TY - JOUR
T1 - Safety and efficacy of vorinostat plus sirolimus or everolimus in patients with relapsed refractory hodgkin lymphoma
AU - Janku, Filip
AU - Park, Haeseong
AU - Call, S. Greg
AU - Madwani, Kiran
AU - Oki, Yasuhiro
AU - Subbiah, Vivek
AU - Hong, David S.
AU - Naing, Aung
AU - Velez-Bravo, Vivianne M.
AU - Barnes, Tamara G.
AU - Hagemeister, Fredrick B.
AU - Falchook, Gerald S.
AU - Karp, Daniel D.
AU - Wheler, Jennifer J.
AU - Piha-Paul, Sarina A.
AU - Garrido-Laguna, Ignacio
AU - Shpall, Elizabeth J.
AU - Fayad, Luis E.
AU - Neelapu, Sattva S.
AU - Meric-Bernstam, Funda
AU - Kurzrock, Razelle
AU - Fanale, Michelle A.
N1 - Funding Information:
This study was supported by the Non-Standard of Care Clinical Charge Program at MD Anderson (to F. Janku), the Sheikh Khalifa Al Nahyan Ben Zayed Institute for Personalized Cancer Therapy at MD Anderson (to F. Janku), the National Center for Advancing Translational Sciences (grant no. UL1 TR000371, to F. Janku, V. Subbiah, D.S. Hong, A. Naing, D.D. Karp, S.A. Piha-Paul, and F. Meric-Bernstam), and the NIH through MD Anderson's Cancer Center Support Grant (P30 CA016672, all authors). Authors would also like to acknowledge Mr. Joseph Munch from the Department of Scientific Publications, the University of Texas MD Anderson Cancer Center for his editorial and grammar assistance.
Funding Information:
This study was a nonrandomized, open-label, dose-escalation phase I clinical trial of vorinostat and sirolimus in patients with histologically confirmed metastatic or locally advanced cancers (NCT01087554) that included an expansion cohort for patients with relapsed/refractory Hodgkin lymphoma. Patients received RP2D of vorinostat 300 mg orally daily and sirolimus 4 mg orally daily as determined by a previously published dose-escalation part of this study (19). The trial was also amended to include a cohort of patients with advanced cancers, including patients with relapsed refractory Hodgkin lymphoma, who received an alternative combination of vorinostat 300 mg orally daily with escalating dose of everolimus 5–10 mg orally daily utilizing 3+3 design (Table 1; Supplementary File 1). Addition of vorinostat and evorolimus cohort was supported by preclinical and
Publisher Copyright:
© 2020 American Association for Cancer Research.
PY - 2021/11/1
Y1 - 2021/11/1
N2 - Purpose: Preclinical and early clinical data suggested that combining histone deacetylase (HDAC) and mTOR inhibitors can synergistically inhibit Hodgkin lymphoma. Patients and Methods: During the dose-escalation study (ClinicalTrials.gov number: NCT01087554) with the HDAC inhibitor vorinostat and the mTOR inhibitor sirolimus (VþS), a patient with Hodgkin lymphoma refractory to nine prior therapies demonstrated a partial response (PR) lasting for 18.5 months, which promoted additional enrollment of patients with Hodgkin lymphoma as well as exploration of an alternative combination of vorinostat and mTOR inhibitor everolimus (VþE). Results: A total of 40 patients with refractory Hodgkin lymphoma received VþS (n ¼ 22) or VþE (n ¼ 18). Patients received a median of five prior therapies, including brentuximab (n ¼ 39), autologous stem cell transplantation (n ¼ 26), and allogeneic stem cell transplantation (n ¼ 12). The most frequent grade ≥3 treatment-related adverse event was thrombocytopenia in 55% and 67% of patients treated with VþS and VþE, respectively. Complete response was reported in 6 (27%) patients treated with VþS and 2 (11%) patients treated with VþE, and PR was reported in 6 patients (27%) treated with VþS and 4 (22%) patients treated with VþE (objective response rate of 55% and 33%, respectively). In summary, combined HDAC and mTOR inhibition had encouraging activity in heavily pretreated patients with relapsed/refractory Hodgkin lymphoma and warrants further investigation. Conclusions: Combined HDAC and mTOR inhibition has salutary activity in patients with relapsed refractory Hodgkin lymphoma and warrants further investigation.
AB - Purpose: Preclinical and early clinical data suggested that combining histone deacetylase (HDAC) and mTOR inhibitors can synergistically inhibit Hodgkin lymphoma. Patients and Methods: During the dose-escalation study (ClinicalTrials.gov number: NCT01087554) with the HDAC inhibitor vorinostat and the mTOR inhibitor sirolimus (VþS), a patient with Hodgkin lymphoma refractory to nine prior therapies demonstrated a partial response (PR) lasting for 18.5 months, which promoted additional enrollment of patients with Hodgkin lymphoma as well as exploration of an alternative combination of vorinostat and mTOR inhibitor everolimus (VþE). Results: A total of 40 patients with refractory Hodgkin lymphoma received VþS (n ¼ 22) or VþE (n ¼ 18). Patients received a median of five prior therapies, including brentuximab (n ¼ 39), autologous stem cell transplantation (n ¼ 26), and allogeneic stem cell transplantation (n ¼ 12). The most frequent grade ≥3 treatment-related adverse event was thrombocytopenia in 55% and 67% of patients treated with VþS and VþE, respectively. Complete response was reported in 6 (27%) patients treated with VþS and 2 (11%) patients treated with VþE, and PR was reported in 6 patients (27%) treated with VþS and 4 (22%) patients treated with VþE (objective response rate of 55% and 33%, respectively). In summary, combined HDAC and mTOR inhibition had encouraging activity in heavily pretreated patients with relapsed/refractory Hodgkin lymphoma and warrants further investigation. Conclusions: Combined HDAC and mTOR inhibition has salutary activity in patients with relapsed refractory Hodgkin lymphoma and warrants further investigation.
UR - http://www.scopus.com/inward/record.url?scp=85100892622&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-20-1215
DO - 10.1158/1078-0432.CCR-20-1215
M3 - Article
C2 - 33055173
AN - SCOPUS:85100892622
SN - 1078-0432
VL - 26
SP - 5579
EP - 5587
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 21
ER -