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Background Conventional phase I algorithms for finding a phase-2 recommended dose (P2RD) based on toxicity alone is problematic because the maximum tolerated dose (MTD) is not necessarily the optimal dose with the most desirable risk–benefit trade-off. Moreover, the increasingly common practice of treating an expansion cohort at a chosen MTD has undesirable consequences that may not be obvious. Patients and methods We review the phase I–II paradigm and the EffTox design, which utilizes both efficacy and toxicity to choose optimal doses for successive patient cohorts and find the optimal P2RD. We conduct a computer simulation study to compare the performance of the EffTox design with the traditional 3 + 3 design and the continuous reassessment method. Results By accounting for the risk–benefit trade-off, the EffTox phase I–II design overcomes the limitations of conventional toxicity-based phase I designs. Numerical simulations show that the EffTox design has higher probabilities of identifying the optimal dose and treats more patients at the optimal dose. Conclusions Phase I–II designs, such as the EffTox design, provide a coherent and efficient approach to finding the optimal P2RD by explicitly accounting for risk–benefit trade-offs underlying medical decisions.

Background ABBV-181 is a humanized anti-PD1 monoclonal antibody; dose finding and early safety, PK and pharmacodynamic data have been reported (ESMO18). This report summarizes data from the head and neck squamous cell carcinoma (HNSCC) and non-small cell lung cancer (NSCLC) expansion cohorts in the Ph1 FIH study (NCT03000257). Methods Patients (pts) with previously treated, advanced HNSCC and NSCLC received ABBV-181 IV, 250 mg Q2W or 500 mg Q4W to progression. Response was assessed by RECIST v1.1 and iRECIST. Results As of April 2019, 81 pts were dosed. Table . 1288P n (%) HNSCC n = 41 NSCLC n = 40 Median days on treatment, range 72, 1–407 71, 1–421 Dose: 250 mg/500 mg 31/10 19/21 AE any grade 40 (98) 40 (100) Grade (G) ≥3 AE 23 (56) 27 (67) ABBV-181 related G ≥ 3 AE 4 (10) 3 (7) Immune-mediated AE 15 (37) 15 (37) AE resulting in discontinuation of ABBV-181 Malignant neoplasm progresion General physical health Confusion Pneumonitis a Acute kidney injury a Hypothyroidism a Immune-mediated hepatitis a Disturbance in attention Dysponea Intracranial hemorrhage Neoplasm progression Acute respiratory distress syndrome Upper respiratory tract infection 5 (12) 2 (5) 1 (2) 0 0 0 1 (2) 0 0 0 0 1 (2) 1 (2) 0 9 (22) 3 (7) 0 1 (2) 1 (2) 1 (2) 1 (2) 1 (2) 1 (2) 1 (2) 1 (2) 0 0 1(2) G 5 AEs b Malignant neoplasm progression Acute respiratory distress syndrome Dyspnea Neoplasm progression Upper respiratory tract infection General physical condition abnormal 7 (17) 4 (10) 1 (2) 0 1 (2) 0 1 (2) 7 (18) 6(15) 0 1 (2) 0 1 (2) 0 a ABBV-181 related. b none considered related to ABBV-181. Most frequent G ≥ 1 AE (n): anemia (20), asthenia (20) and fatigue (16). ABBV-181 PK is approximately dose proportional, with comparable dose-normalized exposures at both doses; trough levels resulted in sustained PD-1 saturation on circulating CD4 T cells. Transient decreases in circulating T cells and increased Ki67+ CD8 T cells and serum CXCL9/CXCL10 were observed at both doses. In pts with ≥ 1 post baseline assessment, responses by investigator: 7/40 HNSCC pts (7 partial response, 6 by RECISTv.1.1, 1 by iRECIST), 6/36 NSCLC (5 PR, 1 complete response, all by RECIST v.1.1). 