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Background: ATR mediates the homologous recombination DNA repair pathway and cellular response to replication stress. VX-970 is a potent and selective inhibitor of ATR (Ki <0.2 nM) that showed enhanced synergy of ATR inhibition with cytotoxic chemotherapy and potential mono ATR inhibitor activity in tumor cell lines with high levels of replication stress, such as defects in the DNA damage repair (DDR) pathway (e.g. ATM loss). A phase I dose-escalation trial of VX-970 (sponsored by Vertex Pharmaceuticals Incorporated) was undertaken to assess the safety and tolerability of an ATR inhibitor as mono and with DNA-damaging chemotherapy, to show evidence of ATR inhibition in tumor tissue, and to explore antitumor activity. Methods: Pts with advanced solid tumors enrolled in 2 sequential parts. Part A: pts received IV VX-970 mono weekly in single-pt cohorts, with 3+3 cohorts initiated if grade (G) ≥2 VX-970-related adverse events (AEs) were observed. Part B: pts received CP on day 1 and VX-970 on days 2 and 9 of a 21-day cycle in a 3+3 dose-escalation design. Paired VX-970 tumor biopsies were obtained in selected CP treated pts pre- and post-VX-970, and pS345 Chk1 levels assessed by IHC. Results: 25 pts were treated; M/F 10/15; median age 67 yr (range 49-76 yr); ECOG PS 0/1: 11/14. In Part A, 11 pts (colorectal [CRC; n = 2]; mesothelioma [n = 2]; other [n = 7]; median prior lines of therapy = 3) received VX-970 at 60 mg/m2 (n = 1), 120 mg/m2 (n = 2), 240 mg/m2 (n = 1) and 480 mg/m2 (n = 7). In Part B, 14 pts (CRC [n = 6]; ovarian [n = 2]; other [n = 6]; median prior lines of therapy = 3) received VX-970 240 mg/m2 + CP AUC5 (n = 3; dose level 1 [DL1]), VX-970 120 mg/m2 + CP AUC5 (n = 3; DL2), VX-970 120 mg/m2 + CP AUC4 (n = 3; DL3) and VX-970 90 mg/m2 + CP AUC5 (n = 5; DL4). In Part A, no dose-limiting toxicities (DLT) or drug-related G3-4 AEs were seen. In Part B, 2 pts had DLT: G4 neutropenia and fever (n = 1; DL1) and G3 hypersensitivity (n = 1; DL2). Non-DLT G3-4 AEs were neutropenia (n = 4; DL1-2) and thrombocytopenia (n = 1; DL2) requiring dose delays. No G3-4 AEs were seen at DL3-4. RP2D cohort expansion is ongoing at DL4. VX-970 displayed linear AUC and Cmax at all DLs; median half-life was 16h with no accumulation. Based on preclinical models, efficacious exposures were achieved. When combined with CP, DL1 and DL2 showed similar VX-970 exposure, suggesting no apparent drug interactions. Decreased Chk1 phosphorylation was seen in 2/2 paired tumor biopsies (74% at DL4; 94% at DL2). An advanced CRC pt (serosal disease and abdominal lymphadenopathy; 3 prior lines of chemotherapy) with complete ATM loss by IHC achieved RECIST complete response to VX-970 mono at 60 mg/m2 and remains on trial at 59+ wks. RECIST stable disease (SD) was seen with VX-970 mono in 4 pts (median duration of SD = 11 wks [11-17.4 wks]) and VX-970 + CP in 7 pts, who were still ongoing (duration of SD = 5+ to 20+ wks), including several pts who had progressed on prior platinum therapy. Conclusion: VX-970 is well tolerated as monotherapy and in combination with CP, with preliminary evidence of target modulation and antitumor activity. VX-970 will be further explored in early phase II studies; in multiple tumor types, including triple-negative breast cancer and non-small cell lung cancer; and in patients with DDR aberrations. Citation Format: Timothy A. Yap, Maria J. de Miguel Luken, Brent O'Carrigan, Desam Roda, Dionysis Papadatos-Pastos, David Lorente, Nina Tunariu, Raquel Perez Lopez, Sasha Gayle, Ruth Riisnaes, Ines Figueiredo, Susana Miranda, Suzanne Carreira, Fang Yang, Sharon Karan, Marina Penney, John Pollard, L. Rhoda Molife, Udai Banerji, Mohammed Asmal, Scott Z. Fields, Johann S. de Bono. Phase I trial of first-in-class ataxia telangiectasia-mutated and Rad3-related (ATR) inhibitor VX-970 as monotherapy (mono) or in combination with carboplatin (CP) in advanced cancer patients (pts) with preliminary evidence of target modulation and antitumor activity. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr PR14.

