First-in-human Phase 1 open label study of the BET inhibitor ODM-207 in patients with selected solid tumours

Background Bromodomain and extra-terminal domain (BET) proteins are reported to be epigenetic anti-cancer drug targets. This first-in-human study evaluated the safety, pharmacokinetics and preliminary anti-tumour activity of the BET inhibitor ODM-207 in patients with selected solid tumours. Methods This was an open-label Phase 1 study comprised of a dose escalation part, and evaluation of the effect of food on pharmacokinetics. ODM-207 was administered orally once daily. The dose escalation part was initiated with a dose titration in the initial cohort, followed by a 3 + 3 design. Results Thirty-five patients were treated with ODM-207, of whom 12 (34%) had castrate-resistant prostate cancer. One dose-limiting toxicity of intolerable fatigue was observed. The highest studied dose achieved was 2 mg/kg due to cumulative toxicity observed beyond the dose-limiting toxicity (DLT) treatment window. Common AEs included thrombocytopenia, asthenia, nausea, anorexia, diarrhoea, fatigue, and vomiting. Platelet count decreased proportionally to exposure with rapid recovery upon treatment discontinuation. No partial or complete responses were observed. Conclusions ODM-207 shows increasing exposure in dose escalation and was safe at doses up to 2 mg/kg but had a narrow therapeutic window.Peer reviewe

Evidence of pseudoprogression in patients treated with PD1/ PDL1 antibodies across tumor types

Background: PD(L)1 antibodies (anti-PD(L)-1) have been a major breakthrough in several types of cancer. Novel patterns of response and progression have been described with anti-PD(L)-1. We aimed at characterizing pseudoprogression (PSPD) among patients with various solid tumor types treated by anti-PD(L)-1. Methods: All consecutive patients (pts) enrolled in phase 1 trials with advanced solid tumors and lymphomas treated in phase I clinical trials evaluating monotherapy by anti-PD(L)-1 at Gustave Roussy were analyzed. We aimed to assess prevalence and outcome of PSPD across tumor types. We also intended to describe potential clinical and pathological factors associated with PSPD. Results: A total of 169 patients treated with anti-PD(L)-1 were included in the study. Most frequent tumor types included melanoma (n = 57) and non-small cell lung cancer (n = 19). At first tumor evaluation 77 patients (46%) presented with immune unconfirmed progressive disease. Six patients (8%) experienced PSPD: 2 patients with partial response; 4 patients with stable disease. Increase in target lesions in the first CT-scan was more frequently associated to PSPD (67% vs 33%; P = .04). Patients with a PSPD had a superior survival when compared to patients progressing (median OS: 10.7 months vs 8.7 months; P = .07). Conclusions: A small subset of PSPD patients may experience response after an initial progression. Assessment of the current strategy for immune-related response evaluations may require further attention

Can molecular biomarker-based patient selection in Phase I trials accelerate anticancer drug development?

Anticancer drug development remains slow, costly and inefficient. One way of addressing this might be the use of predictive biomarkers to select patients for Phase I/II trials. Such biomarkers, which predict response to molecular-targeted agents, have the potential to enrich these trials with patients more likely to benefit. Doing so could maximize the efficiency of anticancer drug development by facilitating earlier clinical qualification of predictive biomarkers and generating valuable information on cancer biology. In this review, we suggest a new model of early clinical trial design, which incorporates patient selection through predictive molecular biomarkers for selected targeted agents

Evidence of pseudoprogression in patients treated with PD1/ PDL1 antibodies across tumor types

Background: PD(L)1 antibodies (anti-PD(L)-1) have been a major breakthrough in several types of cancer. Novel patterns of response and progression have been described with anti-PD(L)-1. We aimed at characterizing pseudoprogression (PSPD) among patients with various solid tumor types treated by anti-PD(L)-1. Methods: All consecutive patients (pts) enrolled in phase 1 trials with advanced solid tumors and lymphomas treated in phase I clinical trials evaluating monotherapy by anti-PD(L)-1 at Gustave Roussy were analyzed. We aimed to assess prevalence and outcome of PSPD across tumor types. We also intended to describe potential clinical and pathological factors associated with PSPD. Results: A total of 169 patients treated with anti-PD(L)-1 were included in the study. Most frequent tumor types included melanoma (n = 57) and non-small cell lung cancer (n = 19). At first tumor evaluation 77 patients (46%) presented with immune unconfirmed progressive disease. Six patients (8%) experienced PSPD: 2 patients with partial response; 4 patients with stable disease. Increase in target lesions in the first CT-scan was more frequently associated to PSPD (67% vs 33%; P = .04). Patients with a PSPD had a superior survival when compared to patients progressing (median OS: 10.7 months vs 8.7 months; P = .07). Conclusions: A small subset of PSPD patients may experience response after an initial progression. Assessment of the current strategy for immune-related response evaluations may require further attention

Ceralasertib (AZD6738), an oral ATR kinase inhibitor, in combination with carboplatin in patients with advanced solid tumors: a Phase I study

