Phase II trial of pharmacodynamically (PDally)-guided optimal biologic dose titration (OBDT) of sorafenib (S) in combination wit

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Author(s): M. A. Quintela-Fandino,
A. Young, S. Webster, M. Grewal, L. Wang, M. J. Moore, M. Krzyzanowska,
T. W. Mak, L. L. Siu; Princess Margaret Hospital, Toronto, ON, Canada;
Ontario Cancer Institute, Toronto, ON, Canada
There is a paucity of reliable PD assays for guiding individual OBDT.
PD effects of kinase inhibitors have been previously measured in static
tissues. We developed a dynamic flow-cytometric PD assay that
quantitates RAF signal transduction capacity (STC) based on the
differential MEK´s phosphor-status in stimulated vs. basal conditions
(phosphor-shift [PS]) in PBMCs. In a pilot study of 7 patients (pt)
with advanced solid tumors in a phase I trial (unpublished data) the %
of PS inhibition (I) 7 days after starting S at 400 mg BID showed a
10-fold interpatient variation and correlation with TTP. PDGFR-B/VEGFR2
blockade plus mC showed synergistic effect in the RIP1-Tag2 mouse NET
model (J Clin Oncol. 23:939) In this phase II trial of aNET a double
antiagniogenic strategy is undertaken: PD-guided OBDT of S + mC.
Eligibility criteria included: unresectable NET with documented PD
within 6 months prior to entry; ECOG 0-2; unlimited prior therapy but
S; octreotide allowed. Therapy: pt start run-in phase with S at 200mg
bid + 50 mg QD fixed dose of mC. After 7 d they escalate to 400 mg BID
of S regardless of RAF STC assay results. RAF STC and toxicity are then
assessed Q14d, escalating S at 200 mg BID increments until any of the
following is achieved: a) 90% RAF STC I; b) maximum S dose of 800 mg
BID; or c) intolerable Gr 2 or G3+ toxicity. Once S dose is determined
based on these criteria, cycle 1 begins. Design: Simon 2-stage optimal;
P0 = 0.05 P1 = 0.2; ? =0.05 ? = 0.1.
Results: Accrual: 10 pt
M:F = 6:4, islet cell:carcinoid = 5:5, age median 56 (40-79), ECOG 0:1
= 5:5. S doses (mg BID) at cycle 1 were 200 (2 pt)/400 (5)/600 (2)/800
(1); corresponding cycle 1 day 1RAF STC I (%) were 5, 53/94, 100, 95,
16, 65/25, 41/71, respectively (R2 = 0.13 p = 0.72) Most
frequent Gr 3 non-hematologic possibly related adverse events in 30
cycles: hand-foot (2 pt), hypertension, abdominal pain, diarrhea,
vomiting, lipase, ileal perforation (1 each). Disease control rate (9
evaluable pt): 78% (95% CI: 52-100%) (1PR, 6 SD).
Conclusions: This
approach appears feasible/safe. Large interpatient S dose differences
are needed to achieve RAF SCT I/toxicity balance. No S dose-RAF SCT I
relation is shown. Disease control rate is promising.