Pediatric CancerPhase 1/2ESMARTNCT02813135
European Proof-of-Concept Therapeutic Stratification Trial of Molecular Anomalies in Relapsed or Refractory Tumors
A Phase 1/2 study testing Ribociclib, Topotecan and Temozolomide in people with Pediatric Cancer, run by Gustave Roussy, Cancer Campus, Grand Paris at 23 sites in 6 countries.
Trial summary
This proof-of-concept platform trial is designed to cover the targeting of several survival pathways in oncogenesis that are currently not adequately employed for pediatric patients in Europe (Geoerger 2017; Geoerger 2019). The aims of the trial are: 1. Read more about this study
- Who is it for?
- Ages Up to 18 years
- Conditions the study is for
- Pediatric Cancer
- What is being tested?
- Ribociclib, Topotecan and Temozolomide
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 472 participants
- Where
- 23 sitesin 6 countries
- Study dates
- 3 Aug 2016to Feb 2031
- Phase
- Phase 1/2
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages Up to 18 years
- All sexes
- No healthy volunteers
- Child, Adult
Who may be able to join
- Patients must be diagnosed with a haematologic or solid tumor malignancy that has progressed despite standard therapy, or for which no effective standard therapy exists.
- Age < 18 years at inclusion; patients 18 years and older may be included after discussion with the sponsor if they have a pediatric recurrent/refractory malignancy.
- Patient must have had advanced molecular profiling (i.e. WES/WGS +/- RNAseq) of their recurrent or refractory tumor i.e. at the time of disease progression/relapse; exceptionally patients with advanced molecular profiling at diagnosis may be allowed.
- Evaluable or measurable disease as defined by standard imaging criteria for the patient's tumor type (RECIST v1.1, RANO criteria for patients with HGG, INRC criteria for patients with NB, Leukemia criteria, etc.).
- Patients with relapsed or refractory leukemia are eligible for this study.
- Performance status: Karnofsky performance status (for patients >12 years of age) or Lansky Play score (for patients ≤12 years of age) ≥ 70%. Patients who are unable to walk because of paralysis or stable neurological disability, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.
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- Life expectancy ≥ 3 months
- Adequate organ function:
- Hematologic criteria (Leukemia patients are excluded from hematological criteria):
- Peripheral absolute neutrophil count (ANC) ≥ 1000/μL(unsupported)
- Platelet count ≥ 100,000/μL (unsupported)
- Hemoglobin ≥ 8.0 g/dL (transfusion is allowed)
- Cardiac function:
- Shortening fraction (SF) >29% (>35% for children < 3 years) and left ventricular ejection fraction (LVEF) ≥50% at baseline, as determined by echocardiography (mandatory only for patients who have received cardiotoxic therapy).
- Absence of QTc prolongation (QTc > 450 msec on baseline ECG, using the Fridericia correction [QTcF formula]) or other clinically significant ventricular or atrial arrhythmia.
- Renal and hepatic function:
- Serum creatinine ≤ 1.5 x upper limit of normal (ULN) for age
- Total bilirubin ≤ 1.5 x ULN
- Alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase (SGPT) ≤ 2,5 x ULN; aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase/SGOT ≤ 2,5 x ULN except in patients with documented tumor involvement of the liver who must have AST/SGOT and ALT/SGPT ≤ 5 x ULN.
- Able to comply with scheduled follow-up and with management of toxicity.
- Females of childbearing potential must have a negative serum or urine pregnancy test within 72 hours prior to initiation of treatment. Sexually active women of childbearing potential must agree to use acceptable and appropriate contraception during the study and for at least 6 months after the last study treatment administration. Sexually active males patients must agree to use condom during the study and for at least 6 months (7 months for arm J) after the last study treatment administration. Acceptable contraception are defined in CTFG Guidelines "Recommendations related to contraception and pregnancy testing in clinical trials"
- For all oral medications patients must be able to comfortably swallow capsules (except for those for which an oral solution is available); nasogastric or gastrostomy feeding tube administration is allowed only if indicated.
