Pharmacodynamic-guided, modified continuous reassessment method (mCRM)-based, do...
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`Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings (Post-Meeting Edition).
`Vol 24, No 18S (June 20 Supplement), 2006: 3020
`© 2006 American Society of Clinical Oncology
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`Abstract
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`Pharmacodynamic-guided, modified continuous reassessment
`method (mCRM)-based, dose finding study of rapamycin in
`adult patients with solid tumors
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`A. Jimeno, P. Kulesza, G. Cusatis, A. Howard, Y. Khan, W. Messersmith, D. Laheru, E.
`Garrett-Mayer, S. D. Baker and M. Hidalgo
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`Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD
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`3020
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`Background: Pharmacodynamic (PD) studies, using either surrogate or tumor tissues, are
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`frequently incorporated in Phase I trials. However, it has been less common to base dose
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`selection, the primary endpoint in Phase I trials, in PD effects. We conducted a PD-based
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`dose selection study with rapamycin (Rap). Methods: We used the modified continuous
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`reassessment method (mCRM), a computer-based dose escalation algorithm, and adapted
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`the logit function from its classic toxicity-based input data to a PD-based input. We coupled
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`this design to a Phase I trial of Rap with 2 parts: a dose estimation phase where PD
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`endpoints are measured in normal tissues and a confirmation phase where tumor tissue is
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`assessed. Patients (pts) had solid tumors refractory to standard therapy. Rap was given
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`starting at 2 mg/day continuously in 3-pt cohorts. The PD endpoint was pP70S6K in skin
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`and tumor. Biopsies were done on days 0 and 28 of cycle 1, and a PD effect was defined
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`as
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` 80% inhibition from baseline. The first 2 dose levels (2 and 3 mgs) were evaluated
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`before implementing the mCRM. The data was then fed to the computer that based on the
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`PD effect calculated the next dose level. The mCRM was set so escalation continued until
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`a dose level elicited a PD effect and the mCRM assigned the same dose to 8 consecutive
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`pts, at which point the effect of that dose will be confirmed in tumor biopsies. Other
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`correlates were PET-CT and pharmacokinetics. Results: Ten pts were enrolled at doses of
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`2 mg (n = 4), 3 mg (n = 3) and 6 mg (n = 3). Toxicity was anemia (4 G1, 1 G2), leucopenia
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`(1 G1, 2 G2), low ANC (2 G2), hyperglycemia (2 G1, 1 G2), hyperlipidemia (4 G1), and
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`mucositis (1 G1, 1 G2). PD responses were seen in 2 and 1 pt at 2 and 3 mg dose levels.
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`Input of data to the mCRM selected a dose of 6 mg for the third cohort, where PD effect
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`was seen in 1 pt, and thus a fourth dose around 9 mg will be tested. No responses by
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`RECIST occurred, but 2 pts had a response by PET. The PK was consistent with prior data
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`(t1/2 24.6 ± 10.2 h, CL 31.4 ± 12.0 L/h, vol of distribution 235 ± 65 L), and exposure
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`increased with dose. Steady-state concentration were in the 5–20 nM range. Conclusions:
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`mCRM-based dose escalation based on real-time PD assessment is feasible and permits
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`the exploitation of PD effects for dose selection in a rational manner.
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`No significant financial relationships to disclose.
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`Abstract presentation from the 2006 ASCO Annual Meeting
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`Prescribing Information, including
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`patients with severe hepatic impairment. Concomitant use of
`VOTRIENT and simvastatin increases the risk of ALT
`elevations and should be undertaken with caution
`Interactions
`during treatment,
`reduce, or discontinue dosing as recommended.
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`Prescribing Information, including
`
`patients with severe hepatic impairment. Concomitant use of
`VOTRIENT and simvastatin increases the risk of ALT
`elevations and should be undertaken with caution
`Interactions
`during treatment,
`reduce, or discontinue dosing as recommended.
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`http://meeting.ascopubs.org/cgi/content/short/24/18_suppl/3020
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`7/20/2016
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`Exhibit 1064
`Page 001
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`West-Ward Pharm.
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