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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04517435
Recruitment Status : Recruiting
First Posted : August 18, 2020
Last Update Posted : August 12, 2021
Sponsor:
Collaborator:
Case Comprehensive Cancer Center
Information provided by (Responsible Party):
Deepa Jagadeesh, Case Comprehensive Cancer Center

Tracking Information
First Submitted Date  ICMJE August 14, 2020
First Posted Date  ICMJE August 18, 2020
Last Update Posted Date August 12, 2021
Estimated Study Start Date  ICMJE October 2021
Estimated Primary Completion Date July 2024   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 14, 2020)
  • 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 ]
    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.
  • Progression free survival (PFS) assessed by Lugano criteria [ Time Frame: 36 months (3 years) after completion of therapy or until death, whichever comes first ]
    PFS, as defined as time from study treatment initiation to documented disease progression per Lugano Criteria, or death from any cause, whichever occurs first.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: August 14, 2020)
  • Number of treatment-related AEs in Phase I [ Time Frame: Up to 24 months after treatment ]
    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.
  • Number of treatment-related AEs in Phase II [ Time Frame: Up to 24 months after treatment ]
    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.
  • Number of days treatment is delayed [ Time Frame: Up to 24 months after treatment ]
    Number of days treatment is delayed
  • Overall Response (OR) assessed by Lugano criteria [ Time Frame: 36 months (3 years) after completion of therapy or until death, whichever comes first ]
    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
  • Complete Response (CR) assessed by Lugano criteria [ Time Frame: 36 months (3 years) after completion of therapy or until death, whichever comes first ]
    CR assessed by Lugano criteria
  • Partial Response (PR) assessed by Lugano criteria [ Time Frame: 36 months (3 years) after completion of therapy or until death, whichever comes first ]
    PR assessed by Lugano criteria
  • Duration of Response (DoR) [ Time Frame: 36 months (3 years) after completion of therapy or until death, whichever comes first ]
    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
  • Overall Survival (OS) [ Time Frame: 36 months (3 years) after completion of therapy or until death, whichever comes first ]
    OS defined as the time from first dose of study treatment to death from any cause
  • Time to Treatment Failure [ Time Frame: 36 months (3 years) after completion of therapy or until death, whichever comes first ]
    Time to Treatment Failure defined as the time from study entry to any treatment failure.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE ME-401 and R-CHOP in Newly Diagnosed Diffuse Large B-Cell Lymphoma
Official Title  ICMJE An Open-Label, Phase I/II Study of ME-401 and R-CHOP in Newly Diagnosed Diffuse Large B-Cell Lymphoma
Brief Summary 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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Diffuse Large B-Cell Lymphoma
Intervention  ICMJE
  • Drug: ME-401
    ME-401 (60 mg) will be given by mouth every 21 days for 6 cycles on days 1-4 (dose level 1) OR days 1-7 (dose level 2) of a 21 day cycle. Dose escalation will be performed in a standard 3+3 design
    Other Name: PWT-143
  • Drug: Rituximab

    375 mg/m2 IV/subcutaneous rituximab day 1 of 21-day cycle.

    First dose of rituximab will be given IV and subsequent doses can be either IV or SQ based on institutional guidelines.

    Other Names:
    • Rituxan
    • Mabthera
  • Drug: Cyclophosphamide
    750 mg/m2 IV Cyclophosphamide day 1 of 21-day cycle
    Other Name: Cytoxan
  • Drug: Doxorubicin
    50 mg/m2 IV Doxorubicin day 1 of 21-day cycle
    Other Name: Doxorubicin Hydrochloride
  • Drug: Vincristine
    1.4 mg/m2 (max 2 mg) IV Vincristine
    Other Name: OncovinTM
  • Drug: Prednisone
    100mg PO Prednisone Days 1-5 of 21-day cycle
Study Arms  ICMJE Experimental: ME-401 + R-CHOP
Participants 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.
Interventions:
  • Drug: ME-401
  • Drug: Rituximab
  • Drug: Cyclophosphamide
  • Drug: Doxorubicin
  • Drug: Vincristine
  • Drug: Prednisone
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: August 14, 2020)
54
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE July 2025
Estimated Primary Completion Date July 2024   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Deepa Jagadeesh, MD, MPH 1-866-223-8100 TaussigResearch@ccf.org
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04517435
Other Study ID Numbers  ICMJE CASE1420
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Plan Description: There are no plans to share individual participant data in order to protect the confidentiality of the subjects who enroll on the study
Responsible Party Deepa Jagadeesh, Case Comprehensive Cancer Center
Study Sponsor  ICMJE Deepa Jagadeesh
Collaborators  ICMJE Case Comprehensive Cancer Center
Investigators  ICMJE
Principal Investigator: Deepa Jagadeesh, MD, MPH Cleveland Clinic Taussig Cancer institute, Case Comprehensive Cancer Center
PRS Account Case Comprehensive Cancer Center
Verification Date August 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP