Phase Ib trial of the PI3K/mTOR inhibitor voxtalisib (SAR245409) in combination with chemoimmunotherapy in patients with relapsed or refractory B-cell malignancies

Farrukh T. Awan, Lia Gore, Lei Gao, Jyoti Sharma, Joanne Lager, Luciano J. Costa

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)55-65
Number of pages11
JournalBritish Journal of Haematology
Volume175
Issue number1
DOIs
StatePublished - Oct 1 2016
Externally publishedYes

Keywords

  • PI3K/mTOR
  • chronic lymphocytic leukaemia
  • non-Hodgkin lymphoma
  • pharmacokinetics
  • rituximab

ASJC Scopus subject areas

  • Hematology

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