Results: Four patients had tumor responses (44%) to AXL1717 treatment. Two of these had stable disease for 12 months (10 cycles at 215-300 mg bid). Due to MRI-detected progression they were then taken off the study. They died 8 and 12 months later, respectively. One patient was treated 8 months (6 cycles with 215 mg bid). He was withdrawn because of disease progression but died after another 25 months. The fourth patient having stable disease died of sepsis due to pancytopenia in the end of cycle 2 on 400 mg bid. A fifth patient underwent surgery after two cycles with 300 mg bid. Pathological analysis demonstrated abundant necrosis and small areas of viable tumor. After one more cycle with 300 mg bid he was withdrawn due to clinical and radiographic worsening and died 11 months later. The other 4 patients did not have any detectable responses and died within 3-13 months after trial entry. Neutropenia was the main adverse effect, which was easily detected and reversible in all but one patient.Conclusion: This clinical phase I study indicates that AXL1717 as a single agent is capable of producing prolonged stable disease and survival of patients with relapsed malignant astrocytomas. The drug was well tolerated. A new formulation of the drug will be used in further investigations in order to better define the optimal dose. www.impactjournals.com/oncotarget/

Harmenberg (2017) Phase II randomized study of the IGF-1R pathway modulator AXL1717 compared to docetaxel in patients with previously treated, locally advanced or metastatic non-small cell lung cancer, Acta Oncologica, 56:3, 441-447, DOI: 10.1080 Background:The primary objective of this study was to compare the progression-free survival (PFS) at 12 weeks between patients treated with IGF-1R pathway modulator AXL1717 (AXL) and patients treated with docetaxel (DCT). Material and methods: The study was conducted at 19 study centers in five countries. A total of 99 patients with previously treated, locally advanced or metastatic non-small cell lung cancer (NSCLC) of the squamous cell carcinoma (SCC) or adenocarcinoma (AC) subtypes in need of additional treatment were randomized and treated with either 300 or 400 mg of AXL as daily BID treatment (58 patients) or DCT given as 75 mg/m 2 in three-week cycles (41 patients) as monotherapy in a 3:2 ratio for each NSCLC subtype. Patients were treated in the primary study treatment period for a maximum of four treatment cycles. Results: The 12-week PFS rate, median PFS and overall survival (OS), as well Kaplan-Meier hazard ratio for PFS and OS, did not show any statistically significant differences between the treatment groups. For the primary endpoint, the AXL group had a lower percentage of patients (25.9%) who were progression-free at Week 12 as compared to the DCT group (39.0%), although the difference was not statistically significant. The most notable difference in the incidence of treatment emergent adverse effects (TEAEs) was the lower incidence of treatment-related grade 3/4 neutropenia in patients treated with AXL. Conclusion: These results suggest neither of the treatments to be superior of the other when treating locally advanced or metastatic NSCLC. Considering the lower incidence of grade 3/4 neutropenia in the AXL group this treatment warrants further research.

Through the use of an aerosol with specific size characteristics, it may be possible to optimize the distribution of a fluid in the respiratory tract and achieve a more homogenous humidification. It is recommended to replicate the study using 25 subjects. Relevance to clinical practice. Direct instillation of saline should not be used with mechanical ventilation.

AXL1717 is an orally bioavailable IGF-1R pathway modulator that has been shown to have anti-tumoral effects. The objectives of the present study were to define maximum tolerated dose and the recommended phase II dose (RPTD) of AXL1717 in combination with gemcitabine HCl and carboplatin in non-small cell lung cancer (NSCLC). Patients with previously untreated, locally advanced, or metastatic NSCLC (squamous cell cancer or adenocarcinoma) in good performance status and with preserved major organ functions were enrolled in the study. The study was an open-label phase I study with planned cohorts of three patients per dose level of AXL1717 (215, 290, and 390 mg BID). In total, 12 patients were enrolled in the study, and of these, two were prematurely excluded. AXL1717 was administered at one dose level, 215 mg BID. A total number of 81 unique adverse events were reported. Bone marrow toxicity was reported in 10 out of 12 patients, and this organ class showed the largest number of related events. AXL1717 in combination with gemcitabine HCl and carboplatin is a possible treatment approach in previously untreated, locally advanced, or metastatic non-small cell lung cancer. However, due to the bone marrow toxicity profile shown in the present study, further dose increases of AXL1717 above 215 mg BID will probably not be feasible. Therefore, 215 mg BID constitutes maximum tolerated dose and RPTD.

