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• W4298007568 abstract "•Recent experience with targeted anticancer drugs and immunotherapies suggest the traditional approach of using the maximal tolerated dose (MTD) is not ideal.•Project Optimus recommends optimizing the dosage of oncology drugs to ensure they are both effective and tolerable.•MDICT developed practical recommendations for the design and conduct of phase I oncology trials. In 2021, the Food and Drug Administration Oncology Center of Excellence announced Project Optimus focusing on dose optimization for oncology drugs. The Methodology for the Development of Innovative Cancer Therapies (MDICT) Taskforce met to review and discuss the optimization of dosage for oncology trials and to develop a practical guide for oncology phase I trials. Defining a single recommended phase II dose based on toxicity may define doses that are neither the most effective nor the best tolerated. MDICT recommendations address the need for robust non-clinical data which are needed to inform trial design, as well as an expert team including statisticians and pharmacologists. The protocol must be flexible and adaptive, with clear definition of all endpoints. Health authorities should be consulted early and regularly. Strategies such as randomization, intrapatient dose escalation, and real-world eligibility criteria are encouraged whereas serial tumor sampling is discouraged in the absence of a strong rationale and appropriately validated assay. Endpoints should include consideration of all longitudinal toxicity. The phase I dose escalation trial should define the recommended dose range for later testing in randomized phase II trials, rather than a single recommended phase II dose, and consider scenarios where different populations may require different dosages. The adoption of these recommendations will improve dosage selection in early clinical trials of new anticancer treatments and ultimately, outcomes for patients. In 2021, the Food and Drug Administration Oncology Center of Excellence announced Project Optimus focusing on dose optimization for oncology drugs. The Methodology for the Development of Innovative Cancer Therapies (MDICT) Taskforce met to review and discuss the optimization of dosage for oncology trials and to develop a practical guide for oncology phase I trials. Defining a single recommended phase II dose based on toxicity may define doses that are neither the most effective nor the best tolerated. MDICT recommendations address the need for robust non-clinical data which are needed to inform trial design, as well as an expert team including statisticians and pharmacologists. The protocol must be flexible and adaptive, with clear definition of all endpoints. Health authorities should be consulted early and regularly. Strategies such as randomization, intrapatient dose escalation, and real-world eligibility criteria are encouraged whereas serial tumor sampling is discouraged in the absence of a strong rationale and appropriately validated assay. Endpoints should include consideration of all longitudinal toxicity. The phase I dose escalation trial should define the recommended dose range for later testing in randomized phase II trials, rather than a single recommended phase II dose, and consider scenarios where different populations may require different dosages. The adoption of these recommendations will improve dosage selection in early clinical trials of new anticancer treatments and ultimately, outcomes for patients. The Methodology for the Development of Innovative Cancer Therapies (MDICT) Taskforce was established in 2006 and is now supported by the European Society of Medical Oncology (ESMO). Whereas the initial focus of the taskforce concentrated on the design of clinical trials testing targeted agents, with publications ranging from phase 0 to phase II designs, more recently, the taskforce focused on immunotherapy agents, resulting in two publications with specific recommendations.1Smoragiewicz M. Adjei A.A. Calvo E. et al.Design and conduct of early clinical studies of immunotherapy: recommendations from the task force on Methodology for the Development of Innovative Cancer Therapies 2019 (MDICT).Clin Cancer Res. 2020; 26: 2461-2465Google Scholar, 2Seymour L.K. Calvert A.H. Lobbezoo M.W. et al.Design and conduct of early clinical studies of two or more targeted anticancer therapies: recommendations from the task force on Methodology for the Development of Innovative Cancer Therapies.Eur J Cancer. 