Clinical Trials /

Inotuzumab Ozogamicin and Chemotherapy in Treating Patients With Recurrent or Refractory B-cell Acute Lymphoblastic Leukemia

NCT03991884

Description:

This phase I trial studies the best dose of inotuzumab ozogamicin in combination with chemotherapy in treating patients with B-cell acute lymphoblastic leukemia that has come back (recurrent) or that does not respond to treatment (refractory). Inotuzumab ozogamicin is a monoclonal antibody, called inotuzumab, linked to a toxic agent called ozogamicin. Inotuzumab attaches to CD22 positive cancer cells in a targeted way and delivers ozogamicin to kill them. Drugs used in chemotherapy, such as etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving inotuzumab ozogamicin in combination with chemotherapy may kill more cancer cells than with chemotherapy alone in treating patients with recurrent or refractory B-cell acute lymphoblastic leukemia.

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

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Inotuzumab Ozogamicin and Chemotherapy in Treating Patients With Recurrent or Refractory B-cell Acute Lymphoblastic Leukemia
  • Official Title: A Phase I Study of Dose-Adjusted Etoposide, Prednisone, Vincristine, Cyclophosphamide, and Doxorubicin Plus Escalating Doses of Inotuzumab Ozogamicin (DA-EPOCH-InO) in Relapsed or Refractory B-Cell Acute Lymphoblastic Leukemia

Clinical Trial IDs

  • ORG STUDY ID: RG1004854
  • SECONDARY ID: NCI-2019-03811
  • SECONDARY ID: 8786
  • SECONDARY ID: P30CA015704
  • NCT ID: NCT03991884

Conditions

  • Blasts 5 Percent or More of Bone Marrow Nucleated Cells
  • Blasts 5 Percent or More of Peripheral Blood White Cells
  • CD22 Positive
  • Recurrent B Acute Lymphoblastic Leukemia
  • Recurrent B Lymphoblastic Lymphoma
  • Refractory B Acute Lymphoblastic Leukemia
  • Refractory B Lymphoblastic Lymphoma

Interventions

DrugSynonymsArms
Etoposide33419-42-0, Demethyl Epipodophyllotoxin Ethylidine Glucoside, EPEG, Lastet, Toposar, Vepesid, VP 16, VP 16-213, VP-16, VP-16-213, VP16, 141540Treatment (DA-EPOCH, rituximab, inotuzumab ozogamicin)
Doxorubicin14-Hydroxydaunomycin, 23214-92-8, Adriablastin, Hydroxydaunomycin, Hydroxyl Daunorubicin, HydroxyldaunorubicinTreatment (DA-EPOCH, rituximab, inotuzumab ozogamicin)
Doxorubicin Hydrochloride123127, 14-Hydroxydaunorubicin Hydrochloride, Adriacin, Adriamycin Hydrochloride, Adriamycin PFS, Adriamycin RDF, Adriamycine, Adriblastina, Adriblastine, Chloridrato de Doxorrubicina, Doxorubicin HCl, Farmiblastina, hydroxydaunorubicin, hydrochloride, RubexTreatment (DA-EPOCH, rituximab, inotuzumab ozogamicin)
Vincristine22-Oxovincaleukoblastine, LEUROCRISTINE, VCR, VincrystineTreatment (DA-EPOCH, rituximab, inotuzumab ozogamicin)
Vincristine Sulfate2068-78-2, 67574, Kyocristine, Leurocristine sulfate, Oncovin, Vincasar, Vincosid, Vincrex, VincristineTreatment (DA-EPOCH, rituximab, inotuzumab ozogamicin)
Prednisone2-Dehydrocortisone, Adasone, Cortancyl, Dacortin, DeCortin, Decortisyl, Decorton, Delta 1-Cortisone, Delta-Dome, Metacortandracin, Ofisolona, Orasone, Paracort, Predicor, Predicorten, Prednicort, Prednidib, Prednilonga, Predniment, Prednisone Intensol, Prednisonum, Prednitone, Promifen, Rayos, Servisone, SK-PrednisoneTreatment (DA-EPOCH, rituximab, inotuzumab ozogamicin)
CyclophosphamideCarloxan, Ciclofosfamida, Ciclofosfamide, Cicloxal, Clafen, Claphene, CP monohydrate, CTX, Cycloblastin, Cycloblastine, Cyclophospham, Cyclophosphamid monohydrate, Cyclophosphamidum, Cyclophosphan, Cyclophosphane, Cyclostin, Cyclostine, Cytoxan, Fosfaseron, Genoxal, Genuxal, Ledoxina, Mitoxan, Neosar, Revimmune, Syklofosfamid, WR- 138719Treatment (DA-EPOCH, rituximab, inotuzumab ozogamicin)
Inotuzumab Ozogamicin635715-01-4, Besponsa, CMC-544, Way 207294, WAY-207294Treatment (DA-EPOCH, rituximab, inotuzumab ozogamicin)
Rituximab174722-31-7, C2B8 Monoclonal Antibody, Chimeric Anti-CD20 Antibody, IDEC-102, IDEC-C2B8 Monoclonal Antibody, MabThera, PF-05280586, Rituxan, Rituximab Biosimilar ABP 798, Rituximab Biosimilar BI 695500, Rituximab Biosimilar CT-P10, Rituximab Biosimilar GB241, Rituximab Biosimilar PF-05280586, Rituximab Biosimilar RTXM83, Rituximab Biosimilar SAIT101, rituximab biosimilar TQB2303, rituximab-abbs, RTXM83, TruximaTreatment (DA-EPOCH, rituximab, inotuzumab ozogamicin)

