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Key Points BET inhibitor RO6870810+venetoclax+rituximab has a manageable safety profile in relapsed/refractory diffuse large B-cell lymphoma.A clinically relevant signal of antitumor activity serves as a proof of principle for this combination, warranting further study., Visual Abstract, Bromodomain and extraterminal (BET) proteins are transcriptional activators for multiple oncogenic processes in diffuse large B-cell lymphoma (DLBCL), including MYC, BCL2, E2F, and toll-like receptor signaling. We report results of a phase 1b dose-escalation study of the novel, subcutaneous BET inhibitor RO6870810 (RO) combined with the BCL-2 inhibitor venetoclax, and rituximab, in recurrent/refractory DLBCL. RO was delivered for 14 days of a 21-day cycle, whereas venetoclax was delivered continuously. A 3 + 3 escalation design was used to determine the safety of the RO+venetoclax doublet; rituximab was added in later cohorts. Thirty-nine patients were treated with a median of 2.8 cycles (range, 1-11). Dose-limiting toxicities included grade 3 febrile neutropenia, grade 4 diarrhea, and hypomagnesemia for the doublet; and grade 3 hyperbilirubinemia and grade 4 diarrhea when rituximab was added. The doublet maximum tolerated dose (MTD) was determined to be 0.65 mg/kg RO+600 mg venetoclax; for RO+venetoclax+rituximab, the MTDs were 0.45 mg/kg, 600 mg, and 375 mg/m2, respectively. The most frequent grade 3 and 4 adverse events were neutropenia (28%) and anemia and thrombocytopenia (23% each). Responses were seen in all cohorts and molecular subtypes. Sustained decreases in CD11b on monocytes indicated pharmacodynamic activity of RO. Overall response rate according to modified Lugano criteria was 38.5%; 48% of responses lasted for ≥180 days. Complete response was observed in 8 patients (20.5%). Optimization of the treatment schedule and a better understanding of predictors of response would be needed to support broader clinical use. This trial is registered on www.clinicaltrials.gov as NCT03255096.

Background Bromodomain and extra-terminal (BET) proteins are epigenetic readers that can drive carcinogenesis and therapy resistance. RO6870810 is a novel, small-molecule BET inhibitor. Methods We conducted a Phase 1 study of RO6870810 administered subcutaneously for 21 or 14 days of 28- or 21-day cycles, respectively, in patients with the nuclear protein of the testis carcinoma (NC), other solid tumours, or diffuse large B-cell lymphoma (DLBCL) with MYC deregulation. Results Fatigue (42%), decreased appetite (35%) and injection-site erythema (35%) were the most common treatment-related adverse events. Pharmacokinetic parameters demonstrated linearity over the dose range tested and support once-daily dosing. Pharmacodynamic assessments demonstrated sustained decreases in CD11b levels in peripheral blood mononuclear cells. Objective response rates were 25% (2/8), 2% (1/47) and 11% (2/19) for patients with NC, other solid tumours and DLBCL, respectively. Responding tumours had evidence of deregulated MYC expression. Conclusions This trial establishes the safety, favourable pharmacokinetics, evidence of target engagement and preliminary single-agent activity of RO6870810. Responses in patients with NC, other solid tumours and DLBCL provide proof-of-principle for BET inhibition in MYC-driven cancers. The results support further exploration of RO6870810 as monotherapy and in combinations. Clinical trials registration NCT01987362.