2013; 49: 1808-1814Google Scholar, 3Booth C.M. Calvert A.H. Giaccone G. Lobbezoo M.W. Eisenhauer E.A. Seymour L.K. Design and conduct of phase II studies of targeted anticancer therapy: recommendations from the task force on Methodology for the Development of Innovative Cancer Therapies (MDICT).Eur J Cancer. 2008; 44: 25-29Google Scholar, 4Booth C.M. Calvert A.H. Giaccone G. Lobbezoo M.W. Seymour L.K. Eisenhauer E.A. Endpoints and other considerations in phase I studies of targeted anticancer therapy: recommendations from the task force on Methodology for the Development of Innovative Cancer Therapies (MDICT).Eur J Cancer. 2008; 44: 19-24Google Scholar, 5Goodwin R. Giaccone G. Calvert H. Lobbezoo M.W. Eisenhauer E.A. Targeted agents: how to select the winners in preclinical and early clinical studies?.Eur J Cancer. 2012; 48: 170-178Google Scholar In 2022, the taskforce met to review and discuss the optimization of dosage for oncology trials. For more than seven decades, the dosage (i.e. both dose and schedule) of cancer therapeutics has been guided by paradigms used for the development of the earliest cytotoxic drugs in the setting of aggressive hematologic malignancies primarily based on drug-related adverse effects. Key assumptions included: (i) there was a dose-response relationship for efficacy; (ii) the therapeutic window was relatively small; (iii) toxicity (primarily myelosuppression) was directly related to drug exposure and efficacy and is both early and dose related; and (iv) it was appropriate to err on the side of higher doses given patients often had rapidly progressing chemosensitive disease. Therefore, the recommended phase II dose (RP2D) has generally been at or near the maximum tolerated dose (MTD).6Le Tourneau C. Lee J.J. Siu L.L. Dose escalation methods in phase I cancer clinical trials.J Natl Cancer Inst. 2009; 101: 708-720Google Scholar,7Hansen A.R. Graham D.M. Pond G.R. Siu L.L. Phase 1 trial design: is 3 + 3 the best?.Cancer Control. 2014; 21: 200-208Google Scholar Indeed, for cytotoxic agents, the assumption that the optimal dose was the MTD was sometimes confirmed retrospectively and in real-world studies where reduced doses were associated with inferior outcomes.8Bonadonna G. Valagussa P. Moliterni A. Zambetti M. Brambilla C. Adjuvant cyclophosphamide, methotrexate, and fluorouracil in node-positive breast cancer: the results of 20 years of follow-up.N Engl J Med. 1995; 332: 901-906Google Scholar, 9Budman D.R. Berry D.A. Cirrincione C.T. et al.Dose and dose intensity as determinants of outcome in the adjuvant treatment of breast cancer.J Natl Cancer Inst. 1998; 90: 1205-1211Google Scholar, 10Chirivella I. Bermejo B. Insa A. et al.Optimal delivery of anthracycline-based chemotherapy in the adjuvant setting improves outcome of breast cancer patients.Breast Cancer Res Treat. 2009; 114: 479-484Google Scholar, 11Havrilesky L.J. Reiner M. Morrow P.K. Watson H. Crawford J. A review of relative dose intensity and survival in patients with metastatic solid tumors.Crit Rev Oncol Hematol. 2015; 93: 203-210Google Scholar The management of select tumor types that could be cured with cytotoxic chemotherapy reinforced this principle. Today, very few new cancer therapeutics in development are cytotoxic agents, and it has become clear that the assumption that the optimal dose for a targeted agent (e.g. selective kinase inhibitor) or monoclonal antibody is not necessarily the MTD, despite still being commonly defined in this way.12Cook N. Hansen A.R. Siu L.L. Abdul Razak A.R. Early phase clinical trials to identify optimal dosing and safety.Mol Oncol. 2015; 9: 997-1007Google Scholar, 13Araujo D.V. Oliva M. Li K. Fazelzad R. Liu Z.A. Siu L.L. Contemporary dose-escalation methods for early phase studies in the immunotherapeutics era.Eur J Cancer. 