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Supplementary Table S1. TUMAPs contained in IMA950 and associated source antigens. Supplementary Table S2. Statistical analysis underlying the recruitment of 20 immune evaluable patients per cohort. Supplementary Table S3. Reasons for HLA-A*02 positive patients not entering the clinical trial. Supplementary Figure S1. Study schedule. Supplementary Figure S2. Exemplary gating strategy used for the primary multimer assay. Supplementary Figure S3. Exemplary immune responses in patients as determined by multimer assay after in vitro sensitization. Supplementary Figure S4. Apparent diffusion coefficient (ADC) in Cohort 1 at each of the four scan points.

Additional detail of materials and methods used. Figure 1. Flow chart detailing dose escalation schema. Figure 2. MVA-EBNA1/LMP2 Vaccination does not alter broad subsets of immune cells. Figure 3. EBNA1 antibody response before and after MVA-EL vaccination. Table 1 MHC class I and II restricted epitope peptides in EBNA1 and LMP2 used as targets in ELIspot assays. Table 2 Summary of EBNA1- and LMP2-specific immune responses stimulated by vaccination of UK NPC patients.

Purpose: To perform a two-cohort, phase I safety and immunogenicity study of IMA950 in addition to standard chemoradiotherapy and adjuvant temozolomide in patients with newly diagnosed glioblastoma. IMA950 is a novel glioblastoma-specific therapeutic vaccine containing 11 tumor-associated peptides (TUMAP), identified on human leukocyte antigen (HLA) surface receptors in primary human glioblastoma tissue.Experimental Design: Patients were HLA-A*02–positive and had undergone tumor resection. Vaccination comprised 11 intradermal injections with IMA950 plus granulocyte macrophage colony-stimulating factor (GM-CSF) over a 24-week period, beginning 7 to 14 days prior to initiation of chemoradiotherapy (Cohort 1) or 7 days after chemoradiotherapy (Cohort 2). Safety was assessed according to NCI CTCAE Version 4.0 and TUMAP-specific T-cell immune responses determined. Secondary observations included progression-free survival (PFS), pretreatment regulatory T cell (Treg) levels, and the effect of steroids on T-cell responses.Results: Forty-five patients were recruited. Related adverse events included minor injection site reactions, rash, pruritus, fatigue, neutropenia and single cases of allergic reaction, anemia and anaphylaxis. Two patients experienced grade 3 dose-limiting toxicity of fatigue and anaphylaxis. Of 40 evaluable patients, 36 were TUMAP responders and 20 were multi-TUMAP responders, with no important differences between cohorts. No effect of pretreatment Treg levels on IMA950 immunogenicity was observed, and steroids did not affect TUMAP responses. PFS rates were 74% at 6 months and 31% at 9 months.Conclusions: IMA950 plus GM-CSF was well-tolerated with the primary immunogenicity endpoint of observing multi-TUMAP responses in at least 30% of patients exceeded. Further development of IMA950 is encouraged. Clin Cancer Res; 22(19); 4776–85. ©2016 AACR.See related commentary by Lowenstein and Castro, p. 4760

Purpose: Epstein–Barr virus (EBV) is associated with several cancers in which the tumor cells express EBV antigens EBNA1 and LMP2. A therapeutic vaccine comprising a recombinant vaccinia virus, MVA-EL, was designed to boost immunity to these tumor antigens. A phase I trial was conducted to demonstrate the safety and immunogenicity of MVA-EL across a range of doses.Experimental Design: Sixteen patients in the United Kingdom (UK) with EBV-positive nasopharyngeal carcinoma (NPC) received three intradermal vaccinations of MVA-EL at 3-weekly intervals at dose levels between 5 × 107 and 5 × 108 plaque-forming units (pfu). Blood samples were taken at screening, after each vaccine cycle, and during the post-vaccination period. T-cell responses were measured using IFNγ ELISpot assays with overlapping EBNA1/LMP2 peptide mixes or HLA-matched epitope peptides. Polychromatic flow cytometry was used to characterize functionally responsive T-cell populations.Results: Vaccination was generally well tolerated. Immunity increased after vaccination to at least one antigen in 8 of 14 patients (7/14, EBNA1; 6/14, LMP2), including recognition of epitopes that vary between EBV strains associated with different ethnic groups. Immunophenotypic analysis revealed that vaccination induced differentiation and functional diversification of responsive T-cell populations specific for EBNA1 and LMP2 within the CD4 and CD8 compartments, respectively.Conclusions: MVA-EL is safe and immunogenic across diverse ethnicities and thus suitable for use in trials against different EBV-positive cancers globally as well as in South-East Asia where NPC is most common. The highest dose (5 × 108 pfu) is recommended for investigation in current phase IB and II trials. Clin Cancer Res; 20(19); 5009–22. ©2014 AACR.