Introduction Multiple myeloma (MM), relapsed or refractory (R/R) to standard of care therapies, represents a treatment indication with a significant unmet clinical need. Transcriptional activation of c-MYC through bromodomain and extra-terminal (BET) proteins contributes to the malignant phenotype of the disease. RO is a novel thienodiazepine, small molecule, non-covalent inhibitor of the BET family of bromodomains. Preclinical studies with BET inhibitors have demonstrated significant single agent in vivo activity in myeloma, accompanied by down-regulation of MYC and MYC target gene expression. We report results of a monotherapy phase 1b study of RO in R/R MM (NCT03068351). Methods Eligible pts with R/R MM included those treated with at least three prior lines of multiple myeloma therapy, including a proteasome inhibitor and an immunomodulatory agent, or who are double-refractory to a proteasome inhibitor and an immunomodulatory agent. Primary refractory myeloma pts were only allowed in the dose escalation portion of the study. In the dose escalation (part I), pts received subcutaneous (SC) escalating doses of RO (0.30-0.65 mg/kg) in a standard 3 + 3 design on days 1 - 14 of 21-day cycles to determine both the maximum tolerated dose (MTD) and recommended dose (RD). In the expansion cohort (part II), pts received RO as monotherapy at the RD level. Primary endpoint was safety (DLT, MTD, RD) and secondary endpoints included evaluation of pharmacodynamics (CD11b expression) and preliminary efficacy assessments based on IMWG criteria. Results Between June 2017 and April 2019, a total of 24 pts were enrolled in the US, the UK and Australia. 13 pts were enrolled in the dose escalation and 11 pts in the expansion part. The median age of pts was 65.5 years (range: 46 - 82 years). The study population was heavily pretreated with a median of 6 (3-9) prior therapies. Pts were refractory to immunomodulatory drugs (63%), proteasome inhibitors (46%), both (46%), or daratumumab (42%). 57 total cycles were administered, with a median of 2 (1-6) cycles per patient (pt). Two DLTs occurred in one pt in the 0.65 mg/kg cohort (thrombocytopenia grade 4, angina pectoris grade 3). The recommended dose is 0.65 mg/kg. Grade 3 treatment emergent AEs in ≥ 5% of pts were thrombocytopenia (11 pts [45.8%]), anemia (7 pts [29.2%]), fatigue (3 pts [12.5%]), injection site reaction, malaise, decreased appetite, and hyponatremia (2 pts [8.3%] each). 3 pts (12.5%) experienced a total of 4 AEs leading to discontinuation of the study treatment; these AEs were left ventricular dysfunction, fatigue, sepsis, and staphylococcal bacteremia (the latter two AEs occurred in the same pt). A total of 8 deaths (33.3%) were reported in the study, all as a consequence of progressive disease. The best overall response recorded was partial response in 4 pts (16.7 %), 3 of whom having received prior daratumumab. One pt experienced a minimal response, and stable disease was reported in 12 out of 24 (50%). There was no evidence for a dose-related increase in efficacy, though data are very limited (Table). Responses obtained during treatment with RO6870810 were short-lived and lasted for appr. 6 weeks. As evidence of target engagement, pharmacodynamic profiling demonstrated decreases in CD11b levels in peripheral blood mononuclear cells (Figure). Conclusions Treatment of MM pts with the BET inhibitor RO as monotherapy resulted in a high incidence of cytopenias, especially grade 3-4 thrombocytopenia and grade 3 anemia. However, none of these events led to study drug discontinuation. Cytopenias are a known side effect of BET inhibitors, with thrombocytopenia frequently reported as a DLT in various pt populations. Pts with NUT carcinoma, other solid tumors, or diffuse large B-cell lymphoma treated in the First in Man trial of RO had a low rate of cytopenias, indicating that the underlying disease and the extensive pre-treatment in MM may play a role in their occurrence (publication submitted). In this heavily pretreated R/R MM population, we have established 0.65 mg/kg as the recommended monotherapy dose. Pharmacodynamics effects were evident at this dose, but as monotherapy in this R/R MM cohort, response rates were low and less durable. Future drug combination approaches may result in an improved benefit / risk ratio. Disclosures Ramasamy: Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Consultancy, Research Funding, Speakers Bureau; Takeda: Consultancy, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Oncopeptides: Consultancy, Honoraria. Nooka:Adaptive Technologies: Consultancy, Honoraria; Oncopeptides: Consultancy, Honoraria; Spectrum Pharmaceuticals: Consultancy; GlaxoSmithKline: Consultancy, Honoraria, Other: Personal Fees: Travel/accomodations/expenses, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria; Karyopharm Therapeutics, Adaptive technologies: Consultancy, Honoraria, Research Funding. Quach:Amgen, Celgene, karyopharm, GSK, Janssen Cilag, Sanofi.: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline, Karyopharm, Amgen, Celgene, Janssen Cilag: Consultancy; GlaxoSmithKline, Karyopharm, Amgen, Celgene, Janssen Cilag: Honoraria; Amgen, sanofi, celgene, Karyopharm, GSK: Research Funding. Htut:City of Hope Medical Center: Current Employment. Popat:AbbVie: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Other: Travel support, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria; GSK: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Liedtke:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Caelum: Membership on an entity's Board of Directors or advisory committees; Adaptive: Membership on an entity's Board of Directors or advisory committees. Tuchman:Caelum: Honoraria; Sanofi: Honoraria, Research Funding; Amgen: Research Funding; Janssen: Research Funding; Oncopeptides: Consultancy; Roche: Research Funding; Karyopharm: Honoraria, Research Funding; Celgene: Honoraria, Research Funding, Speakers Bureau. Hertzberg:Gilead: Membership on an entity's Board of Directors or advisory committees; MSD: Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria; BMS: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support of parent study and funding of editorial support. Demario:BioNTech SE: Current Employment, Current equity holder in publicly-traded company; Hoffmann-La Roche Ltd.: Current equity holder in publicly-traded company, Ended employment in the past 24 months. Nueesch:Hoffmann-La Roche Ltd.: Current Employment, Current equity holder in publicly-traded company. Chesne:Hoffmann-La Roche Ltd.: Current Employment, Current equity holder in publicly-traded company. Franjkovic:Hoffmann-La Roche Ltd.: Current Employment, Current equity holder in publicly-traded company. Lechner:Roche Diagnostics GmbH: Current Employment, Current equity holder in publicly-traded company. Kornacker:Hoffmann-La Roche Ltd.: Current Employment, Current equity holder in publicly-traded company.

Bromodomain and extra-terminal (BET) proteins can drive carcinogenesis and therapy resistance. RO6870810 (RO) is a novel, small-molecule BET inhibitor. We conducted a study in 32 patients with relapsed/refractory acute myeloid leukemia and hypomethylating agent-refractory myelodysplastic syndrome (NCT02308761). Pharmacodynamic assessments showed decreases in CD11b in peripheral blood mononuclear cells at RO concentrations above 120 ng/mL. Treatment emergent adverse events were generally mild and the most frequent were fatigue, injection site reactions, diarrhea, decreased appetite and nausea. There were no treatment-related deaths. Potential drug-related dose limiting toxicities included decreased appetite, congestive cardiac failure, hypertension, fatigue, increased conjugated bilirubin and increased gamma glutamyltransferase. One AML patient achieved complete remission after withdrawal from study. Eleven AML patients experienced SD. For AML, the median OS was 72.0 days. For MDS, two patients experienced SD. Further development of RO as monotherapy was discontinued due to lack of efficacy, but combinations with other agents are under consideration.

Background Neoantigens arising from mutations in cancer cell DNA are important targets for T cell mediated anti-tumor immunity. NEO-PV-01 is a personal neoantigen vaccine of up to 20 peptides (14–35 amino acids) based on a patient‘s HLA profile and bioinformatic analysis of tumor neoantigens. We report here clinical and immune data for NT-002, a Phase 1b study of NEO-PV-01 with pemetrexed, carboplatin, and pembrolizumab as first-line therapy for advanced non-squamous NSCLC. Methods Patients received 12 weeks of pembrolizumab (Q3W) plus carboplatin and pemetrexed. NEO-PV-01 was then given subcutaneously in a prime-boost format spanning 12 weeks, followed by pembrolizumab for up to 2 years. The primary objective was safety; secondary objectives included overall response rate (ORR), clinical benefit rate (CBR), progression-free survival (PFS), and overall survival (OS). Comprehensive immune assessments were performed with peripheral blood mononuclear cells and biopsies collected at weeks 0, 12, and 24. Results A total of 38 patients initiated study treatment (ITT population); 21 patients received at least 1 dose NEO-PV-01 (vaccinated group, VAX). The demographics included 61% women and 82% with a smoking history. The regimen was well tolerated consistent with the pembrolizumab plus pemetrexed/carboplatin safety profile, with transient low-grade injection site reactions present in VAX (29%). Treatment-related study discontinuations were rare (2/38). The ORR/CBR for the ITT and VAX were 37%/69% and 57%/95%, respectively. Median PFS was 7.2 months (95% CI: 5.6,16.8) for both the ITT and VAX, and median OS 16.8 months (95% CI: 11.6, NR) for both groups. Interim immune analysis on 8 patients revealed neoantigen-specific CD4+ and CD8+ T cell responses against 48% of vaccine peptides. T cell responses were durable at 52 weeks and exhibited a memory phenotype with cytolytic potential. Epitope spread was observed in 3 of 5 patients analyzed thus far. Further, assessments of immune and molecular correlates of clinical response identified both tumor mutation burden and baseline levels of T cell infiltration in tumor as highly predictive of durable PFS (p= 0.005 and p= 7.2e-07 (for CD8), respectively). Additional correlates of clinical outcomes with molecular and immunologic responses will be presented. Conclusions NEO-PV-01 in combination with pembrolizumab and carboplatin/pemetrexed is feasible, has a good safety profile, and induces de novo immune responses in first line non-squamous NSCLC. The association of baseline disease characteristics to prolonged PFS suggests future patient enrichment strategies for evaluation of this novel regimen in a phase 2 trial. Trial Registration NCT03380871 Ethics Approval The clinical study is conducted in accordance with ethical principles founded in the Declaration of Helsinki and approved by the local institutional review board and health authorities.