2021; 158: 85-98Google Scholar, 14Shah M. Rahman A. Theoret M.R. Pazdur R. The drug-dosing conundrum in oncology-when less is more.N Engl J Med. 2021; 385: 1445-1447Google Scholar, 15Serritella A.V. Strohbehn G.W. Goldstein D.A. Lichter A.S. Ratain M.J. Interventional pharmacoeconomics: a novel mechanism for unlocking value.Clin Pharamacol Ther. 2020; 108: 487-493Google Scholar Furthermore, MTD-based dosing often results in unnecessary morbidity and most concerningly, toxicity that can even be fatal.16Ratain M.J. Moslehi J.J. Lichter A.S. Ibrutinib’s cardiotoxicity-an opportunity for postmarketing regulation.JAMA Oncol. 2021; 7: 177-178Google Scholar Moreover, for protein-based therapeutics such as monoclonal antibodies, phase I studies may never reach the MTD.17Postel-Vinay S. Aspeslagh S. Lanoy E. Robert C. Soria J.C. Marabelle A. Challenges of phase 1 clinical trials evaluating immune checkpoint-targeted antibodies.Ann Oncol. 2016; 27: 214-224Google Scholar Additional complexity in dosing of these agents arises as drug exposure may change over time due to the impact of protein catabolism in cachectic patients, changes in tumor burden,18Liu C. Yu J. Li H. et al.Association of time-varying clearance of nivolumab with disease dynamics and its implications on exposure response analysis.Clin Pharmacol Ther. 2017; 101: 657-666Google Scholar,19Freshwater T. Kondic A. Ahamadi M. et al.Evaluation of dosing strategy for pembrolizumab for oncology indications.J Immunother Cancer. 2017; 5: 43Google Scholar and potentially development of anti-drug antibodies, although in this situation typically further development of the agent is curtailed.20de Spéville B.D. Moreno V. Antidrug antibodies and drug development: challenges in the immunotherapy era.Clin Cancer Res. 2021; 27: 2669-2671Google Scholar There are now numerous examples of drugs for which dosages lower than that in the product monograph/prescribing information are routinely used in clinical practice,21Hennessy B.T. Gauthier A.M. Michaud L.B. et al.Lower dose capecitabine has a more favorable therapeutic index in metastatic breast cancer: retrospective analysis of patients treated at M. D. Anderson Cancer Center and a review of capecitabine toxicity in the literature.Ann Oncol. 2005; 16: 1289-1296Google Scholar, 22Bekaii-Saab T.S. Ou F.-S. Ahn D.H. et al.Regorafenib dose-optimisation in patients with refractory metastatic colorectal cancer (ReDOS): a randomised, multicentre, open-label, phase 2 study.Lancet Oncol. 2019; 20: 1070-1082Google Scholar, 23Brose M.S. Panaseykin Y. Konda B. et al.A randomized study of lenvatinib 18 mg vs 24 mg in patients with radioiodine-refractory differentiated thyroid cancer.J Clin Endocrinol Metab. 2022; 107: 776-787Google Scholar in many cases due to drug tolerability. Even if the optimal dose is the MTD, early clinical trials are often limited to highly selected patient populations,24Flannery M.A. Culakova E. Canin B.E. Peppone L. Ramsdale E. Mohile S.G. Understanding treatment tolerability in older adults with cancer.J Clin Oncol. 2021; 39: 2150-2163Google Scholar,25Singh H. Kanapuru B. Smith C. et al.FDA analysis of enrollment of older adults in clinical trials for cancer drug registration: a 10-year experience by the U.S. Food and Drug Administration.J Clin Oncol. 2017; 35: 10009Google Scholar protocols may consider toxicity only from the first one or two cycles—even though some drugs, such as molecularly targeted agents, elicit >50% of severe toxicities after the dose-limiting toxicity period26Postel-Vinay S. Gomez-Roca C. Molife L.R. et al.Phase I trials of molecularly targeted agents: should we pay more attention to late toxicities?.J Clin Oncol. 2011; 29: 1728-1735Google Scholar, 27Postel-Vinay S. Collette L. Paoletti X. et al.Towards new methods for the determination of dose limiting toxicities and the assessment of the recommended dose for further studies of molecularly targeted agents – Dose-Limiting Toxicity and Toxicity Assessment Recommendation Group for Early Trials of Targeted Therapies, an European Organisation for Research and Treatment of Cancer-led study.Eur J Cancer. 