- Written informed consent from parents/legal representative, patient, and age-appropriate assent before any study-specific screening procedures are conducted according to local, regional or national guidelines.
- Patient affiliated to a social security regimen or beneficiary of the same according to local requirements.
Who cannot join
- Patients with symptomatic central nervous system (CNS) metastases who are neurologically unstable or require increasing doses of corticosteroids or local CNS-directed therapy to control their CNS disease. Patients on stable doses of corticosteroids for at least 7 days prior to receiving study drug may be included.
- Impairment of gastrointestinal (GI) function or GI disease that may significantly alter drug absorption of oral drugs (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, or malabsorption syndrome).
- Clinically significant, uncontrolled heart disease (including history of any cardiac arrhythmias, e.g., ventricular, supraventricular, nodal arrhythmias, or conduction abnormality, unstable ischemia,congestive heart failure within 12 months of screening)
- Active viral hepatitis or known human immunodeficiency virus (HIV) infection or any other uncontrolled infection.
- Presence of any ≥ CTCAE grade 2 treatment-related toxicity with the exception of alopecia, ototoxicity or peripheral neuropathy.
- Systemic anticancer therapy within 21 days of the first study dose or 5 times its half-life, whichever is less.
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- Previous myeloablative therapy with autologous hematopoietic stem cell rescue within 8 weeks of the first study drug dose
- Allogeneic stem cell transplant within 3 months prior to the first study drug dose. Patients receiving any agent to treat or prevent graft-versus host disease (GVHD) post bone marrow transplant are not eligible for this trial.
- Radiotherapy (non-palliative) within 21 days prior to the first dose of drug (or within 6 weeks for therapeutic doses of MIBG or craniospinal irradiation).
- Major surgery within 21 days of the first dose. Gastrostomy, ventriculo-peritoneal shunt, endoscopic ventriculostomy, tumor biopsy and insertion of central venous access devices are not considered major surgery, but for these procedures, a 48 hour interval must be maintained before the first dose of the investigational drug is administered.
- Currently taking medications with a known risk of prolonging the QT interval or inducing Torsades de Pointes (Refer to Appendix 8).
- Currently taking medications that are mainly metabolized by CYP3A4/5, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or the drug transporters Pgp (MDR1), BCRP, OATP1B1, OATP1B3, OCT1 and OCT2 and have a low therapeutic index that cannot be discontinued at least 7 days or 5 x reported elimination half-life prior to start of treatment with any of the investigational drugs and for the duration of the study (Refer to Appendix 9).
- Known hypersensitivity to any study drug or component of the formulation.
- Pregnant or nursing (lactating) females.
- Vaccinated with live, attenuated vaccines within 4 weeks of the first dose of study drug.
Trial locations and contacts
23 sites in 6 countries. Contact the study team or a site near you to ask about taking part.
23 sites in 6 countries
France10 sites, 10 recruiting
- Recruiting
CHU Angers
Angers, 49933
Claire Brisset
- Recruiting
CHU Pellegrin
Bordeaux, 33076
Stephane Ducassou
- Recruiting
Centre Oscar Lambret
Lille, 59020
Sandra Raimbault
- Recruiting
Centre Léon Bérard
Lyon, 69373
Nadège Corradini
- Recruiting
Hôpital de La Timone
Marseille, 13385
Nicolas André
- Recruiting
