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Voxtalisib (XL765) in patients with relapsed or refractory non-Hodgkin lymphoma or chronic lymphocytic leukaemia: an open-label, phase 2 trial.
Lancet Haematol. 2018 Apr; 5(4):e170-e180.LH

Abstract

BACKGROUND

Patients with relapsed or refractory lymphoma or chronic lymphocytic leukaemia have a poor prognosis. Therapies targeting more than one isoform of PI3K, as well as mTOR, might increase antitumour activity. We aimed to investigate the efficacy and safety of voxtalisib (also known as XL765 or SAR245409), a pan-PI3K/mTOR inhibitor, in patients with relapsed or refractory lymphoma, or chronic lymphocytic leukaemia/small lymphocytic lymphoma.

METHODS

We did a non-randomised, open-label, phase 2 trial at 30 oncology clinics in the USA, Belgium, Germany, France, the Netherlands, and Australia. Patients aged 18 years or older with Eastern Cooperative Oncology Group (EGOG) performance status score of 2 or lower and relapsed or refractory mantle cell lymphoma, follicular lymphoma, diffuse large B-cell lymphoma, or chronic lymphocytic leukaemia/small lymphocytic lymphoma were enrolled and treated with voxtalisib 50 mg orally twice daily in 28-day continuous dosing cycles until progression or unacceptable toxicity. The primary endpoint was the proportion of patients in each disease-specific cohort who achieved an overall response, defined as a complete response or partial response. All patients who received more than 4 weeks of treatment and who completed a baseline and at least one post-baseline tumour assessment were analysed for efficacy and all patients were analysed for safety. This study is registered with ClinicalTrials.gov, number NCT01403636, and has been completed.

FINDINGS

Between Oct 19, 2011, and July 24, 2013, 167 patients were enrolled (42 with mantle cell lymphoma, 47 with follicular lymphoma, 42 with diffuse large B-cell lymphoma, and 36 with chronic lymphocytic leukaemia/small lymphocytic lymphoma. The median number of previous anticancer regimens was three (IQR 2-4) for patients with lymphoma and four (2-5) for patients with chronic lymphocytic leukaemia/small lymphocytic lymphoma. Of 164 patients evaluable for efficacy, 30 (18·3%) achieved an overall response (partial, n=22; complete, n=8); 19 (41·3%) of 46 with follicular lymphoma, five (11·9%) of 42 with mantle cell lymphoma, two (4·9%) of 41 with diffuse large B-cell lymphoma, and four (11·4%) of 35 with chronic lymphocytic leukaemia/small lymphocytic lymphoma. The safety profile was consistent with that of previous studies of voxtalisib. The most frequently reported adverse events were diarrhoea (in 59 [35%] of 167 patients), fatigue (in 53 [32%]), nausea (in 45 [27%]), pyrexia (in 44 [26%,]), cough (in 40 [24%]), and decreased appetite (in 35 [21%]). The most frequently reported grade 3 or worse adverse events were anaemia (in 20 [12%] of 167 patients), pneumonia (in 14 [8%]), and thrombocytopenia (in 13 [8%]). Serious adverse events occurred in 97 (58·1%) of 167 patients.

INTERPRETATION

Voxtalisib 50 mg given orally twice daily had an acceptable safety profile, with promising efficacy in patients with follicular lymphoma but limited efficacy in patients with mantle cell lymphoma, diffuse large B-cell lymphoma, or chronic lymphocytic leukaemia/small lymphocytic lymphoma.

FUNDING

Sanofi.