Purpose

This phase I trial studies the best dose of inotuzumab ozogamicin in combination with chemotherapy in treating patients with B-cell acute lymphoblastic leukemia that has come back (recurrent) or that does not respond to treatment (refractory). Inotuzumab ozogamicin is a monoclonal antibody, called inotuzumab, linked to a toxic agent called ozogamicin. Inotuzumab attaches to CD22 positive cancer cells in a targeted way and delivers ozogamicin to kill them. Drugs used in chemotherapy, such as etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving inotuzumab ozogamicin in combination with chemotherapy may kill more cancer cells than with chemotherapy alone in treating patients with recurrent or refractory B-cell acute lymphoblastic leukemia.

Detailed Description

      This is a dose-escalation study of inotuzumab ozogamicin.

      Patients receive etoposide, doxorubicin, and vincristine intravenously (IV) via continuous
      infusion on days 1-4, prednisone orally (PO) or IV twice daily (BID) on days 1-5, and
      cyclophosphamide IV over 1 hour on day 5. Patients also receive inotuzumab ozogamicin IV over
      1 hour on days 8 and 15. Patients who are CD20 positive may also receive rituximab IV on day
      1 or 5. Treatment repeats every 28 days for up to 4 cycles in the absence of disease
      progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up at 30 days then annually for up
      to 5 years.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (DA-EPOCH, rituximab, inotuzumab ozogamicin)ExperimentalPatients receive etoposide, doxorubicin, and vincristine IV via continuous infusion on days 1-4, prednisone PO or IV BID on days 1-5, and cyclophosphamide IV over 1 hour on day 5. Patients also receive inotuzumab ozogamicin IV over 1 hour on days 8 and 15. Patients who are CD20 positive may also receive rituximab IV on day 1 or 5. Treatment repeats approximately every 28 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity.
  • Etoposide
  • Doxorubicin
  • Doxorubicin Hydrochloride
  • Vincristine
  • Vincristine Sulfate
  • Prednisone
  • Cyclophosphamide
  • Inotuzumab Ozogamicin
  • Rituximab

Eligibility Criteria

        Inclusion Criteria:

          -  Patients must have a confirmed diagnosis of CD22-positive, Philadelphia chromosome
             (Ph)-positive or Ph-negative B-cell acute lymphoblastic leukemia or lymphoblastic
             lymphoma. CD22 expression will be determined by multiparameter flow cytometry (MFC) or
             immunohistochemistry.

          -  Relapsed or refractory disease, as defined by any of the following:

               -  Unable to achieve complete response (CR) despite >= 4 weeks of initial course of
                  systemic therapy.

               -  Recurrence of disease at any point after CR was achieved. (Note: patients with
                  Ph-positive disease must have received >= 1 second- or third-generation ABL
                  kinase inhibitor as part of their prior treatment to be eligible.)

          -  Detectable disease, as defined by the following:

               -  Presence of >= 5% abnormal blasts in the bone marrow or peripheral blood by
                  morphology or MFC.

               -  Patients with isolated extramedullary disease will be permitted if there is >= 1
                  site of disease that measures >= 1.5 cm in longest diameter on cross-sectional
                  imaging.

          -  Absolute neutrophil count (ANC) >= 1,000/uL

          -  Hemoglobin >= 8 g/dL

          -  Platelets >= 50,000/uL.

          -  Note: Transfusions and growth factor support will be permitted within 3 days of
             initiation of study treatment to reach these thresholds. As patients with
             relapsed/refractory ALL frequently have cytopenias due to marrow infiltration by the
             disease, no hematologic parameters will be required for enrollment if cytopenias can
             be attributed to disease.

