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The first-in-patient (FIP) starting dose for oncology agents should be reasonably safe and provide potential therapeutic benefit to the patient. For late-stage oncology patients, this dose is often based on the ICH S9 guidance, which was developed primarily based on experience with cytotoxic chemotherapeutic agents using the rodent STD10 or non-rodent HNSTD and an appropriate safety factor. With the increase in molecularly targeted chemotherapeutics, it is prudent to re-evaluate how the FIP dose is derived to ensure that the appropriate balance between risk and therapeutic benefit to the patient is achieved. Blinded data on 92 small molecule oncology compounds from 12 pharmaceutical companies who are members of the IQ DruSafe consortium were gathered to investigate if a NOAEL-based starting dose without a safety factor would have been tolerated in the FIP trial and if so, estimating how many dose escalation cohorts could have been reduced. Our analysis suggests that the NOAEL-based alternative starting dose would have been tolerated in most cases evaluated, with an anticipated mean reduction of 2.3 cohorts. Of the 12 cases where the alternative approach resulted in a starting dose that would have exceeded the MTD/RP2D, none of the nonclinical toxicities in these cases were considered irreversible and would be monitorable in all but one instance. Most non-tolerated cases were within two–threefold of the MTD/RP2D, with the clinical AEs considered manageable and mitigated by dose de-escalation. No one method of FIP dose calculation will likely be appropriate for all oncology small molecules and starting dose selection should be performed using a case-by-case approach. However, the NOAEL-based method that does not utilize a safety factor should be considered when appropriate to minimize the number of patients exposed to sub-therapeutic doses of an investigational oncology agent and accelerating development to RP2D. [ABSTRACT FROM AUTHOR]

Cyclin-dependent kinases (CDKs) play a significant role in the control of cell-cycle progression and exhibit aberrant regulation in various neoplastic diseases. AG-024322 is a potent inhibitor of CDK1, CDK2, and CDK4 that produces cell-cycle arrest and antitumor activity in preclinical models. This study evaluated the toxicity of AG-024322 when given by intravenous (IV) infusion to cynomolgus monkeys, including reversibility of effects. Male and female monkeys received AG-024322 by 30-min IV infusion once daily for 5 days at doses of 2, 6, and 10 mg/kg (24, 72, and 120 mg/m2, respectively). Controls received vehicle alone which was aqueous 5% dextrose, pH 3.8. Three animals/sex/group were necropsied on day 6, and two animals/sex/group at 6 and 10 mg/kg were necropsied on day 22 (reversal cohort). Doses were based upon the results of a dose range-finding study in monkeys; decreased white blood cells occurred at ≥3 mg/kg and 12 mg/kg produced central nervous system effects and was above the maximum-tolerated dose. No deaths occurred and clinical signs of toxicity, including swelling at the IV administration site, were seen at ≥6 mg/kg. AG-024322 at ≥6 mg/kg produced pancytic bone marrow hypocellularity, lymphoid depletion, and vascular injury at the injection site. Renal tubular degeneration occurred at 10 mg/kg. These changes were either reversible or in a process of repair following the 17-day recovery period. Hematology changes included decreases in reticulocytes and/or granulocytes at ≥6 mg/kg, which were reversible and consistent with changes in the bone marrow. Lymphoid and bone marrow depletion are consistent with pharmacologic inhibition of CDKs by AG-024322 and were expected findings. On day 22, vacuolar degeneration of pancreatic acinar cells with increased serum amylase and lipase levels occurred in one female at 10 mg/kg. Neither sex-related differences in toxicokinetics nor plasma accumulation over 5 days of dosing were seen. Terminal phase overall mean half-life on day 5 ranged from 6.69 to 8.87 h (across dose levels) and was not dose dependent. The no-adverse-effect dose of AG-024322 was 2 mg/kg and associated with overall mean plasma AUC(0–24.5) of 2.11 μg h/mL. [ABSTRACT FROM AUTHOR]