphamide)
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-28453Experimental (venetoclax, vincristine, cyclophosphamide)
DexamethasoneAacidexam, Adexone, Aknichthol Dexa, Alba-Dex, Alin, Alin Depot, Alin Oftalmico, Amplidermis, Anemul mono, Auricularum, Auxiloson, Baycuten, Baycuten N, Cortidexason, Cortisumman, Decacort, Decadrol, Decadron, 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, Dexamethasonum, Dexamonozon, Dexapos, Dexinoral, Dexone, Dinormon, Fluorodelta, Fortecortin, Gammacorten, Hexadecadrol, Hexadrol, Lokalison-F, Loverine, Methylfluorprednisolone, Millicorten, Mymethasone, Orgadrone, Spersadex, VisumetazoneExperimental (venetoclax, vincristine, cyclophosphamide)
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-19039Experimental (venetoclax, vincristine, cyclophosphamide)
Nelarabine2-Amino-6-methoxypurine arabinoside, 506U78, Arranon, Compound 506U78, GW506U78Experimental (venetoclax, vincristine, cyclophosphamide)
PegaspargaseL-Asparaginase with Polyethylene Glycol, Oncaspar, PEG-Asparaginase, PEG-L-Asparaginase, PEG-L-Asparaginase (Enzon - Kyowa Hakko), PEGLA, Polyethylene Glycol L-Asparaginase, Polyethylene Glycol-L-AsparaginaseExperimental (venetoclax, vincristine, cyclophosphamide)
Prednisone.delta.1-Cortisone, 1, 2-Dehydrocortisone, Adasone, Cortancyl, Dacortin, DeCortin, Decortisyl, Decorton, Delta 1-Cortisone, Delta-Dome, Deltacortene, Deltacortisone, Deltadehydrocortisone, Deltasone, Deltison, Deltra, Econosone, Lisacort, Meprosona-F, Metacortandracin, Meticorten, Ofisolona, Orasone, Panafcort, Panasol-S, Paracort, PRED, Predicor, Predicorten, Prednicen-M, Prednicort, Prednidib, Prednilonga, Predniment, Prednisonum, Prednitone, Promifen, Servisone, SK-PrednisoneExperimental (venetoclax, vincristine, cyclophosphamide)
RituximabABP 798, BI 695500, C2B8 Monoclonal Antibody, Chimeric Anti-CD20 Antibody, CT-P10, IDEC-102, IDEC-C2B8, IDEC-C2B8 Monoclonal Antibody, MabThera, Monoclonal Antibody IDEC-C2B8, PF-05280586, Rituxan, Rituximab Biosimilar ABP 798, Rituximab Biosimilar BI 695500, Rituximab Biosimilar CT-P10, Rituximab Biosimilar GB241, Rituximab Biosimilar IBI301, Rituximab Biosimilar PF-05280586, Rituximab Biosimilar RTXM83, Rituximab Biosimilar SAIT101, RTXM83Experimental (venetoclax, vincristine, cyclophosphamide)
VenetoclaxABT-0199, ABT-199, ABT199, GDC-0199, RG7601, VenclextaExperimental (venetoclax, vincristine, cyclophosphamide)
VincristineLEUROCRISTINE, VCR, VincrystineExperimental (venetoclax, vincristine, cyclophosphamide)

Purpose

This phase I/II trial studies the side effects and best dose of venetoclax and how well it works in combination with low-intensity chemotherapy in patients with B- or T-cell acute lymphoblastic leukemia that has not responded to treatment or that has come back. Venetoclax may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, including vincristine, cyclophosphamide, dexamethasone, rituximab, methotrexate, and cytarabine, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving venetoclax with low-intensity chemotherapy may work better in treating patient with B- or T-cell acute lymphoblastic leukemia.

Detailed Description

      PRIMARY OBJECTIVES:

      I. Determine the maximum tolerated dose (MTD) and dose-limited toxicities (DLTs) of
      venetoclax in combination with low-intensity chemotherapy in patients with
      relapsed/refractory acute lymphoblastic leukemia (ALL) (Phase I).

