Celeste Rojas

Phase I Trial of Weekly and Twice-Weekly Bortezomib with Rituximab, Cyclophosphamide, and Prednisone in Relapsed or Refractory Non-Hodgkin Lymphoma

Purpose: To determine the safety and efficacy of substituting weekly or twice-weekly bortezomib for vincristine in the R-CVP (rituximab, cyclophosphamide, vincristine, and prednisone) regimen in patients with relapsed/refractory indolent and mantle cell lymphoma (MCL). Experimental Design: Of the 57 patients in this phase I trial, 55 participated in 1 of 2 dosing schedules that included rituximab (375 mg/m2) and cyclophosphamide (750 or 1,000 mg/m2) administered on day 1 of each 21-day cycle and prednisone (100 mg orally) days 2 to 6. In the once-weekly schedule, bortezomib was administered on days 2 and 8; on the twice-weekly schedule, bortezomib was given on days 2, 5, 9, and 12. Bortezomib and cyclophosphamide were alternately escalated. A separate cohort of 10 patients in the twice-weekly schedule received concurrent pegfilgrastim (PegG) on day 2. Results: Both schedules of R-CBorP (rituximab, cyclophosphamide, bortezomib, and prednisone) were well tolerated. Most toxicities across all dose levels and cycles were grade 1 or 2. The overall response rates for patients on the weekly (n = 13) and twice-weekly (n = 33) schedules were 46% [23% complete response/complete response unconfirmed (CR/CRu)] and 64% (36% CR/CRu), respectively. Concurrent PegG did not increase hematologic toxicities in this regimen. A randomized phase II study is under way to further compare toxicity and efficacy of the 2 dosing schedules. Conclusions: R-CBorP is a safe and effective regimen in patients with relapsed/refractory indolent and MCLs. Most toxicities were grade 1 or 2, and a promising response rate was seen in this phase I study. Clin Cancer Res; 17(8); 2493–501. ©2011 AACR.

Brentuximab vedotin plus bendamustine in relapsed or refractory Hodgkin's lymphoma: an international, multicentre, single-arm, phase 1–2 trial

BACKGROUND Brentuximab vedotin is currently approved for patients with relapsed or refractory Hodgkins lymphoma who previously received an autologous stem cell transplant or two previous multiagent chemotherapy regimens, and for patients with relapsed or refractory systemic anaplastic large-T-cell lymphoma who previously received at least one chemotherapy regimen. A high proportion of patients with CD30-expressing relapsed or refractory lymphomas have durable responses to single-agent brentuximab vedotin and show longer progression-free survival than do patients treated with chemotherapy. In patients with Hodgkins lymphoma and peripheral T-cell lymphoma, treatment with bendamustine alone only achieves modest improvements in progression-free survival compared with that for chemotherapy. The objective of this study was to explore the safety and clinical activity of the combination of brentuximab vedotin plus bendamustine in heavily pretreated patients with relapsed or refractory Hodgkins lymphoma and anaplastic large-T-cell lymphoma. METHODS In this international, multicentre, single-arm, phase 1-2 trial, eligible patients were aged 18 years or older, had histologically confirmed relapsed or refractory Hodgkins lymphoma or anaplastic large-T-cell lymphoma, had biopsy-proven CD30-positive tumours, had an Eastern Cooperative Oncology Group performance status of 2 or less, and received at least one previous multiagent chemotherapy regimen. In phase 1, patients were assigned following a 3+3 dose-escalation design to one of four cohorts to receive one dose of either 1·2 mg/kg or 1·8 mg/kg of brentuximab vedotin intravenously on day 1 of a 21 day cycle, plus one dose of bendamustine (70 mg/m2, 80 mg/m2, or 90 mg/m2) on days 1 and 2 of the treatment cycle. In phase 2, all patients were assigned to receive brentuximab vedotin plus bendamustine at the recommended phase 2 dose from phase 1. The primary endpoints were maximum tolerated dose and dose-limiting toxicity for phase 1, and the proportion of patients achieving an overall response in phase 2. For both phases 1 and 2, all patients receiving at least one dose of study drug were evaluable for toxicity and all patients completing at least one cycle of therapy were evaluable for response. The study is ongoing but no longer recruiting patients. This trial is registered with ClinicalTrials.gov, number NCT01657331. FINDINGS Between July 26, 2012, and May 31, 2017, we enrolled and assigned 65 patients to treatment (64 [98%] with Hodgkins lymphoma and one [2%] with anaplastic large-T-cell lymphoma; 28 [43%] during phase 1 and 37 [57%] during phase 2). In the phase 1 part, the maximum tolerated dose of the combination was not reached. Dose-limiting toxicities were observed in three (11%) of 28 patients, including grade 4 neutropenia at 1·8 mg/kg brentuximab vedotin plus 80 mg/m2 of bendamustine in two (7%) patients and diffuse rash at 1·2 mg/kg brentuximab vedotin plus 70 mg/m2 of bendamustine in one (4%) patient. The recommended phase 2 dose was deemed to be 1·8 mg/kg of brentuximab vedotin and 90 mg/m2 of bendamustine, which are the standard doses of the drugs when given as single agents. In the phase 2 part, an overall response was achieved in 29 (78% [95% CI 62-91]) of 37 patients. Serious adverse events included grade 3 lung infection in five (14%) of 37 patients in the phase 2, and grade 3-4 neutropenia in 16 (25%) of 65 patients across phases 1 and 2. There were no treatment-related deaths. INTERPRETATION This study shows that brentuximab vedotin plus bendamustine, with a favourable safety profile, is an active salvage regimen for heavily pretreated patients with relapsed or refractory Hodgkins lymphoma. This salvage regimen can potentially serve as an efficacious and safe alternative to platinum-based chemotherapy before autologous stem cell transplant. FUNDING Seattle Genetics, Lymphoma Research Fund of Columbia University and National Center for Advancing Translational Sciences, and National Institutes of Health.

