Targeting the ataxia telangiectasia and Rad3-related (ATR) enzyme represents a promising anticancer strategy for tumors with DNA damage response (DDR) defects and replication stress, including inactivation of ataxia telangiectasia mutated (ATM) signaling. We report the dose-escalation portion of the phase I first-inhuman trial of oral ATR inhibitor BAY 1895344 intermittently dosed 5-80 mg twice daily (BID) in 21 patients with advanced solid tumors. The maximum tolerated dose was 40 mg BID 3 days on/4 days off. Commonest adverse events were manageable and reversible hematological toxicities. Partial responses were achieved in 4 patients and stable disease in 8 patients. Median duration of response was 315.5 days. Responders had ATM protein loss and/or deleterious ATM mutations and received doses 40 mg BID. Overall, BAY 1895344 is well tolerated with antitumor activity against cancers with certain DDR defects, including ATM loss. An expansion phase continues in patients with DDR deficiency. SIGNIFICANCE Oral BAY 1895344 was tolerable with antitumor activity in heavily pre-treated patients with various advanced solid tumors, particularly those with ATM deleterious mutations and/or loss of ATM protein; pharmacodynamic results supported a mechanism of action of increased DNA damage. Further study is warranted in this patient population.

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3007 Background: The ATR kinase is a key regulator of the DNA damage response (DDR) machinery, activated by DNA damage and replication stress. BAY 1895344 is a novel, potent, and selective ATR inhibitor with anti-tumor activity in preclinical models with DDR defects. Methods: Pts with advanced metastatic solid tumors resistant or refractory to standard treatment, with and without DDR defects, received BAY 1895344 BID, 3 days (d) on/4 d off continuously in 3-weekly cycles. Results: As of December 20, 2018, 18 pts with colorectal (4), breast (3), prostate (2), and ovarian (2) cancers were enrolled across 6 cohorts (5 mg, 10 mg, 20 mg, 40 mg, 60 mg, and 80 mg BID). Median prior lines of treatment was 5. No dose-limiting toxicities (DLTs) were reported in the 5-40 mg cohorts. 2/3 pts had DLTs in the 80 mg cohort (grade [G] 4 neutropenia, G4 neutropenia and G4 thrombocytopenia) and 2/7 had DLTs in the 60 mg cohort (G4 neutropenia, G2 fatigue). 40 mg BID 3 on/4 off was defined as the maximum tolerated dose. Most common treatment-emergent adverse events included anemia, neutropenia, nausea, and fatigue. Pharmacokinetics appeared dose proportional. Pharmacodynamic analyses showed modulation of pH2AX and/or pKAP1 in paired tumor biopsies at exposures associated with preclinical anti-tumor activity. In 13 pts with and without DDR defects treated at dose levels ≥40 mg BID, the objective response rate was 30.7%, including 2/2 pts at 40 mg (appendix and urothelial cancer), 1/8 pts at 60 mg (breast), and 1/3 pts at 80 mg (endometrial). All responders had ATM protein loss of expression and/or ATM mutation; median treatment duration was 347 d (range 293-364 d). A BRCA1-mutant, olaparib-resistant ovarian cancer pt (60 mg) had a CA125 response and stable disease >10 months. 41 additional pts have been enrolled in ongoing expansion cohorts in cancers with DDR defects (prostate, breast, gynecologic, colorectal) or ATM protein loss (all comers) with responses observed. Conclusions: The ATR inhibitor BAY 1895344 is tolerated at biologically active doses with anti-tumor activity against cancers with certain DDR defects, including ATM protein loss. Clinical trial information: NCT03188965.

Background: Preclinical experiments in-vitro show MEK inhibitors can cause upregulation of p-FAK in KRASM cells. The combination of a MEK and FAK inhibitor could overcome this in-vitro and in-vivo. Methods: We are conducting an open label phase I dose escalation with expansion study (NCT03875820). Dose escalation evaluated a twice a week schedule (Mon/Thurs) CH5126766/VS-6766 (CH) 3 weeks out of 4 with a twice a day dosing schedule of defactinib (Def) administered 3 weeks out of 4. The dose levels explored were cohort 1 (CH 3.2 mg, 200 mg Def), cohort 2a (CH 4 mg Def 200 mg) and cohort 2b (CH 3.2 mg and Def 400 mg). Pharmacokinetic data were collected at cycle 1 d15 when both drugs were administered. In a subset of patients consenting to multiple biopsies, 3 biopsies were performed (baseline, after a single dose of CH run in and after 8-15 days of the combination therapy). At the recommended phase 2 dose (R2PD), expansion cohorts in patients with low grade ovarian cancer (LGSOC, n=20), KRASM non-small cell lung cancer (NSCLC, n=20) and KRASM colorectal cancer (CRC, n=10) will be treated. Results: Forty two patients have been treated on the trial so far. There were no dose limiting toxicities (DLTs) in the first 3 patients in cohort 1 and thus patients were recruited to cohort 2a and 2b. The cohort 2b dose level was deemed intolerable because of 2/3 patients experiencing DLTs of grade 2 rash not allowing dosing of 75% of the planned dose. No DLTs were seen in the first 6 patients treated on schedule 2a. However, given chronic grade 2 toxicities in patients on treatment > 6 months, the RP2D was deemed to be cohort 1. The most common side effects in the study were rash, CK elevation, AST elevation, hyperbilirubinemia and nausea, most of which were NCI CTC grade 1-2. All changes were reversible. The mean AUC of CH and Def at R2PD was 6179 ng*hr/ml and 2071 ng*hr/ml, respectively, which is in the range of what was seen in the single agent dose escalation studies. Sequential biopsies were obtained in 7 patients and 6/7 showed an increase in p-FAK following single agent CH which was reduced in 5/7 with combined CH and Def therapy. The response rate was 67% (4/6) or 50% (4/8) in KRASM LGSOC or all LGSOC patients treated to date, respectively. A range of KRASM were found in tumors of LGSOC patients who responded (G12V, G12A and G12D). Of the 4 patients with LGSOC who have responded to treatment, 3 have had a prior MEK inhibitor and are currently are on study for a median of 20.5 months (range 7-23 months). Expansion cohorts in LGSOC and KRASM NSCLC and CRC are ongoing and will be presented. Conclusion: We report a novel intermittent schedule of the combination of a RAF-MEK and FAK inhibitor with very promising clinical activity in patients with KRASM LGSOC including those who had been previously treated with a MEK inhibitor. Citation Format: Rajiv Shinde, Angelika Terbuch, Martin Little, Reece Caldwell, Roopa Kurup, Ruth Riisnaes, Mateus Crespo, Ruth Ruddle, Bora Gurel, Adam Stewart, Jenny King, Mona Parmar, Alison Turner, Florence Raynaud, Muneeb Mahmud, Christina Yap, Jonathan A. Pachter, Gordon B. Mills, Anna Minchom, Juanita Lopez, Susana N. Banerjee, Johann S. de Bono, Matthew Krebs, Udai Banerji. Phase I study of the combination of a RAF-MEK inhibitor CH5126766 and FAK inhibitor defactinib in an intermittent dosing schedule with expansions in KRAS mutant cancers [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 CT143.