Abstract
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.
| Original language | English |
|---|---|
| Pages (from-to) | 5579-5587 |
| Number of pages | 9 |
| Journal | Clinical Cancer Research |
| Volume | 26 |
| Issue number | 21 |
| DOIs | |
| State | Published - Nov 1 2021 |
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Safety and efficacy of vorinostat plus sirolimus or everolimus in patients with relapsed refractory hodgkin lymphoma. / Janku, Filip; Park, Haeseong; Call, S. Greg; Madwani, Kiran; Oki, Yasuhiro; Subbiah, Vivek; Hong, David S.; Naing, Aung; Velez-Bravo, Vivianne M.; Barnes, Tamara G.; Hagemeister, Fredrick B.; Falchook, Gerald S.; Karp, Daniel D.; Wheler, Jennifer J.; Piha-Paul, Sarina A.; Garrido-Laguna, Ignacio; Shpall, Elizabeth J.; Fayad, Luis E.; Neelapu, Sattva S.; Meric-Bernstam, Funda; Kurzrock, Razelle; Fanale, Michelle A.
In: Clinical Cancer Research, Vol. 26, No. 21, 01.11.2021, p. 5579-5587.Research output: Contribution to journal › Article › peer-review
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: F. Janku reports grants from Novartis, Genentech, BioMed, Valley Discoveries, Astellas, Agios, Plexxikon, Piqur, Symphogen, Bristol-Myers Squibb, Asana, and Proximagen (research); grants and other from Deciphera (research, advisory board); other from Guardant Health, IFM Therapeutics, and Synlogic (advisory board); personal fees and other from Trovagene (consultant, ownership interests); and personal fees from Immunomet (consultant) during the conduct of the study. H. Park serves as site PI for clinical trials funded by the following entities (all fees paid to the institution): Ambrx, Amgen, Aprea Therapeutics AB, Array BioPharma, Bayer BeiGene, BJ Bioscience, Bristol-Myers Squibb, Daiichi Pharmaceutical, Eli Lilly, EMD Serono, Five Prime Therapeutics, Genentech, Gilead Sciences, GlaxoSmithKline, Gossamer Bio, Hoffman-LaRoche, ImmuneOncia Therapeutics, Immunomedics, Incyte, Jounce Therapeutics, Mabspace Biosciences, MacroGenics, Medimmune, Medivation, Merck, Mirati Therapeutics, Novartis Pharmaceuticals, Oncologie, Pfizer, PsiOxus Therapeutics, Puma Biotechnology, Regeneron Pharmaceuticals, Seattle Genetics, Synermore Biologics, Taiho Pharmaceutical, TopAlliance Biosciences, Turning Point Therapeutics, Vedanta Biosciences, Vertex Pharmaceuticals, and Xencor Inc. S.G. Call reports grants from Non-Standard of Care Clinical Charge Program at MD Anderson, Sheikh Khalifa Al Nahyan Ben Zayed Institute for Personalized Cancer Therapy at MD Anderson, National Center for Advancing Translational Sciences, and NIH through MD Anderson Cancer Center Support Grant during the conduct of the study. Y. Oki reports other from Genentech (current employment) outside the submitted work. V. Subbiah reports grants from Novartis (clinical trials research support) outside the submitted work; research funding/grant support for clinical trials from Roche/Genentech, Novartis, Bayer, GlaxoSmithKline, Nanocarrier, Vegenics, Celgene, Northwest Biotherapeutics, Berghealth, Incyte, Fujifilm, Pharmamar, D3, Pfizer, Multivir, Amgen, Abbvie, Alfa-sigma, Agensys, Boston Biomedical, Idera Pharma, Inhibrx, Exelixis, Blueprint Medicines, Loxo Oncology, Medimmune, Altum, Dragonfly Therapeutics, Takeda, National Comprehensive Cancer Network, NCI-CTEP and UT MD Anderson Cancer Center, Turning Point Therapeutics, and Boston Pharmaceuticals; travel support from Novartis, Pharmamar, ASCO, ESMO, Helsinn, Incyte; consultancy/advisory board at Helsinn, Loxo Oncology/Eli