      II. Evaluate the overall response rate (complete response [CR] + CR with inadequate count
      recovery [CRi]) of the regimen after 2 cycles. (Phase II)

      SECONDARY OBJECTIVES:

      I. Evaluate other clinical efficacy endpoints (minimal residual disease [MRD] negativity,
      duration of response [DOR], event-free survival [EFS] and overall survival [OS]).

      II. Determine the safety of the combination regimen.

      EXPLORATORY OBJECTIVES:

      I. To correlate apoptotic protein expression and Bcl-2 dependency on response and resistance
      to the combination regimen.

      OUTLINE: This is a phase I, dose-escalation study of venetoclax, followed by a phase II
      study.

      CHEMOTHERAPY AND VENETOCLAX:

      COURSE 1: Patients receive venetoclax orally (PO) once daily (QD) on days 1-21, vincristine
      intravenously (IV) over 15 minutes on days 7 and 17, cyclophosphamide IV twice daily (BID)
      over 3 hours on days 7-9, and dexamethasone IV over 30 minutes or PO QD on days 7-10 and
      17-20. Patients may also receive rituximab IV over 4-6 hours on days 7 and 17 per physician
      discretion.

      COURSES 2, 4, 6, and 8: Patients receive venetoclax PO QD on days 1-21, methotrexate IV over
      24 hours on day 1, and cytarabine IV BID over 3 hours on days 2 and 3. Patients may also
      receive rituximab IV over 4-6 hours on days 1 and 8 per physician discretion.

      COURSES 3, 5, and 7: Patients receive venetoclax PO QD on days 1-21, cyclophosphamide IV BID
      over 3 hours on days 1-3, vincristine IV over 15 minutes on days 1 and 11, and dexamethasone
      IV over 30 minutes or PO QD on days 1-4 and 11-14. Patients may also receive rituximab IV
      over 4-6 hours on days 1 and 11 per physician discretion.

      T-CELL ALL: After the first 4 courses, patients receive nelarabine IV over 2 hours on days
      1-5 and pegaspargase IV over 2 hours on day 5. Courses repeat every 28 days for 2 courses
      (after couse 4 and 5) in the absence of disease progression or unacceptable toxicity.

      MAINTENANCE THERAPY: Patients may receive prednisone PO QD on days 1-5, vincristine IV over
      15 minutes on day 1, and venetoclax, PO QD on days 1-21. Courses repeat every 28 days for 2
      years in the absence of disease progression or unacceptable toxicity.

      T-CELL ALL (MAINTENANCE THERAPY): After the first 5 courses of maintenance therapy, patients
      who received nelarabine and pegaspargase will receive nelarabine IV QD over 2 hours on days
      1-5 and pegaspargase IV over 2 hours on day 5 during maintenance courses 6 and 7 instead of
      prednisone, vincristine, and venetoclax.

      After completion of study treatment, patients are followed up for 30 days and then every 3
      months thereafter.
    

Trial Arms

NameTypeDescriptionInterventions
Experimental (venetoclax, vincristine, cyclophosphamide)ExperimentalSee Detailed Description.
  • Cyclophosphamide
  • Cytarabine
  • Dexamethasone
  • Methotrexate
  • Nelarabine
  • Pegaspargase
  • Prednisone
  • Rituximab
  • Venetoclax
  • Vincristine

Eligibility Criteria

        Inclusion Criteria:

          -  Patients with relapsed/refractory B- or T-cell ALL

          -  Performance status =< 3 (Eastern Cooperative Oncology Group [ECOG] Scale)

          -  Total serum bilirubin =< 2 x upper limit of normal (ULN), unless due to Gilbert's
             syndrome

          -  Alanine aminotransferase (ALT) =< 3 x ULN

          -  Aspartate aminotransferase (AST) =< 3 x ULN

          -  Creatinine clearance >= 30 mL/min

          -  For females of childbearing potential, a negative pregnancy test must be documented
             within 1 week of starting treatment

          -  Female and male patients who are fertile must agree to use an effective form of
             contraception (birth control methods while on study, such as birth control pills or
             injections, intrauterine devices [IUDs]), or double-barrier methods (for example, a
             condom in combination with spermicide) with their sexual partners for 4 months after
             the end of treatment

