A first-in-human phase 1 dose escalation study of spartalizumab (PDR001), an anti–PD-1 antibody, in patients with advanced solid tumors
Background Spartalizumab is a humanized IgG4κ monoclonal antibody that binds programmed death-1 (PD-1) and blocks its interaction with PD-L1 and PD-L2. This phase 1/2 study was designed to assess the safety, pharmacokinetics, and preliminary efficacy of spartalizumab in patients with advanced or met...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMJ Publishing Group
2020-05-01
|
| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/8/1/e000530.full |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1846172699474264064 |
|---|---|
| author | Hans Gelderblom Patrick M Forde Aung Naing Matthew Taylor Jennifer Mataraza Marcus O Butler Todd M Bauer Justin F Gainor Chia-Chi Lin Sunil Sharma Maria Ochoa de Olza Andrea Varga Jan H M Schellens Hongqian Wu Haiying Sun Antonio P Silva Jason Faris Scott Cameron |
| author_facet | Hans Gelderblom Patrick M Forde Aung Naing Matthew Taylor Jennifer Mataraza Marcus O Butler Todd M Bauer Justin F Gainor Chia-Chi Lin Sunil Sharma Maria Ochoa de Olza Andrea Varga Jan H M Schellens Hongqian Wu Haiying Sun Antonio P Silva Jason Faris Scott Cameron |
| author_sort | Hans Gelderblom |
| collection | DOAJ |
| description | Background Spartalizumab is a humanized IgG4κ monoclonal antibody that binds programmed death-1 (PD-1) and blocks its interaction with PD-L1 and PD-L2. This phase 1/2 study was designed to assess the safety, pharmacokinetics, and preliminary efficacy of spartalizumab in patients with advanced or metastatic solid tumors.Methods In the phase 1 part of the study, 58 patients received spartalizumab, intravenously, at doses of 1, 3, or 10 mg/kg, administered every 2 weeks (Q2W), or 3 or 5 mg/kg every 4 weeks (Q4W).Results Patients had a wide range of tumor types, most commonly sarcoma (28%) and metastatic renal cell carcinoma (10%); other tumor types were reported in ≤3 patients each. Most patients (93%) had received prior antineoplastic therapy (median three prior lines) and two-thirds of the population had tumor biopsies negative for PD-L1 expression at baseline. The maximum tolerated dose was not reached. The recommended phase 2 doses were selected as 400 mg Q4W or 300 mg Q3W. No dose-limiting toxicities were observed, and adverse events included those typical of other PD-1 antibodies. The most common treatment-related adverse events of any grade were fatigue (22%), diarrhea (17%), pruritus (14%), hypothyroidism (10%), and nausea (10%). Partial responses occurred in two patients (response rate 3.4%); one with atypical carcinoid tumor of the lung and one with anal cancer. Paired tumor biopsies from patients taken at baseline and on treatment suggested an on-treatment increase in CD8+ lymphocyte infiltration in patients with clinical benefit.Conclusions Spartalizumab was well tolerated at all doses tested in patients with previously treated advanced solid tumors. On-treatment immune activation was seen in tumor biopsies; however, limited clinical activity was reported in this heavily pretreated, heterogeneous population. The phase 2 part of this study is ongoing in select tumor types.Trial registration number NCT02404441. |
| format | Article |
| id | doaj-art-d6d1da80e61d43f995ed1d456acbc093 |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2020-05-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-d6d1da80e61d43f995ed1d456acbc0932024-11-09T09:10:08ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262020-05-018110.1136/jitc-2020-000530A first-in-human phase 1 dose escalation study of spartalizumab (PDR001), an anti–PD-1 antibody, in patients with advanced solid tumorsHans Gelderblom0Patrick M Forde1Aung Naing2Matthew Taylor3Jennifer Mataraza4Marcus O Butler5Todd M Bauer6Justin F Gainor7Chia-Chi Lin8Sunil Sharma9Maria Ochoa de Olza10Andrea Varga11Jan H M Schellens12Hongqian Wu13Haiying Sun14Antonio P Silva15Jason Faris16Scott Cameron17Department of Medical Oncology, Leiden University Medical Center, Leiden, The NetherlandsDepartment of Oncology, The Sidney Kimmel Comprehensive Cancer Center and the Bloomberg–Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, Maryland, USA14 Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA11 Providence Cancer Center, Portland, Oregon, USAOncology Translational Research, Novartis