2014; 50: 2040-2049Google Scholar, 28Edgerly M. Fojo T. Is there room for improvement in adverse event reporting in the era of targeted therapies?.J Natl Cancer Inst. 2008; 100: 240-242Google Scholar and dosage recommendations do not usually consider patient perceptions of chronic mild to moderate symptomatic adverse events.29Altzerinakou M.A. Collette L. Paoletti X. Cumulative toxicity in targeted therapies: what to expect at the recommended phase II dose.J Natl Cancer Inst. 2019; 111: 1179-1185Google Scholar In the 1990s, it was common practice to conduct at least two first-in-human (FIH) phase I trials of new cancer therapeutics, typically testing different schedules (for example, continuous versus intermittent dosing), in some instances with subsequent trials identifying the ‘best’ dose and schedule in randomized or ‘pick-the-winner’ designs.30Simon R. Wittes R.E. Ellenberg S.S. Randomized phase II clinical trials.Cancer Treat Rep. 1985; 69: 1375-1381Google Scholar,31Mandrekar S.J. Sargent D.J. Pick the winner designs in phase II cancer clinical trials.J Thorac Oncol. 2006; 1: 5-6Google Scholar The general objective for such designs has been to identify the most promising treatment among multiple competing experimental regimens, although they were rarely powered for formal hypothesis testing. Conversely, the current strategy usually involves a single large multicentric phase I trial (with dozens of sites), including multiple endpoints that may not focus on dose optimization. Furthermore, only one schedule may be tested in phase I and then used for subsequent trials. Dose optimization is then deferred to later trial phases, or after marketing, if conducted at all. Harmonized guidelines were introduced in the 1990s, particularly ICH E432ICH E4 Dose response information to support drug registration. 1994Google Scholar which recommended rigorously defining the dose-response relationship for both efficacy and toxicity. Later recommendations by academic investigators4Booth C.M. Calvert A.H. Giaccone G. Lobbezoo M.W. Seymour L.K. Eisenhauer E.A. Endpoints and other considerations in phase I studies of targeted anticancer therapy: recommendations from the task force on Methodology for the Development of Innovative Cancer Therapies (MDICT).Eur J Cancer. 2008; 44: 19-24Google Scholar,26Postel-Vinay S. Gomez-Roca C. Molife L.R. et al.Phase I trials of molecularly targeted agents: should we pay more attention to late toxicities?.J Clin Oncol. 2011; 29: 1728-1735Google Scholar,27Postel-Vinay S. Collette L. Paoletti X. et al.Towards new methods for the determination of dose limiting toxicities and the assessment of the recommended dose for further studies of molecularly targeted agents – Dose-Limiting Toxicity and Toxicity Assessment Recommendation Group for Early Trials of Targeted Therapies, an European Organisation for Research and Treatment of Cancer-led study.Eur J Cancer. 2014; 50: 2040-2049Google Scholar to define a dose range to be tested, especially for targeted agents, and to better define the RP2D, have generally not been adopted. In 2022, most oncology phase I trials still aim to define a single precise RP2D based on toxicity. Given interpatient variation in drug absorption and metabolism, particularly for oral agents, this single RP2D inevitably means that some patients will be underdosed and, based on current evidence, many (if not most) patients will be overdosed. Clearly, revisions to standard oncology phase I designs are long overdue to improve dosage selection. The benefits of such a strategy are clear, and include reduced morbidity and mortality for patients, reduced costs due to adverse effects, and potentially faster new drug approvals if the need to repeat studies to refine dosage late in development is minimized. For drugs already on the market, post-marketing dose optimization studies have the potential to reduce costs to patients and payers, and are thus unlikely to be conducted by industry, unless required by regulatory authorities. It is important to maintain an efficient development process to ensure rapid access to effective treatments, however, including recognition that exposure to subtherapeutic drug dosages should be minimized, especially in the phase I setting. In 2021, the Food and Drug Administration (FDA) Oncology Center of Excellence announced it will be placing an emphasis on dose optimization for oncology drugs (Project Optimus).14Shah M. Rahman A. Theoret M.R. Pazdur R. The drug-dosing conundrum in oncology-when less is more.N Engl J Med. 2021; 385: 1445-1447Google Scholar,33FDA. Project Optimus. Available at https://www.fda.gov/about-fda/oncology-center-excellence/project-optimus. Accessed April 6, 2022.Google