3103 Background: CDC7, a protein with key roles in regulating cell-cycle progression is often over-expressed in malignant cells, particularly those with TP53 mutations. LY3143921, an orally administered ATP-competitive CDC7 inhibitor, demonstrated favorable pre-clinical anti-cancer activity in colorectal cancer (CRC) and squamous non-small cell lung cancer (sqNSCLC), particularly in TP53 mutant models. Methods: Phase Ia (dose escalation) recruited patients (pts) with advanced solid tumors enriched for malignancies associated with TP53 mutation. Pts received LY3143921 OD or BD continuously on a 21-day schedule, using an accelerated 3+3 escalation design, starting at 30 mg OD. Phase Ib recruited pts with CRC or sqNSCLC treated continuously at RP2D, or pts with other advanced tumors treated at RP2D on days 1-3 every 7 days. Radiological assessment was performed every 2 cycles initially. Pts in phase Ib could consent to pre- and on-treatment skin +/- tumor biopsies. Primary objectives: assess safety/tolerability and determine MTD and RP2D of LY3143921. Secondary objectives: evaluate preliminary efficacy and pharmacokinetic (PK) profile of LY3143921. Exploratory objective: correlate efficacy to baseline molecular/genetic alterations, including TP53 mutation and measure markers including pMCM2 in pre- and on- treatment tumor and skin samples. Results: 68 pts were recruited and 67 treated (38 phase Ia, 29 phase Ib). Most frequent drug-related CTCAEs (all grades): nausea (75%), orthostatic hypotension (50%), vomiting (47%), fatigue (45%) & diarrhea (44%). Grade 3-4 LY3143921 related AEs occurred in 17 pts. In phase Ia 8 DLTs occurred in 5 pts (G3 nausea, vomiting, fatigue & hyponatraemia and G2 diarrhea, anorexia & lethargy). RP2D was 360 mg BD (continuous non-fasted dosing schedule). 37 pts were evaluable for radiological response with no complete or partial responses seen, and stable disease (SD) was observed in 24 pts (65%). In phase Ia 3 pts achieved long term SD of 1, 2.5 and 3+ years duration. For evaluable pts treated in phase Ib, SD was seen in 8/12 CRC pts, 1/2 sqNSCLC pts and 2/2 pts treated with the intermittent schedule (median duration 15 weeks, range 6-18+). 2 pts remain on-study. Recruitment ceased due to lack of radiological response according to RECIST. Dose-dependent increases in LY3143921 exposure (Cmax & AUC0-24) were seen. IHC analyses of skin biopsies demonstrated reductions in pMCM2, indicating on-target activity of LY3143921. Pre-clinical testing of combination with standard of care agents is ongoing. Additional PD and PK data will be presented. Conclusions: LY3143921 is well tolerated, exhibits dose-dependent increases in plasma exposure and demonstrates evidence of target inhibition. Significant monotherapy clinical activity was not observed; further analyses should investigate potential predictive response biomarkers and rational combination approaches. Clinical trial information: NCT03096054.

