Clinical Trials /

Safety, PD & Efficacy of MT-3724 for the Treatment of Patients With Relapsed or Refractory DLBCL

NCT02361346

Description:

The purpose of this study is to evaluate the safety and tolerability of MT-3724 in subjects with relapsed or refractory B-Cell NHL or relapsed and refractory CLL (Part 1 only) and relapsed and refractory DLBCL (Part 2 and Part 3). Part 3 evaluates the efficacy of MT-3724.

Related Conditions:
  • B-Cell Non-Hodgkin Lymphoma
  • Chronic Lymphocytic Leukemia
  • Diffuse Large B-Cell Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Safety, PD & Efficacy of MT-3724 for the Treatment of Patients With Relapsed or Refractory DLBCL
  • Official Title: Safety, Pharmacodynamics and Efficacy of MT-3724 for the Treatment of Patients With Relapsed or Refractory DLBCL

Clinical Trial IDs

  • ORG STUDY ID: MT-3724_NHL_001
  • NCT ID: NCT02361346

Conditions

  • Non-Hodgkin's B-cell Lymphoma
  • Leukemia, Lymphocytic, Chronic, B-Cell
  • Small Lymphocytic Leukemia
  • Diffuse Large B Cell Lymphoma
  • Blood Cancer
  • Hematological Malignancy

Interventions

DrugSynonymsArms
MT-3724 Phase 1MT-3724 Phase 1 5 mcg/kg/dose
MT-3724 Phase 2MT-3724 Phase 2 50 mcg/kg/dose

Purpose

The purpose of this study is to evaluate the safety and tolerability of MT-3724 in subjects with relapsed or refractory B-Cell NHL or relapsed and refractory CLL (Part 1 only) and relapsed and refractory DLBCL (Part 2 and Part 3). Part 3 evaluates the efficacy of MT-3724.

Detailed Description

      This is a three-part Phase 2 study

      Part 1: (MT-3724 Dose Escalation) Define the maximum tolerated dose (MTD) of MT-3724
      [Completed]

      Part 2: (MTD Expansion Cohort) Confirm the safety and tolerability of the MTD of MT-3724 in
      the MTD Expansion Cohort.

      Part 3: (Phase 2 MTD Expansion Cohort) Determine the efficacy of MT-3724 as monotherapy in
      subjects with relapsed or refractory DLBCL based on the overall response rate (ORR) by the
      revised Lugano Classification for Lymphoma adjusted according to LYRIC.

      It is anticipated that up to 100 patients will be enrolled in Part 3. Treatment will continue
      for up to six 21 days cycles. If the subject exhibits SD, CR or PR after the end of Cycle 6
      and the investigator determines that the benefit-risk ratio is favorable, then the treatment
      with MT-3724 may be continued after discussion with the sponsor.
    

Trial Arms

NameTypeDescriptionInterventions
MT-3724 Phase 1 5 mcg/kg/doseExperimentalPhase 1: MT-3724 5 mcg/kg/dose IV for 6 doses over 12 days, followed by dose escalations (Phase 1) until recommended phase 2 dose of MT-3724 is determined
  • MT-3724 Phase 1
MT-3724 Phase 1 10 mcg/kg/doseExperimentalPhase 1: MT-3724 10 mcg/kg/dose IV for 6 doses over 12 days, followed by dose escalations (Phase 1) until recommended phase 2 dose of MT-3724 is determined
  • MT-3724 Phase 1
MT-3724 Phase 1 20 mcg/kg/doseExperimentalPhase 1: MT-3724 20 mcg/kg/dose IV for 6 doses over 12 days, followed by dose escalations (Phase 1) until recommended phase 2 dose of MT-3724 is determined
  • MT-3724 Phase 1
MT-3724 Phase 1 50 mcg/kg/doseExperimentalPhase 1: MT-3724 50 mcg/kg/dose IV for 6 doses over 12 days, followed by dose escalations (Phase 1) until recommended phase 2 dose of MT-3724 is determined
  • MT-3724 Phase 1
MT-3724 Phase 1 100 mcg/kg/doseExperimentalPhase 1: MT-3724 100 mcg/kg/dose IV for 6 doses over 12 days, followed by dose escalations (Phase 1) until recommended phase 2 dose of MT-3724 is determined
  • MT-3724 Phase 1
MT-3724 Phase 1 75 mcg/kg/doseExperimentalPhase 1b: MT-3724 IV for 6 doses over 12 days of 21-Day cycle for up to 4 additional cycles to explore safety, tolerability and tumor response to repeat doses of MT-3724 (subject will continue with dose that was tolerated in the Phase 1 portion of the study)
  • MT-3724 Phase 1
MT-3724 Phase 1b 50 mcg/kg/doseExperimentalPhase 1b: MT-3724 IV for 6 doses over 12 days of 21-Day cycle for up to 4 additional cycles to explore safety, tolerability and tumor response to repeat doses of MT-3724
  • MT-3724 Phase 1
MT-3724 Phase 2 50 mcg/kg/doseExperimentalPhase 2: MT-3724 IV for 6 doses administered within 14 days of 21-Day cycle up to 6 Cycles. If the Subject exhibits stable disease or PR after end of Cycle 6 and investigator determines ratio is favorable, treatment with MT- 3724 may be continued for up to additional 6 cycles.
  • MT-3724 Phase 2

