Background The PI3K–mTORC pathway is upregulated in diffuse large B-cell lymphoma (DLBCL) and can be targeted with the mTOR complex 1 (mTORC1) inhibitor everolimus. Everolimus has activity in relapsed DLBCL. These data provide the rationale to combine everolimus with standard treatment for DLBCL of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone delivered in a 21-day cycle (R-CHOP-21) for six cycles. Methods We did a phase 1 and feasibility study (NCCTG 1085) of oral everolimus 10 mg/day plus R-CHOP-21 in patients aged at least 18 years with new, untreated, CD20-positive DLBCL (stages II–IV) in the NCCTG (Alliance) National Cancer Institute Cooperative Group (USA). Patients received standard R-CHOP-21 (intravenous rituximab 375 mg/m2, intravenous cyclophosphamide 750 mg/m2, intravenous doxorubicin 50 mg/m2, and intravenous vincristine 1·4 mg/m2 [maximum 2·0 mg] all on day 1 of the 21-day cycle; and oral prednisone 100 mg/m2 each day on days 1–5 of the cycle) for six cycles with scheduled subcutaneous pegfilgrastim 6 mg on day 2 of each cycle. We tested two schedules: everolimus given in the fasting state either on days 1–10 or days 1–14 of the R-CHOP cycle. The primary endpoint of the phase 1 portion of this study was to establish the maximum tolerated dose of everolimus that could be combined with R-CHOP-21. The primary endpoint of the feasibility portion of the study was to determine the feasibility of the regimen, which was assessed by determining the rate of significant toxicity. Secondary endpoints were the proportion of patients who achieved an overall response, a complete response, event-free survival at 12 months and 24 months from enrolment, progression-free survival, and overall survival; relapse of DLBCL; and duration of response. We deemed patients as assessable for the primary endpoint in the phase 1 portion if they completed the first cycle as planned. In the feasibility portion, all patients who received at least one dose of everolimus were included. This trial is registered with ClinicalTrials.gov, number NCT01334502. Findings Between March 21, 2012, and Sept 15, 2014, we enrolled 26 patients into the study. Two were ineligible, therefore results are presented for 24 eligible patients. Nine patients were enrolled into the phase 1 portion of the trial (three given everolimus on days 1–10, and six given everolimus on days 1–14) without any dose-limiting toxicities; therefore, everolimus 10 mg/day given on days 1–14 with R-CHOP-21 was tested in 15 additional patients for a total of 24. One (5%, 95% CI 0–24%) of 21 patients had a toxicity during the feasibility phase—a treatment delay of 12 days due to grade 3 hypokalaemia possibly related to everolimus. The median follow-up was 21·5 months (IQR 17–29). 23 (96%, 95% CI 79–100%) of 24 patients achieved an overall response, and all 23 (96%, 79–100%) also attained a complete metabolic response by PET. The remaining patient withdrew consent after in cycle 1 and attained a complete response with R-CHOP alone. All 24 (100%) patients met 12-month event-free survival, and nine had sufficient follow-up data to be event-free at 24 months. None of the 24 patients had died by the last follow-up (March 30, 2016), and none had had a relapse with DLBCL. Because no events occurred during the study or follow-up, we were unable to assess the duration of response or progression-free survival. The most common grade 3–4 adverse events were haematological; the most common of these was grade 4 neutropenia in 18 (75%) of 24 patients. Five (21%) of 24 had grade 3 febrile neutropenia. Interpretation The mTORC1 inhibitor everolimus given for 14 days in combination with R-CHOP-21 for patients with DLBCL is safe. These findings suggest that drugs that target the PI3K–mTORC pathway add benefit when combined with standard R-CHOP. The everolimus with R-CHOP regimen should be tested against standard R-CHOP alone in a randomised trial, to support the benefits of this novel combination noted in this study. Funding National Cancer Institute of the US National Institutes of Health.
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