Purpose: Many cancers suffer from dysfunctional redox status. MTH1 protects cancer cells from oxidative DNA damage by preventing incorporation of oxidized nucleotides. OXC-101 (Karonudib) is a dual-action mitotic disruptor and MTH1 inhibitor, preventing exit from mitosis and sanitation of oxidative damage to DNA subunits in cancer cells. MASTIFF, (MTH1, A Phase I, Study on Tumors Inhibition, First in Human, First in Class), is a first- in- human phase 1 study, with the primary aim to assess safety, tolerability, and pharmacokinetics (PK) of OXC-101 in patients (pts) with advanced solid malignant tumors (NCT03036228). Methods: Phase 1a study with 3+3 design and intra-patient dose escalation. New cohorts were opened following review of safety and PK data by the safety data monitoring board after the first treatment cycle of 4 weeks (w). All patients had progressive stage IV disease with no treatment options in SOC at inclusion. Radiological tumor response evaluation (RECIST 1.1) was performed 8w of the first 24w, 12w thereafter. The first 29 patients (cohort 1-10) obtained an oral solution. From cohort 11 pts obtained 100mg tablets. Results: 50 subjects (50% female, 50% male) were enrolled at 16 dose levels of OXC-101 at varying posology: 25-900 mg BID, 800-1000mg QD; every second day, once or twice weekly. Mean age was 52 years (range:20-74). 92% of pts had received previous chemotherapy (mean: 5 lines, range:0-34), 18% endocrine therapy and 52% other therapies (incl immunotherapy). OXC-101 was generally well tolerated and with manageable toxicity for dose levels for an average of 121 days (range:2-513 days), and 43/50 subjects discontinued due to disease progression. A total of 20 SAEs were reported: 8 SAEs in 7 subjects were considered related/possibly related to OXC-101 and included pneumonia (3/8), febrile neutropenia (2/8), ileus (1/8), unspecified infection (1/8) and fever (1/8). There were 14 dose-limiting toxicities (DLTs) reported in 7 subjects. At 510mg every second day (1785mg weekly) 2/5 subjects reported G4 neutropenia; at 500mg BID/1000mg QD, twice per week (2000 mg weekly) 2/9 subjects reported G4 neutropenia; at 900mg BID, once weekly (1800 mg weekly) 3/3 subjects reported decrease in white blood count incl. neutropenia. PK was robust and predictable with good exposure correlation between solution and tablet formulation, with an average half-life of 10 hrs in plasma. 15/49 (31%) of the subjects showed stable disease at first radiological evaluation. One subject had stable disease during 73 weeks on OXC-101 treatment. IHC and western blot analysis on tumor biopsies confirmed mechanism of action. A dose of 900mg (500mg mane, 400mg nocte) twice a week (total weekly dose 1800mg) was determined as the Recommended Phase 2 Dose (RP2D). This will be further explored in tumor specific cohorts. Conclusion: OXC-101 has a favorable safety profile with an RP2D of 900mg twice a week. Citation Format: Jeffrey Yachnin, Lars Ny, Teresa Sandvall, Kumar Sanjiv, Martin Scobie, Björn Platzack, Pawel Barancewski, Olof Breuer, Vassilis Gorgoulis, Ioannis S. Pateras, Maria Klockare, Austin Smith, Ulrika Warpman Berglund, Thomas Helleday. OXC-101 shows favorable safety profile in first in human phase 1 trial in patients with advanced solid cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT182.