Eligibility Criteria

        Inclusion Criteria:

          -  Men or women, age 18 years or older

        Part 1:

        • Histology based upon bone marrow biopsies and/or fine needle aspirates as the sole means
        of diagnosis are not acceptable. All subtypes of B-cell NHL may be considered for the
        MT-3724 dose escalation. Presence of lymphadenopathy and/or splenomegaly with
        histopathological evaluation of a lymph node biopsy consistent with CLL.

        Part 2:

          1. Diffuse large B cell lymphoma (DLBCL). Histology based upon bone marrow biopsies
             and/or fine needle aspirates as the sole means of diagnosis are not acceptable.

          2. Subjects must have received at least one anti-CD20 antibody containing regimen that
             resulted in initial measurable response (partial or complete remission), followed by
             relapse/ recurrence.

          3. Life expectancy > 3 months.

          4. Eastern Cooperative Oncology Group (ECOG) performance score of ≤2.

          5. All lymphoma subjects are required to have measurable disease

          6. Patients must be at least 28 days past their last course of lymphoma

          7. Received any amount of anti-CD20 MAb therapy within the following periods before the
             start of treatment

          8. Received any amount of anti-CD20 MAb within the following periods before the start of
             treatment:

               1. Rituximab (Rituxan®): if a subject had received any amount of rituximab within
                  365 days of planned dose day 1 then a serum rituximab level must be negative
                  (<500 ng/ml) at the screening period

               2. Obinutuzumab (Gazyva®): 184 days

               3. Ofatumumab (Arzerra®): 88 days

               4. ibritumomab tiuxetan (Zevalin®): 10 days

          9. Adequate kidney function, assessed by the estimated glomerular filtration rate (eGFR)
             ≥60 mL/min

         10. Female patients of childbearing potential must have a negative serum or urine
             pregnancy test within 3 days prior to initiating dosing. Male and female subjects with
             reproductive potential must agree to use acceptable contraceptive methods until the
             end of study visit.

         11. Patients with known central nervous system metastases may be enrolled if they have
             received radiotherapy, do not require chronic steroid therapy, have had computed
             tomography or magnetic resonance imaging of the brain within 1 month of study entry
             that shows stable disease and they have no neurological symptoms other than low grade
             neuropathy.

        Exclusion Criteria:

          1. History of another cancer other than basal cell carcinoma or cervical intraepithelial
             neoplasia (CIN; i.e., cervical cancer in situ).

          2. Potential subjects cannot have experienced a significant (CTCAE Grade 3 or 4 with or
             without neutropenia) infection within 2 weeks of the first dose of MT-3724.

          3. Ongoing use of any approved or investigational antineoplastic therapies

          4. Systemic corticosteroid therapy at a prednisone dose > 20mg/day (or equivalent) within
             14 days prior to study enrollment

          5. Potential subjects with pre-existing AEs at screening that are severe or life
             threatening by CTCAE, v. 4.03 should not be enrolled.

          6. Patients with uncontrolled or severe cardiovascular disease, including myocardial
             infarct or unstable angina within 6 months prior to start of study treatment, New York
             Heart Association (NYHA) Class II or greater congestive heart failure, serious
             arrhythmias requiring medication for treatment, clinically significant pericardial
             disease, or cardiac amyloidosis may not be enrolled.

