Citations 2
Acalabrutinib Plus Bendamustine-Rituximab in Untreated Mantle Cell Lymphoma
Wang, Michael , Song, Yuqin, Jurczak, Wojciech, Kahl, Brad S. , Chu, Michael P., Kryachok, Iryna, Fogliatto, Laura, Cheah, Chan Y. , Morawska, Marta , Li, Yufu, Patti, Caterina , Forsyth, Cecily , Lesley, Robin, Ramadan, Safaa, Rule, Simon, Dreyling, Martin , investigators, for the ECHO, Cazap, Nicolás, Foncuberta, María Cecilia, Garate, Gonzalo, Gustavo, Jarchum, Pavlovsky, Miguel Arturo , Riveros, Dardo, Baker, Ross, Butler, Jason, Cannell, Paul , Cheah, Chan, Forsyth, Cecily, Giri, Pratyush, Johnston, Amanda, Lee, Denise , Lee, Hui‐Peng, Mapp, Sally, Roncolato, Fernando , Thant, Aung , Walker, Patricia, Doo, Nicole Wong, Demuynck, Hilde, Offner, Fritz , Hende, Vanessa Van, Vergote, Vibeke, Wu, Ka Lung , Chiattone, Carlos, Azevedo, Sergio de, Fogliatto, Laura, Fonseca, Ana, Hamerschlak, Nelson, Lazaretti, Nicolas, Rocha, Vanderson, Salvino, Marco, Santucci, Rodrigo, Schaan, Mariza, Scheliga, Adriana, Vieira, Garles Miller, Berinstein, Neil, Boutin, Mélina , Chu, Michael, Keating, Mary‐Margaret, Schattner, Ariah, Restrepo, Diego Villa, Cen, Xinan, Du, Xin, Feng, Ru, Gao, Sujun, Huang, Haiwen, Ji, Jie, Jin, Jie, Ke, Xiaoyan, Li, Dengju, Li, Fei, Li, Jianyong, Li, Junmin, Li, Yan, Li, Yufu, Li, Zhenyu, Lin, Li'e, Liu, Tingbo, Lv, Fangfang , Shuang, Yuerong, Sun, Lan, Sun, Xiuhua, Wang, Zhao, Wu, Huijing, Xi, Yaming, Xia, Ruixiang, Xue, Hongwei, Yang, Haiyan, Yi, Shuhua, Zhang, Cheng, Zhang, Huilai, Zhang, Mingzhi, Zhang, Qingyuan, Zhao, Xielan, Zhou, Hui, Hajek, Roman, Jindra, Pavel , Mayer, Jiri, Novak, Jan, Abraham, Julie, Bijou, Fontanet, Bouabdallah, Kamal , Cymbalista, Florence, Guilbert, Sophie, Laribi, Kamel, Rodon, Philippe, Decker, Thomas, Dreger, Peter, Dreyling, Martin, Hess, Georg, Lenz, Georg, Stilgenbauer, Stephan, Tummes, Dirk, Anargyrou, Konstantinos , Dimopoulos, Meletios-Athanassios, Kapsali, Eleni, Kyriakou, Despoina, Panayiotidis, Panayiotis, Pappa, Vasiliki , Stavroyianni, Niki, Cheng, Hoi Ching, Kwong, Yok-Lam, Lee, Harold, Ng, Ting Ying, Wong, Raymond, Borbényi, Zita , Illés, Árpád, Lázár, Zsolt, Nagy, Ãgnes , Nagy, Zsolt, Schneider, Tamas, Avivi, Irit, Gurion, Ronit, Horowitz, Netanel, Ronson, Aaron, Arcaini, Luca, Boccomini, Carola, Ghia, Paolo, Luminari, Stefano, Plenteda, Caterina, Santoro, Armando, Zilioli, Vittorio Ruggero, Zinzani, Pier Luigi, Choi, Ilseung , Ennishi, Daisuke , Ichikawa, Satoshi, Ishikawa, Takayuki, Izutsu, Koji, Kato, Koji, Maruyama, Dai, Nagai, Hirokazu, Ota, Shuichi, Saito, Toko, Sakai, Rika, Suzuki, Ritsuro, Uoshima, Nobuhiko , Yano, Takahiro, Yoshida, Isao, Eom, Ki-Seong, Kim, Jin Seok, Kim, Seok Jin, Lee, Jung-Hee, Mun, Yeung Chul, Yoon, Sung Soo , Arreguin, Elsa Veronica Avila, Andrade, Adriana Dominguez, Almaguer, David Gómez, Vera, Maria Silvia Rivas, Anaya, Luis Solís, Berkahn, Leanne, Pemberton, Lucy, Simpson, David, Beltrán, Brady, Quintana, Shirely, Revilla, Jose Carlos, Vargas, Ernesto, Grosicki, Sebastian , Hałka, Janusz , Jedrzejczak, Wieslaw, Knopińska-Posłuszny, Wanda, Krzanowski, Jacek, Lech-Maranda, Ewa, Robak, Tadeusz, Rzepecki, Piotr , Wróbel, Tomasz, Borsaru, Gabriela, Ciuleanu, Tudor Eliade, Danaı̈la, Catalin, Lazaroiu, Mihaela, Alexeeva, Julia, Chistyakov, Valeriy, Manikhas, Georgy, Mikhailova, Natalia, Proydakov, Andrey, Volodicheva, Elena , Voloshin, Sergey, Bastos, Mariana, Cordoba, Raul, Codina, José , Gonzalez, Eva Maria, Marin, Ana, Panizo, Carlos, Rodriguez, Guillermo, Salar, Antonio, Sancho, Juan-Manuel, Velo, Jose A, Chiu, Chang-Fang, Hsiao, Liang-Tsai, Kuo, Ching-Yuan, Lin, Tung-Liang, Lysa, Tamila, Maslyak, Zvenyslava, Nogaieva, Larysa, Polenkov, Sergey, Usenko, Ganna, Agajanian, Richie, Anz, Bertrand, Chaudhry, Arvind, Chiu, Alden , Cultrera, Jennifer, D’Olimpio, James, Dunleavy, Kieron, Fanning, Suzanne, Flinn, Ian, Gabrail, Nashat, Gallinson, David, Goldenberg, Alec, Graf, Solomon, Grover, N., Hess, Brian, Hoffman, Marc, Isufi, Iris, Kahl, Brad, Kambhampati, Suman , Kirkel, Dean, Diaz, Guillermo Lazo, Levy, Moshe, Liu, Delong, Mead, Monica , Paludo, Jonas, Patel, Anjan, Peles, Shachar, Persky, Daniel, Portell, Craig, Rosenthal, Allison, Sano, Dahlia , Smith, Sonali , Smith, Stephen, Spurgeon, Stephen, Tache, Jason, Tsai, Michaela, Veltri, Lauren, Wang, Michael, Yimer, Habte, Bach, Quoc Khanh, Đỗ, Huyền Nga, Luu, Hung Vu, Khoa, Trọng, Phạm, Như Hiệp, Panizo, Carlos , Kriachok, Iryna , Kahl, Brad S , Paludo, Jonas , Cheah, Chan Yoon , Morawska, Marta , Sancho, Juan-Manuel , Forsyth, Cecily , Dreyling, Martin , Belada, David , Song, Yuqin , Paludo, Jonas , Fogliatto, Laura , Zhang, Jingyang , Lesley, Robin, Ramadan, Safaa Mahmoud , Garate, Gonzalo, Riveros, Dardo Alberto, Cannell, Paul , Cochrane, Tara , Giri, Pratyush, Mapp, Sally , Doo, Nicole Wong , Demuynck, H, Hende, Vanessa Van, Vergote, Vibeke K. J. , CHIATTONE, CARLOS SÉRGIO , Farias, João Samuel de Holanda , Fonseca, Ana Rita Da , Rocha, Vanderson , Oliveira, José Salvador Rodrigues de , Scheinberg, Phillip , Scheliga, Adriana , Vieira, Garles Miller Matias , Berinstein, Neil Lorne , Shuang, Yuerong , Hájek, Roman , Mayer, Jiřı́ , Bijou, Fontanet , Cymbalista, Florence, Delwail, Vincent , Genet, Philippe , Dreger, Peter , Heß, Georg , Lenz, Georg , Stilgenbauer, Stephan , Kapsali, Eleni , Katodritou, Eirini , Kyriakou, Despoina S, Panayiotidis, Panayiotis G. , Symeonidis, Argiris , Schneider, Tamas J., Avivi, Irit, Gurion, Ronit , Horowitz, Netanel A. , Arcaini, Luca , Boccomini, Carola , Luminari, Stefano , Santoro, Armando, Zilioli, Vittorio Ruggero , Zinzani, Pier Luigi , Fukushima, Kentaro , Izutsu, Koji , Maruyama, Dai , Tatetsu, Hiro , Kim, Sang‐A , Oh, Sung Yong , Arreguin, Elsa Ávila, Gómez‐Almaguer, David , Issa, Samar , Revilla, Jose C., Vargas, Ernesto, Lech-Maranda, Ewa, Robak, Tadeusz , Borsaru, Gabriela, Ciuleanu, Tudor–Eliade , Danaila, Catalin-Doru , Alexeeva, Julia, Briones, Javier , Salar, Antonio , Yuste, Victor Jimenez, Chen, Chien‐Yuan , Kuo, Ching‐Yuan, Anz, Bertrand, Cultrera, Jennifer L. , D’Olimpio, James, Dunleavy, Kieron , Gabrail, Nashat , Gallinson, David, Goldenberg, Alec S., Goy, Andre Henri , Graf, Solomon A. , Hess, Brian, Kirkel, Dean, Portell, Craig A. , Rosenthal, Allison , Stevens, Don, Veltri, Lauren Westfall , Yimer, Habte, Tran, Thanh Tung
Journal of Clinical Oncology | May 1, 2025 | Volume: 43 | Issue: 20 | Pages: 2276-2284
