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

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Diffuse Large B-Cell Lymphoma

Intervention / Treatment
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* Drug: ME-401
* Drug: Rituximab
* Drug: Cyclophosphamide
* Drug: Doxorubicin
* Drug: Vincristine
* Drug: Prednisone


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ME-401 + R-CHOP<br>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. | Drug: ME-401<br>* 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<br>* Other names: PWT-143;Drug: Rituximab<br>* 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.<br>* Other names: Mabthera;Drug: Cyclophosphamide<br>* 750 mg/m2 IV Cyclophosphamide day 1 of 21-day cycle<br>* Other names: Cytoxan;Drug: Doxorubicin<br>* 50 mg/m2 IV Doxorubicin day 1 of 21-day cycle<br>* Other names: Doxorubicin Hydrochloride;Drug: Vincristine<br>* 1.4 mg/m2 (max 2 mg) IV Vincristine<br>* Other names: OncovinTM;Drug: Prednisone<br>* 100mg PO Prednisone Days 1-5 of 21-day cycle<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of clinically significant non-hematologic grade 3 or 4 treatment-related AEs or hematologic grade 3 or 4 treatment related AEs | 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. | Up to 24 months after treatment | 
| Progression free survival (PFS) assessed by Lugano criteria | PFS, as defined as time from study treatment initiation to documented disease progression per Lugano Criteria, or death from any cause, whichever occurs first. | 36 months (3 years) after completion of therapy or until death, whichever comes first | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of treatment-related AEs in Phase I | 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. | Up to 24 months after treatment | 
| Number of treatment-related AEs in Phase II | 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. | Up to 24 months after treatment | 
| Number of days treatment is delayed | Number of days treatment is delayed | Up to 24 months after treatment | 
| Overall Response (OR) assessed by Lugano criteria | 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 | 36 months (3 years) after completion of therapy or until death, whichever comes first | 
| Complete Response (CR) assessed by Lugano criteria | CR assessed by Lugano criteria | 36 months (3 years) after completion of therapy or until death, whichever comes first | 
| Partial Response (PR) assessed by Lugano criteria | PR assessed by Lugano criteria | 36 months (3 years) after completion of therapy or until death, whichever comes first | 
| Duration of Response (DoR) | 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 | 36 months (3 years) after completion of therapy or until death, whichever comes first | 
| Overall Survival (OS) | OS defined as the time from first dose of study treatment to death from any cause | 36 months (3 years) after completion of therapy or until death, whichever comes first | 
| Time to Treatment Failure | Time to Treatment Failure defined as the time from study entry to any treatment failure. | 36 months (3 years) after completion of therapy or until death, whichever comes first |