          7. Patients with a known history of drug abuse or any chronic neurologic, psychiatric,
             endocrine, metabolic, immunologic, hepatic or renal disease (including a history of
             hemolytic uremic syndrome) that in the opinion of the Investigator would adversely
             affect study participation.

          8. Potential subjects must not have received any vaccines for 28 days prior to
             administration of their first dose of MT-3724 and should not receive any vaccine
             during the study or within 28 days after their last dose of MT-3724. The single
             exception to this exclusion is for the annual influenza (flu) vaccine which can be
             given up to 14 days prior to first dose.

          9. History of hypersensitivity to study drug or to compounds of a similar class, or whose
             past history suggests an increased potential for an adverse hypersensitivity reaction
             to MT-3724 should not be enrolled.

         10. Patients with known active Hepatitis A or C, HIV or a present history of Hepatitis B

         11. Potential subjects who have undergone allogeneic hematopoietic stem cell
             transplantation.

         12. Women who are pregnant or breastfeeding.

         13. Potential subjects who have had major surgery within 6 weeks prior to the first dose
             of study drug or have major surgery planned during the first 12 weeks post MT 3724
             exposure.

        Part 3

        Inclusion Criteria:

          1. Subjects must have relapsed or refractory diffuse large B-cell lymphoma (DLBCL)
             according to the Revised European American Lymphoma/World Health Organization
             (REAL/WHO) classification.

          2. Subjects must have received at least 2 standard of care regimens for NHL treatment.

          3. Subjects must have at least one tumor lesion at screening

          4. Subjects must have life expectancy of >3 months from the start of treatment.

          5. Subjects must have ECOG performance status of 0-2.

          6. Adequate kidney function

          7. QTcF (Fridericia) ≤480 ms determined as the average of three QTcF values from the
             triplicate ECG obtained at screening.

          8. LVEF ≥45% by MUGA or echocardiogram obtained at screening.

          9. Female patients of childbearing potential must not be pregnant.. Male and female
             subjects with reproductive potential must agree to use acceptable contraceptive
             methods until the end of study visit.

         10. Subject must be able to comply with all study-related procedures and medication use.

        Exclusion Criteria:

          1. Received any amount of anti-CD20 MAb within the following periods before the start of
             treatment:

               1. Rituximab (Rituxan®/MabThera® or rituximab biosimilar): if administered within 12
                  to 37 weeks before the start of treatment, then serum rituximab level must be
                  assessed during the screening and confirmed as negative (<500 ng/mL)

               2. Obinutuzumab (Gazyva®/Gazyvaro®): 184 days.

               3. Ofatumumab (Arzerra®): 88 days.

          2. Received approved or investigational treatment for NHL (except anti-CD20 MAb and
             radioimmunoconjugates) within 4 weeks before the start of treatment.
             Radioimmunoconjugates are excluded within 12 weeks before the start of treatment.

          3. Received radiation therapy to target lesions ) within 4 weeks before the start of
             treatment, unless the lesions exhibited objective progression between radiation
             therapy and screening

             a. Palliative radiation therapy to non-target lesions within 4 weeks before the start
             of treatment may be permitted at the investigator's discretion.

          4. Received systemic immunosuppressive agents (except prescribed corticosteroids at doses
             ≤20 mg/day prednisone equivalent) within 2 weeks before the start of treatment

          5. Received any vaccines except injectable flu (inactivated or recombinant) vaccine
             within 4 weeks before the start of treatment, or likely to require any vaccines except
             injectable flu vaccine at any time from the start of treatment until 28 days after the
             last dose of MT-3724.

          6. Received allogeneic stem cell transplant.

          7. Current evidence of CTCAE Grade ≥2 (significant) 1 toxicity before the start of
             treatment, except for hair loss and those significant toxicities permitted in other
             eligibility criteria. Subjects with significant permitted in other eligibility
             criteria. Subjects with significant

          8. History or current evidence of significant infection, systemic infection or wound
             within 2 weeks before the start of treatment.

             a. Subjects with significant infection that has stabilized or improved with oral
             antibiotics before the start of treatment may be eligible at the investigator's
             discretion.

          9. Known or suspected hypersensitivity to the study drug or excipients contained in the
             study drug formulation.

