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

NCT04517435 | Terminated Phase 1 Results DMC FDA Drug

• 1 other identifier: CASE1420
• Study Type: interventional
• Target: 13
• Locations: 1 country
• Sites: 1

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.

Conditions

Diffuse Large B-Cell Lymphoma

Outcome Measures

Primary Outcomes (2)

• Phase I: 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

• Phase II: 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.

  24 months (2 years)

Secondary Outcomes (9)

• Phase I: Number of Treatment-related AEs

  Up to 24 months after treatment

• Phase II: Number of Treatment-related AEs

  Up to 24 months after treatment

• Phase II: Number of Days Treatment is Delayed

  Up to 24 months after treatment

• Phase II: Overall Response (OR) Assessed by Lugano Criteria

  24 months (2 years)

• Complete Response (CR) Assessed by Lugano Criteria

  24 months (2 years)

Study Arms (1)

ME-401 + R-CHOP

EXPERIMENTAL

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; Drug: Rituximab; Drug: Cyclophosphamide; Drug: Doxorubicin; Drug: Vincristine; Drug: Prednisone

Interventions

ME-401 DRUG

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

Also known as: PWT-143

ME-401 + R-CHOP

Rituximab DRUG

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.

Also known as: Rituxan, Mabthera

ME-401 + R-CHOP

Cyclophosphamide DRUG

750 mg/m2 IV Cyclophosphamide day 1 of 21-day cycle

Also known as: Cytoxan

ME-401 + R-CHOP

Doxorubicin DRUG

50 mg/m2 IV Doxorubicin day 1 of 21-day cycle

Also known as: Doxorubicin Hydrochloride

ME-401 + R-CHOP

Vincristine DRUG

1.4 mg/m2 (max 2 mg) IV Vincristine

Also known as: OncovinTM

ME-401 + R-CHOP

Prednisone DRUG

100mg PO Prednisone Days 1-5 of 21-day cycle

ME-401 + R-CHOP

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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).

You may not qualify if:

• 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.

Sponsors & Collaborators

• Deepa Jagadeesh: lead
• Case Comprehensive Cancer Center: collaborator

Study Sites (1)

Cleveland Clinic Taussig Cancer institute, Case Comprehensive Cancer Center

Cleveland, Ohio, 44195, United States

Location

MeSH Terms

Conditions

Lymphoma, Large B-Cell, Diffuse

Interventions

ME-401; Rituximab; Cyclophosphamide; Doxorubicin; Vincristine; Prednisone

Condition Hierarchy (Ancestors)

Lymphoma, B-Cell; Lymphoma, Non-Hodgkin; Lymphoma; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Daunorubicin; Anthracyclines; Naphthacenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Polycyclic Compounds; Aminoglycosides; Glycosides; Carbohydrates; Vinca Alkaloids; Secologanin Tryptamine Alkaloids; Indole Alkaloids; Alkaloids; Heterocyclic Compounds; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Indolizidines; Indolizines; Pregnadienediols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds

Limitations and Caveats

The pharmaceutical company, MEI Pharma, withdrew funding, therefore leading to a premature termination and follow-up was discontinued for all patients. All outcome analyses are based on only a small number of participants that were followed for a short period of time.

Results Point of Contact

• Title: Dr. Deepa Jagadeesh
• Organization: Cleveland Clinic Taussig Cancer Center, Case Comprehensive Cancer Center

TaussigResearch@ccf.org

1-866-223 8100

Study Officials

• Deepa Jagadeesh, MD, MPH

  Cleveland Clinic Taussig Cancer institute, Case Comprehensive Cancer Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: August 14, 2020
• First Posted: August 18, 2020
• Study Start: April 28, 2021
• Primary Completion: May 17, 2023
• Study Completion: May 17, 2023
• Last Updated: February 7, 2025
• Results First Posted: February 7, 2025

Record last verified: 2025-01

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)