Phase I prognostic online (PIPO): A web tool to improve patient selection for oncology early phase clinical trials.

Purpose: Patient selection in phase 1 clinical trials (Ph1t) continues to be a challenge. The aim of this study was to develop a user-friendly prognostic calculator for predicting overall survival (OS) outcomes in patients to be included in Ph1t with immune checkpoint inhibitors (ICIs) or targeted agents (TAs) based on clinical parameters assessed at baseline.
Methods: Using a training cohort with consecutive patients from the VHIO phase 1 unit, we constructed a prognostic model to predict median OS (mOS) as a primary endpoint and 3-month (3m) OS rate as a secondary endpoint. The model was validated in an internal cohort after temporal data splitting and represented as a web application.
Results: We recruited 799 patients (training and validation sets, 558 and 241, respectively). Median follow-up was 21.2 months (m), mOS was 10.2 m (95% CI, 9.3-12.7) for ICIs cohort and 7.7 m (95% CI, 6.6-8.6) for TAs cohort. In the multivariable analysis, six prognostic variables were independently associated with OS - ECOG, number of metastatic sites, presence of liver metastases, derived neutrophils/(leukocytes minus neutrophils) ratio [dNLR], albumin and lactate dehydrogenase (LDH) levels. The phase 1 prognostic online (PIPO) calculator showed adequate discrimination and calibration performance for OS, with C-statistics of 0.71 (95% CI 0.64-0.78) in the validation set. The overall accuracy of the model for 3m OS prediction was 87.2% (95% CI 85%-90%).
Conclusions: PIPO is a user-friendly objective and interactive tool to calculate specific survival probabilities for each patient before enrolment in a Ph1t. The tool is available at https://pipo.vhio.net/.
Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships that may be considered as potential competing interests: IM reports receiving an ESMO Research Fellowship sponsored by Roche and honoraria for serving as a speaker bureau for MSD. CH reports a grant from Bayer and Merck., personal fees from MSD, Merck and Amgen. JML reports receiving a grant from Sanofi, honoraria for consultancy from Novartis, Roche, BMS, Pierre Fabre, Sanofi, Highlight Therapeutics and personal fees from Novartis, Roche, MSD, Pfizer, BMS, Astellas Pharma, Pierre Fabre and Sanofi. IB reports honoraria for consultancy from Orion Pharma, BMS, Astrazeneca, Merck Serono, Rakutan Pharma, Roche, Sanofi, MSD eTheRNA Immunotherapies and Achilles Therapeutics Limited. AA reports honoraria for consultancy from AMCURE and research funding from AMCURE. OM reports personal fees from MSD and Janssen. IG reports fees for a speaker for MSD and Roche. AH reports travel grants from Kyowa & Kirin, MSD and Merck and funding from Hold’em for Life Oncology Fellowship, TTCC and SEOM and CRIS Foundations. GA reports no conflict of interest. VG reports no conflict of interest. MO reports fees for consultancy from MSD. JR reports receiving fees for a speaker for Sanofi. EMC reports receiving fees for serving as a member of scientific advisory boards from Amgen, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche, Sanofi, and personal fees from Amgen, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche, and participation as principal investigator in clinical trials from Amgen, Bristol-Myers Squibb, GlaxoSmithKline, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche, Sanofi. EE reports research funding from Array Biopharma, MSD, Abbvie, Amgen, GlaxoSmithKline, Astrazeneca, Merck Sharp & Dohme Corp., Bristol Myers Squibb, Novartis, Boehringer Ingelheim, Hoffman La-Roche and honoraria for consulting from Hoffman La - Roche, Bristol Myers Squibb, Servier, Amgen, Merck Serono, Array Biopharma, Sanofi. Dr Rodon reports non financial support and reasonable reimbursement for travel from European Journal of Cancer, Vall d’Hebron Institut of Oncology, Chinese University of Hong Kong, SOLTI, Elsevier, GLAXOSMITHKLINE,; receiving consulting and travel fees from Novartis, Eli Lilly, Orion Pharmaceuticals, Servier Pharmaceuticals, Peptomyc, Merck Sharp & Dohme, Kelun Pharmaceutical/Klus Pharma, Spectrum Pharmaceuticals Inc, Pfizer, Roche Pharmaceuticals, Ellipses Pharma, NovellusDx, iOnctura and Molecular Partners (including serving on the scientific advisory board from 2015 to the present), receiving research funding from Blueprint Pharmaceuticals, Bayer and Novartis, and serving as investigator in clinical trials with Spectrum Pharmaceuticals, Tocagen, Symphogen, BioAtla, Pfizer, GenMab, CytomX, KELUN-BIOTECH, Takeda-Millennium, GLAXOSMITHKLINE, IPSEN and travel fees from ESMO, US Department of Defense, Louisiana State University, Huntsman Cancer Institute, Cancer Core Europe, Karolinska Cancer Institute and King Abdullah International Medical