Ibrutinib, obinutuzumab, and venetoclax in relapsed and untreated patients with mantle cell lymphoma: a phase 1/2 trial

Abstract

Ibrutinib, obinutuzumab plus venetoclax demonstrate synergy in pre-clinical models of mantle-cell lymphoma (MCL). OAsIs (NCT02558816), a single-arm multi-center prospective phase I/II trial, aimed to determine the maximum tolerated dose (MTD) of venetoclax in combination with fixed doses of ibrutinib and obinutuzumab, in relapsed MCL patients. At the venetoclax MTD, extension cohorts were opened for relapsed and untreated patients. Safety and efficacy were secondary objectives. Minimal residual disease (MRD) was assessed by allele-specific oligonucleotide-quantitative polymerase chain reaction (ASO-qPCR). Between Oct 14, 2015 to May 29, 2018, forty-eight patients were enrolled. No dose limiting toxicity (DLT) was reported, and venetoclax at 400mg per day was chosen for extension. Eighteen (75%) relapsed and 8 (53%) untreated patients experienced grade 3/4 adverse events (AEs). The complete response rate assessed by positron-emission tomography at the end of cycle 6 was 67% in relapsed and 86.6% in untreated patients. MRD clearance for evaluable patients was seen in 71.5% of relapsed (10 out of 14) and 100% of untreated MRD-evaluable patients (n=12), at the end of three cycles. The median follow-up (mFU) for relapsed patients was 17 months (range, 10 to 35). The 2-years PFS was 69.5% (95% CI, 52.9- 91.4%) and 68.6% (95% CI, 49.5- 95.1%) for OS. The mFU was 14 months (range, 5 to 19) for untreated patients, the 1-year PFS was 93.3% (95% CI, 81.5- 100%). Obinutuzimab, ibrutinib and venetoclax combination is well tolerated and provides high response rates including at the molecular level in relapsed and untreated MCL patients.

Dose Finding Study of Ibrutinib and Venetoclax in Relapsed or Refractory Mantle Cell Lymphoma

“…Our approach was novel in finding the optimal dose, instead of the maximum tolerated dose, utilizing a CRM to allocate participants based on prior participant's efficacy and toxicity. Our primary finding shows that the optimal dose was Arm B (IBR 420mg PO daily, VEN 200mg PO daily), which is lower than other studies are using (SYMPATICO study, NCT03112174) 33,34 or have used (AIM or OAsIs study) 28,29,35 in relapsed MCL. The SYMPATICO 33,34 , AIM 28,35 , and OAsIs 29 studies utilize IBR 560mg PO daily and VEN 400mg PO daily in MCL, a dose combination that we were not able to test due to DLTs and adequate response at lower dose levels.…”

“…We present the only known phase I dose-finding study of IBR and VEN in NHL that evaluates dosing of both drugs. Prior clinical studies 28,29 of the IBR and VEN combination have utilized the single-agent approved doses in combination as Phase II studies or have attempted to increase the approved doses in phase I study. Our approach was novel in finding the optimal dose, instead of the maximum tolerated dose, utilizing a CRM to allocate participants based on prior participant's efficacy and toxicity.…”

“…OAsIs combined obinutuzumab with IBR plus VEN in a staged, Phase I/II manner. IBR was fixed at 560mg PO daily and VEN was given at 400mg, 600mg and 800mg daily in a dose escalation strategy 29 . However, as patients treated at higher doses experienced more transfusion support and, as the pre-clinical rationale showed no improvement in efficacy at doses higher than 400mg, 400mg PO daily was used as the Phase II dose.…”

Long-term Follow-up of Patients with Relapsed or Refractory Non–Hodgkin Lymphoma Treated with Venetoclax in a Phase I, First-in-Human Study

“…© 2021 American Association for Cancer clincancerres.aacrjournals.org Downloaded from Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on June 3, 2021; DOI: 10.1158/1078-0432.CCR-20-4842 MCL(19), and if positive, would extend the initial benefits seen in this study with venetoclax monotherapy to a much larger proportion of patients with NHL.…”

Relapsed Mantle Cell Lymphoma: Current Management, Recent Progress, and Future Directions

“…A wide range of combination treatment approaches have been previously studied for relapsed MCL, with selected results from previously published trials shown in Table 1 [16,[73][74][75][76][77]. The combination of ibrutinib and rituximab was studied in a phase 2 trial enrolling 50 patients with r/r MCL and demonstrated an ORR of 88% (44%) with more favorable response rate noted in patients with Ki67 < 50% (ORR 100%, 54% CR) compared with high-risk patients with Ki67 ≥ 50% (ORR 50%, 17% CR) [16].…”