CHU Nantes
Nantes, 44093
Morgane Cleirec
- Recruiting
Institut Curie
Paris, 75005
Isabelle Aerts
- Recruiting
Hôpital Armand Trousseau
Paris, 75012
Arnaud Petit
- Recruiting
Hôpital de Hautepierre
Strasbourg, 67098
Natacha Entz-Werle
- Recruiting
Gustave Roussy
Villejuif, Val de Marne, 94805
Pablo Berlanga, MD
United Kingdom5 sites, 5 recruiting
- Recruiting
Birmingham Children's Hospital
Birmingham, B4 6NH
Gerard Millen
- Recruiting
Great Ormond Street Hospital
London, WC1N 3JH
Giuseppe Barone
- Recruiting
Royal Manchester Children's Hospital
Manchester, M13 9WL
Guy Makin
- Recruiting
Royal Victoria Infirmary
Newcastle, NE1 4LP
Quentin Campbell-Hewson
- Recruiting
Pediatric and Adolescent Oncology The Royal Marsden Hospital
Sutton
Lynley Marshall, MD, +44 208 661 3678, Lynley.Marshall@icr.ac.uk
Italy3 sites, 3 recruiting
- Recruiting
Istituto Giannina Gaslini
Genova, 16147
Teresa Battaglia
- Recruiting
Fondazione IRCCS Istituto Nazionale dei Tumori
Milan
Michela Casanova, MD, +39 02 23 90 25 94, Michela.Casanova@istitutotumori.mi.it
- Recruiting
Ospedale Infantile Regina Margherita
Torino, 10126
Franca Fagioli
Spain3 sites, 3 recruiting
- Recruiting
Vall d'Hebron
Barcelona, 08035
Raquel Hladun
- Recruiting
Hospital del Nino Jesus
Madrid, 28009
Alba Rubio
- Recruiting
Hospital Universitario La Fe
Valencia, 46026
Adela Cañete
Denmark1 site, 1 recruiting
- Recruiting
Rigshospitalet
Copenhagen, 2100
Karsten Nyson, MD, +45 35 45 08 09, karsten.nysom@regionh.dk
Netherlands1 site
- Active, not recruiting
Prinses Maxima Centrum
Utrecht, 3584 EA
About this study
This proof-of-concept platform trial is designed to cover the targeting of several survival pathways in oncogenesis that are currently not adequately employed for pediatric patients in Europe (Geoerger 2017; Geoerger 2019).
The aims of the trial are:
- To determine the recommended phase II dose (RP2D) of a specific anticancer agent and/or a relevant combination in a pediatric population, to document its tolerability and
- To explore first signals of activity in a molecularly enriched study population.
Read the detailed description
The first molecular profiling protocols have been launched in Europe (MOSCATO-01 (Geoerger 2014), MAPPYACTS, INFORM, iTHER, SM-PAEDS, etc.) determining multiple actionable alterations in pediatric recurrent cancers. Increasingly, stratified approaches are being implemented to enrich clinical trials of molecularly targeted agents and possibly improve outcomes in specific populations i.e. a molecularly enriched/predictive biomarker-driven approach. The diversity and heterogeneity of the detected molecular alterations and the low number of pediatric patients mandate an adapted, innovative trial design for the attributed treatment options in order to satisfy the current unmet medical need.
This basket trial is designed to cover the targeting of several survival pathways in oncogenesis that are currently not adequately employed for pediatric patients in Europe.
- Conditions
- Pediatric Cancer
- Being tested
- Ribociclib, Topotecan, Temozolomide, Everolimus, Adavosertib
- Keywords
- Children, Adolescents, Young adults, Recurrent malignancies, Refractory malignancies
- Medical subject headings
- Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
RibociclibDrug
Also called Kisqali, LEE011
TopotecanDrug
Also called Hycamtin
TemozolomideDrug
Also called Temodar
EverolimusDrug
Also called Afinitor, votubia
AdavosertibDrug
Also called AZD1775
CarboplatinDrug
Also called Paraplatin
OlaparibDrug
Also called Lynparza
IrinotecanDrug
Also called Camptosar, CPT-11
VistusertibDrug
Also called AZD2014
NivolumabDrug
Also called Opdivo