Background: KRAS G12C oncogenic mutations occur in ~13% of non-small cell lung cancers (NSCLCs) and up to 4% of other solid tumors. JDQ443 is a selective, covalent, orally bioavailable, investigational KRASG12C inhibitor that irreversibly traps KRASG12C in the inactive, GDP-bound state. JDQ443 is structurally unique and forms novel interactions with KRAS in the switch II pocket. Methods: KontRASt-01 (NCT04699188) is a Phase Ib/II, open-label, multicenter, dose-escalation and dose-expansion trial of JDQ443 as monotherapy or in combination with TNO155 (SHP2 inhibitor) and/or tislelizumab (anti-PD-1 monoclonal antibody). Primary objectives of dose escalation are to assess safety and tolerability, and identify the maximum tolerated doses (MTDs) and/or recommended doses (RDs) and regimens for future studies. The primary objective of dose expansion is to assess efficacy. Key inclusion criteria: advanced, KRAS G12C-mutated solid tumors; previous standard-of-care treatment; age ≥18 yrs; ECOG PS 0-1. Key exclusion criteria for the JDQ443 monotherapy arm: active brain metastases, prior KRASG12C inhibitor treatment. Here, we present preliminary results for JDQ443 monotherapy dose escalation. Results: As of Nov 3, 2021, 39 pts were treated with JDQ443 PO continuously across 4 dose levels: 200 mg once daily (QD) (n=10), 400 mg QD (n=11), 200 mg twice daily (BID) (n=11), and 300 mg BID (n=7). Median age was 60 yrs (range 26-76), median prior lines of therapy was 3 (range 1-7), and indications included NSCLC (n=20) and colorectal cancer (CRC) (n=16). Median duration of exposure was 9.1 wks (range 0.9-21), with ongoing treatment in most pts (61.5%) at the time of cut-off. Treatment-related adverse events (TRAEs) occurred in 25 (64.1%) pts. Most TRAEs were Grade (Gr) 1-2. Four Gr 3 TRAEs occurred in 4 (10.3%) separate pts; there were no Gr 4-5 TRAEs. The most common TRAEs (occurring in ≥10% of pts) were fatigue (25.6%), nausea (15.4%), edema (12.8%), pruritus (10.3%), and vomiting (10.3%). There was one DLT (Gr 3 fatigue) and one treatment-related serious AE (Gr 3 photosensitivity reaction), each in separate pts treated at 300 mg BID. TRAEs led to dose reduction in 1 pt and discontinuation in 1 pt. A MTD was not reached. The RD was declared as 200 mg BID. At the RD, PK and PD modeling for JDQ443 predicted average KRASG12C target occupancy of >90% in >82% of pts. Using an efficacy cut-off date of Dec 13, 2021, for the 20 pts with NSCLC among the same 39 pts, the ORR (confirmed complete response or partial response) by RECIST 1.1 was 30.0% (6/20) across dose levels and 43.0% (3/7) at the RD. Additional data will be available at the time of presentation. Conclusions: JDQ443 demonstrates an acceptable safety and tolerability profile, with early signs of clinical activity in pts with NSCLC. Enrollment is ongoing to NSCLC and CRC dose-expansion groups for JDQ443 monotherapy at the RD, and to JDQ443 + TNO155 dose escalation. Citation Format: Daniel S. Tan, Toshio Shimizu, Benjamin Solomon, Rebecca S. Heist, Martin Schuler, Maria J. De Miguel Luken, Anas Gazzah, Martin Wermke, Christophe Dooms, Herbert H. Loong, Neeltje Steeghs, Enriqueta Felip, Conor E. Steuer, Eric van Cutsem, Ross A. Soo, Ashley C. Jaeger, Jaeyeon Kim, Kun Xu, Xueying Chen, Xiaoming Cui, Heather Burks, Anna Farago, Philippe A. Cassier. KontRASt-01: A phase Ib/II, dose-escalation study of JDQ443 in patients (pts) with advanced, KRAS G12C-mutated solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT033.