Lilly, R-Pharma US, Incyte, QED Pharma, Medim-mune, Novartis, Signant Health; and other from Medscape. D.S. Hong reports research/grant funding from AbbVie, Adaptimune, Aldi-Norte, Amgen, Astra-Zeneca, Bayer, BMS, Daiichi Sankyo, Eisai, Fate Therapeutics, Genentech, Genmab, Ignyta, Infinity, Kite, Kyowa, Lilly, Loxo, Merck, Medimmune, Mirati, miRNA, Molecular Templates, Mologen, NCI-CTEP, Novartis, Pfizer, Seattle Genetics, Takeda, and Turning Point Therapeutics; travel, accommodations, expenses from Bayer, Loxo, miRNA, Genmab, AACR, ASCO, and SITC; consulting or advisory roles with Alpha Insights, Acuta, Amgen, Axiom, Adaptimmune, Baxter, Bayer, COG, Ecorl, Genentech, GLG, Group H, Guidepoint, Infinity, Janssen, Merrimack, Medscape, Numab, Pfizer, Prime Oncology, Seattle Genetics, Takeda, Trieza Therapeutics, and WebMD; and other ownership interests in Molecular Match (advisory); OncoResponse (founder); Presagia Inc (advisor). A. Naing reports grants from NCI, EMD Serono, Medimmune, Karyopharm Therapeutics, Incyte, Neon Therapeutics, Calithera Biosciences, Top Alliance Biosciences, Eli Lilly, Kymab, PsiOxus, Arcus Biosciences, and NeoImmune-Tech; grants and nonfinancial support from ARMO BioSciences (travel and accommodation expense);grantsandpersonal fees fromNovartis(advisoryboard), Regeneron, Merck, BMS, Pfizer, CytomX Therapeutics (advisory board); and personal fees from Genome & Company (advisory board) outside the submitted work. G.S. Falchook reports royalties from Wolters Kluwer (self, 2014–present); advisory roles with Fujifilm (to institution, 2018) and EMDSerono(self, 2010, 2011); travel(self,for workorresearch related to institution) from Bristol Myers Squibb (2015), EMD Serono (2011–2013), Fujifilm (2018), Millennium (2013), and Sara Cannon Research Institute; speakers honorarium for CME from Total Health Conferencing (2019) and Rocky Mountain Oncology (2020); and research funding to institution from 3-V Biosciences, Abbisko, Abbvie, ADC Therapeutics, Aileron, American Society of Clinical Oncology, Amgen, ARMO, AstraZeneca, BeiGene, Bioatla, Bioinvent, Biothera, Bicycle, Celldex, Celgene, Ciclomed, Curegenix, Curis, Cyteir, Daiichi, DelMar, eFFECTOR, Eli Lilly, EMD Funding Information: Serono, Epizyme, Exelixis, Fujifilm, Genmab, GlaxoSmithKline, Hutchison Medi-Pharma, Ignyta, Incyte, Jacobio, Jounce, Kolltan, Loxo, MedImmune, Millennium, Merck, miRNA Therapeutics, NIH, Novartis, OncoMed, Oncorus, Oncothyreon, Poseida, Precision Oncology, Prelude, Regeneron, Rgenix, Ribon, Sapience, Strategia, Syndax, Synthorx, Taiho, Takeda, Tarveda, Tesaro, Tocagen, Turning Point Therapeutics, U.T. MD Anderson Cancer Center, Vegenics, and Xencor. D.D. Karp reports grants from MD Anderson Cancer Center (Cancer Center support grant and NIH Clinical Translational Science Award grant) during the conduct of the study; other from Wolters Kluwer Publishers (royalties for Handbook of Targeted Cancer Therapy & Immunotherapy); personal fees from Black Beret Life Sciences (consulting); and grants from Phosplatin Therapeutics (principal investigator) outside the submitted work. S.A. Piha-Paul reportsotherfromAbbVie, Inc.,ABM Therapeutics, Inc.,Acepodia,Inc.,Alkermes, Aminex Therapeutics, Amphivena Therapeutics, Inc., BioMarin Pharmaceutical, Inc., Boehringer Ingelheim, Bristol-Myers Squibb, Cerulean Pharma, Inc., Chugai Pharmaceutical Co., Ltd., Curis, Inc., Daiichi Sankyo, Eli Lilly, ENB Therapeutics, Five Prime Therapeutics, Gene Quantum, Genmab A/S, GlaxoSmithKline, Helix