CyclophosphamideDrug
Also called Cytoxan
SelumetinibDrug
Also called Koselugo
EnasidenibDrug
Also called Idhifa
LirilumabDrug
Also called BMS-986015
FadraciclibDrug
Also called CYC065
CytarabineDrug
Also called Arabinosylcytosine, Cytosar-U
DexamethasoneDrug
Also called Decadron, Dexasone, Diodex, Hexadrol
CeralasertibDrug
Also called AZD6738
FutibatinibDrug
Also called Tas-120
CapmatinibDrug
Also called Tabrecta, INC280
AvelumabDrug
Also called BAVENCIO
PeposertibDrug
CapivasertibDrug
Also called TRUQAP, AZD5363
VinorelbineDrug
Also called Navelbine
| Study group | Role | What they receive |
|---|---|---|
| Arm A. Ribociclib + Topotecan and Temozolomide | Experimental | Topotecan iv QD and temozolomide capsules orally QD Days 1 to 5; Ribociclib capsules or oral solution orally QD from Day 6 to 20 of a 28 day cycle. Receives: Drug: Ribociclib; Drug: Topotecan; Drug: Temozolomide |
| Arm B. Ribociclib + Everolimus | Experimental | Ribociclib capsules or oral solution orally QD for 21 days of each 28 day cycle; Everolimus orodispersible tablets orally QD for 28 days. Receives: Drug: Ribociclib; Drug: Everolimus |
| ARM C. Adavosertib + Carboplatin | Experimental | Adavosertib capsules orally BID 3 days on / 4 days off in week 1; Carboplatin iv QD AUC 5 on Day 1 of a 21 day cycle. Receives: Drug: Adavosertib; Drug: Carboplatin |
| Arm D. Olaparib + Irinotecan | Experimental | Olaparib tablets orally BID on Day 1-10 of a 21 day cycle Irinotecan iv QD on Day 4-8 of a 21 day cycle. Receives: Drug: Olaparib; Drug: Irinotecan |
| Arm E. Vistusertib single agent | Experimental | Vistusertib tablets orally BID 2 days on/5 days off per week of a 28 day cycle. Receives: Drug: Vistusertib |
| Arm F. Vistusertib + Topotecan and Temozolomide | Experimental | Topotecan iv QD and temozolomide capsules orally QD Days 1 to 5; Vistusertib tablets orally BID 3 days on/4 days off per week of a 28 day cycle. Receives: Drug: Topotecan; Drug: Temozolomide; Drug: Vistusertib |
| Arm G. Nivolumab + Cyclophosphamide +/- Radiotherapy | Experimental | Nivolumab iv QD every 2 weeks of a 28 day cycle (Days 1 and 15); Cyclophosphamide tablets or oral solution orally BID, 1 week on/1 week off; Palliative irradiation/radiofrequency/cryotherapy starting 2 weeks after the first nivolumab injection. Receives: Drug: Nivolumab; Drug: Cyclophosphamide |
| Arm H. Selumetinib + Vistusertib | Experimental | Selumetinib capsules twice daily on a continous administration. Vistusertib orally twice daily on an intermittent schedule : 2 days on / 5 days off per week of a 28 day cycle. Receives: Drug: Vistusertib; Drug: Selumetinib |
| Arm I. Enasidenib | Experimental | Enasidenib tablets or sprinkle solution orally on a continuous dosing once daily (QD) per 28 day cycle. Receives: Drug: Enasidenib |
| Arm J. Lirilumab + Nivolumab | Experimental | Nivolumab iv QD on Day 1 and 15 of a 28 day cycle; Lirilumab iv QD on Day 1 of a 28 day cycle Receives: Drug: Nivolumab; Drug: Lirilumab |
| Arm K. Fadraciclib (CYC065) + Temozolomide | Experimental | Fadraciclib iv QD on Day 1 (+/- 15) of a 28 day cycle Temozolomide capsules orally QD on Day 1-5 of a 28 day cycle Receives: Drug: Temozolomide; Drug: Fadraciclib |
| Arm L. Fadraciclib (CYC065) + Cytarabine | Experimental | Fadraciclib iv QD on Day 1 (+/- 15) of a 28 day cycle Cytarabine iv or sc on Day 2-5 and Day 8-11 of a 28 day cycle Receives: Drug: Fadraciclib; Drug: Cytarabine |
| Arm M. Ribociclib + Everolimus +/- Dexamethasone | Experimental | Ribociclib capsules or tablets orally QD on Day 1-21 of a 28 day cycle. Everolimus dispersible tablets orally QD on a continuous dosing per 28 day cycle.