PURPOSE The combination of the Bruton tyrosine kinase inhibitor ibrutinib with bendamustine-rituximab for first-line treatment of mantle cell lymphoma (MCL) prolonged progression-free survival (PFS), but without improvement in overall survival (OS), likely because of toxicity. Acalabrutinib was shown to be efficacious and less toxic than ibrutinib in a head-to-head trial in chronic lymphocytic leukemia and therefore might lead to better outcomes in MCL. METHODS Patients 65 years and older with previously untreated MCL received acalabrutinib (100 mg twice daily) or placebo (until disease progression or unacceptable toxicity), plus six cycles of bendamustine (90 mg/m 2 once daily; days 1 and 2) and rituximab (375 mg/m 2 as a single dose; day 1) followed by rituximab maintenance in responding patients for 2 years. Crossover to acalabrutinib at disease progression was permitted. The primary end point was PFS per the independent review committee; overall response rate and OS were secondary end points. RESULTS In total, 598 patients were randomly assigned, with 299 in each arm. At a median follow-up of 49.8 months using the reverse Kaplan-Meier method, the median PFS was 66.4 months in the acalabrutinib arm and 49.6 months in the placebo arm (hazard ratio [HR], 0.73 [95% CI, 0.57 to 0.94]; P = .0160). Benefit was seen across all subgroups, including those with high-risk features. Overall response/complete response rates were 91.0%/66.6% and 88.0%/53.5% in the acalabrutinib and placebo arms, respectively. OS was not significantly different (HR, 0.86 [95% CI, 0.65 to 1.13]; P = .27). Grade 3 or greater adverse events were reported in 88.9% and 88.2% in the acalabrutinib and placebo arms, respectively. CONCLUSION The combination of acalabrutinib with bendamustine-rituximab significantly improved PFS. Clinical benefit of acalabrutinib with bendamustine-rituximab was achieved with manageable toxicity.
First-in-Human Phase 1 Study of SAR442257 in Patients with Relapsed/Refractory Multiple Myeloma and Non-Hodgkin Lymphoma
Polgárová, Kamila , Pour, Luděk , Yoon, Sung Soo , Rubia, Javier de la , Martínez‐López, Joaquín , Villambrosía, Sonia González de, Kapoor, Prashant , Hoffman, James E. , Jhunjhunwala, Kunal, Zhao, Liang , Wang, Zhini, Morisse, Mony, Velde, Helgi van de , Martinez-Lopez, Joaquin , Schjesvold, Fredrik , Jelı́nek, Tomáš , Kim, Won Gu , Fosså, Alexander , Miguel, Jesús F. San , Canales, Miguel , Rodríguez‐Otero, Paula , Oriol, Albert , Landgren, Ola , Raje, Noopur , Wang, Hongfang , Nathwani, Nitya
Blood | December 5, 2024 | Volume: 144 | Issue: Supplement 1 | Pages: 1992-1992
Background: SAR442257 (SAR'257) is a trispecific antibody that targets CD38, CD3 and CD28. Simultaneous CD3 and CD28 binding triggers T cell co-signaling, and additional CD38 recognition directs the T cells to CD38+ cancer cells such as multiple myeloma (MM) and non-Hodgkin lymphoma (NHL). This is a first-in-human phase 1 study investigating the safety, efficacy, pharmacokinetic (PK) and pharmacodynamic (PD) profile of SAR'257 in patients (pts) with refractory and relapsed (rr) MM and rrNHL. Methods: This is a multicenter, international, open-label, dose-escalation study (NCT04401020) of SAR'257 in pts with rrMM refractory to standard-of-care (SOC) options, including anti-CD38 monoclonal antibodies, and in pts rrNHL without any SOC options. SAR'257 was administered intravenously with lead-in doses (Day 1−5) in the first week, followed by twice weekly (BIW) or once weekly (QW) dosing; 11 target dose levels (TDLs) in pts with rrMM (9 TDLs: 0.06-11 µg/kg BIW; 2 TDLs: 18-27 µg/kg QW), and 2 TDLs in pts with rrNHL (2 µg/kg BIW and 4 µg/kg QW). Results: As of February 19, 2024, 47 pts (rrMM, n=40; rrNHL, n=7) received SAR'257. The median