3 HNSCC and 2 NSCLC responders had PD-L1+ tumors. Conclusions Safety, PK and PD data support dosing ABBV-181 at 250 mg Q2W or 500 mg Q4W with expected biological and pharmacodynamic activity for an anti-PD-1 agent. Efficacy data demonstrate clinical activity per RECISTv.1.1 and iRECIST supporting continued development of ABBV-181. Clinical trial identification NCT03000257. Editorial acknowledgement Fatemeh Atashi (AbbVie employee). Legal entity responsible for the study AbbVie Inc. Funding AbbVie Inc. Disclosure A. Italiano: Advisory / Consultancy: Roche, Daiichi Sankyo, ImmuneDesign, Epizyme, Bayer, Lilly; Honoraria (self): Bayer, Daiichi Sankyo, Lilly, Epizyme, Novartis, Roche; Research grant / Funding (self): Roche, Bayer, AstraZeneca/MedImmune, PharmaMar, MSD Oncology, Merck Serono. P. Cassier: Honoraria (self): Novartis, Roche/Genentech, Blueprint Medicines, Amgen; Research grant / Funding (institution): Novartis, Roche/Genentech, Lilly, Blueprint Medicines, Bayer, AstraZeneca, Celgene, Plexxikon, AbbVie, Bristol-Myers Squibb, Merck Serono, Merck, Sharp and Dohme. C. Lin: Advisory / Consultancy: Novartis, Boehringer Ingelheim, Blueprint Medicines; Travel / Accommodation / Expenses: Lilly, Daiichi Sankyo, BeiGene, Novartis; Honoraria (self): Novartis, Roche, Daiichi Sankyo. K. Peltola: Advisory / Consultancy: Orion Pharma, BMS, MSD, Pfizer, Ipsen and Roche; Shareholder / Stockholder / Stock options: Faron Pharmaceuticals; Speaker Bureau / Expert testimony: BMS, Pfizer, MSD; Speaker Bureau / Expert testimony: Ipsen; Travel / Accommodation / Expenses: Roche and BMS. A. Gazzah: Travel / Accommodation / Expenses: Boehringer, Novartis, Pfizer, Roche. E. Calvo: Advisory / Consultancy: Novartis, Nanobiotix, Janssen-Cilag, PsiOxus, Seattle Genetics, EUSA Pharma, AbbVie, Celgene, AstraZeneca, Guidepoint Global, Roche/Genentech, GLG, Pfizer, Servier, Amcure; Speaker Bureau / Expert testimony: Novartis; Research grant / Funding (self): AstraZeneca, BeiGene, Novartis, START, Oncoart Associated, ; Leadership role: President and Founder of Foundation Intheos. D. Tosi: Advisory / Consultancy: Biomarin ; Research grant / Funding (self): Novartis, Astellas, Janssen; Travel / Accommodation / Expenses: Janssen, Pfizer, and Astellas Pharma, Nutricia and Amicus. B. Gao: Advisory / Consultancy: MSD. L. warburton: Travel / Accommodation / Expenses: MSD, Merck. M. Tanner: Advisory / Consultancy: Roche, Novartis and Pfizer; Speaker Bureau / Expert testimony: Roche, Novartis, Pfizer and Amgen. S. Englert: Full / Part-time employment: AbbVie Inc.; Shareholder / Stockholder / Stock options: AbbVie Inc. S. Lambert: Full / Part-time employment: AbbVie Inc.; Shareholder / Stockholder / Stock options: AbbVie Inc. A. Parikh: Shareholder / Stockholder / Stock options: AbbVie Inc.; Full / Part-time employment: AbbVie Inc. D. Afar: Shareholder / Stockholder / Stock options: AbbVie Inc.; Full / Part-time employment: AbbVie Inc. G. Vosganian: Shareholder / Stockholder / Stock options: AbbVie Inc.; Full / Part-time employment: AbbVie Inc. V. Moreno: Advisory / Consultancy: Merck; Travel / Accommodation / Expenses: Regeneron/Sanofi; Research grant / Funding (self): Medscape/Bayer. All other authors have declared no conflicts of interest.