         10. Current evidence of hypersensitivity or other underlying illness requiring systemic
             corticosteroids at doses >20 mg/day prednisone equivalent

         11. Patients with known active Hepatitis C, HIV or a present history of Hepatitis B

         12. Current evidence of incomplete recovery from surgery or radiotherapy at screening, or
             planned surgery or radiotherapy from the start of treatment until the short term
             follow-up visit, except minor elective surgery or palliative radiation therapy to
             non-target lesions deemed acceptable by the investigator.

         13. History of cardiovascular, renal, hepatic or any other disease within ≤3 months before
             the start of treatment

         14. History of another primary malignancy within the past 3 years (except for ductal
             breast cancer in situ, non-melanoma skin cancer, prostate cancer not requiring
             treatment, and cervical carcinoma in situ) that required systemic drug therapy or
             radiotherapy.

         15. Current evidence of new or growing brain or spinal metastases during screening.

         16. Women who are pregnant or breastfeeding.

         17. History of non-adherence to the schedule of procedures or medication use
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Tolerability as measured by number of subjects with dose limiting toxicities
Time Frame:28 days (Part 1), 21 Days (Part 2 and Part 3)
Safety Issue:
Description:Evaluation of tolerability of MT-3724 measured by number of subjects with dose limiting toxicities (DLTs)

