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.

3094 Background: SRA737 is a potent, highly selective and orally-bioavailable inhibitor of checkpoint kinase 1 (Chk1). SRA737-01 was designed to investigate the safety and tolerability of continuous, daily dosing with SRA737 and to evaluate preliminary efficacy in expansion cohorts of prospectively-selected genetically-defined subjects with advanced tumors. Methods: The escalation phase employed an accelerated titration design starting at 20 mg administered orally in 28-day cycles. Incremental 100% dose escalations in single-subject cohorts were followed by a rolling-6 design once SRA737-related ≥ Grade 2 toxicity was observed during Cycle 1. The expansion phase enrolled subjects prospectively selected by next-generation sequencing with: high grade serous ovarian, colorectal, metastatic castration-resistant prostate, non-small cell lung, and head and neck cancers. Results: In escalation, 18 subjects received SRA737 in 9 dose level cohorts, from 20 to 1300 mg QD; median treatment duration 62.5 days (range 1 to 226). Of these subjects, 3 experienced dose limiting toxicity (DLT; inability to receive 75% of the planned dose); 2 at 1300 mg QD due to gastrointestinal intolerability and 1 at 500 mg BID due to thrombocytopenia. The maximum tolerated dose (MTD) was established at 1000 mg QD or 500 mg BID. The Cmax and AUC0-24 at 1000 mg QD were 2391 ng/mL and 26795 ng∙h/mL respectively and the Cmin (411 ng/mL) exceeded that determined in preclinical models to be effective. Doses ≥ 300 mg QD also exceeded this level. Of 462 subjects prospectively screened for genetic alterations associated with Chk1 sensitivity, 93 were enrolled in expansion across all tumor types. Overall, the most commonly reported treatment-emergent adverse events were diarrhea (70%), nausea (64%), vomiting (51%), and fatigue (47%); the majority were of mild to moderate severity. Conclusions: In this first-in-human trial of SRA737 monotherapy, the MTD was 1000 mg/day and based on overall tolerability and PK, the recommended Phase 2 dose is 800 mg/day. The successful enrollment of prospectively-selected genetically-defined subjects will allow response data to be correlated with genomic profiles hypothesized to confer sensitivity to Chk1 inhibition. Clinical trial information: NCT02797964.

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.

No abstract

Background:We investigated selumetinib (AZD6244, ARRY-142886), an oral, potent, and highly selective, allosteric MEK1/2 inhibitor, plus platinum-doublet chemotherapy for patients with advanced/metastatic non-small cell lung cancer.Methods:In this Phase I, open-label study (NCT01809210), treatment-naïve patients received selumetinib (50, 75, 100 mg BID PO) plus standard doses of gemcitabine or pemetrexed plus cisplatin or carboplatin. Primary objectives were safety, tolerability, and determination of recommended Phase II doses.Results:Fifty-five patients received treatment: selumetinib 50 or 75 mg plus gemcitabine/cisplatin (n=10); selumetinib 50 mg plus gemcitabine/carboplatin (n=9); selumetinib 50, 75 or 100 mg plus pemetrexed/carboplatin (n=21); selumetinib 75 mg plus pemetrexed/cisplatin (n=15). Most frequent adverse events (AEs) were fatigue, nausea, diarrhoea and vomiting. Grade ⩾3 selumetinib-related AEs were reported in 30 (55%) patients. Dose-limiting toxicities (all n=1) were Grade 4 anaemia (selumetinib 75 mg plus gemcitabine/cisplatin), Grade 4 thrombocytopenia/epistaxis and Grade 4 thrombocytopenia (selumetinib 50 mg plus gemcitabine/carboplatin), Grade 4 febrile neutropenia (selumetinib 100 mg plus pemetrexed/carboplatin), and Grade 3 lethargy (selumetinib 75 mg plus pemetrexed/cisplatin). Partial responses were confirmed in 11 (20%) and unconfirmed in 9 (16%) patients.Conclusions:Standard doses of pemetrexed/carboplatin or pemetrexed/cisplatin were tolerated with selumetinib 75 mg BID. The selumetinib plus gemcitabine-containing regimens were not tolerated.