Clinical Trials /

ME-401 and R-CHOP in Newly Diagnosed Diffuse Large B-Cell Lymphoma

NCT04517435

Description:

This study is being done to evaluate if ME-401 can improve the treatment of patients with diffuse large b-celllymphoma (DLBCL). Many patients with DLBCL that are treated with the standard of care (R-CHOP) are cured. However, a little less than half of patients will have their cancer come back despite being treated. Once DLBCL comes back, it is much harder to treat and treatment is much more aggressive. This study will combine ME-401 with R-CHOP. There are 2 parts to this study: part1 referred to as phase I and part 2 referred to as phase 2. The goal of the phase I study is to find the safest dose to give patients in combination with R-CHOP. The goal of the phase 2 study is to use the safest dose (found in phase 1) in combination with R-CHOP to see if it decreases the rate of cancer coming back after it is treated.

Related Conditions:
  • Diffuse Large B-Cell Lymphoma
  • Transformed Non-Hodgkin Lymphoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: ME-401 and R-CHOP in Newly Diagnosed Diffuse Large B-Cell Lymphoma
  • Official Title: An Open-Label, Phase I/II Study of ME-401 and R-CHOP in Newly Diagnosed Diffuse Large B-Cell Lymphoma

Clinical Trial IDs

  • ORG STUDY ID: CASE1420
  • NCT ID: NCT04517435

Conditions

  • Diffuse Large B-Cell Lymphoma

Interventions

DrugSynonymsArms
ME-401PWT-143ME-401 + R-CHOP
RituximabRituxan, MabtheraME-401 + R-CHOP
CyclophosphamideCytoxanME-401 + R-CHOP
DoxorubicinDoxorubicin HydrochlorideME-401 + R-CHOP
VincristineOncovinTMME-401 + R-CHOP
PrednisoneME-401 + R-CHOP

Purpose

This study is being done to evaluate if ME-401 can improve the treatment of patients with diffuse large b-celllymphoma (DLBCL). Many patients with DLBCL that are treated with the standard of care (R-CHOP) are cured. However, a little less than half of patients will have their cancer come back despite being treated. Once DLBCL comes back, it is much harder to treat and treatment is much more aggressive. This study will combine ME-401 with R-CHOP. There are 2 parts to this study: part1 referred to as phase I and part 2 referred to as phase 2. The goal of the phase I study is to find the safest dose to give patients in combination with R-CHOP. The goal of the phase 2 study is to use the safest dose (found in phase 1) in combination with R-CHOP to see if it decreases the rate of cancer coming back after it is treated.

Detailed Description

      This study is a multi-institution, open-label, phase I/II study designed to evaluate the
      safety and efficacy of R-CHOP + ME-401 for participants with newly diagnosed DLBCL.

      Objectives for the phase I portion of this study are as follows:

      Primary objectives:

        -  To determine the recommended phase 2 dose (RP2D) of ME-401in combination with R-CHOP for
           participants with newly diagnosed DLBCL.

        -  To describe tolerability of ME-401 in combination with R-CHOP for participants with
           newly diagnosed DLBCL.

      Objectives for the phase II portion of this study are as follows:

        -  To estimate the clinical activity of ME-401 in combination with R-CHOP in participants
           with newly diagnosed DLBCL, as measured by 1 year PFS rate

        -  To estimate the response rates (complete and partial remission),duration of response
           (DOR), time to progression (TTP), and overall survival (OS) with ME-401 plus R-CHOP.

        -  To characterize treatment-related AEs in participants treated with ME-401 plus R-CHOP.
    

Trial Arms

NameTypeDescriptionInterventions
ME-401 + R-CHOPExperimentalParticipants will receive ME-401 dose dependent on dose-escalation schedule at time of enrollment - all will receive standard dose R-CHOP. ME-401 (60 mg) will be given on days 1-4 (dose level 1) OR days 1-7 (dose level 2) of a 21 day cycle with standard dose R-CHOP x 6 cycles.
  • ME-401
  • Rituximab
  • Cyclophosphamide
  • Doxorubicin
  • Vincristine
  • Prednisone

Eligibility Criteria

        Inclusion Criteria:

          -  Participants must have histologically confirmed diffuse large B-cell lymphoma (DLBCL).
             Participants with previously diagnosed indolent lymphoma (follicular and marginal zone
             lymphoma but not small lymphocytic lymphoma) who have transformed to DLBCL are
             eligible only if they have not previously been treated for indolent lymphoma.