For patients with leukemia and lymphoma:
Dexamethasone orally or iv on Day 1-7 of each 28 day cycle. For patients with ALL, AML and Non-Hodgkin Lymphoma (NHL), Intrathecal chemotherapy will be administered additionally as per standard practice depending on CNS status. Receives: Drug: Ribociclib; Drug: Everolimus; Drug: Dexamethasone |
| Arm N. Ceralasertib (AZD6738) + Olaparib | Experimental | Olaparib tablets orally BID per 28 days Ceralasertib tablets QD or BID per 28 day cycle Receives: Drug: Olaparib; Drug: Ceralasertib |
| Arm O. Futibatinib (TAS-120) | Experimental | Futibatinib tablets orally on a continuous dosing QD per 28 day cycle Receives: Drug: Futibatinib |
| Arm P. Capmatinib (INC280) + Everolimus | Experimental | Capmatinib tablets orally on a continuous dosing BID per 28 day cycle. Everolimus dispersible tablets orally QD on a continuous dosing per 28 day cycle. Receives: Drug: Everolimus; Drug: Capmatinib |
| Arm Q. Peposertib + Avelumab and Metronomic Temozolomide | Experimental | Peposertib tablets orally on a continuous dosing BID per 28 day cycle Avelumab IV QD on Day 1 and Day 15 of a 28 day cycle Temozolomide capsules orally QD 5 days/week of a 28 day cycle Receives: Drug: Temozolomide; Drug: Avelumab; Drug: Peposertib |
| Arm R. Capivasertib + metronomic Vinorelbine | Experimental | Capivasertib tablets orally BID on Day 1-4/week (4 days on/3 days off, every week) of a 28 day cycle.
Vinorelbine soft capsules orally once daily on Day 1, 3 and 5/week of a 28 day cycle. Receives: Drug: Capivasertib; Drug: Vinorelbine |
What is being measured
The primary outcome is the main question the study is designed to answer.
Recommended phase II dose (RP2D)
Defined as the adult recommended dose (adjusted for weight or BSA) if toxicity and/or PK profiling are similar in children and in adults, or a higher dose, providing it is below or equal to the maximum tolerated dose (MTD)
Measured: During the first cycle
Maximum Tolerated Dose (MTD)
The MTD will be defined as the dose associated with or closest to 25% of Dose Limiting Toxicities (DLTs)
Measured: During the first cycle
Objective Response Rate (ORR)
Defined as the proportion of participants who achieved a confirmed complete response (CR) or partial response (PR) assessed by investigators.
In patients with leukemia, ORR is defined as the percentage of patients attaining CR, CRi or CRp.
Measured: During treatment period
Secondary outcomes (3)
Pharmacokinetics (PK)
To characterize single or multiple-dose PK of the agent(s)
Measured: Depending on the treatment arm
Progression Free Survival (PFS)
Defined as the time from treatment initiation until the date of first documented progression (clinically or radiologically) or death from any cause. Patients alive and free of progression at the cut-off date will be censored at the last assessment date.
Measured: From treatment initiation until the date of first documented progression or death
Evaluation of duration of response (DoR)
Defined as the time period between the first documented response (complete response (CR) or partial response (PR)) and the time of progression, according to RECIST v1.1, RANO criteria for patients with HGG, INRC criteria for patients with NB, etc.
Measured: Between the first document response and the time of first documented progression
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted24 Jun 2016 (estimated)
- Study start3 Aug 2016
- Primary completionFeb 2031 (estimated)
- Study completionFeb 2031 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (7)Papers the sponsor has linked to this study.
- Other trials for Pediatric CancerStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 472 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Gustave Roussy, Cancer Campus, Grand Paris
- Sponsor type
- University, hospital or other
- Collaborators
- National Cancer Institute, France, Fight Kids Cancer, Fondation ARC
- Responsible party
- Sponsor
- Investigators
- Birgit Geoerger, MD, Study chair, Gustave Roussy, Cancer Campus, Grand Paris
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02813135
- Sponsor's protocol ID
- 2016-000133-40
- Other IDs
- 2016/2396, 2024-514791-40-00, 2016
- Acronym
- ESMART
- Status last verified
- Jul 2026
- First submitted
- 16 Jun 2016
- Last updated
- 10 Jul 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Lee WG, Kim ES. Precision Oncology in Pediatric Cancer Surgery. Hematol Oncol Clin North Am. 2026 Oct;40(5):895-931. doi: 10.1016/j.hoc.2026.05.022.