Scholar MDICT 2022 brought together academic experts in oncology phase I trials to develop a practical guide on the design and conduct of phase I trials of anticancer therapeutics; phase II trial design was not addressed. Academic, international experts in phase I methodology who were attending TAT2022 or were MDICT Taskforce members were invited to participate in MDICT. In addition, representatives from the European Medicines Agency and FDA were invited to participate (Table 1). After the meeting, a writing committee was convened who drafted the manuscript and guidelines. The guidelines and the manuscript were circulated to all attendees and voting conducted to ensure agreement. Where necessary, dissension was recorded.Table 1MDICT 2022 attendeesaThe views are those of the authors and not those of the affiliation, institution, or scientific committees.NameAffiliationNameAffiliationFabrice AndreInstitut Gustave Roussy, FranceJoan PetriePatient representativeDaniel AraujobSpeaker, session moderator, or scribe.Hospital de Base, BrazilRuth PlummerNorthern Centre for Cancer CareSusan BatesColumbia University, NY, USASantiago PonceInstitut Gustave Roussy, FranceArnaud BayleInstitut Gustave Roussy, FranceSophie Postel-VinaybSpeaker, session moderator, or scribe.Institut Gustave Roussy, FranceEmiliano CalvobSpeaker, session moderator, or scribe.START Madrid, SpainMark RatainbSpeaker, session moderator, or scribe.University of Chicago, IL, USALuis Castelo-BrancoESMO Scientific and Medical DivisionLesley SeymourCanadian Cancer Trials Group (CCTG), CanadaJohann de BonoInstitute of Cancer Research, University of London, and The Royal MarsdenMirat ShahbSpeaker, session moderator, or scribe.Food and Drug Administration (FDA), USAAlexander DrilonbSpeaker, session moderator, or scribe.Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, NY, USALillian SiuPrincess Margaret Cancer Centre, CanadaElena GarraldabSpeaker, session moderator, or scribe.Vall d´Hebron Institute of Oncology, SpainAnna SpreaficoPrincess Margaret Cancer Centre, CanadaAlastair GreystokebSpeaker, session moderator, or scribe.Northern Centre for Cancer Care, UKAnastasios StathisOncology Institute of Southern Switzerland, EOC, Bellinzona, SwitzerlandPercy IvyNational Cancer Institute, USA Cancer Therapy Evaluation Program Investigational Drug Branch (NCI/CTEP/IDB)Neeltje SteeghsThe Netherlands Cancer Institute, The NetherlandsOlga KholmanskikhEuropean Medical AgencyChristina YapThe Institute of Cancer Research, UKIgnacio MeleroCUN and CIMA. University of Navarra. Pamplona SpainTimothy A. YapUniversity of Texas, MD Anderson Cancer Center, TX, USAGeorge PentheroudakisESMOCIMA, Center for Applied Medical Research; CTEP, Cancer Therapy Evaluation Program; CUN, Clinica Universidad de Navarra; ESMO, European Society for Medical Oncology; IDB, Investigational Drug Branch; MDICT, Methodology for the Development of Innovative Cancer Therapies; NCI, National Cancer Institute.a The views are those of the authors and not those of the affiliation, institution, or scientific committees.b Speaker, session moderator, or scribe. Open table in a new tab CIMA, Center for Applied Medical Research; CTEP, Cancer Therapy Evaluation Program; CUN, Clinica Universidad de Navarra; ESMO, European Society for Medical Oncology; IDB, Investigational Drug Branch; MDICT, Methodology for the Development of Innovative Cancer Therapies; NCI, National Cancer Institute. Although MDICT believes that methodological changes are needed, it recognizes that any general guidelines such as these must also be tailored for different drug classes (e.g. drugs targeting oncogene addicted cancers versus multikinase targeted agents) (Table 2) or patient populations [e.g. patients with central nervous system (CNS) metastasis]. As can be seen in Table 3 the definition of a recommended dosage (RD) requires both a dose escalation (to define an RD range (RDR), as well as a dosage confirmation component, generally requiring a randomized dose ranging trial. This report focuses on practical guidelines for the design and conduct of a dose escalation trial for a new oncology therapeutic to define an RDR (Figure 1) but does not address the design of the dose ranging/confirmation trial which randomizes across the RDR.Table 2Examples of