BioPharma Corp., Icyte Corp., Jacobio Pharmaceuticals Co., Medimmune, LLC, Medivation, Inc., Merck Sharp & Dohme Corp., Novartis Pharmaceuticals, Pieris Pharmaceuticals, Inc., Pfizer, Principia Biopharma, Inc., Puma Biotechnology, Inc., Rapt Therapeutics, Inc., Seattle Genetics, Silverback Therapeutics, Taiho Oncology, Tesaro, Inc. (clinical trial research support received through the institution), and NCI/CIH Core grant (CCSG shared resources) No. P30CA016672 (clinical trial research support received through the institution) outside the submitted work. I. Garrido-Laguna reports other from Pfizer, BMS, Tolero, Incyte, Tizona, Array, Novartis, GSK, OncoMed, Genetech, Halozyme, Lilly, Glenmark, Redhill, Bayer, Taiho, Medimmune, Amgen, Rafael, and Seattle Genetics (payment to institution for role as study PI) outside the submitted work; and ad-hoc advisory boards for Pfizer, Array, and Eisai. E.J. Shpall reports personal fees from Novartis (consulting fees, honorarium), Magenta (consulting fees, honorarium), Adap-timmune (consulting fees), Cellgene (consulting fees), Partner Therapeutics (consulting fees, honorarium),Mesoblast (consulting fees), and Axio (consulting fees) outside the submitted work, and is listed as a coinventor on a provisional patent application that is owned by MD Anderson and licensed to Takeda. S.S. Neelapu reports grants and personal fees from Kite/Gilead, Bristol-Myers Squibb, Allogene, Unum Therapeutics, Precision Biosciences, and Merck; grants from Cellectis; personal fees from Pfizer, Poseida, Karus, Acerta, Celgene, Novartis, Cell Medica/Kuur, Incyte, Legend Biotech, Adicet Bio, Calibr; and other from Takeda Pharmaceuticals (royalty income) outside the submitted work. F. Meric-Bernstam reports personal fees from Arduro BioTech (consulting), Alkermes (consulting), F. Hoffman-LaRoche Ltd. (consulting), IBM Watson (consulting), Jackson Laboratory (consulting), Kolon Life Science (consulting), OrigiMed (consulting), PACT Pharma (consulting), Paraxel International (consulting), Pfizer Inc. (consulting), Samsung Bioepis (consulting), Seattle Genetics (consulting, advisory board), Tyra Biosciences (consulting), Xencor (consulting), Zymeworks (consulting), Immunomedics (advisory board), Inflection Biosciences (advisory board), and Mersana Therapeutics (advisory board); grants and personal fees from DebioPharm (consulting, sponsored research), eFFECTOR Therapeutics (consulting, sponsored research), Genentech Inc. (consulting, sponsored research), Puma Biotechnology (advisory board, sponsored research), Silverback Therapeutics (advisory board), Spectrum Pharmaceuticals (advisory board), Zentalis (advisory board); grants from Aileron Therapeutics (sponsoredresearch),AstraZeneca(sponsoredresearch), BayerHealthcare Pharmaceutical (sponsored research), Calithera Biosciences (sponsored research), Curis Inc. (sponsored research), CytomX Therapeutics Inc (sponsored research), Daiichi Sankyo Co. Ltd. (sponsored research), Guardant Health (sponsored research), Millennium Pharmaceuticals (sponsored research), Novartis (sponsored research), Taiho Pharmaceutical Co. (sponsored research); and other from Chugai Biopharmaceuticals (honoraria - speaking engagement), Mayo Clinic (honoraria - speaking engagement), Rutgers Cancer Institute of New Jersey (honoraria - speaking engagement), and Beth 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
VL - 26
SP - 5579
EP - 5587
JO - Clinical Cancer Research
JF - Clinical Cancer Research
SN - 1078-0432
IS - 21
ER -