PubMed 42686334Rubio-San-Simon A, Marshall LV, Karamouza E, Andre N, Abbou S, Rubino J, Nebchi S, Aerts I, Thebaud E, Brisset C, Ducassou S, Le Teuff G, Geoerger B. Phase I/II Study of the CDK2/9 Inhibitor Fadraciclib in Combination with Chemotherapy in Children with Advanced Malignancies: Arm K of the AcSe-ESMART Trial. Target Oncol. 2026 Mar;21(2):199-211. doi: 10.1007/s11523-026-01208-1. Epub 2026 Mar 16.
PubMed 41838385Berlanga P, Pierron G, Lacroix L, Chicard M, Adam de Beaumais T, Marchais A, Harttrampf AC, Iddir Y, Larive A, Soriano Fernandez A, Hezam I, Chevassus C, Bernard V, Cotteret S, Scoazec JY, Gauthier A, Abbou S, Corradini N, Andre N, Aerts I, Thebaud E, Casanova M, Owens C, Hladun-Alvaro R, Michiels S, Delattre O, Vassal G, Schleiermacher G, Geoerger B. The European MAPPYACTS Trial: Precision Medicine Program in Pediatric and Adolescent Patients with Recurrent Malignancies. Cancer Discov. 2022 May 2;12(5):1266-1281. doi: 10.1158/2159-8290.CD-21-1136.
PubMed 35292802Morscher RJ, Brard C, Berlanga P, Marshall LV, Andre N, Rubino J, Aerts I, De Carli E, Corradini N, Nebchi S, Paoletti X, Mortimer P, Lacroix L, Pierron G, Schleiermacher G, Vassal G, Geoerger B. First-in-child phase I/II study of the dual mTORC1/2 inhibitor vistusertib (AZD2014) as monotherapy and in combination with topotecan-temozolomide in children with advanced malignancies: arms E and F of the AcSe-ESMART trial. Eur J Cancer. 2021 Nov;157:268-277. doi: 10.1016/j.ejca.2021.08.010. Epub 2021 Sep 17.
PubMed 34543871Bautista F, Paoletti X, Rubino J, Brard C, Rezai K, Nebchi S, Andre N, Aerts I, De Carli E, van Eijkelenburg N, Thebaud E, Corradini N, Defachelles AS, Ducassou S, Morscher RJ, Vassal G, Geoerger B. Phase I or II Study of Ribociclib in Combination With Topotecan-Temozolomide or Everolimus in Children With Advanced Malignancies: Arms A and B of the AcSe-ESMART Trial. J Clin Oncol. 2021 Nov 10;39(32):3546-3560. doi: 10.1200/JCO.21.01152. Epub 2021 Aug 4.
PubMed 34347542Pasqualini C, Rubino J, Brard C, Cassard L, Andre N, Rondof W, Scoazec JY, Marchais A, Nebchi S, Boselli L, Grivel J, Aerts I, Thebaud E, Paoletti X, Minard-Colin V, Vassal G, Geoerger B. Phase II and biomarker study of programmed cell death protein 1 inhibitor nivolumab and metronomic cyclophosphamide in paediatric relapsed/refractory solid tumours: Arm G of AcSe-ESMART, a trial of the European Innovative Therapies for Children With Cancer Consortium. Eur J Cancer. 2021 Jun;150:53-62. doi: 10.1016/j.ejca.2021.03.032. Epub 2021 Apr 20.
PubMed 33892407Rossoni C, Bardet A, Geoerger B, Paoletti X. Sequential or combined designs for Phase I/II clinical trials? A simulation study. Clin Trials. 2019 Dec;16(6):635-644. doi: 10.1177/1740774519872702. Epub 2019 Sep 20.
PubMed 31538815