BackgroundNeoantigens are tumor-specific antigens that are important in the anti-tumor immune response. These antigens are not subject to central immune tolerance and are therefore potentially more immunogenic than tumor-associated antigens. Here, we present the results of a proof-of-concept, pre-clinical study with multiple successful patient material runs generating a neoantigen-specific T-cell product (BNT221/NEO-PTC-01) using leukaphereses from patients with ovarian cancer. These products contain specific T-cell responses targeting multiple neoantigens from each individual patient‘s tumor.MethodsLeukapheresis and tumor biopsy samples were obtained from multiple patients with ovarian cancer and metastatic melanoma cancer under IRB approval using the N16NEON protocol at the Netherlands Cancer Institute subsidized by BioNTech US. Patient-specific neoantigens from the patient‘s biopsy were predicted using our RECON® bioinformatics platform and the best scoring neoantigens were encoded into synthetic peptides or mRNA molecules and were utilized in our ex vivo stimulation protocol, NEO-STIM®, which is used to prime, activate, and expand memory and de novo T-cell responses from both the CD4+ and the CD8+ compartment. High-throughput flow cytometric analysis was performed to characterize the specificity and functionality (cytokine production and cytolytic capacity) of the induced T-cell responses.ResultsNEO-STIM generates T-cell products specific to neoantigens from the peripheral blood of patients. Data will be presented showing the successful induction of 2–10 CD8+ and 4–13 CD4+ T-cell responses per patient, generated using peripheral blood mononuclear cells from patients with ovarian cancer using our NEO-STIM platform. We extensively characterized these T-cell responses and demonstrate that these responses are polyfunctional, specific and have the capacity to degranulate. T cells in the induced product are of effector memory and central memory phenotypes.ConclusionsNEO-STIM is a novel platform that generates ex vivo T-cell responses to high-quality neoantigen targets. Efforts are ongoing to upscale the manufacturing process and move this into a phase I study. BNT221, the neoantigen-specific T cell product generated from this process, is a potent adoptive cell therapy targeting multiple immunogenic neoantigens in patients with metastatic ovarian cancer.Ethics ApprovalLeukapheresis and tumor biopsy samples were obtained from multiple patients with ovarian cancer and metastatic melanoma cancer under IRB approval using the N16NEON protocol at the Netherlands Cancer Institute subsidized by BioNTech US.