Purpose: To perform a two-cohort, phase I safety and immunogenicity study of IMA950 in addition to standard chemoradiotherapy and adjuvant temozolomide in patients with newly diagnosed glioblastoma. IMA950 is a novel glioblastoma-specific therapeutic vaccine containing 11 tumor-associated peptides (TUMAP), identified on human leukocyte antigen (HLA) surface receptors in primary human glioblastoma tissue. Experimental Design: Patients were HLA-A*02–positive and had undergone tumor resection. Vaccination comprised 11 intradermal injections with IMA950 plus granulocyte macrophage colony-stimulating factor (GM-CSF) over a 24-week period, beginning 7 to 14 days prior to initiation of chemoradiotherapy (Cohort 1) or 7 days after chemoradiotherapy (Cohort 2). Safety was assessed according to NCI CTCAE Version 4.0 and TUMAP-specific T-cell immune responses determined. Secondary observations included progression-free survival (PFS), pretreatment regulatory T cell (Treg) levels, and the effect of steroids on T-cell responses. Results: Forty-five patients were recruited. Related adverse events included minor injection site reactions, rash, pruritus, fatigue, neutropenia and single cases of allergic reaction, anemia and anaphylaxis. Two patients experienced grade 3 dose-limiting toxicity of fatigue and anaphylaxis. Of 40 evaluable patients, 36 were TUMAP responders and 20 were multi-TUMAP responders, with no important differences between cohorts. No effect of pretreatment Treg levels on IMA950 immunogenicity was observed, and steroids did not affect TUMAP responses. PFS rates were 74% at 6 months and 31% at 9 months. Conclusions: IMA950 plus GM-CSF was well-tolerated with the primary immunogenicity endpoint of observing multi-TUMAP responses in at least 30% of patients exceeded. Further development of IMA950 is encouraged. Clin Cancer Res; 22(19); 4776–85. ©2016 AACR. See related commentary by Lowenstein and Castro, p. 4760

Background: LY3143921 hydrate is an orally administered ATP-competitive inhibitor of CDC7, a serine/threonine kinase regulatory protein overexpressed in many cancer types. Following successful preclinical studies, a first-in-human phase I trial of LY3143921 hydrate was initiated in patients with advanced solid tumors. We report the pharmacokinetics of LY3143921 hydrate in this ongoing Cancer Research UK study. Methods: Eligible patients were those with histologically proven advanced/metastatic solid tumors for which no further standard therapy options were available. Patients were administered LY3143921 hydrate as a single oral dose on Day -7, followed by daily administration (dose levels 30-270mg) or twice daily administration (dose levels 150 and 180mg) on study days 1-21. Drug administration was carried out with patients in either a fasted or fed state as shown in Table 1. Samples for pharmacokinetic analysis were obtained following a single drug dose on Day -7 at 0.25, 0.5, 1, 2, 4, 6, 8, 12, 24, 48 and 72 hours. Additional samples were taken on Day 1 of treatment at doses of 150 and 180mg to investigate potential differences in pharmacokinetics in fed versus fasted states (Day -7 fed versus Day 1 fasted). Samples were analysed using a validated LC-MS/MS assay with a LLOQ of 0.1 ng/mL. Pharmacokinetic analysis was carried out using Certara WinNonlin software (version 6.3) to determine Cmax, Tmax, area under the curve (AUC), plasma half-life, apparent volume of distribution (Vz/F) and apparent clearance (CL/F) of LY3143921 hydrate. Assessment of dose proportionality was made by assessment of graphical plots of AUC versus dose level. Table 1:Summary of LY3143921 hydrate pharmacokinetic data on Day -7 (single dose data)Dose level (mg)Number of patientsFed / fastedCmax (ng/mL)AUC0-24h (ng/mL.h)Half-life (h)CL/F (L/h)Vz/F (L)301Fasted184.44253.3570.1339601Fasted175.05022.42119.44181201Fasted113031382.1738.212018010Fasted144 - 8142505 ± 9904.2 ± 4.079.5 ± 23.9475 ± 4732704Fasted474 - 15126374 ± 14753.4 ± 1.843.8 ± 8.9226 ± 1581503Fed334 - 6321997 ± 4964.4 ± 1.977.2 ± 16.4514 ± 2881803Fed492 - 16002994 ± 9793.2 ± 0.864.2 ± 19.4290 ± 112 Results: Table 1 provides a summary of the pharmacokinetic parameters obtained on Day -7 following a single dose of LY3143921 hydrate (data expressed as range or mean ± SD as appropriate). Overall dose-dependent increases in exposure (based on Cmax and AUC) were observed. There was a general trend towards higher Cmax and AUC values following administration in a fasted versus fed state following a dose of 180 mg, but this was inconsistent across the limited number of patients for who these data were available on both Day -7 (fed) and Day 1 (fasted). Conclusion: The pharmacokinetic data generated to date are consistent with dose dependent increases in drug exposure observed with a flat dosing regimen for LY3143921 hydrate. Citation Format: Shelby Barnett, Melanie Griffin, Richard H. Wilson, Elizabeth R. Plummer, Jeffry T. Evans, Victoria Coyle, Sally Clive, Lisa Godfrey, Nicola Dobbs, Lesley McGuigan, Sue Brook, Gavin Halbert, Gareth J. Veal. Pharmacokinetics of the CDC7 inhibitor LY3143921 hydrate, a CRUK first-in-human phase I trial in patients with advanced solid tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3014.