PURPOSE: This study reports the safety, tolerability, MTD, recommended phase II dose (RP2D), pharmacokinetic/pharmacodynamic profile, and preliminary antitumor activity of ceralasertib combined with carboplatin in patients with advanced solid tumors. It also examined exploratory predictive and pharmacodynamic biomarkers. PATIENTS AND METHODS: Eligible patients (n = 36) received a fixed dose of carboplatin (AUC5) with escalating doses of ceralasertib (20 mg twice daily to 60 mg once daily) in 21-day cycles. Sequential and concurrent combination dosing schedules were assessed. RESULTS: Two ceralasertib MTD dose schedules, 20 mg twice daily on days 4–13 and 40 mg once daily on days 1–2, were tolerated with carboplatin AUC5; the latter was declared the RP2D. The most common treatment-emergent adverse events (Common Terminology Criteria for Adverse Events grade ≥3) were anemia (39%), thrombocytopenia (36%), and neutropenia (25%). Dose-limiting toxicities of grade 4 thrombocytopenia (n = 2; including one grade 4 platelet count decreased) and a combination of grade 4 thrombocytopenia and grade 3 neutropenia occurred in 3 patients. Ceralasertib was quickly absorbed (t(max) ∼1 hour), with a terminal plasma half-life of 8–11 hours. Upregulation of pRAD50, indicative of ataxia telangiectasia mutated (ATM) activation, was observed in tumor biopsies during ceralasertib treatment. Two patients with absent or low ATM or SLFN11 protein expression achieved confirmed RECIST v1.1 partial responses. Eighteen of 34 (53%) response-evaluable patients had RECIST v1.1 stable disease. CONCLUSIONS: The RP2D for ceralasertib plus carboplatin was established as ceralasertib 40 mg once daily on days 1–2 administered with carboplatin AUC5 every 3 weeks, with pharmacokinetic and pharmacodynamic studies confirming pharmacodynamic modulation and preliminary evidence of antitumor activity observed

La déficience de PBRM1 confère une létalité synthétique aux inhibiteurs de la réparation de l'ADN dans le cancer

International audienceInactivation of Polybromo 1 (PBRM1), a specific subunit of the PBAF chromatin remodeling complex, occurs frequently in cancer, including 40% of clear cell renal cell carcinomas (ccRCC). To identify novel therapeutic approaches to targeting PBRM1-defective cancers, we used a series of orthogonal functional genomic screens that identified PARP and ATR inhibitors as being synthetic lethal with PBRM1 deficiency. The PBRM1/PARP inhibitor synthetic lethality was recapitulated using several clinical PARP inhibitors in a series of in vitro model systems and in vivo in a xenograft model of ccRCC. In the absence of exogenous DNA damage, PBRM1-defective cells exhibited elevated levels of replication stress, micronuclei, and R-loops. PARP inhibitor exposure exacerbated these phenotypes. Quantitative mass spectrometry revealed that multiple R-loop processing factors were downregulated in PBRM1-defective tumor cells. Exogenous expression of the R-loop resolution enzyme RNase H1 reversed the sensitivity of PBRM1-deficient cells to PARP inhibitors, suggesting that excessive levels of R-loops could be a cause of this synthetic lethality. PARP and ATR inhibitors also induced cyclic GMP-AMP synthase/stimulator of interferon genes (cGAS/STING) innate immune signaling in PBRM1-defective tumor cells. Overall, these findings provide the preclinical basis for using PARP inhibitors in PBRM1-defective cancers. SIGNIFICANCE: This study demonstrates that PARP and ATR inhibitors are synthetic lethal with the loss of PBRM1, a PBAF-specific subunit, thus providing the rationale for assessing these inhibitors in patients with PBRM1-defective cancer.L'inactivation de Polybromo 1 (PBRM1), une sous-unité spécifique du complexe de remodelage de la chromatine PBAF, se produit fréquemment dans le cancer, y compris dans 40% des carcinomes rénaux à cellules claires (ccRCC). Afin d'identifier de nouvelles approches thérapeutiques pour cibler les cancers déficients en PBRM1, nous avons utilisé une série de cribles génomiques fonctionnels orthogonaux qui ont identifié les inhibiteurs PARP et ATR comme étant synthétiquement létaux en cas de déficience en PBRM1. La létalité synthétique des inhibiteurs de PBRM1/PARP a été récapitulée en utilisant plusieurs inhibiteurs cliniques de PARP dans une série de systèmes modèles in vitro et in vivo dans un modèle de xénogreffe de ccRCC. En l'absence de lésions exogènes de l'ADN, les cellules déficientes en PBRM1 présentaient des niveaux élevés de stress de réplication, de micronoyaux et de boucles R. L'exposition à un inhibiteur de PARP a exacerbé la létalité synthétique. L'exposition à un inhibiteur de PARP a exacerbé ces phénotypes. La spectrométrie de masse quantitative a révélé que plusieurs facteurs de traitement des boucles R étaient régulés à la baisse dans les cellules tumorales défectueuses de PBRM1. L'expression exogène de l'enzyme de résolution des boucles R, la RNase H1, a inversé la sensibilité des cellules PBRM1 déficientes aux inhibiteurs de la PARP, ce qui suggère que des niveaux excessifs de boucles R pourraient être une cause de cette létalité synthétique. Les inhibiteurs de PARP et d'ATR ont également induit une signalisation immunitaire innée de type GMP cyclique-AMP synthase/stimulateur des gènes de l'interféron (cGAS/STING) dans les cellules tumorales déficientes en PBRM1. Dans l'ensemble, ces résultats fournissent une base préclinique pour l'utilisation des inhibiteurs de PARP dans les cancers déficients en PBRM1. SIGNIFICATION : Cette étude démontre que les inhibiteurs de PARP et d'ATR sont synthétiquement létaux en cas de perte de PBRM1, une sous-unité spécifique du PBAF, ce qui justifie l'évaluation de ces inhibiteurs chez les patients atteints d'un cancer déficient en PBRM1