No abstract

Background: A frequent mechanism of dysregulation of the PI3K/AKT/mTOR pathway, commonly altered in cancer, is loss of function of the tumour suppressor PTEN, leading to increased PI3K signalling, particularly through the PI3Kβ isoform. AZD8186 is a potent and selective inhibitor of PI3Kβ/δ with significant activity in PTEN-deficient preclinical models. We report the dose-finding portion of the study, assessing the safety/tolerability of an intermittent dosing schedule of AZD8186. Trial design and eligibility criteria: AZD8186 tablets were administered twice daily 5 days on treatment, 2 days off (5/2 schedule) in 3 week cycles. Escalating doses of AZD8186 were evaluated in cohorts of 3-6 evaluable patients treated until confirmed disease progression, unacceptable toxicity, or withdrawal of consent. A safety review committee reviewed all available safety data and dose limiting toxicities (DLTs) prior to each dose modification. The dose/schedule finding, safety and activity will be updated at time of presentation. Adult patients were recruited with tumor types known to be PTEN deficient or to have prevalent PTEN loss, such as castration-resistant prostate cancer (CRPC), triple negative breast cancer, squamous non-small cell lung cancer or, that had relapsed and/or were refractory to suitable therapies. Results: As of 25 Oct, 32 patients have received treatment (30 mg n = 7, 60 mg n = 6, 120 mg n = 5; 240 mg n = 6, 360 mg n = 6; 300 mg n = 2). Pharmacokinetic parameters show that systemic exposures to parent drug and its major active metabolite increased in a dose proportional manner and exceeded preclinical exposures that have demonstrated robust anti-tumour activity in PTEN deficient xenograft models. DLTs of maculopapular rash (CTCAE Grade 3) were observed at 360 mg (in 2/6 patients) and at 300 mg (2/2 patients). Additional AEs occurring in >10% of patients included diarrhea, nausea, vomiting, fatigue, rash, decreased appetite and QTc prolongation. AEs of ≥ grade 3 included: rash, hypophosphatemia, hypokalemia, diarrhea elevated aspartate transaminase and 1st degree atrioventricular block; there were no grade 5 events. Overall, 11 patients remained on study for at least 60 days; one CRPC patient remained on study for more than 160 days with minor PSA response, symptomatic improvement and stable disease by CT and bone scan. Conclusions: AZD8186 is a potent oral inhibitor of PI3Kβ/δ, with potential for treatment of PTEN-deficient tumors. Investigation of the safety/tolerability of the 5/2 schedule is continuing. This agent may hold potential for treatment of PTEN deficient tumors. Citation Format: Lillian L. Siu, Johann De Bono, Kari B. Wisinski, Celestia S. Higano, Natalie Cook, Maria Jose De Miguel Luken, Rajiv Kumar, Joshua Lang, Gurkamal S. Chatta, Sara M. Tolaney, Stefan M. Symeonides, Gilmour Morrison, Patrick D. Mitchell, David G. Brooks, Geoffrey I. Shapiro. Phase I study of the PI3Kβ/δ inhibitor AZD8186 in patients with advanced castration resistant prostate cancer, triple negative breast cancer, squamous non-small cell lung cancer or PTEN deficient solid tumors: update from dose-finding. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT329. doi:10.1158/1538-7445.AM2015-CT329

Purpose Ceritinib is an ALK receptor tyrosine kinase inhibitor approved as first- and second-line treatment in adult patients with ALK + metastatic non-small cell lung cancer (NSCLC). The study investigated the drug–drug interaction (DDI) potential of ceritinib when coadministered with midazolam and warfarin as probe substrates for CYP3A and CYP2C9 activity, respectively. Methods This was a phase I, multicenter, open-label, single sequence, crossover DDI study in 33 adult patients with ALK + NSCLC or other advanced tumors. A single dose of a cocktail consisting of midazolam and warfarin was administered with and without concomitant administration of ceritinib. The primary objective was to evaluate the pharmacokinetics of midazolam and warfarin. Secondary objectives included pharmacokinetics, safety, tolerability, overall response rate (ORR), and duration of response (DOR) of ceritinib 750 mg once daily. Results Ceritinib inhibited CYP3A-mediated metabolism of midazolam, resulting in a markedly increased AUC (geometric mean ratio [90% confidence interval]) by 5.4-fold (4.6, 6.3). Ceritinib also led to an increase in the AUC of S-warfarin by 54% (36%, 75%). The pharmacokinetics and safety profile of ceritinib in this study are consistent with previous reports and no new safety signals were reported. Among the 19 patients with NSCLC, efficacy (ORR: 42.1% and DCR: 63.2%) was similar to that reported previously in studies of pretreated patients with ALK + NSCLC. Conclusion Ceritinib is a strong CYP3A inhibitor and a weak CYP2C9 inhibitor. These findings should be reflected as actionable clinical recommendations in the prescribing information for ceritinib with regards to concomitant medications whose pharmacokinetics may be altered by ceritinib.