Authors+Show Affiliations

Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA. Electronic address: Jennifer_brown@dfci.harvard.edu.Department of Medicine, West Virginia University, Morgantown, WV, USA; Division of Hematology and Oncology, Medical College of Wisconsin, Milwaukee, WI, USA.Markey Cancer Center, University of Kentucky, Lexington, KY, USA.Department of Haematology, Universitaire Ziekenhuizen Leuven, Leuven, Belgium.Siteman Cancer Center, Washington University School of Medicine, St Louis, MO, USA.Department of Haematology, Division of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, UK.Division of Hematology and Oncology, Beth Israel Deaconess Medical Center, Boston, MA, USA.Department of Haematology and INSERM U1245, Centre Henri Becquerel, Rouen University, Rouen, France.Department of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA.Dienst Hematologie, Universitair Ziekenhuis Gent, Gent, Belgium.Gabrail Cancer Center, Canton, OH, USA.Division of Hematology/Oncology, University of Kansas Medical Center, Kansas City, KS, USA.Division of Hematology-Oncology, Mayo Clinic, Jacksonville, FL, USA.Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.Department of Hematology, Academic Medical Center, Amsterdam, Netherlands; Lymphoma and Myeloma Center Amsterdam, Amsterdam, Netherlands.Erasmus MC Cancer Institute, Rotterdam, Netherlands.Sanofi, Cambridge, MA, USA.Sanofi, Cambridge, MA, USA.Sanofi, Cambridge, MA, USA.Sanofi Oncology, Vitry sur Seine, France.Department of Hematology, Academic Medical Center, Amsterdam, Netherlands; Lymphoma and Myeloma Center Amsterdam, Amsterdam, Netherlands.

Pub Type(s)

