Dose Reduction and Treatment interruptions. 53 4.5 Potential Drug Interactions, Excluded Concomitant Medications and Procedures 54
Dose Reduction and Treatment interruptions. Subjects will be monitored continuously for adverse events (AEs) while on study from the time of signing informed consent through 30 days after the date of the decision to permanently discontinue study treatment. Subjects will be requested to notify their physician immediately for any occurring AE. Causality assessment of AEs should include at minimum confounding factors such as disease and concomitant medications. Adverse event severity will be categorized according to CTCAE v.5.0. The following criteria should be taken into consideration in decisions regarding dose modifications (reductions or interruptions): - As a general approach all AEs should be managed with supportive care at the earliest signs of toxicity. Should this be ineffective, dose reductions or interruptions should be considered to prevent worsening of toxicity. - The assigned cabozantinib starting dose for study treatment is 60 mg qd. When dose reduction is necessary, it is recommended to reduce to 40 mg daily, and then to 20 mg daily. Summary of cabozantinib dose reductions will be permitted (see section 3.0, table 6A-B): 60 mg qd to 40 mg qd (level 1) 40 mg qd to 20 mg qd (level 2) - Dose reductions are recommended for events that, if persistent, could become serious or intolerable. Dose modification criteria for study treatments are shown in Table 7. Doses may be modified at any time on study treatment. - Dose interruptions are recommended for management of CTCAE grade 3 or greater toxicities or intolerable grade 2 toxicities. - If the subject recovers from his or her AEs to CTCAE v.5.0 Grade ≤ 1 or to the baseline value (or lower) and the AE was unrelated to study treatments, then study treatment may be restarted with no change in dose. - If the subject recovers from his or her AEs to Grade ≤ 1 or to the baseline value (or lower) the toxicity was deemed possibly related to study treatments, then study treatment may be restarted at a reduced dose (see Table 6A-B for the schedule of dose reductions). Subjects receiving a daily cabozantinib dose of 20 mg may be restarted at the same dose if deemed safe at the discretion of the investigator. Subjects unable to tolerate a cabozantinib daily dose of 20 mg will discontinue study treatment. - Dose modifications may also occur in the setting of lower grade toxicity than defined in Table 7, if the investigator feels it is in the interest of a subject’s safety. - Dose interruptions of study treatment for any reason are allowed for up to 6 weeks....