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:
- 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.
- 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
- 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
- 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
- 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
- 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?
- 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
- 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