ages (years) were 64 (rrMM; range: 40−84) and 70 (rrNHL; range: 18−75). The median number of prior lines was 5 (range: 3−12) for rrMM and 5 (range: 2−7) for rrNHL cohort. In rrMM cohort, all (100%) pts had prior exposure to an anti-CD38 monoclonal antibody (MAb) and were refractory to anti-CD38 and in rrNHL cohort all were anti-CD38 naïve. The median time from last anti-CD38 dose was 2.7 (range: 1−65) months for rrMM cohort. Safety analysis revealed that 68% (n=32) pts had treatment-emergent adverse events (TEAEs; 26 pts in rrMM and 6 pts in rrNHL); 21.3% pts (n=10) Grade (G) ≥3 TEAEs (7 in rrMM and 3 in rrNHL). Cytokine release syndrome (CRS) was the most common TEAE, occurring in 52.5% of rrMM pts across all TDLs (n=21; G≥3 in 1 pt from 11 µg/kg BIW TDL) and in 57.1% of rrNHL pts (n=4; no G≥3) at the two TDLs tested. Repetitive CRS episodes (>1 episode) were more frequent at higher TDLs. Infusion-related reactions (IRRs; any G) were observed in 22.5% pts with rrMM (n=9; no G≥3) and in 28.5% pts with rrNHL (n=2; G≥3 in 1 pt). Epstein-Barr virus (EBV) infection/reactivation was reported in 17.5% (n=7; G≥3 in 4 pts) and 28.6% (n=2; no G≥3) pts with rrMM and rrNHL respectively. Further, 15% (n=6, G≥3 in 2 pts) from rrMM and 14.3% (n=1; G2 CMV reactivation) pts from rrNHL cohort reported cytomegalovirus (CMV) infection/reactivation. One case of immune effector cell-associated neurotoxicity syndrome (ICANS) was reported (G4) in the rrNHL cohort. Four dose-limiting toxicities (DLTs) were observed in the rrMM cohort [1 at 4 µg/kg BIW (G3 hepatotoxicity); 1 at 11 µg/kg BIW (G5 CRS−EBV reactivation; and 2 at 27 µg/kg QW (G3 CMV infection reactivation and G3 febrile neutropenia in same pt)]. Three DLTs were observed in the rrNHL cohort (2 at 2 µg/kg BIW [G4 neutropenia and G4 thrombocytopenia; same pt] and 1 at 4 µg/kg QW [ICANS G4]). For pts with rrMM, the maximum plasma concentration of SAR'257 reached within or above the theoretical efficacious range (0.1−1nM; extrapolated from ex vivo models), starting at 8 µg/kg BIW and 18 µg/kg QW in the first treatment cycle. As of July 08, 2024, the overall response rate (ORR), defined as partial response (PR) or better, was 5% (n=2) in the rrMM cohort: 1 pt exhibited stringent complete response (duration of response [DOR]=8.1 months, on-going) and 1 showed a complete response (CR) at 27 µg/kg QW TDL. In rrNHL cohort, the ORR was 14.3%, 1 pt achieved PR (DOR=7.1 months) at 2 µg/kg BIW TDL. The disease control rate (stable disease or better for >8 weeks) was 60% (n=24) and 28.6% (n=2) in the rrMM and rrNHL cohorts respectively. For both cohorts exploratory biomarker analysis revealed that: (1) SAR'257 treatment activated peripheral blood T cells and reduced regulatory T cell numbers and CD4/CD8 ratio; (2) CD38 expression on plasma cells positively corelated with time since the last anti-CD38 MAb dose; (3) Among the pts experiencing CRS, the peak values of cytokines (Interleukin (IL)-6, IL-8, and C-reactive protein) were significantly higher during the first cycle in comparison to subsequent cycles. Conclusion: This Phase 1 study of SAR'257 showed an anti-tumor response in a small number of pts from the rrMM and rrNHL cohorts. Due to safety concerns, in particular high rates of EBV and CMV reactivation and recurrent episodes of CRS in the higher dose levels, the study was terminated during dose escalation.