drugs requiring a tailored drug-development planMutant and isoform-selective agentsKinase family-selective agentsMultikinase inhibitor agentsImmune checkpoint inhibitorsExampleSotorasibErdafitinibLenvatinibPembrolizumabOff-target effectsaRefers to both incidence and severity.MinimalModerateHighModerate (however, unpredictable magnitude of effect)Relevance of preclinical dataHighly relevantHighly relevantHighly relevantMay be hard to extrapolate to humansTherapeutic windowWideModerateNarrowUnclearTarget populationHighly selectedSelectedNot clearNot cleara Refers to both incidence and severity. Open table in a new tab Table 3Terminology for endpointsExisting termSuggested new termRationaleTermAbbreviationTermAbbreviationDose-limiting toxicityDLTTreatment-limiting toxicityTLTToxicity may limit not only individual dosage but also duration; factors in non-dose-dependent, chronic or incremental toxicityMaximum tolerated doseMTDRecommended dosage rangeRDRDosage escalation studies will define a range of dosages to be tested in a randomized setting. Although not always required, in some situations dose escalation studies can continue to escalate to what was previously termed as MTDRecommended phase II doseRP2DRecommended dosageRDDosage ranging/dosage confirmation studies will define a recommended dosage for later phase trials (such as phase III or combination studies)Maximum administered doseMADNo change—None—Minimal reproducibly active dosageMRADMinimal reproducibly active dosage—i.e. more than 1 patient with clear tumor shrinkage (minor or partial response) and within the predicted effective range (PER) from non-clinical data if available/robustPhase IDosage escalation studyWill define an RDR. May be feasible to incorporate dose confirmation into the same study for certain drugs/scenarios(May consider a phase I study with expansion cohorts or a separate phase II study)Dosage ranging/dosage confirmation studyWill define an RD, typically by randomizing between 2 or more dosages. It is feasible that RD may need to be separately defined for different patients (e.g. based on tumor burden), genetic aberrations, or tumor sites (e.g. brain) Open table in a new tab There are a number of core, general principles and requirements that apply to the design of any early clinical trial (Table 4).Table 4Core definitions applicable to the design of any early clinical trialAppropriate non-clinical packageTo inform the designTeam basedClinical, statistical, biomarker, pharmacologyConsult with health authoritiesBefore FIH trials and after dose escalationFlexible and adaptive designsParticularly important for novel agents where dosage and trial conduct must be adapted to emerging data; minimize prolonged holds for amendmentsUse all data to refine and adaptAll data, including longitudinal toxicity, efficacy, real time PK and where possible/feasible biomarker/pharmacodynamic dataClear protocol definitionsThe protocol should prospectively define how TLT, RD, or the RDR will be defined. Usage of terms such as ‘considered relevant by investigator’ are discouraged if flexibility can be assured. Reports should summarize deviations.FIH, first-in-human; PK, pharmacokinetics; RD, recommended dosage; RDR, recommended dosage range; TLT, treatment-limiting toxicity. Open table in a new tab FIH, first-in-human; PK, pharmacokinetics; RD, recommended dosage; RDR, recommended dosage range; TLT, treatment-limiting toxicity. Discussing the generation of preclinical data and the optimal non-clinical package is out of the scope of this manuscript, but is well described in the literature and health authority recommendations.5Goodwin R. Giaccone G. Calvert H. Lobbezoo M.W. Eisenhauer E.A. Targeted agents: how to select the winners in preclinical and early clinical studies?.Eur J Cancer. 2012; 48: 170-178Google Scholar,34FDA. Content and format of Investigational New Drug Applications (INDs) for Phase 1 Studies of Drugs, Including Well-Characterized, Therapeutic, Biotechnology-derived Products. Center for Drug Evaluation and Research (CDER).CfBEaRC. 