             --If participants received single rituximab (maximum 4-8 doses with no maintenance)
             for their low grade lymphoma ≥12 months prior to starting study drug are eligible to
             participate

          -  Participants must have radiographically measurable disease. At least one
             bi-dimensionally measurable nodal lesion ≥1.5 cm in its longest diameter by CT scan or
             MRI, as defined by the Lugano Classification

          -  Patients participating in the phase II part are allowed to receive brief (<15 days)
             treatment with glucocorticoids (max dose of prednisone 40 mg) and/or 1 cycle of
             chemotherapy such as R-CHOP [or some component(s) thereof] for the diagnosis of B-cell
             lymphoma provided they had all necessary staging tests performed prior to R-CHOPor
             steroids including CT and/or PET/CTscans, and bone marrow biopsy. Treatment must occur
             within 30 days prior to enrollment.

          -  No prior therapy with PI3K inhibitors or Bruton tyrosine kinase (BTK) inhibitors

          -  ECOG Performance status ≤2. Performance Status of 3 will be accepted if impairment is
             caused by DLBCL complications and improvement is expected once therapy is initiated.

          -  Participants must have adequate hematologic, hepatic, and renal function as defined
             below:

               -  Hemoglobin ≥9.0g/dl unless the anemia is clearly due to DLBCL. If there is BM
                  involvement, this criteria can be waived after discussion with the Sponsor
                  Investigator (per investigators discretion).

               -  Absolute neutrophil count≥1,000/mcL, unless the neutropenia is clearly due to
                  DLBCL. If there is BM involvement, this criteria can be waived after discussion
                  with the Sponsor Investigator(per investigator discretion)

               -  Platelet count ≥75,000/mcl unless thrombocytopenia is clearly due to DLBCL. If
                  there is BM involvement, this criteria can be waived after discussion with the
                  Sponsor Investigator(per investigator discretion)

               -  Bilirubin ≤ 2.0 x ULN unless considered secondary to Gilbert's syndrome, in which
                  case ≤ 3 x ULN

               -  AST (SGOT) < 2.0 x institutional upper limit of normal

               -  ALT (SGPT) < 2.0 x institutional upper limit of normal

               -  Creatinine clearance ≥45 mL/min calculated by Cockcroft-Gault or 24 hour
                  collection

          -  Adequate cardiac function left ventricular ejection fraction (LVEF) ≥50% as assessed
             by echocardiogram or MUGA (Multi Gated Acquisition Scan).

          -  QT-interval corrected according to Fridericia's formula (QTcF) ≤450 milliseconds (ms);
             participants with QTc < 480 msec may be enrolled provided the QTc prolongation is due
             to a right bundle branch block and stable .

          -  Negative pregnancy test in women of child-bearing age. The effects of ME-401 on the
             developing human fetus are unknown. For this reason and because chemotherapeutic
             agents used in this study are known to be teratogenic, women of child-bearing
             potential and men must agree to use adequate contraception (double barrier method of
             birth control or abstinence) 2 weeks prior to initiation of treatment, for the
             duration of study participation and for 3 months after completing treatment. Should a
             woman become pregnant or suspect that she is pregnant while she or her partner is
             participating in this study, she should inform the treating physician immediately. Men
             must agree to refrain from sperm donation for at least 90 days after the last dose of
             ME-401

          -  Participants must have the ability to understand and the willingness to sign a written
             informed consent document.

          -  International Prognostic Index must be documented:

               -  ECOG performance status ≥2

               -  Age ≥60 years

               -  extranodal sites ≥ 2

               -  LDH >upper limit of normal

               -  Ann Arbor Stage III or IV

               -  Is there evidence of transformation from indolent lymphoma?

        Exclusion Criteria:

          -  Participants receiving any other investigational agents.

          -  Known CNS involvement by lymphoma. Participants at high risk for secondary CNS
             involvement but without neurologic symptoms suspected to be due to lymphoma are
             allowed to be enrolled and receive prophylactic intrathecal chemotherapy including but
             not limited to methotrexate, cytarabine and glucocorticoids. Participants who are
             enrolled and subsequently identified to have pathologic confirmation of CNS
             involvement by lymphoma may be continued on study at the discretion of the principal
             investigator.

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to R-CHOP.

          -  Participants with ongoing uncontrolled illness including, but not limited to ongoing
             significantly active infections requiring intravenous antibiotics, hypertension,
             angina, arrhythmias, pulmonary disease, or autoimmune dysfunction.

          -  Uncontrolled autoimmune hemolytic anemia or immune thrombocytopenia.

          -  Ongoing drug-induced pneumonitis.