No abstract

Background: PD-L1 expression is associated with reduced survival and an unfavorable prognosis in a wide range of cancers. LY3300054 (LY) is a PD-L1 inhibitor that blocks the interaction between PD-L1 and its receptors. The added benefit of combining a second therapeutic agent is an area of active interest. This study (NCT02791334) will assess the safety, tolerability and efficacy of LY as monotherapy and in combination with ramucirumab (R), abemaciclib (A) and merestinib (M). Here we report phase 1a safety and preliminary efficacy results from completed LY, LY+R and LY+M cohorts. Methods: This ongoing, phase 1a/b, multi-center, dose escalation and expansion study enrolled pts with histologically or cytologically confirmed advanced solid tumor having ECOG PS 0-1 and with measurable disease. Primary objective for Phase 1a was to assess safety and tolerability. Secondary objectives include assessment of pharmacokinetics, efficacy and biomarkers (exploratory). Pts received intravenous infusions of LY: Q2W at 70, 200, 700 mg; Q3W at 1000 mg; Q4W at 1800 mg; LY+R: LY (Q2W 200, 700 mg; Q3W 1400 mg) + R (Q2W, Q3W 8 mg/kg); LY+M: LY (Q2W 200, 700 mg) + M (QD 120 mg oral). Adverse events (AEs) were assessed per NCI CTCAE v4.0. Tumor assessments were performed using RECIST v1.1. Results: As of 4 September 2017, 38 pts ([LY: Q2W, n=10; Q3W, n=3; Q4W, n=3]; LY+R [(Q2W, n=7; Q3W, n=3)]; LY+M Q2W, n=12) were treated. No DLTs were observed and there were no deaths due to AEs while on treatment. Pts with Gr3 treatment-related AEs (TRAEs) were: LY Q3W (n=1) with nausea, vomiting and fatigue; LY+R Q2W (n=2) with decreased appetite, pulmonary embolism and hypertension; Q3W (n=1) with lipase and amylase increase; no Gr 4/5 TRAEs were reported. Serious adverse events possibly related to study treatment were LY Q3W (n=1) Gr3 nausea and vomiting, and LY+R (n=1) Gr3 pulmonary embolism. There were no TRAEs leading to discontinuation of study treatment. The pharmacokinetics of LY was linear in the dose range tested, with a half-life of approximately 3 weeks, which did not appear to be affected by concomitant doses of M or R. Tumor tissue and blood were collected for biomarker analysis, including but not limited to, PD-L1 and CD8 expression by IHC and whole blood immunophenotyping; preliminary biomarker data will be presented. Preliminary efficacy data showed confirmed partial response in LY +R Q2W: 1pt (esophageal cancer), LY +M Q2W: 1pt (pancreatic cancer) and stable disease in LY Q2W: 3pts, LY+R: Q2W 4pts, Q3W 2pts as their best response. As of the data cut-off, 11 pts (29%) remain on treatment. Conclusions: LY alone or in combination with R or M appears to be well tolerated and demonstrated preliminary antitumor activity in pts with advanced solid tumors. The PK characteristics of LY support Q2W, Q3W, and possibly the Q4W dosing regimens. Citation Format: Amita Patnaik, Yung-Jue Bang, Hyun C. Chung, María José de Miguel Luken, Timothy A. Yap, Leijun Hu, Anna M. Szpurka, Danni Yu, Anindya Chatterjee, Shivani Nanda, Burkhard Vangerow, Mythili Koneru, Johanna Bendell. Interim safety and clinical activity in patients (pts) with advanced refractory solid tumors from a phase Ia/b study investigating the novel anti-PD-L1 antibody (LY3300054) administered alone or in combination with other agents [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT018.