          -  Total serum bilirubin =< 1.5 x upper limit of normal (ULN); (unless due to Gilbert
             syndrome or hemolysis; =< 2 x ULN for hepatic abnormalities considered
             disease-related).

          -  Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x ULN.

          -  Serum creatinine =< 1.5 x ULN or serum creatinine level associated with a measured or
             calculated creatinine clearance of >= 40 mL/min.

          -  Corrected QT (QTc) interval =< 500 msec; if assessed, left ventricular ejection
             fraction >= 40%.

          -  An Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.

          -  Must agree to the use of effective contraception while on study treatment, unless they
             are highly unlikely to conceive (defined as [1] surgically sterilized, or [2] women
             who are and men whose sexual partner[s] is/are postmenopausal [i.e., a woman who is >
             50 years old or who has not had menses for >= 1 year], or [3] not heterosexually
             active for the duration of the study).

        Exclusion Criteria:

          -  Patients with a circulating blast count of > 10,000/uL; systemic therapy with either
             hydroxyurea, vincristine, and/or corticosteroids will be permitted within 3 days of
             initiation of study treatment to reduce the blast count.

          -  Except for management of circulating blasts noted above, adequate duration from prior
             therapy must be achieved before initiation of study treatment, as defined below:

               -  No cytotoxic or targeted systemic therapy < 2 weeks.

               -  No blinatumomab < 2 weeks.

               -  No radiation therapy < 4 weeks.

               -  No monoclonal antibody therapy < 6 weeks (except for prior InO, as discussed
                  below).

          -  Patients previously treated with InO will be eligible, unless they meet ANY of the
             following criteria:

               -  > 6 individual doses (e.g., > 2 standard cycles) were administered.

               -  Any documented hepatic toxicity observed was grade 3 or higher.

               -  The most recent dose was administered < 3 months from the initiation of study
                  treatment.

          -  For patients that have received prior allogeneic HCT, they must be >= 4 months from
             the date of stem cell infusion, with no prior history of sinusoidal obstruction
             syndrome/veno-occlusive disease (SOS/VOD), and off all treatment for graft-vs-host
             disease (GVHD) for >= 2 weeks. Patients with minimal active symptoms that can be
             controlled with topical therapies and/or the equivalent of prednisone =< 10 mg/day
             will be eligible.

          -  For patients that have received other forms of cellular immunotherapy (e.g., chimeric
             antigen receptor-modified [CAR] T cells), they must be >= 21 days from cell infusion,
             and any specific manifestations of cytokine release syndrome or neurologic toxicity
             attributable to the cellular therapy have completely resolved (i.e., < grade 1)

          -  Patients with a known history of chronic liver disease, including but not limited to
             cirrhosis, steatohepatitis, and chronic viral hepatitis. Patients with a history of
             GVHD of the liver will be permitted, provided they meet all of the other eligibility
             criteria.

          -  Patients with isolated testicular or central nervous system disease.

          -  Known hypersensitivity or intolerance to any of the agents under investigation.

          -  May not be pregnant or nursing.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum tolerated dose (MTD) of inotuzumab ozogamicin (InO)
Time Frame:Up to 5 years
Safety Issue:
Description:Will be defined as the highest dose of InO administered in which the incidence of dose limiting toxicities (DLTs) is < 33%, assuming at least 6 patients have been treated at this dose. DLTs assessed by: Non-hematologic toxicities >= grade 4 evaluated using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0 (except for febrile neutropenia/infection, unless felt to be a direct consequence of treatment-related toxicity [e.g., intestinal infection following mucosal barrier breakdown]). Any instance of possible, probably, or definite SOS/VOD Inability to complete 1 full cycle due to treatment-related adverse events Any treatment delays > 3 weeks (i.e., to Day 50 of Cycle 1) for recovery of prolonged toxicity

Secondary Outcome Measures

Measure:Complete response (CR) rate
Time Frame:Up to 5 years
Safety Issue:
Description:Rate of complete response (CR) by bone marrow morphology and/or imaging.
Measure:Rate of complete minimal residual disease (MRD) response
Time Frame:Up to 5 years
Safety Issue:
Description:Assessed by multiparameter flow cytometry (MFC).
Measure:Progression-free survival
Time Frame:Up to 5 years
Safety Issue:
Description:
Measure:Relapse-free survival
Time Frame:Up to 5 years
Safety Issue:
Description:
Measure:Overall survival
Time Frame:Up to 5 years
Safety Issue:
Description:
Measure:Rate at which patients proceed to subsequent allogeneic hematopoietic cell transplantation (HCT)
Time Frame:Up to 5 years
Safety Issue:
Description:

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:University of Washington

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