Research Center (KAIMRC), Molecular Partners. CS reports receiving fees for serving as a member of scientific advisory boards or receiving travel grants from AstraZeneca, Celgene, Daiichi Sankyo, Eisai, F. Hoffmann - La Roche Ltd, Genomic Health, Merck, Sharp and Dhome España S.A., Novartis, Odonate Therapeutics, Pfizer, Philips Healthwork, Pierre Fabre, prIME Oncology, Puma, Synthon and Sanofi Aventis and paid directly to her Institution: AstraZeneca, Daiichi Sankyo, Eli Lilly and Company, Genentech, Immunomedics, Macrogenics, Merck, Sharp and Dhome España S.A., Novartis, Pfizer, Piqur Therapeutics, Puma, Roche, Synthon and Zenith Pharma. TM reports receiving fees for consulting Roche, AstraZeneca, PharmaMar, Clovis Oncology, Tesaro, Inmunogen, Genmab, Mersana Therapeutic, GSK and Deciphera Pharmaceutical and received support for travel or accommodation from Roche, AstraZeneca, and PharmaMar and institutional personal interest paid directly to her institution: Agios, Aslan, AstraZecena, Bayer, Celgene, Genentech, Hallozyme, Immunomedics, Lilly, Merimarck, Millenim, Novartis, Pfizer, Pharmacyclics and Roche. AO reports receiving fees for consulting from Roche, AstraZeneca, PharmaMar, Clovis Oncology, Tesaro, Inmunogen, Genmab, Mersana Therapeutic, GSK and Deciphera Pharmaceutical and received support for travel or accommodation from Roche, AstraZeneca, and PharmaMar, and institutional financial interest paid directly to her institution: Abbvie Deutschland, Ability Pharmaceuticals, Advaxis Inc., Aeterna Zentaris, AMGEM, SA, Aprea Therapeutics AB, Clovis Oncology Inc, EISAI limited LTD, F. Hoffmann – La Roche LTD, Regeneron Pharmaceuticals, Immunogen Inc., Merck, Sharp & Dohme de España SA, Millennium Pharmaceuticals Inc., Pharma Mar SA, Tesaro Inc., BMS, Bristol Meyers Squibb. JC reports receiving fees for advisory board from Bayer, Johnson & Johnson,Bristol-Myers Squibb, Astellas Pharma, Pfizer, Sanofi, MSD Oncology, Roche, AstraZéneca and for speakers bureau from Bayer, Johnson & Johnson, Asofarma, Astellas Pharma, travel from BMS, Ipsen, Roche, AstraZéneca, and research grants from AB Science, Aragon Pharmaceuticals, Arog Pharmaceuticals, INC, Astellas Pharma., Astrazeneca AB, Aveo Pharmaceuticals INC, Bayer AG, Blueprint Medicines Corporation, BN Immunotherapeutics INC, Boehringer Ingelheim España, S.A., Bristol-Myers Squibb International Corporation (BMS), Clovis Oncology, INC, Cougar Biotechnology INC, Deciphera Pharmaceuticals LLC, Exelixis INC, F. Hoffmann-La Roche LTD, Genentech INC, Glaxosmithkline, SA, Incyte Corporation, Janssen-Cilag International NV, Karyopharm Therapeutics INC., Laboratoires Leurquin Mediolanum SAS, Lilly, S.A., Medimmune, Millennium Pharmaceuticals, INC., Nanobiotix SA, Novartis Farmacéutica, S.A., Pfizer, S.L.U, Puma Biotechnology, INC, Sanofi-Aventis, S.A., SFJ Pharma LTD. II, Teva Pharma S.L.U. EF reports research funding from Fundacion Merck Salud, personal fees for consulting from ABBVIE, Astrazeneca, Blueprint Medicines, Boehringer Ingelheim, BMS, ELI Lilly, Guardant Health, Jansenn, Merck, Novartis, Pfizer, Roche, Samsung, Takeda, GSK and Bayer, personal fees for speakers bureao from Astrazeoncology, Roche, Takeda, Boehringer Ingelheim, BMS, ELI Lilly, Medsxape, Merck, Novartis, Pfizer, Prime Oncology, Roche, Takeda, Touchime and in Grifols independent member of the board. Josep Tabernero reports personal financial interest in the form of scientific consultancy role for Array Biopharma, AstraZeneca, Bayer, BeiGene, Boehringer Ingelheim, Chugai, Genentech, Inc., Genmab A/S, Halozyme, Imugene Limited, Inflection Biosciences Limited, Ipsen, Kura Oncology, Lilly, MSD, Menarini, Merck Serono, Merrimack, Merus, Molecular Partners, Novartis, Peptomyc, Pfizer, Pharmacyclics, ProteoDesign SL, Rafael Pharmaceuticals, F. Hoffmann-La Roche Ltd, Sanofi, SeaGen, Seattle Genetics, Servier, Symphogen, Taiho, VCN Biosciences, Biocartis, Foundation Medicine, HalioDX SAS and Roche Diagnostics. RD declares advisory role for Roche, Boehringer Ingelheim, received a speaker’s fee from Roche, Ipsen, Amgen, Servier, Sanofi, Merck Sharp & Dohme, and research grants from Merck and Pierre Fabre. EG reportspersonal financial interest in the form of scientific consultancy role for Roche/Genentech - F.Hoffmann/La Roche, Ellipses Pharma, Neomed Therapeutics1 Inc, Boehringer Ingelheim, Janssen Global Services, SeaGen, TFS, Alkermes, Thermo Fisher, Bristol-Mayers Squibb, MabDiscovery, Anaveon; fees for speakers bureau from Merck Sharp & Dohme, Roche, Thermo Fisher, Roche, Lilly; travel grants from Bristol-Mayers Squibb, Merck Sharp & Dohme, Menarini, Glycotope; research grants from Novartis, Roche, Thermo Fisher, AstraZeneca, Taiho, BeiGene.The remaining authors declare no conflicts of interest.
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