          -  History of clinically significant gastrointestinal (GI) conditions, particularly:

               -  Known GI condition that would interfere with swallowing or the oral absorption or
                  tolerance of study drug

               -  Pre-existing malabsorption syndrome or other clinical situation that would

          -  Active congestive heart failure (New York Heart Association [NYHA] Class>2),
             symptomatic ischemia, or conduction abnormalities uncontrolled by conventional
             intervention or myocardial infarction within six months prior to enrollment.

          -  Participants who have tested positive for hepatitis B surface antigen and/or hepatitis
             B core antibody PLUS have detectable viral load on hepatitis B polymerase chain
             reaction (PCR) assay (participants with a negative PCR assay are permitted with
             appropriate anti-viral prophylaxis)

          -  Positive hepatitis C virus antibody (HCV Ab) participants with positive hepatitis C
             antibody are eligible if they are negative for hepatitis C virus by PCR

          -  HIV-positive participants on combination antiretroviral therapy are ineligible because
             of the potential for pharmacokinetic interactions with ME-401

          -  Pregnant or breastfeeding women are excluded from this study because there are no
             studies assessing the reproductive and developmental toxicity or excretion into breast
             milk of ME-401. Because there is an unknown, but potential risk for adverse events in
             nursing infants secondary to treatment of the mother with ME-401, breastfeeding should
             be discontinued if the mother is treated with ME-401. These potential risks may also
             apply to other drugs used in this study.

          -  Other malignancies within the past 3 years except for adequately treated carcinoma of
             the cervix or basal or squamous cell carcinomas of the skin, or low-risk prostate
             cancer after curative therapy.

          -  Participants who have had major surgical procedures or significant traumatic injury
             within 28 days prior to study treatment.

          -  Psychiatric illness/social situations that would interfere with study compliance
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Number of clinically significant non-hematologic grade 3 or 4 treatment-related AEs or hematologic grade 3 or 4 treatment related AEs
Time Frame:Up to 24 months after treatment
Safety Issue:
Description:Dose limiting toxicity (DLT) as defined by non-hematologic clinically significant grade 3 or 4 treatment-related AEs or hematologic grade 3 or 4 treatment related AEs that are clinically significant during the first cycle, graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0.

Secondary Outcome Measures

Measure:Number of treatment-related AEs in Phase I
Time Frame:Up to 24 months after treatment
Safety Issue:
Description:Number of treatment-related AEs in Phase I. Participants will be followed for toxicity for 30 days after treatment has been discontinued or until death, whichever occurs first. The clinical course of each event will be followed until resolution, stabilization, or until it has been determined that the study treatment or participation is not the cause with a cut off of 24 months after completion of therapy.
Measure:Number of treatment-related AEs in Phase II
Time Frame:Up to 24 months after treatment
Safety Issue:
Description:Number of treatment-related AEs in Phase II Participants will be followed for toxicity for 30 days after treatment has been discontinued or until death, whichever occurs first. The clinical course of each event will be followed until resolution, stabilization, or until it has been determined that the study treatment or participation is not the cause with a cut off of 24 months after completion of therapy.
Measure:Number of days treatment is delayed
Time Frame:Up to 24 months after treatment
Safety Issue:
Description:Number of days treatment is delayed
Measure:Overall Response (OR) assessed by Lugano criteria
Time Frame:36 months (3 years) after completion of therapy or until death, whichever comes first
Safety Issue:
Description:OR assessed by Lugano criteria. OR is defined as achieving either CR or PR at any stage from time of commencement of protocol treatment to time of treatment cessation for whatever reason
Measure:Complete Response (CR) assessed by Lugano criteria
Time Frame:36 months (3 years) after completion of therapy or until death, whichever comes first
Safety Issue:
Description:CR assessed by Lugano criteria
Measure:Partial Response (PR) assessed by Lugano criteria
Time Frame:36 months (3 years) after completion of therapy or until death, whichever comes first
Safety Issue:
Description:PR assessed by Lugano criteria
Measure:Duration of Response (DoR)
Time Frame:36 months (3 years) after completion of therapy or until death, whichever comes first
Safety Issue:
Description:DoR defined as the time from documented response (CR or PR) to the time of confirmed disease progression or death due to any cause, whichever occurs first
Measure:Overall Survival (OS)
Time Frame:36 months (3 years) after completion of therapy or until death, whichever comes first
Safety Issue:
Description:OS defined as the time from first dose of study treatment to death from any cause
Measure:Time to Treatment Failure
Time Frame:36 months (3 years) after completion of therapy or until death, whichever comes first
Safety Issue:
Description:Time to Treatment Failure defined as the time from study entry to any treatment failure.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Deepa Jagadeesh

Last Updated

August 14, 2020