Background Checkpoint inhibitors (CPIs) have transformed treatment of many malignancies. However, to date, response to checkpoint blockade in unselected gastrointestinal (GI) cancers has been disappointing. Tumours which display a non-T-cell inflamed phenotype such as mismatch repair proficient (MMRp) oesophagogastric (OG) and colorectal cancers (CRC) respond less frequently to CPIs. Changes in tumour expression of antigens and increased immune infiltrate are associated with improved response to CPIs. Epigenetic modulation of tumours using HDAC inhibitors can lead to increased tumour antigen presentation, immune cell infiltrates and thereby may increase the chance of response to immunotherapy. Trial design EMERGE is designed to evaluate the safety and efficacy of domatinostat, a selective class 1 histone deacetylase inhibitor in combination with avelumab, an anti-PD-L1 monoclonal antibody in patients with previously treated, inoperable or metastatic MMRp OG and CRC. The trial is conducted in 2 stages: Phase IIA will establish a safe and tolerated dose of domatinostat plus avelumab using a 3 + 3 dose finding design and escalating doses of domatinostat will be examined, dosing of avelumab will remain constant. The phase IIB will use a Simon two stage optimal design to assess efficacy of the combination in achieving radiological response according to RECIST v1.1. The primary endpoint of the phase IIB is best objective response rate (ORR) at 6 months. To rule out an ORR of 5% in the CRC cohort, while aiming for 20%, 1/10 and 4/29 responses are required in the 1st and 2nd stages respectively. To rule out an ORR of 15% in the OG cohort while aiming for 35%, 2/9 and 9/34 responses are required in the 1st and 2nd stages respectively with a 1-sided alpha of 5% and 80% power. Secondary endpoints are DoOR, PFS, OS, DCR, safety and tolerability. Exploratory objectives will investigate dynamic changes in expression of tumour associated antigens and immune infiltrates in baseline and on-treatment biopsies and correlate baseline tumour characteristics and circulating biomarkers with tumour response and survival. Recruitment commenced in January 2019, 83 patients will be recruited over 3 years. (ClinTrials.gov. ID: NCT03812796). Legal entity responsible for the study Royal Marsden Hospital NHS Foundation Trust. Funding Royal Marsden Hospital NHS Foundation Trust, 4SC. Disclosure M. Hubank: Research grant / Funding (self), Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (self), Research grant / Funding (institution): Roche Diagnostics; Research grant / Funding (self), Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (self), Research grant / Funding (institution): Guardant Health; Research grant / Funding (self), Research grant / Funding (institution): Celgene; Research grant / Funding (self), Research grant / Funding (institution): Eli Lilley. I. Chau: Honoraria (self): Eli-Lilly; Research grant / Funding (institution): Eli-Lilly; Research grant / Funding (institution): Janssen-Cilag; Research grant / Funding (institution): Sanofi Oncology; Research grant / Funding (institution): Merck-Serono; Advisory / Consultancy: Eli Lilly; Advisory / Consultancy: Bristol Meyers Squibb; Advisory / Consultancy: MSD; Advisory / Consultancy: Bayer; Advisory / Consultancy: Roche; Advisory / Consultancy: Merck-Serono; Advisory / Consultancy: Five Prime Therapeutics; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Oncologie International; Advisory / Consultancy: Pierre Fabre. N. Starling: Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Pfizer; Travel / Accommodation / Expenses: AstraZeneca; Travel / Accommodation / Expenses: BMS; Travel / Accommodation / Expenses: Eli Lilly; Travel / Accommodation / Expenses: Merck; Travel / Accommodation / Expenses: Roche; Honoraria (self): AstraZeneca; Honoraria (self): Eli Lilly; Honoraria (self): Merck; Honoraria (self): Servier; Advisory / Consultancy: Pfizer; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Servier. D. Cunningham: Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Celgene; Research grant / Funding (institution): MedImmune; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): 4SC; Research grant / Funding (institution): Clovis; Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): Janssen; Research grant / Funding (institution): Merck. All other authors have declared no conflicts of interest.

Background More than 95% of published phase I trials have used the 3 + 3 design to identify the dose to be recommended for phase II trials. However, the statistical community agrees on the limitations of the 3 + 3 design compared with model-based approaches. Moreover, the mechanisms of action of targeted agents strongly challenge the hypothesis that the maximum tolerated dose constitutes the optimal dose, and more outcomes including clinical and biological activity increasingly need to be taken into account to identify the optimal dose. Patients and methods We review key elements from clinical publications and from the statistical literature to show that the 3 + 3 design lacks the necessary flexibility to address the challenges of targeted agents. Results The design issues raised by expansion cohorts, new definitions of dose-limiting toxicity and trials of combinations are not easily addressed by the 3 + 3 design or its extensions. Conclusions Alternative statistical proposals have been developed to make a better use of the complex data generated by phase I trials. Their applications require a close collaboration between all actors of early phase clinical trials.