Background: Neoantigens arising from mutations in cancer cell DNA are important targets for T cell-mediated anti-tumor immunity. NEO-PV-01 is a personal neoantigen vaccine of up to 20 peptides (14-35 amino acids) based on a patient's HLA profile and bioinformatic analysis of tumor neoantigens. We report here relationships between baseline tumor characteristics, immune response, and clinical outcomes from NT-002, a Phase 1b study of NEO-PV-01 with pemetrexed, carboplatin, and pembrolizumab as first-line therapy for advanced non-squamous NSCLC (NCT03380871). The primary objective of this study was to evaluate the safety of the combination. Materials: Serial blood and tumor biopsies were collected at: i) prior to treatment, ii) after 12 weeks of chemotherapy-pembrolizumab treatment, and iii) after completion of NEO-PV-01 vaccination. Tumor biopsies were characterized by immunohistochemistry for immune and tumor markers, gene expression, whole-exome and TCR sequencing, and single-cell analysis. Antigen-specific responses were measured in blood samples by IFNγ ELISpot, intracellular cytokine staining and functional phenotyping by FACS. Results: A total of 38 patients initiated study treatment (ITT); 21 patients received at least 1 dose of NEO-PV-01 (VAX). The regimen was well-tolerated and consistent with the pembrolizumab plus pemetrexed/carboplatin safety profile. The overall response rate (ORR)/clinical benefit rate (CBR) for the ITT and VAX were 37%/69% and 57%/95%, respectively. Median PFS was 7.2 months (95% CI: 5.6,16.8) for both the ITT and VAX, and median OS 16.8 months (95% CI: 11.6, NR) for both groups. Immune analysis on 12 patients with available samples revealed neoantigen-specific CD4+ and CD8+ T cell responses in all patients tested with an average of 55% of vaccine peptides generating an immune response post-vaccination. Vaccine-induced immune responses were mutant-specific and durable at 52-week treatment timepoint. T cell responses were polyfunctional, as evident by secretion of multiple cytokines (TNFα, IL2, IFNγ), and were activated memory cells with a cytotoxic phenotype. Epitope spread was observed in 7 of 11 patients analyzed thus far. Comprehensive analysis by gene expression, ctDNA and TCR repertoire analysis demonstrated correlations to extended PFS. Additional data on single-cell sequencing of neoantigen-specific T cells and tumor biopsies and correlates to clinical outcomes will be presented. Conclusions: NEO-PV-01 in combination with pembrolizumab and carboplatin/pemetrexed has a good safety profile and induces de novo immune responses in first-line non-squamous NSCLC. The association of baseline disease characteristics to prolonged PFS suggests future patient enrichment strategies for evaluation of this novel regimen in a phase 2 trial. Citation Format: Mark M. Awad, Ramaswamy Govindan, David R. Spigel, Edward B. Garon, Victoria Kohler, Rohit Vyasamneni, Suchitra Ramesh, Tracey E. Sciuto, Melissa A. Moles, Jennifer Tepper, Amy Wanamaker, Zakaria S. Khondkar, John Srouji, Jesse Z. Dong, Kristen N. Balogh, Asaf Poran, Meghan E. Bushway, Mark DeMario, Richard B. Gaynor, Lakshmi Srinivasan. A personal neoantigen vaccine NEO-PV-01 in combination with chemotherapy and pembrolizumab induces broad de novo immune responses in first-line non-squamous NSCLC: Associations with clinical outcomes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 73.

Background: Transcriptional activation of c-MYC through bromodomain and extra-terminal (BET) proteins contributes to the malignant phenotype of OC and TNBC. RO is a novel thienodiazepine, small molecule, non-covalent inhibitor of the BET family of bromodomains. BET inhibition may also play a role in immune modulation via downregulation of CD47 and PD-L1. We hypothesized that RO may enhance the clinical potential of A. We report results of a phase 1b study of RO in combination with A in advanced OC and TNBC (NCT03292172). Methods: Patients with advanced OC or TNBC were eligible. In the dose escalation part, pts received subcutaneous escalating doses of RO (0.30, 0.45, 0.65 mg/kg) on days 1 - 14 of 21-day cycles in combination with A at 1200 mg IV on Day 1 of each cycle. In the expansion part, pts received RO at 0.45 mg/kg. Primary objectives were safety, tolerability and preliminary clinical activity of the combination. Results: Between Nov 2017 and Dec 2018, a total of 36 pts were enrolled, 27 pts in the dose escalation and 9 pts in the expansion part at 6 sites in the US, Canada, Denmark and Australia. The median age was 53 (34 - 72) years. 