Purpose: Epstein–Barr virus (EBV) is associated with several cancers in which the tumor cells express EBV antigens EBNA1 and LMP2. A therapeutic vaccine comprising a recombinant vaccinia virus, MVA-EL, was designed to boost immunity to these tumor antigens. A phase I trial was conducted to demonstrate the safety and immunogenicity of MVA-EL across a range of doses. Experimental Design: Sixteen patients in the United Kingdom (UK) with EBV-positive nasopharyngeal carcinoma (NPC) received three intradermal vaccinations of MVA-EL at 3-weekly intervals at dose levels between 5 × 107 and 5 × 108 plaque-forming units (pfu). Blood samples were taken at screening, after each vaccine cycle, and during the post-vaccination period. T-cell responses were measured using IFNγ ELISpot assays with overlapping EBNA1/LMP2 peptide mixes or HLA-matched epitope peptides. Polychromatic flow cytometry was used to characterize functionally responsive T-cell populations. Results: Vaccination was generally well tolerated. Immunity increased after vaccination to at least one antigen in 8 of 14 patients (7/14, EBNA1; 6/14, LMP2), including recognition of epitopes that vary between EBV strains associated with different ethnic groups. Immunophenotypic analysis revealed that vaccination induced differentiation and functional diversification of responsive T-cell populations specific for EBNA1 and LMP2 within the CD4 and CD8 compartments, respectively. Conclusions: MVA-EL is safe and immunogenic across diverse ethnicities and thus suitable for use in trials against different EBV-positive cancers globally as well as in South-East Asia where NPC is most common. The highest dose (5 × 108 pfu) is recommended for investigation in current phase IB and II trials. Clin Cancer Res; 20(19); 5009–22. ©2014 AACR.

TPS3167 Background: CDC7 is a protein with key roles in DNA replication initiation, the intra-S-phase checkpoint and M-phase completion. CDC7 is over-expressed in malignant compared to non-malignant cells, particularly those with TP53 mutations, making it an attractive therapeutic target. LY3143921 hydrate is an orally administered ATP-competitive CDC7 inhibitor. Pre-clinical studies in colorectal cancer (CRC) and squamous non-small cell lung cancer (sqNSCLC) demonstrate favourable anti-cancer activity, particularly in squamous NSCLC and in CRC with TP53 null and missense mutations. We hypothesise that solid tumours mutated in TP53 will be sensitive to LY3143921 therapy. Methods: This is a first-in-human, phase I trial of LY3143921 hydrate (LY3143921) monotherapy given twice daily, continuously on a 21 day schedule until disease progression, patient (pt) withdrawal or unacceptable toxicity (NCT03096054). Eligible pts have histologically proven advanced/metastatic solid tumours for which no further standard therapy exists and WHO PS 0-1. Pts have regular clinical assessment and tumour imaging every 2 cycles. Phase Ia (dose escalation) is recruiting in a 3+3 design following 3 initial single patient cohorts (starting dose 30 mg OD), enriching for patients with malignancies associated with p53 mutations (CRC, sqNSCLC, high grade serous ovarian, squamous cell oesophageal, squamous cell head & neck, urothelial, pancreatic and triple negative breast cancer). Recruitment to cohort 6 (180 mg BD) is ongoing. On determination of the maximum tolerated dose (MTD) and recommended phase II dose and schedule (RP2D), 2 expansion cohorts (≤ 25 pts each) of patients with CRC and sqNSCLC will be evaluated. Primary objectives: assess safety and tolerability of LY3143921, determine MTD and RP2D. Secondary objectives: evaluate preliminary efficacy and PK profile of LY3143921. All pts will have archival tumour tissue retrospectively analysed, while patients in phase Ib will also have pre- and on-treatment tumour biopsies. Evaluation of potential predictive and pharmacodynamic biomarkers including p53 mutations, phosphorylated MCM2, cyclin B1 and molecular subgroups of target tumours will be included. Clinical trial information: NCT03096054.