Temsirolimus in Combination with Three Different Immuno-Chemotherapy Regimens in Relapse and Refractory Mantle Cell Lymphoma, Final Results of the T³ Phase IB Trial of the Lysa Group

Temsirolimus has shown clinical activity in heavily pretreated patients with mantle cell lymphoma (MCL) leading to evaluate tolerability and efficacy of combinations regimens. The T³ trial is a multicenter, Phase IB, dose escalation study (3+3) of Temsirolimus administered in combination with three chemotherapy regimens in relapse or refractory (R/R) mantle cell lymphoma (MCL) patients. The primary objective was to determine the maximum tolerated dose (MTD). DLT was assessed during the first two cycles.

Study design: Temsirolimus was added for 6 cycles to R-CHOP (R-CHOP-T) administered every 3 weeks or to or R-FC (R-FC-T) and R plus high dose cytarabine and dexamethasone (R-DHA-T) administered every 4 weeks. Temsirolimus was administered IV at day 2, 8 and 15. Three dose levels of Temsirolimus was tested: 15 mg, 25 mg (starting dose) and 50 mg. Patients were treated with one of these 3 chemotherapy regimens according to the choice of local investigator and no randomization was performed. LYSARC was the sponsor and the trial was conducted with a financial support of Pfizer Results: forty-one patients (R-CHOP-T n=10; R-FC-T n=14 and R-DHA-T, n=17)were enrolled. At time of inclusion, median age of patients was 68y (56-79), 32 patients were male, median time from last therapy to inclusion was 23,1m (2-143), MIPI score was low in 8, intermediate in 13 and high in 19 cases (missing=1). Previous lines of treatment included autologous stem cell transplantation in 18 patients. Among patients treated in the R-CHOP-T arm, all patients (n=4) presented grade 3 toxicities at the 25mg dose level. At the 15mg dose level (n=6), one DLT occurs (Thrombopenia). Consequently, the maximum tolerated dose (MTD) of Temsirolimus in the R-CHOP-T was 15 mg. Among patients of the R-FC-T arm (n=14) and R-DHA-T, the recommended dose of Temsirolimus has not been found because of toxicities that occurred at all Temsirolimus doses (25 and 15mg). Hematologic grade 3/4 toxicities were the most frequent, mainly thrombocytopenia (n=28). In term of efficacy, ORR (CR/CRu/PR) during treatment period was 40% for R-CHOP-T including 2 patients who reached CR, 35,7% for R-FC-T including 3 patients who reached CR and 47,1% for R-DHA-T including 6 patients who reached CR. For all patients, mFU is 30.5 m (23-39). The mPFS and mOS according to treatment arms and for all patients (n=41) are as followed: 15,1m and not reached for R-CHOP-T (n= 10); 8.6m and 17.8 m for R-FC-T (n=14) ; 11.9m and 24.2m for R-DHA-T (n=17).

In conclusion, the recommended dose of Temsirolimus for R-CHOP-T is 15mg D1,8,15. We are not able to recommend a dose of Temisrolimus for both R-DHA-T and R-FC-T. Hematologic toxicity was the main concern in all arms. A good efficacy in term of response rates PFS and OS was observed in all arms suggesting that Temsirolimus-based chemotherapy regimen should be further investigated in prospective trials but dose of Temsirolimus should be carefully investigated.