99 total cycles were completed, with a median of 2 (1-14) cycles per pt. During dose escalation, one pt at 0.65 mg/kg + A experienced a DLT of Grade 3 febrile neutropenia. Grade ≥ 3 treatment emergent AEs in ≥ 5% of all pts were immune-related AEs (irAEs) associated with laboratory findings suggestive of secondary hemophagocytic lymphohistiocytosis (HLH), anemia and hyponatremia (11.1% each), abdominal pain, fatigue and small intestinal obstruction (8.3% each), thrombocytopenia, ALT increased and hyperglycemia (5.6% each). Organ toxicities associated with the 4 cases of suspected HLH included fever and febrile neutropenia, myocarditis, encephalitis and pneumonitis; there was no clear correlation between RO exposure and these events. irAEs were observed in an additional 4 pts. AEs leading to treatment discontinuation were reported in 22.2% of pts, with suspected HLH being the most common AE (11.1%). A total of 15 deaths were reported in the study: 9 deaths due to progressive disease, and 6 deaths reported during long-term follow-up where the cause of death was reported as unknown. Two PRs were noted; one each at 0.30 mg/kg + A and at 0.45 mg/kg + A. 15 pts had SD and 14 pts had PD as best response. Median duration of disease control was 93 (95% CI 51-178) days. Response assessment of 5 pts was missing. Conclusions: While suspected HLH/HLH is rare for RO or A given as monotherapy, the safety profile of the combination was considered unacceptable as noted by the high frequency and severity of irAEs including suspected HLH. A limited anti-tumor activity was observed with PR as best overall response in 2 pts. The trial was terminated early due to the unfavorable risk-benefit profile. Citation Format: Stephanie Lheureux, Iben Spangaard, Erika Hamilton, George Au-Yeung, Debra Richardson, Mark DeMario, Emily Labriola-Tompkins, Barbara Brennan, Eveline Nueesch, Evelyne Chesne, Izolda Franjkovic, Katharina Lechner, Martin Kornacker, Geoffrey I. Shapiro. Dose-Finding/Expansion Phase Ib Study to Evaluate the Safety and Activity of BET Inhibitor RO6870810 (RO) and Atezolizumab (A) in Patients (pts) with Advanced Ovarian Cancer (OC) or Triple Negative Breast Cancer (TNBC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB104.

Purpose To determine the maximum-tolerated dose (MTD) and assess safety, pharmacokinetics, pharmacodynamics, and evidence of antitumor activity of RO4929097, a gamma secretase inhibitor of Notch signaling in patients with advanced solid malignancies. Patients and Methods Patients received escalating doses of RO4929097 orally on two schedules: (A) 3 consecutive days per week for 2 weeks every 3 weeks; (B) 7 consecutive days every 3 weeks. To assess reversible CYP3A4 autoinduction, the expanded part of the study tested three dosing schedules: (B) as above; modified A, 3 consecutive d/wk for 3 weeks; and (C) continuous daily dosing. Positron emission tomography scans with [18F]fluorodeoxyglucose (FDG-PET) were used to assess tumor metabolic effects. Results Patients on schedule A (n = 58), B (n = 47), and C (n = 5; expanded cohort) received 302 cycles of RO4929097. Common grade 1 to 2 toxicities were fatigue, thrombocytopenia, fever, rash, chills, and anorexia. Transient grade 3 hypophosphatemia (dose-limiting toxicity, one patient) and grade 3 pruritus (two patients) were observed at 27 mg and 60 mg, respectively; transient grade 3 asthenia was observed on schedule A at 80 mg (one patient). Tumor responses included one partial response in a patient with colorectal adenocarcinoma with neuroendocrine features, one mixed response (stable disease) in a patient with sarcoma, and one nearly complete FDG-PET response in a patient with melanoma. Effect on CYP3A4 induction was observed. Conclusion RO4929097 was well tolerated at 270 mg on schedule A and at 135 mg on schedule B; the safety of schedule C has not been fully evaluated. Further studies are warranted on the basis of a favorable safety profile and preliminary evidence of clinical antitumor activity.