Brentuximab vedotin and bendamustine produce high complete response rates in patients with chemotherapy refractory Hodgkin lymphoma.

K.L., Gray, T.A., Saulino, A. & Collins, F.S. (1991) Interactions of Sp1 with the human c globin promoter: binding and transactivation of normal and mutant promoters. Blood, 78, 1853–1863. Jane, S.M., Gumucio, D.L., Ney, P.A., Cunningham, J.M. & Nienhuis, A.W. (1993) Methylation-enhanced binding of Sp1 to the stage selector element of the human c-globin gene promoter may regulate development specificity of expression. Molecular and Cellular Biology, 13, 3272–3281. Jiang, Z., Luo, H.Y., Huang, S., Farrell, J.J., Davis, L., Th eberge, R., Benson, K., Riolueang, S., Viprakasit, V., Al-Allawi, N.A.S., € Unal, S., G€ umr€ uk, F., Akar, N., Bas ak, A.N., Osorio, L., Badens, C., Pissard, S., Joly, P., Campbell, A.D., Gallagher, P.G., Steinberg, M.H., Forget, B.G. & Chui, D.H.K. (2016) The genetic basis of asymptomatic codon 8 frame-shift (HBB: c.25_26delAA) b-thalassemia homozygotes. British Journal of Haematology, 172, 958–965. Lek, M., Karczewski, K.J., Minikel, E.V., Samocha, K.E., Banks, E., Fennell, T., O’Donnell-Luria, A.H., Ware, J.S., Hill, A.J., Cummings, B.B., Tukiainen, T., Birnbaum, D.P., Kosmicki, J.A., Duncan, L.E., Estrada, K., Zhao, F., Zou, J., Pierce-Hoffman, E., Berghout, J., Cooper, D.N., Deflaux, N., DePristo, M., Do, R., Flannick, J., Fromer, M., Gauthier, L., Goldstein, J., Gupta, N., Howrigan, D., Kiezun, A., Kurki, M.I., Moonshine, A.L., Natarajan, P., Orozco, L., Peloso, G.M., Poplin, R., Rivas, M.A., RuanoRubio, V., Rose, S.A., Ruderfer, D.M., Shakir, K., Stenson, P.D., Stevens, C., Thomas, B.P., Tiao, G., Tusie-Luna, M.T., Weisburd, B., Won, H.H., Yu, D., Altshuler, D.M., Ardissino, D., Boehnke, M., Danesh, J., Donnelly, S., Elosua, R., Florez, J.C., Gabriel, S.B., Getz, G., Glatt, S.J., Hultman, C.M., Kathiresan, S., Laakso, M., McCarroll, S., McCarthy, M.I., McGovern, D., McPherson, R., Neale, B.M., Palotie, A., Purcell, S.M., Saleheen, D., Scharf, J.M., Sklar, P., Sullivan, P.F., Tuomilehto, J., Tsuang, M.T., Watkins, H.C., Wilson, J.G., Daly, M.J. & MacArthur, D.G.; for the Exome Aggregation Consortium (2016) Analysis of protein-coding genetic variation in 60,706 humans. Nature, 536, 285–291. Menzel, S., Garner, C., Gut, I., Matsuda, F., Yamaguchi, M., Heath, S., Foglio, M., Zelenika, D., Boland, A., Rooks, H., Best, S., Spector, T.D., Farrall, M., Lathrop, M. & Thein, S.L. (2007) A QTL influencing F cell production maps to a gene encoding a zinc-finger protein on chromosome 2p15. Nature Genetics, 39, 1197–1199. Ronchi, A., Nicolis, S., Santoro, C. & Ottolenghi, S. (1989) Increased Sp1 binding mediates erythroid-specific overexpression of a mutated (HPFH) c-globin promoter. Nucleic Acids Research, 17, 10231–10234. Sykes, K. & Kaufman, R. (1990) A naturally occurring c-globin gene mutation enhances SP1 binding activity. Molecular and Cellular Biology, 10, 95–102.