Lymphoma, Diffuse Large B-Cell, Treatment Naïve (DB102-02)
A Randomized, Placebo-Controlled, Phase 3 Study to Evaluate the Ability of a Novel Genomic Biomarker to Predict Survival of Treatment Naïve, High Risk Subjects with Diffuse Large B-Cell Lymphoma Treated with R-CHOP plus Enzastaurin
This randomized, placebo-controlled phase 3 study is planned to enroll approximately 235 treatment-naïve subjects with high-risk Diffuse Large B-Cell Lymphoma (DLBCL). Subjects will be randomized 1:1 to R-CHOP plus enzastaurin or R CHOP (plus placebo during induction). All subjects will receive up to 6 cycles (3 weeks per cycle) of treatment. PET/ CT will be used to assess radiographic response at the end of treatment. Each subject's treatment assignment will be unblinded after initial phase of treatment. Subjects randomized to the enzastaurin arm who have a response will be offered maintenance treatment of the study drug for up to 2 additional years.
Key Inclusion Criteria
For a patient to be eligible for participation in this study, all of the following criteria must apply.
- Male or female at least 18 years of age and able to provide informed consent.
- Histologically-confirmed diagnosis of CD20-positive DLBCL based on the WHO classification (2016); the diagnosis must be confirmed at the enrolling site. Subjects with high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements and high-grade B-cell lymphoma, NOS are eligible.
- Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2.
- International Prognostic Index (IPI) score of at least 3.
- Estimated life expectancy of at least 12 weeks.
- Adequate organ function as follows (within 14 days prior to randomization):
- Hepatic: total bilirubin ≤1.5 times upper limit of normal (ULN); alanine transaminase (ALT) and aspartate transaminase (AST) ≤1.5 times ULN (<5 times ULN if liver involvement)
- Renal: creatinine clearance of >50 mL/min by Cockcroft- Gault equation
- Bone marrow: platelets ≥75 x 109/L, absolute neutrophil count (ANC) ≥1.5 x 109/L, hemoglobin ≥10 g/dL. (Platelets ≥50 x 109/L, ANC ≥1.0 x 109/L, hemoglobin ≥8 g/dL permitted if documented bone marrow involvement)
- Male or female with reproductive potential, must be willing to use an approved contraceptive method (for example, intrauterine device (IUD), birth control pills, or barrier device) during and for 3 months after discontinuation of study treatment. Women of childbearing potential must have a negative serum pregnancy test within 7 days prior to randomization.
- Men are considered of reproductive potential unless they have undergone a vasectomy and confirmed sterile by a post-vasectomy semen analysis.
- Women are considered of reproductive potential unless they have undergone hysterectomy and/or surgical sterilization (at least 6 weeks following a bilateral oophorectomy, bilateral tubal ligation, or bilateral tubal occlusive procedure that has been confirmed in accordance with the device's label) or achieved postmenopausal status (defined as cessation of regular menses for greater than 12 consecutive months in women at least 45 years of age).
- Left ventricular ejection fraction ≥50% by echocardiography or nuclear medicine multi-gated scan.
- Must be able to swallow tablets.
- Must be able to comply with study protocol procedures.
- Willing to consent to have blood stored for possible future biomarker and disease analysis.
- Must have available and willing to submit pre-systemic treatment DLBCL tumor biopsy tissue/slides for central pathology review.
Key Exclusion Criteria
A patient will not be eligible for participation in this study if any of the following criteria apply.
- Received treatment with an investigational drug within the last 30 days.
- Receiving or has received radiation or any other systemic anticancer treatment for lymphoma (Up to 7 days of corticosteroids are permitted but must be administered after eligibility IPI determination and imaging scans).
- History of indolent lymphoma or follicular Grade 3b lymphoma.
- Primary mediastinal (thymic) large B-cell lymphoma.
- B-cell lymphoma, unclassifiable, with features. intermediate between DLBCL and classical Hodgkin lymphoma.
- Burkitt lymphoma.
- Pregnancy or breastfeeding.
- Known central nervous system (CNS) involvement.
- Any significant concomitant disorder based on the discretion of the investigator, including but not limited to active bacterial, fungal, or viral infection, incompatible with participation in the study.
- A second primary malignancy (except adequately treated non-melanoma skin cancer); subjects who have had another malignancy in the past, but have been disease-free for more than 5 years, and subjects who have had a localized malignancy treated with curative intent and disease free for more than 2 years are eligible.
- Use of a strong inducer or moderate or strong inhibitor of CYP3A4 within 7 days prior to start of study therapy or expected requirement for use on study therapy.
- Personal or immediate family history of long QT syndrome, QTc interval >450 msec (males) or >470 msec (females) at screening (recommended that QTc be calculated using Fridericia correction formula, QTcF: see Section 6.2.1), or a history of unexplained syncope.
- Use of any medication that can prolong the QT/QTc interval within 7 days prior to start of study therapy or expected requirement for use on study therapy.
- History of severe allergic or anaphylactic reaction to monoclonal antibody therapy.
- Confirmed diagnosis of progressive multifocal leukoencephalopathy.
- Ongoing grade 2 or higher peripheral neuropathy.
- Have any of the following cardiac disorders: uncontrolled hypertension, unstable angina, myocardial infarction within 8 weeks of Day1, NYHA Grade 2 or higher congestive heart failure, ventricular arrhythmia requiring medication within 1 year of Day 1, NYHA Grade 2 or higher peripheral vascular disease.
- Received a live vaccine within 28 days of study Day 1.
- HIV positive.
- Evidence of chronic hepatitis C infection as indicated by antibody to HCV with positive HCV-RNA.
- Evidence of chronic hepatitis B infection as indicated by either:
- HBsAg+ or
- HBcAb+ with HBV-DNA+ (any detectable amount is considered positive)
To learn more, visit ClinicalTrials.Gov
Roberto Ferro, MD
Denovo Biopharma LLC