Discussion
NOAEL-based, toxicity, cancer, toxicities, ICH, FIP
CANCER, FIP
The primary goal of selecting a FIP starting dose for cancer patients should be to define a safe dose level that is sufficiently high to potentially result in clinical benefit and to enable rapid identification of the RP2D [Similarly, Le Tourneau et al. reviewed the Scopus abstract database for FIP trials of MTAs in cancer patients and concluded the derivation of the starting dose was safe but was based on diverse practices using a variety of nonclinical toxicological parameters (e.g., MTD, TDL, LD10, NOAEL). This analysis showed that starting doses for MTAs were based on rodent and non-rodent data in similar proportions, and overall, starting doses selected using a toxicity-based method did not exceed the human MTD in 96% of clinical trials reviewed. A median of five dose levels was required from the starting dose to the clinical MTD, which is a similar number of cohorts reported by Mittapalli [The analysis performed in this paper provides an opportunity to review the optimal starting dose algorithm(s) to enable a reduction in the number of cancer patients starting clinical trials at sub-optimal therapeutic doses and to minimize the number of dose escalation steps and time needed to reach MTD or RP2D. An analysis of 92 small molecule oncology compounds from 12 pharmaceutical companies showed that in more than half of cases the approach used was more conservative than the ICH S9 guideline dictates. In some cases, a less aggressive starting dose was justified based on the data. However, it was rare for starting doses to be significantly more aggressive than the guideline.Our analysis demonstrates that a less conservative approach to starting dose selection, such as basing the FIP dose on the nonclinical NOAEL without a safety factor, would generally be safe and would reduce the number of dose levels tested in the clinic. To encourage sponsors to be more aggressive in starting dose selection for small molecule oncology therapeutics, thereby reducing the number of patients treated at sub-efficacious dose levels and accelerating drugs to approval, we encourage sponsors to propose and discuss with regulatory agencies using this alternative NOAEL-based method to justify higher starting doses when the data supports it as outlined in Fig. Proposed decision tree for justifying starting dose for FIP oncology studiesIn the majority of cases evaluated (82%), the NOAEL-based alternative starting dose would have been safe. The number increases to 93% when evaluating those that originally used the HNSTD or STD10 approach. The reasons for not using the HNSTD or STD10 approach vary, but one common alternative is the use of MABEL. The MABEL is typically applied to immune-oncology agents, mostly those with agonist activity, for which the pharmacological activity is of great safety concern and the translation from nonclinical to clinical safety has lower confidence [Of the 12 (18%) cases where the NOAEL-based alternative starting dose would have exceeded the MTD/RP2D, nonclinical toxicities would have been monitorable in all but one instance. Of these 12 cases, only 3 used HNSTD or STD10 to select the actual starting dose. Others used MABEL, NOAEL with safety factors, or pharmacokinetic/pharmacodynamic modeling. Of the 12 cases, 8 NOAEL-based alternative starting doses were within two–threefold of the clinical MTD/RP2D. Those within twofold of the RP2D would not likely have resulted in significant toxicity as this is within a typical single cohort escalation. Those within threefold might be a slightly more, but possibly acceptable, risk of causing toxicity. Of the remaining 4 cases with NOAEL-based starting doses between 4.5- and 20-fold the MTD/RP2D, 2 were IO agents using IT delivery, one of which did not determine the clinical MTD (implying RP2D was not based on tolerability). IT delivery is often limited by the maximum feasible dose determined by formulation or delivery volume restrictions. In the other 2 cases, both with a NOAEL-based alternative starting dose sixfold the MTD/RP2D, 1 used a NOAEL-based approach with a 50-fold safety factor, implying heightened safety concern, while the other used a LOAEL-based approach with a sixfold safety factor. It should be noted that in the latter case, the actual starting dose was not only the same as the NOAEL-based alternative but was not tolerated and the RP2D was 1/5 the starting dose. Therefore, these 4 cases would not be likely candidates for the NOAEL-based alternative method.Extensive analysis of translation from nonclinical toxicology studies to clinical findings have been previously published [The decision tree (Fig. In conclusion, retrospective analysis of previously determined starting doses for oncology therapeutics clearly indicate more aggressive starting dose selection should be considered to reduce the use of sub-therapeutic dose levels in oncology patients, and accelerate patient access to effective drugs [