Secondary Outcome Measures

Measure:PK Assessment of MT-3724 by Cmax
Time Frame:Days 1, 5, 8, 12, 23 and 28 (Part 1, 1 cycle-28 days; and Part 2, 21-day cycles); Day 1 and Day 12 of Cycle 1 (each day is 21 cycles) (Part 3)]
Safety Issue:
Description:Cmax is the maximum observed serum concentration of free MT-3724 include
Measure:PK Assessment of MT-3724 by tmax
Time Frame:Days 1, 5, 8, 12, 23 and 28 (Part 1, 1 cycle-28 days; and Part 2, 21-day cycles); Day 1 and Day 12 of Cycle 1 (each day is 21 cycles) (Part 3)]
Safety Issue:
Description:tmax is the time to maximum observed serum concentration of free MT-3724
Measure:PK Assessment of MT-3724 by AUC0-4
Time Frame:Days 1, 5, 8, 12, 23 and 28 (Part 1, 1 cycle-28 days; and Part 2, 21-day cycles); Day 1 and Day 12 of Cycle 1 (each day is 21 cycles) (Part 3)]
Safety Issue:
Description:AUC0-4 is area under the concentration versus time curve (AUC) from time zero to 4 hours after the end of infusion
Measure:PK Assessment of MT-3724 by AUC0-inf
Time Frame:Days 1, 5, 8, 12, 23 and 28 (Part 1, 1 cycle-28 days; and Part 2, 21-day cycles); Day 1 and Day 12 of Cycle 1 (each day is 21 cycles) (Part 3)]
Safety Issue:
Description:AUC0-inf is area under the concentration versus time curve (AUC) from time zero extrapolated to infinity
Measure:PK Assessment of MT-3724 by AUClast
Time Frame:Days 1, 5, 8, 12, 23 and 28 (Part 1, 1 cycle-28 days; and Part 2, 21-day cycles); Day 1 and Day 12 of Cycle 1 (each day is 21 cycles) (Part 3)]
Safety Issue:
Description:AUClast is area under the concentration versus time curve (AUC) from time zero to the last sampling time point within the dosing interval
Measure:PK Assessment of MT-3724 by t1/2
Time Frame:Days 1, 5, 8, 12, 23 and 28 (Part 1, 1 cycle-28 days; and Part 2, 21-day cycles); Day 1 and Day 12 of Cycle 1 (each day is 21 cycles) (Part 3)]
Safety Issue:
Description:t1/2 is elimination half-life
Measure:PK Assessment of MT-3724 by Vz
Time Frame:Days 1, 5, 8, 12, 23 and 28 (Part 1, 1 cycle-28 days; and Part 2, 21-day cycles); Day 1 and Day 12 of Cycle 1 (each day is 21 cycles) (Part 3)]
Safety Issue:
Description:Vz is a volume of distribution
Measure:PK Assessment of MT-3724 by CL
Time Frame:Days 1, 5, 8, 12, 23 and 28 (Part 1, 1 cycle-28 days; and Part 2, 21-day cycles); Day 1 and Day 12 of Cycle 1 (each day is 21 cycles) (Part 3)]
Safety Issue:
Description:CL is clearance
Measure:PD as measured by clinical symptoms, immunogenicity
Time Frame:Days 1, 5, 8, 12, 23 and 28 (Part 1, 1 cycle-28 days; and Part 2, 21-day cycles); Day 1 and Day 12 of Cycle 1 (each day is 21 cycles) (Part 3)]Days 1, 5, 8, 12, 23, and 28 (Part 1 and 2); Day 1, Day 12 of Cycle 1 (Part 3)
Safety Issue:
Description:Evaluation of the pharmacodynamic profile of MT-3724
Measure:Efficacy of MT-3724 (Part 3) as based on ORR
Time Frame:up to 47 weeks (baseline, every 6 weeks during treatment and at the end of treatment visit, which should occur 10-14 days after the last dose)
Safety Issue:
Description:ORR defined as the proportion of subjects with either a CR or a PR as determined by investigator assessment determined by investigator assessment
Measure:Efficacy of MT-3724 (Part 3) as based on DOR
Time Frame:up to 47 weeks (baseline, every 6 weeks during treatment and at the end of treatment visit, which should occur 10-14 days after the last dose)
Safety Issue:
Description:Time from initial documentation of tumor response (PR or CR) to disease progression.
Measure:Efficacy of MT-3724 (Part 3) as based on DCR
Time Frame:up to 47 weeks (baseline, every 6 weeks during treatment and at the end of treatment visit, which should occur 10-14 days after the last dose)
Safety Issue:
Description:Description: Percentage of subjects who have achieved CR, PR and SD (defined as SD for 3 months or longer).
Measure:Efficacy of MT-3724 (Part 3)as based on PFS
Time Frame:up to 47 weeks (baseline, every 6 weeks during treatment and at the end of treatment visit, which should occur 10-14 days after the last dose)
Safety Issue:
Description:PFS is defined as the time from study enrollment to the earliest date of disease progression or death from any cause.
Measure:Efficacy of MT-3724 (Part 3) as based on OS
Time Frame:up to 47 weeks (baseline, every 6 weeks during treatment and at the end of treatment visit, which should occur 10-14 days after the last dose)
Safety Issue:
Description:Overall survival is defined as the time from study enrollment to death from any cause
Measure:PD as measured by B-cell count and immunophenotype in peripheral blood as determined by flow cytometry measured against MT-3724 serum concentrations at pre-specified time points
Time Frame:up to 47 weeks (screening, day 1 of cycle 1, day 12 of cycle 1 (cycle is 21 days), and end of treatment, which should occur 10-14 days after the last dose)
Safety Issue:
Description:Evaluation of the pharmacodynamic profile of MT-3724
Measure:Immunogenicity as measured by MT-3724 anti-drug antibody (ADA) titer
Time Frame:up to 47 weeks (screening, day 1 of cycle 1, day 12 of cycle 1 (cycle is 21 days), and end of treatment, which should occur 10-14 days after the last dose)
Safety Issue:
Description:Evaluation of the Immunogenicity profile of MT-3724
Measure:Quality of life as assessed through Euro-QoL Questionnaire (Part 3)
Time Frame:up to 50 weeks (screening, day 1 of every other cycle (each cycle is 21 days), at end of treatment (which is 10-14 days after the last dose), and short-term follow-up visit (which is up to 33 days after the last dose)
Safety Issue:
Description:The Euro-Quality-of-Life-5 -dimension questionnaire assesses five states (mobility, self care, usual activities, pain / discomfort, and anxiety / depression) at five different levels - no problems, slight problems, moderate problems, severe problems, and extreme problems.
Measure:Safety as measured by number of subjects with Adverse Events using CTCAE
Time Frame:21 days
Safety Issue:
Description:Safety measured by number of subjects with Adverse Events using CTCAE v 5.0 (Part 3)

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Molecular Templates, Inc.

Trial Keywords

  • CD20
  • immunotoxin
  • NHL
  • non-Hodgkin's lymphoma
  • lymphoma
  • cancer
  • antibodies
  • immunotherapy
  • safety
  • pharmacokinetics
  • maximum tolerated dose
  • MT-3724
  • relapsed
  • refractory
  • leukemia
  • CLL
  • SLL
  • DLBCL
  • efficacy

Last Updated

October 30, 2019