Institutes for BioMedical Research Inc, Cambridge, Massachusetts, USAPrincess Margaret Hospital Cancer Centre, Toronto, Ontario, CanadaSarah Cannon Research Institute, Nashville, Tennessee, USAMassachusetts General Hospital, Boston, Massachusetts, USA6 National Taiwan University Hospital, Taipei, Taiwan2Stingray Therapeutics, Houston, TX1 Immuno-oncology Service, Department of Oncology, CHUV, Lausanne, Vaud, SwitzerlandPalliative Care Unit, Gustave Roussy Institute, Villejuif, France11 Utrecht University, Utrecht, The Netherlands12 Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA12 Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA13 Novartis Institutes for BioMedical Research, Basel, Switzerland14 Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA14 Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USABackground Spartalizumab is a humanized IgG4κ monoclonal antibody that binds programmed death-1 (PD-1) and blocks its interaction with PD-L1 and PD-L2. This phase 1/2 study was designed to assess the safety, pharmacokinetics, and preliminary efficacy of spartalizumab in patients with advanced or metastatic solid tumors.Methods In the phase 1 part of the study, 58 patients received spartalizumab, intravenously, at doses of 1, 3, or 10 mg/kg, administered every 2 weeks (Q2W), or 3 or 5 mg/kg every 4 weeks (Q4W).Results Patients had a wide range of tumor types, most commonly sarcoma (28%) and metastatic renal cell carcinoma (10%); other tumor types were reported in ≤3 patients each. Most patients (93%) had received prior antineoplastic therapy (median three prior lines) and two-thirds of the population had tumor biopsies negative for PD-L1 expression at baseline. The maximum tolerated dose was not reached. The recommended phase 2 doses were selected as 400 mg Q4W or 300 mg Q3W. No dose-limiting toxicities were observed, and adverse events included those typical of other PD-1 antibodies. The most common treatment-related adverse events of any grade were fatigue (22%), diarrhea (17%), pruritus (14%), hypothyroidism (10%), and nausea (10%). Partial responses occurred in two patients (response rate 3.4%); one with atypical carcinoid tumor of the lung and one with anal cancer. Paired tumor biopsies from patients taken at baseline and on treatment suggested an on-treatment increase in CD8+ lymphocyte infiltration in patients with clinical benefit.Conclusions Spartalizumab was well tolerated at all doses tested in patients with previously treated advanced solid tumors. On-treatment immune activation was seen in tumor biopsies; however, limited clinical activity was reported in this heavily pretreated, heterogeneous population. The phase 2 part of this study is ongoing in select tumor types.Trial registration number NCT02404441.https://jitc.bmj.com/content/8/1/e000530.full |
| spellingShingle | Hans Gelderblom Patrick M Forde Aung Naing Matthew Taylor Jennifer Mataraza Marcus O Butler Todd M Bauer Justin F Gainor Chia-Chi Lin Sunil Sharma Maria Ochoa de Olza Andrea Varga Jan H M Schellens Hongqian Wu Haiying Sun Antonio P Silva Jason Faris Scott Cameron A first-in-human phase 1 dose escalation study of spartalizumab (PDR001), an anti–PD-1 antibody, in patients with advanced solid tumors Journal for ImmunoTherapy of Cancer |
| title | A first-in-human phase 1 dose escalation study of spartalizumab (PDR001), an anti–PD-1 antibody, in patients with advanced solid tumors |
| title_full | A first-in-human phase 1 dose escalation study of spartalizumab (PDR001), an anti–PD-1 antibody, in patients with advanced solid tumors |
| title_fullStr | A first-in-human phase 1 dose escalation study of spartalizumab (PDR001), an anti–PD-1 antibody, in patients with advanced solid tumors |
| title_full_unstemmed | A first-in-human phase 1 dose escalation study of spartalizumab (PDR001), an anti–PD-1 antibody, in patients with advanced solid tumors |
| title_short | A first-in-human phase 1 dose escalation study of spartalizumab (PDR001), an anti–PD-1 antibody, in patients with advanced solid tumors |
| title_sort | first in human phase 1 dose escalation study of spartalizumab pdr001 an anti pd 1 antibody in patients with advanced solid tumors |
| url | https://jitc.bmj.com/content/8/1/e000530.full |