A genomics-based approach to identify pharmacodynamic biomarkers was used for a cyclin-dependent kinase inhibitory drug. R547 is a potent cyclin-dependent kinase inhibitor with a potent antiproliferative effect at pharmacologically relevant doses and is currently in phase I clinical trials. Using preclinical data derived from microarray experiments, we identified pharmacodynamic biomarkers to test in blood samples from patients in clinical trials. These candidate biomarkers were chosen based on several criteria: relevance to the mechanism of action of R547, dose responsiveness in preclinical models, and measurable expression in blood samples. We identified 26 potential biomarkers of R547 action and tested their clinical validity in patient blood samples by quantitative real-time PCR analysis. Based on the results, eight genes (FLJ44342, CD86, EGR1, MKI67, CCNB1, JUN, HEXIM1, and PFAAP5) were selected as dose-responsive pharmacodynamic biomarkers for phase II clinical trials. [Mol Cancer Ther 2009;8(9):2517–25]

Purpose: This is a dose-finding Phase I study of oral Ro 31-7453, a new class of antimitotic drug with promising preclinical activity in several chemoresistant models. Experimental Design: Two schedules of oral Ro 31-7453 (every 12 h) given for either 7 or 14 consecutive days repeated every 4 weeks were explored consecutively. Results: Thirty-seven patients with refractory cancer entered the study (14 on the 7-day schedule and 23 on the 14-day schedule). Median age was 63 years (range, 40–77 years), and median Karnofsky performance status was 80 (range, 60–100); the most frequent diagnosis was colorectal carcinoma (16 patients). Dose levels of 100, 200, 240, and 280 mg/m2 twice daily (bid) for 7 days and 70, 100, 125, and 150 mg/m2 bid for 14 days were explored. A total of 110 cycles were administered, the median number of cycles received was 3 (range, 1–7); six patients completed 6 or more cycles. Myelosuppression and mucositis were dose-limiting with both schedules. Fatigue and gastrointestinal toxicities other than mucositis were frequent but generally mild. The maximum tolerated doses were 200 mg/m2 bid and 125 mg/m2 bid for the 7- and 14-day schedules, respectively. Pharmacokinetic analysis showed rapid absorption and metabolism. The area under the concentration-time curve and trough concentrations of Ro 31-7453 and two active metabolites appeared dose proportional with a t1/2 of ∼9 h and a tmax of ∼4 h. One patient with pretreated lung cancer had a partial response. Conclusions: Both Ro 31-7453 regimens were feasible, but the 14-day schedule at the recommended dose of 125 mg/m2 bid was selected for further monotherapy Phase II evaluation because of its higher preclinical activity. This regimen is convenient, well tolerated, and has a favorable pharmacokinetic profile.

2502 Background: Aberrant Notch signaling is implicated in many human cancers. RO4929097 (R) is a potent, selective oral inhibitor of gamma-secretase, a key enzyme in Notch activation. Preclinicall...

3528 Background: R547, a potent inhibitor of CDKs 1, 2, 4, 7, and 9, has shown broad antitumor activity in preclinical models. This phase Ia study assessed safety, pharmacokinetic (PK), and pharmacodynamic (PD) endpoints. Methods: R547 given as a 90 or 180 min infusion D1, D8 (21 day cycle). Key inclusion criteria: ECOG 0–2, adequate hematologic, hepatic, and renal function. Exclusion: brain metastases, NYHA III/IV CHF, CVA, current antihypertensive therapy. Blood samples on cycle 1, D1, D8 for PK and PD. PD endpoint is inhibition of retinoblastoma phosphorylation (pRB) in PBMCs. Results: 41 pts received R547 over dose range 8.6 - 195 mg/m2; 31 pts on 90 min and 10 pts on 180 min schedule. Mean age 53.4 yrs (20–81), 25F:16M. Mean R547 cycles 3.1(2. Toxicities: principal related events were nausea (54%), fatigue (34%), emesis (34%), headache (34%), and hypotension (32%). All of these limited to gr 1/ 2, except 4 gr 3 fatigue (1 in cycle 1) and 1 gr 3 nausea. DLTs: 90 min- gr 3 somnolence, gr 3 confusion, gr 3 fatigue, 1 pt each, all at 195 mg/m2; 180 min- 1 DLT of prolonged gr 3 pruritis at 195 mg/m2. PK: Mean AUC for 20 pts with PK receiving ≥ 155 mg/m2 R547 exceeds exposures efficacious in xenograft studies. At equivalent doses, the 180 min schedule produces equivalent AUC but 30% reduction of Cmax. PD: for pts with available data (n=21), an exposure-dependent decrease in pRB/total RB ratio was observed 1.5 to 24 hrs post R547. Activity: tumor regression in 1 pt with metastatic squamous ca skin; 8 additional pts received ≥ 4 cycles. Conclusions: Treatment with R547 is tolerable at a dose of 155 mg/m2 on D1, D8 (21 day cycle) for both 90 and 180 min schedules. Nausea, emesis, headache, and transient hypotension are manageable with anti-emetic, analgesic, and iv fluid support. The DLTs observed in the 90 min schedule have not occurred in pts receiving 180 min infusions, a schedule which maintains R547 exposure but reduces Cmax. Exposures predictive of preclinical efficacy have been achieved. Inhibition of a relevant PD marker (pRB) and antitumor activity have each been confirmed in the clinic. Phase II trials in advanced solid tumors and hematologic malignancies are planned. No significant financial relationships to disclose.