PB2132: COPANLISIB PLUS RITUXIMAB-BENDAMUSTINE FOR RELAPSED-REFRACTORY DIFFUSE LARGE B-CELL LYMPHOMA: RECRUITMENT UPDATE ON AN ONGOING PHASE II TRIAL OF THE FONDAZIONE ITALIANA LINFOMI (FIL_COPA-RB)

Abstract

Background: Diffuse large B cell lymphoma (DLBCL) is curable in 50-60% of cases with frontline RCHOP. Relapsed/refractory (R/R) DLBCL can be cured with salvage treatments in roughly 40-50% of cases with standard available treatments which include high dose-chemotherapy plus autologous stem cell transplant (ASCT) in fit patients, and chimeric antigen receptor T-cells (CAR-T), permitted as third or subsequent line in patients with no major comorbidities. The outcome of R/R DLBCL unresponsive or ineligible to ASCT or CAR-T is highly unfavorable and new treatment options are needed. Rituximab plus bendamustine (RB) is active in R/R DLBCL with overall response rates (ORR) of 40-60% but generally short-lasting. Copanlisib is an intravenous pan-class I PI3K inhibitor with predominant activity against PI3K-α and -δ isoforms, active as single agent in DLBCL with ORR 25% (NCT02391116). The combination of copanlisib plus RB (Copa-RB) has showed a safe toxicity profile in R/R indolent lymphomas (iNHL) (NCT02626455). Aims: To assess the safety and efficacy of Copa-RB followed by copanlisib maintenance in R/R DLBCL not eligible or relapsed after ASCT or CAR-T. Methods: FIL Copa-RB is a multicentric open-label single arm, phase II trial. An estimated 81 patients will be enrolled, from 30 centers in Italy. Main inclusion criteria are patients aged ≥ 18 affected by DLBCL (including de-novo DLBCL, DLBCL transformed by iNHL and high-grade lymphoma) or FL grade IIIb R/R after ≤ 3 previous lines of therapy, ineligible or R/R to ASCT or CART, ECOG PS ≤ 2. Patients with primary mediastinal B cell lymphoma histology, significant organ dysfunction, uncontrolled hypertension and hyperglycemia (HbA1c> 8.5%) are excluded. Treatment consists of an induction phase with six 28-day cycles of Copa-RB (copanlisib 60 mg intravenously on day (D) 1, D8 and D15, rituximab 375 mg/m2 on D1, bendamustine 90 mg/m2 on D1-D2) followed by a maintenance phase of twelve 28-day cycles of copanlisib 60 mg given on D1 and D15. The primary endpoint is progression free survival (PFS) defined as the time between the date of enrolment and the date of disease progression, relapse or death from any cause, whichever occurs earlier, with an expected improvement of 12-month PFS from 20% to 35%. Secondary endpoints include overall survival, ORR, complete response (CR) rate, duration of response and rate of response improvement during maintenance. Exploratory analysis will include association between outcome and cell of origin, MYC, BCL2 and BCL6 overexpression and rearrangements, and mutational analysis of selected genes possibly involved in predicting response to copanlisib. The expected study duration from first patient’s first visit to last patient’s last visit is approximately 4 years. Results: The recruitment started in November 2020; at March 1st, 27/81 patients have been enrolled. Results for this study are not yet available. Summary/Conclusion: The treatment of R/R DLBCL ineligible or R/R to ASCT or CAR-T is still an unmet clinical need and new therapeutic strategies are warranted. Copanlisib as single agent has been already shown a moderate activity in DLBCL and the association Copa-RB plus copanlisib maintenance could be a new treatment option to improve the outcome of these patients. Biomarkers studies may further elucidate patients who are more likely to respond to this treatment. Funding: The study is sponsored by the Fondazione Italiana Linfomi; Bayer partly supported the study and kindly provided Copanlisib; Sandoz kindly provided Rituximab.