| work_keys_str_mv | AT hansgelderblom afirstinhumanphase1doseescalationstudyofspartalizumabpdr001anantipd1antibodyinpatientswithadvancedsolidtumors AT patrickmforde afirstinhumanphase1doseescalationstudyofspartalizumabpdr001anantipd1antibodyinpatientswithadvancedsolidtumors AT aungnaing afirstinhumanphase1doseescalationstudyofspartalizumabpdr001anantipd1antibodyinpatientswithadvancedsolidtumors AT matthewtaylor afirstinhumanphase1doseescalationstudyofspartalizumabpdr001anantipd1antibodyinpatientswithadvancedsolidtumors AT jennifermataraza afirstinhumanphase1doseescalationstudyofspartalizumabpdr001anantipd1antibodyinpatientswithadvancedsolidtumors AT marcusobutler afirstinhumanphase1doseescalationstudyofspartalizumabpdr001anantipd1antibodyinpatientswithadvancedsolidtumors AT toddmbauer afirstinhumanphase1doseescalationstudyofspartalizumabpdr001anantipd1antibodyinpatientswithadvancedsolidtumors AT justinfgainor afirstinhumanphase1doseescalationstudyofspartalizumabpdr001anantipd1antibodyinpatientswithadvancedsolidtumors AT chiachilin afirstinhumanphase1doseescalationstudyofspartalizumabpdr001anantipd1antibodyinpatientswithadvancedsolidtumors AT sunilsharma afirstinhumanphase1doseescalationstudyofspartalizumabpdr001anantipd1antibodyinpatientswithadvancedsolidtumors AT mariaochoadeolza afirstinhumanphase1doseescalationstudyofspartalizumabpdr001anantipd1antibodyinpatientswithadvancedsolidtumors AT andreavarga afirstinhumanphase1doseescalationstudyofspartalizumabpdr001anantipd1antibodyinpatientswithadvancedsolidtumors AT janhmschellens afirstinhumanphase1doseescalationstudyofspartalizumabpdr001anantipd1antibodyinpatientswithadvancedsolidtumors AT hongqianwu afirstinhumanphase1doseescalationstudyofspartalizumabpdr001anantipd1antibodyinpatientswithadvancedsolidtumors AT haiyingsun afirstinhumanphase1doseescalationstudyofspartalizumabpdr001anantipd1antibodyinpatientswithadvancedsolidtumors AT antoniopsilva afirstinhumanphase1doseescalationstudyofspartalizumabpdr001anantipd1antibodyinpatientswithadvancedsolidtumors AT jasonfaris afirstinhumanphase1doseescalationstudyofspartalizumabpdr001anantipd1antibodyinpatientswithadvancedsolidtumors AT scottcameron afirstinhumanphase1doseescalationstudyofspartalizumabpdr001anantipd1antibodyinpatientswithadvancedsolidtumors AT hansgelderblom firstinhumanphase1doseescalationstudyofspartalizumabpdr001anantipd1antibodyinpatientswithadvancedsolidtumors AT patrickmforde firstinhumanphase1doseescalationstudyofspartalizumabpdr001anantipd1antibodyinpatientswithadvancedsolidtumors AT aungnaing firstinhumanphase1doseescalationstudyofspartalizumabpdr001anantipd1antibodyinpatientswithadvancedsolidtumors AT matthewtaylor firstinhumanphase1doseescalationstudyofspartalizumabpdr001anantipd1antibodyinpatientswithadvancedsolidtumors AT jennifermataraza firstinhumanphase1doseescalationstudyofspartalizumabpdr001anantipd1antibodyinpatientswithadvancedsolidtumors AT marcusobutler firstinhumanphase1doseescalationstudyofspartalizumabpdr001anantipd1antibodyinpatientswithadvancedsolidtumors AT toddmbauer firstinhumanphase1doseescalationstudyofspartalizumabpdr001anantipd1antibodyinpatientswithadvancedsolidtumors AT justinfgainor firstinhumanphase1doseescalationstudyofspartalizumabpdr001anantipd1antibodyinpatientswithadvancedsolidtumors AT chiachilin firstinhumanphase1doseescalationstudyofspartalizumabpdr001anantipd1antibodyinpatientswithadvancedsolidtumors AT sunilsharma firstinhumanphase1doseescalationstudyofspartalizumabpdr001anantipd1antibodyinpatientswithadvancedsolidtumors AT mariaochoadeolza firstinhumanphase1doseescalationstudyofspartalizumabpdr001anantipd1antibodyinpatientswithadvancedsolidtumors AT andreavarga firstinhumanphase1doseescalationstudyofspartalizumabpdr001anantipd1antibodyinpatientswithadvancedsolidtumors AT janhmschellens firstinhumanphase1doseescalationstudyofspartalizumabpdr001anantipd1antibodyinpatientswithadvancedsolidtumors AT hongqianwu firstinhumanphase1doseescalationstudyofspartalizumabpdr001anantipd1antibodyinpatientswithadvancedsolidtumors AT haiyingsun firstinhumanphase1doseescalationstudyofspartalizumabpdr001anantipd1antibodyinpatientswithadvancedsolidtumors AT antoniopsilva firstinhumanphase1doseescalationstudyofspartalizumabpdr001anantipd1antibodyinpatientswithadvancedsolidtumors AT jasonfaris firstinhumanphase1doseescalationstudyofspartalizumabpdr001anantipd1antibodyinpatientswithadvancedsolidtumors AT scottcameron firstinhumanphase1doseescalationstudyofspartalizumabpdr001anantipd1antibodyinpatientswithadvancedsolidtumors |