1995; (Available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/content-and-format-investigational-new-drug-applications-inds-phase-1-studies-drugs-including-well. Accessed April 6, 2022.)Google Scholar For novel agents, non-clinical data, preferably conducted in multiple models, are important to inform the design of the trial, including minimal predicted effective dose range, efficacy and toxicity schedule/dose dependency, drug penetrance (including sanctuary sites), pharmacokinetics and potential food effect, pharmacodynamic (PD) markers, including mechanistic and target saturation, potential biomarkers (predictors of response or resistance), differential drug delivery to normal tissue versus tumor, and metabolism and toxicology. These data can provide valuable insights to guide drug development for all oncology drugs, although it seems likely that drugs targeting oncogene-addicted cancers, e.g. sotorasib for KRAS G12C-mutant non-small-cell cancer, might be most impacted, as drugs targeting loss of function mutations often have a narrower therapeutic index (due to off-target effects) than a highly selective drug targeting a mutant oncogene. Despite the importance of non-clinical data, there are well described limitations in extrapolating data due interspecies differences in pharmacokinetics and PDs. For instance, murine models for immunotherapeutics cannot be reliably extrapolated, although in some instances they are informative (for example knock-in models or humanized mouse models).35Olson B. Li Y. Lin Y. Lin E.T. Patnaik A. Mouse models for cancer immunotherapy research.Cancer Discov. 2018; 8: 1358-1365Google Scholar, 36Sanmamed M.F. Chester C. Melero I. Kohrt H. Defining the optimal murine models to investigate immune checkpoint blockers and their combination with other immunotherapies.Ann Oncol. 2016; 27: 1190-1198Google Scholar, 37Voabil P. de Bruijn M. Roelofsen L.M. et al.An ex vivo tumor fragment platform to dissect response to PD-1 blockade in cancer.Nat Med. 2021; 27: 1250-1261Google Scholar In such circumstances, studies in healthy volunteers utilizing a lower than the expected pharmacologically active dosage (phase 0 studies)38de las Heras B. Bouyoucef-Cherchalli D. Reeve L. et al.Healthy volunteers in first-in-human oncology drug development for small molecules.Br J Clin Pharmacol. 2022; 88: 1773-1784Google Scholar or ‘window of opportunity’ studies could be considered to generate relevant data before FIH phase I studies.38de las Heras B. Bouyoucef-Cherchalli D. Reeve L. et al.Healthy volunteers in first-in-human oncology drug development for small molecules.Br J Clin Pharmacol. 2022; 88: 1773-1784Google Scholar, 39Glimelius B. Lahn M. Window-of-opportunity trials to evaluate clinical activity of new molecular entities in oncology.Ann Oncol. 2011; 22: 1717-1725Google Scholar, 40Schmitz S. Duhoux F. Machiels J.P. Window of opportunity studies: do they fulfil our expectations?.Cancer Treat Rev. 2016; 43: 50-57Google Scholar It is recognized, however, that many new oncology therapeutics are not suitable for testing in healthy volunteers, nor in window of opportunity studies in the curative setting. Ensuring patient safety is a fundamental requirement of any clinical trial, and as such the evaluation of toxicity and tolerability are an important endpoint of any study, including dose escalation trials. Nonetheless, in the current era, toxicity and tolerability should limit (but not define) the RDR. Described below are endpoints that should be considered in such decisions•Efficacy: tumor shrinkage, especially when durable, remains the most validated and reliable biomarker of response to date and can be assessed by conventional imaging (e.g. RECIST v1.1); emerging imaging techniques [e.g. positron emission tomography (PET) or radiomics] are also being tested. Other potentially useful biomarkers may include serum markers [e.g. prostate-specific antigen (PSA), cancer antigen 125 (CA-125)] and quantitation of circulating tumor DNA (ctDNA) or cell-free tumor DNA (i.e. liquid biopsies). Although blood-based biomarkers such as ctDNA have not yet been validated as surrogate endpoints, it is hoped" @default.
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• W4298007568 title "Oncology phase I trial design and conduct: time for a change - MDICT Guidelines 2022" @default.
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• W4298007568 doi "https://doi.org/10.1016/j.annonc.2022.09.158" @default.
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