Clinical Trial, Phase II
Journal Article

Language

eng

PubMed ID

29550382

Citation

Brown, Jennifer R., et al. "Voxtalisib (XL765) in Patients With Relapsed or Refractory non-Hodgkin Lymphoma or Chronic Lymphocytic Leukaemia: an Open-label, Phase 2 Trial." The Lancet. Haematology, vol. 5, no. 4, 2018, pp. e170-e180.
Brown JR, Hamadani M, Hayslip J, et al. Voxtalisib (XL765) in patients with relapsed or refractory non-Hodgkin lymphoma or chronic lymphocytic leukaemia: an open-label, phase 2 trial. Lancet Haematol. 2018;5(4):e170-e180.
Brown, J. R., Hamadani, M., Hayslip, J., Janssens, A., Wagner-Johnston, N., Ottmann, O., Arnason, J., Tilly, H., Millenson, M., Offner, F., Gabrail, N. Y., Ganguly, S., Ailawadhi, S., Kasar, S., Kater, A. P., Doorduijn, J. K., Gao, L., Lager, J. J., Wu, B., ... Kersten, M. J. (2018). Voxtalisib (XL765) in patients with relapsed or refractory non-Hodgkin lymphoma or chronic lymphocytic leukaemia: an open-label, phase 2 trial. The Lancet. Haematology, 5(4), e170-e180. https://doi.org/10.1016/S2352-3026(18)30030-9
Brown JR, et al. Voxtalisib (XL765) in Patients With Relapsed or Refractory non-Hodgkin Lymphoma or Chronic Lymphocytic Leukaemia: an Open-label, Phase 2 Trial. Lancet Haematol. 2018;5(4):e170-e180. PubMed PMID: 29550382.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Voxtalisib (XL765) in patients with relapsed or refractory non-Hodgkin lymphoma or chronic lymphocytic leukaemia: an open-label, phase 2 trial. AU - Brown,Jennifer R, AU - Hamadani,Mehdi, AU - Hayslip,John, AU - Janssens,Ann, AU - Wagner-Johnston,Nina, AU - Ottmann,Oliver, AU - Arnason,Jon, AU - Tilly,Hervé, AU - Millenson,Michael, AU - Offner,Fritz, AU - Gabrail,Nashat Y, AU - Ganguly,Siddhartha, AU - Ailawadhi,Sikander, AU - Kasar,Siddha, AU - Kater,Arnon P, AU - Doorduijn,Jeanette K, AU - Gao,Lei, AU - Lager,Joanne J, AU - Wu,Bin, AU - Egile,Coumaran, AU - Kersten,Marie José, Y1 - 2018/03/14/ PY - 2017/09/27/received PY - 2018/02/05/revised PY - 2018/02/20/accepted PY - 2018/3/20/pubmed PY - 2018/9/5/medline PY - 2018/3/19/entrez SP - e170 EP - e180 JF - The Lancet. Haematology JO - Lancet Haematol VL - 5 IS - 4 N2 - BACKGROUND: Patients with relapsed or refractory lymphoma or chronic lymphocytic leukaemia have a poor prognosis. Therapies targeting more than one isoform of PI3K, as well as mTOR, might increase antitumour activity. We aimed to investigate the efficacy and safety of voxtalisib (also known as XL765 or SAR245409), a pan-PI3K/mTOR inhibitor, in patients with relapsed or refractory lymphoma, or chronic lymphocytic leukaemia/small lymphocytic lymphoma. METHODS: We did a non-randomised, open-label, phase 2 trial at 30 oncology clinics in the USA, Belgium, Germany, France, the Netherlands, and Australia. Patients aged 18 years or older with Eastern Cooperative Oncology Group (EGOG) performance status score of 2 or lower and relapsed or refractory mantle cell lymphoma, follicular lymphoma, diffuse large B-cell lymphoma, or chronic lymphocytic leukaemia/small lymphocytic lymphoma were enrolled and treated with voxtalisib 50 mg orally twice daily in 28-day continuous dosing cycles until progression or unacceptable toxicity. The primary endpoint was the proportion of patients in each disease-specific cohort who achieved an overall response, defined as a complete response or partial response. All patients who received more than 4 weeks of treatment and who completed a baseline and at least one post-baseline tumour assessment were analysed for efficacy and all patients were analysed for safety. This study is registered with ClinicalTrials.gov, number NCT01403636, and has been completed. FINDINGS: Between Oct 19, 2011, and July 24, 2013, 167 patients were enrolled (42 with mantle cell lymphoma, 47 with follicular lymphoma, 42 with diffuse large B-cell lymphoma, and 36 with chronic lymphocytic leukaemia/small lymphocytic lymphoma. The median number of previous anticancer regimens was three (IQR 2-4) for patients with lymphoma and four (2-5) for patients with chronic lymphocytic leukaemia/small lymphocytic lymphoma. Of 164 patients evaluable for efficacy, 30 (18·3%) achieved an overall response (partial, n=22; complete, n=8); 19 (41·3%) of 46 with follicular lymphoma, five (11·9%) of 42 with mantle cell lymphoma, two (4·9%) of 41 with diffuse large B-cell lymphoma, and four (11·4%) of 35 with chronic lymphocytic leukaemia/small lymphocytic lymphoma. The safety profile was consistent with that of previous studies of voxtalisib. The most frequently reported adverse events were diarrhoea (in 59 [35%] of 167 patients), fatigue (in 53 [32%]), nausea (in 45 [27%]), pyrexia (in 44 [26%,]), cough (in 40 [24%]), and decreased appetite (in 35 [21%]). The most frequently reported grade 3 or worse adverse events were anaemia (in 20 [12%] of 167 patients), pneumonia (in 14 [8%]), and thrombocytopenia (in 13 [8%]). Serious adverse events occurred in 97 (58·1%) of 167 patients. INTERPRETATION: Voxtalisib 50 mg given orally twice daily had an acceptable safety profile, with promising efficacy in patients with follicular lymphoma but limited efficacy in patients with mantle cell lymphoma, diffuse large B-cell lymphoma, or chronic lymphocytic leukaemia/small lymphocytic lymphoma. FUNDING: Sanofi. SN - 2352-3026 UR - https://www.unboundmedicine.com/medline/citation/29550382/Voxtalisib__XL765__in_patients_with_relapsed_or_refractory_non_Hodgkin_lymphoma_or_chronic_lymphocytic_leukaemia:_an_open_label_phase_2_trial_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S2352-3026(18)30030-9 DB - PRIME DP - Unbound Medicine ER -