Background ICONIC is a single arm phase 2 trial investigating the safety and efficacy of 4 cycles pre-operative and 4 cycles post-operative FLOT-A in resectable OGA. We report results from the safety run-in phase and early translational biomarker data. Methods Eligible pts were enrolled into the 3 + 3 design dose finding stage. Standard dose FLOT was administered with 10mg/kg iv avelumab q2 weeks (dose level 0). Dose limiting toxicities (DLTs) were assessed for 28d. Biopsies were taken at baseline and post cycle 2. Results At data cut-off (12/4/19) 6 pts were enrolled and completed pre-operative treatment. 1/6 pts experienced a DLT (chest pain during 5FU infusion), and dose level 0 was established as the safe dose for the efficacy stage of the trial. During pre-operative FLOT-A all pts experienced at least one grade 1-2 adverse event (AE), most commonly diarrhoea (5/6 pts), fatigue, nausea, peripheral neuropathy and hypokalaemia (all 4/6 pts); 3/6 pts experienced at least one grade 3-4 AE: neutropenia and elevated liver enzymes (1 pt), thrombotic event (1 pt) and cardiac chest pain (1 pt). 4/6 pts reported any grade chest pain and underwent cardiac work up: 1 episode was due to PE, 1 of likely GI origin and 2 cardiac in nature, which then recurred in one pt who was re-exposed to FLOT without avelumab. 3/6 pts completed 4 cycles pre-operative FLOT-A: 1 pt discontinued avelumab due to diarrhoea, 2 pts discontinued FLOT-A due to cardiac chest pain and switched to a regimen without 5FU. 5 pts have undergone surgery at data cut-off, without unexpected complications. Immunofluorescence shows changes of CD8-, memory- and regulatory T cell infiltrates between baseline and on-treatment biopsies, and detailed results will be presented. Conclusions This is the first data showing that FLOT can be combined with a PD-L1-inhibitor with FLOT-A having a manageable safety profile at dose level 0 (standard dose FLOT + 10mg/kg avelumab). As chest pain of variable aetiologies was observed in 4/6 patients this will be closely monitored and assessed during the efficacy phase. No unexpected complications have been observed during surgery following FLOT-A treatment. Clinical trial identification 2016-003306-13. Legal entity responsible for the study Royal Marsden Hospitals NHS Foundation Trust. Funding Royal Marsden Hospital NHS Foundation Trust Institute of Cancer Research, Merck Pharmaceuticals. Disclosure M. Davidson: Travel / Accommodation / Expenses: Celgene. N. Starling: Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Merck; Honoraria (institution): AstraZeneca. I. Chau: Advisory / Consultancy: Eli-Lilly; Advisory / Consultancy: BMS; Advisory / Consultancy: MSD; Advisory / Consultancy: Bayer; Advisory / Consultancy: Roche; Advisory / Consultancy: Merck-Serono; Advisory / Consultancy: Five Prime Therapeutics; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Oncologie International; Advisory / Consultancy: Pierre Fabre; Research grant / Funding (institution): Eli-Lilly; Research grant / Funding (institution): Janssen Cilag; Research grant / Funding (institution): Sanofi Oncology; Research grant / Funding (institution): Merck-Serono; Honoraria (institution): Eli-Lilly. D. Cunningham: Research grant / Funding (institution): Amgen; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Celgene; Research grant / Funding (institution): Merck-Serono; Research grant / Funding (institution): Medimmune; Research grant / Funding (institution): Merrimack; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Sanofi. D. Morganstein: Advisory / Consultancy: MSD; Advisory / Consultancy: BMS; Advisory / Consultancy: Roche. M.D. Forster: Research grant / Funding (institution): Merck; Honoraria (institution): Merck. M. Gerlinger: Research grant / Funding (institution): Merck; Research grant / Funding (institution): BMS. All other authors have declared no conflicts of interest.

Poster Development of a new promising rescue agent for high-dose methotrexate (HDMTX) treatment in osteosarcoma - a safety and dose-finding study.