          -  Signed informed consent

        Exclusion Criteria:

          -  Patients with Philadelphia chromosome-positive ALL or Burkitt leukemia

          -  Active serious infection not controlled by oral or intravenous antibiotics

          -  Active secondary malignancy other than skin cancer (e.g., basal cell carcinoma or
             squamous cell carcinoma) that in the investigator's opinion will shorten survival to
             less than 1 year

          -  Known hepatitis B or C infection, or known seropositivity for human immunodeficiency
             virus (HIV)

          -  Active Grade III-V cardiac failure as defined by the New York Heart Association
             Criteria

          -  Patients with a cardiac ejection fraction (as measured by either multigated
             acquisition [MUGA] or echocardiogram) < 40%

          -  Received CYP3A inhibitors (such as fluconazole, ketoconazole, voriconazole, and
             clarithromycin) within 3 days of starting venetoclax; received strong CYP3A inducers
             (such as rifampin, rifabutin, phenytoin, carbamazepine, and St. John's Wort) within 3
             days of starting venetoclax

          -  Consumed grapefruit, grapefruit products, Seville oranges, or star fruit within 3 days
             prior to starting venetoclax

          -  Prior history of treatment with venetoclax

          -  Treatment with any investigational antileukemic agents or chemotherapy agents in the
             last 7 days before study entry, unless full recovery from side effects has occurred or
             patient has rapidly progressive disease judged to be life-threatening by the
             investigator. Exception: Treatment with hydroxyurea and/or dexamethasone are allowed
             prior to study treatment, without window of exclusion

          -  Pregnant and lactating women will not be eligible; women of childbearing potential
             should have a negative pregnancy test prior to entering on the study and be willing to
             practice methods of contraception. Women do not have childbearing potential if they
             have had a hysterectomy or are postmenopausal without menses for 12 months. In
             addition, men enrolled on this study should understand the risks to any sexual partner
             of childbearing potential and should practice an effective method of birth control

          -  History of significant bleeding disorder unrelated to cancer, including: Diagnosed
             congenital bleeding disorders (e.g., von Willebrand's disease); diagnosed acquired
             bleeding disorder within one year (e.g., acquired anti-factor VIII antibodies)
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum tolerated dose (MTD) (Phase I)
Time Frame:Up to 28 days
Safety Issue:
Description:The MTD is the highest dose level in which < 2 patients of 6 develop first cycle dose-limiting toxicity (DLT).

Secondary Outcome Measures

Measure:Overall response rate (Phase II)
Time Frame:Up to 56 days (2 courses)
Safety Issue:
Description:Will be defined as the percentage of patients achieving a complete response (CR) or CR with inadequate count recovery (CRi). Will estimate the overall response (OR) for the combination treatment, along with the 95% credible interval.
Measure:Minimal residual disease (MRD) negativity
Time Frame:Up to 4 years
Safety Issue:
Description:Will be summarized using descriptive statistics such as mean, standard deviation, median and range.
Measure:Duration of response (DOR)
Time Frame:Up to 4 years
Safety Issue:
Description:Will be summarized using descriptive statistics such as mean, standard deviation, median and range. The association between response and patient's clinical characteristics will be examined by Wilcoxon's rank sum test or Fisher's exact test, as appropriate.
Measure:Event-free survival (EFS)
Time Frame:From the first day of treatment until any failure (resistant disease, relapse, or death), assessed up to 4 years
Safety Issue:
Description:The association between response and patient's clinical characteristics will be examined by Wilcoxon's rank sum test or Fisher's exact test, as appropriate.
Measure:Overall survival (OS)
Time Frame:From the first day of treatment to time of death from any cause, assessed up to 4 years
Safety Issue:
Description:The association between response and patient's clinical characteristics will be examined by Wilcoxon's rank sum test or Fisher's exact test, as appropriate.
Measure:Incidence of adverse events
Time Frame:Up to 4 years
Safety Issue:
Description:Will be summarized using descriptive statistics such as mean, standard deviation, median and range.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:M.D. Anderson Cancer Center

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