Abstract PO-008: Phase I/II study of VIP152 (enitociclib), venetoclax, and prednisone (VVIP) in relapsed/refractory (R/R) lymphoid malignancies
Authors: Melani Christopher , Gordon Max , Lakhotia Rahul , Pittaluga Stefania , Simard Jillian , Muppidi Jagan , Phelan James D. , Pack Svetlana , Pradhan Amynah , Morrison Candis , Tadese Atekelt , Juanitez Anna M. , Johnson Amy J. , Frigault Melanie M. , Hamdy Ahmed , Roschewski Mark , Staudt Louis M. , Wilson Wyndham H. 
Published: June 2024

Background: Relapsed/refractory (R/R) aggressive lymphomas, including diffuse large B-cell lymphoma (DLBCL), high-grade B-cell lymphoma double-hit (HGBCL-DH), and peripheral T-cell lymphoma (PTCL), have poor outcomes with standard therapy. VIP152 (enitociclib) leads to rapid depletion of short-lived mRNA transcripts such as MYC and MCL1 through CDK9 inhibition. Preclinical studies have identified BCL2 overexpression as a mechanism of resistance to CDK9 inhibition, and synergistic cytotoxicity has been shown with venetoclax (BCL2 inhibitor), steroids, and CDK9 inhibitors in DLBCL. Based on this preclinical data, we hypothesized that the combination of VIP152 with venetoclax and prednisone (VVIP) would result in acceptable safety and improved efficacy in R/R lymphoid malignancies.

Methods: R/R non-GCB DLBCL, MYC-rearranged DLBCL/HGBCL-DH, and PTCL pts after 2 prior systemic therapies are eligible. In phase I, pts are treated at 4 dose levels (DL) of VIP152 and venetoclax in combination with fixed-dose prednisone to identify the recommended phase II dose (RP2D). VIP152 (15mg, 22.5mg, or 30mg) is given IV on days 2 and 9 in combination with venetoclax (600mg or 800mg) PO and prednisone 100 mg PO on days 1-10 every 21 days. Phase II expansion cohorts are included at the RP2D. VVIP x 12 cycles is given for pts who achieve complete response (CR), with a max of 24 cycles for pts not in CR. TLS, G-CSF, and PCP prophylaxis are given to all pts. Baseline CT, PET, and BM are performed with CT after cycles 1 and 2 then every 2 cycles and PET after cycles 6 and 12. CT is then performed q3m x 1y, q4m x 1y, q6m x 1y, then q12m x 2y post-therapy.

Results: As of March 26, 2024, 5 pts were enrolled (3 at DL1 and 2 at DL2), including 3 PTCL, 1 non-GCB DLBCL, and 1 HGBCL-DH. Median (range) age was 56 (55-77) yrs, with stage 3/4 disease in 100%, &gt;/=2 extranodal sites in 100%, IPI &gt;/=3 in 80%, and elevated LDH in 40%. Median (range) prior therapies were 3 (3-6), with prior ASCT, allo-HSCT, and CAR-T in 1 (20%) pt each, and 80% of pts refractory per SCHOLAR-1 criteria. All 5 pts completed the dose-limiting toxicity (DLT) window with no DLTs observed. The most common adverse events (AEs) (% pts) included hypokalemia (100%), thrombocytopenia (80%), neutropenia (80%), and anemia (80%). Two (40%) pts had G3-4 neutropenia and 1 (20%) pt had G3 hypokalemia, with no other &gt;/=G3 AEs observed. No dose reductions occurred and only 1 pt required a dose delay due to infection. Tumor reduction was observed in 80% (4/5) of pts, with an overall response rate of 60% (3/5). Partial responses include 1 HGBCL-DH pt refractory to both CAR-T and epcoritamab (71% tumor reduction) and 2 PTCL pts refractory to CHOP and targeted therapy (86% and 91% tumor reduction). Four pts have progressed, and no pts have died.

Conclusions: Preliminary results show VVIP to be safe and well tolerated with no DLTs observed. Early activity is noted in pts with HGBCL-DH and PTCL. Enrollment continues to identify the RP2D and to further assess the safety and efficacy of VVIP in R/R aggressive lymphomas.

Citation Format: Christopher Melani, Max Gordon, Rahul Lakhotia, Stefania Pittaluga, Jillian Simard, Jagan Muppidi, James D. Phelan, Svetlana Pack, Amynah Pradhan, Candis Morrison, Atekelt Tadese, Anna M. Juanitez, Amy J. Johnson, Melanie M. Frigault, Ahmed Hamdy, Mark Roschewski, Louis M. Staudt, Wyndham H. Wilson. Phase I/II study of VIP152 (enitociclib), venetoclax, and prednisone (VVIP) in relapsed/refractory (R/R) lymphoid malignancies [abstract]. In: Proceedings of the Fourth AACR International Meeting on Advances in Malignant Lymphoma: Maximizing the Basic-Translational Interface for Clinical Application; 2024 Jun 19-22; Philadelphia, PA. Philadelphia (PA): AACR; Blood Cancer Discov 2024;5(3_Suppl):Abstract nr PO-008.