Phase Ib trial of the PI3K/mTOR inhibitor voxtalisib (SAR245409) in combination with chemoimmunotherapy in patients with relapsed or refractory B-cell malignancies.
This phase Ib, dose-escalation study investigated the maximum tolerated dose (MTD), recommended phase II dose (RP2D), safety, pharmacokinetics (PK) and preliminary efficacy of the pan-class I phosphoinositide 3-kinase (PI3K) and mechanistic target of rapamycin (mTOR) inhibitor voxtalisib [30 or 50 mg twice daily (BID)], in combination with rituximab (voxtalisib+rituximab) or rituximab plus bendamustine (voxtalisib+rituximab+bendamustine), in relapsed or refractory indolent B-cell non-Hodgkin lymphoma (NHL), mantle cell lymphoma and chronic lymphocytic leukaemia (CLL). MTD and RP2D of voxtalisib were determined using a 3 + 3 dose-escalation design. Adverse events (AEs), plasma PK and disease response were recorded. Thirty-seven patients were enrolled. The RP2D of voxtalisib in combination with rituximab or rituximab+bendamustine was 50 mg BID. Four patients experienced a total of five dose-limiting toxicities. The most frequent AEs were nausea (45·9%), fatigue (37·8%) headache (32·4%) and pyrexia (32·4%). The most frequent grade ≥3 AEs were neutropenia (27·0%), thrombocytopenia (24·3%), anaemia (16·2%) and febrile neutropenia (10·8%). Voxtalisib PK parameters were not affected by co-administration with rituximab or rituximab+bendamustine. Of 35 efficacy-evaluable patients, four (11·4%) achieved complete response and 13 (37·1%) achieved partial response. Voxtalisib, in combination with rituximab or rituximab+bendamustine, demonstrated an acceptable safety profile and encouraging anti-tumour activity in relapsed or refractory B-cell malignancies.
The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA. farrukh.awan@osumc.edu.
Farrukh T
FT
Awan
Developmental Therapeutics Program, University of Colorado Comprehensive Cancer Center, Aurora, CO, USA.
Lia
L
Gore
Sanofi, Cambridge, MA, USA.
Lei
L
Gao
Sanofi, Bridgewater, NJ, USA.
Jyoti
J
Sharma
Sanofi, Cambridge, MA, USA.
Joanne
J
Lager
University of Alabama, Birmingham, AL, USA.
Luciano J
LJ
Costa
D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D000069461:Bendamustine Hydrochloride / Q000008:administration & dosage; D004334:Drug Administration Schedule; D016903:Drug Monitoring; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D015448:Leukemia, B-Cell / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D016393:Lymphoma, B-Cell / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011810:Quinoxalines / Q000008:administration & dosage; D012008:Recurrence; D019233:Retreatment; D000069283:Rituximab / Q000008:administration & dosage; D013449:Sulfonamides / Q000008:administration & dosage; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D016896:Treatment Outcome
D000081082:Phosphoinositide-3 Kinase Inhibitors; D011810:Quinoxalines; D013449:Sulfonamides; C576808:XL765; D000069283:Rituximab; D000069461:Bendamustine Hydrochloride; D058570:TOR Serine-Threonine Kinases
PI3K/mTOR; chronic lymphocytic leukaemia; non-Hodgkin lymphoma; pharmacokinetics; rituximab