TRESR Study Identifies Tolerable Dosing Schedule for ATR Inhibitor RP-3500

Results from 3 dosing cohorts in the phase 1/2a TRESR study (NCT04497116) evaluating RP-3500 identified a 160-mg dose on a 3 days on/4 days off continuous cycle as most tolerable for patients with selected ATR-inhibitor–sensitizing DNA damage response alterations, according to data presented during the 2022 European Society of Medical Oncology Targeted Anticancer Therapies Congress in March

“We were able to explore multiple drug dosing schedules. [Dosing] schedules were guided by drug exposure, target engagement analysis, and tolerability,” said lead investigator Elisa Fontana, MD, PhD, a translational oncologist and research fellow at Sarah Cannon Research UK in London, England.

Preclinical in vivo pharmacokinetic (PK)/ pharmacodynamic (PD) models, clinical PK, PD biomarkers, circulating tumor (ct) DNA, and safety data were used to develop an optimal dosing schedule and resulted in the recommended phase 2 dose schedule (3 days on/4 days off) and efficacious dose level (> 100 mg) for target inhibition. The investigators used the decrease in ctDNA mean variant allele frequency as a surrogate for RP-3500 activity, and hematology data from cycle 1 were used to develop a nomogram to mitigate anemia, a commonly reported on-target toxicity.

The 3 dosing cohorts were characterized by a 120 mg once daily dose on a 3 days on/ 4 days off cycle (n = 25; cohort A); 160 mg once daily dose on a 3 days on/4 days off cycle (n = 34; cohort B); and 160 mg once daily dose on a 3 days on/4 days off, 2 weeks on/1 week off cycle (n = 26; cohort C).

In cohort A, the median number of cycles completed was 3 (range, 1-9); for cohorts B and C, the median number of cycles completed was 2 each (cohort B: range, 0-12; cohort C: range, 0-8), respectively.

The investigators reported more than 3 interruptions that were attributed to adverse events (AEs) in 3 patients (12.0%) in cohort A and 1 patient in cohort C (3.8%). Two interrup- tions in dosage were reported in 3 patients (12.0%) in cohort A, 4 patients (11.8%) in cohort B, and 1 patient (3.8%) in cohort C. In cohort A, 6 patients (24.0%) reported 1 interruption, and 4 patients each (11.8% and 15.4%, respectively) reported 1 interruption in cohorts B and C.

Six patients (17.6%) in cohort B reported 1 dose reduction. Additionally, 3 patients (12.0%) in cohort A, and 1 patient (3.8%) in cohort C reported dose reduction. Two dose reductions were reported in 1 patient each for cohort A (4.0%) and cohort C (3.8%), respectively.

“Overall, the 3 dosing schedules show a similar toxicity profile by dose level,” Fontana said. “Blood transfusions are most frequently required in patients in the higher dose schedule; however, this is easily miti- gated by omission of the third week of treat- ment,” she said.

Regarding safety, treatment-related AEs were also similar across the cohorts with less than 25% of patients experiencing them. The most common treatment-related AE was on-target anemia. Further, there were minimal gastrointestinal toxicities or fatigue observed.

Declining ctDNA dynamics also were seen across the 3 cohorts. Fontana noted that ctDNA may represent a potential surrogate of activity once final readouts are available in the upcoming months.

The investigators developed a nomogram that tracks anemia to predict the expected level of hemoglobin in cycles 2 and 3 after 7 days of treatment. “We observed a highly significant correlation between observed and predicted levels of hemoglobin using the phase 1 data, and we are now planning on prospectively testing the tool in ongoing studies,” Fontana said. It is hoped that this tool will help to identify patients at increased risk of anemia at the initial dose/schedule and reduce the need for dosage holds or transfusions, Fontana said.

_REFERENCE

_{Fontana E, Lee E, Rosen E, et al. Comprehensive dose finding strategy for single agent RP-3500, a highly selective inhibitor of ataxia telangi- ectasia and RAD3 related (ATR) kinase. Ann Oncology. 2022:33(suppl 1):S3-S6. doi:10.1016/j.annonc.2022.01.068}