Study Design–Part (P)1, for dose selection, P2: added (Ad), “It is possible for another dosing regimen to be selected for P2, or selected regimen to be modified after initiation of P2, as a result of Sponsor’s periodic medical review of cumulative clinical safety and tolerability findings during study.” Synopsis: Definition of dose-limiting toxicity: exclude Grade (G) 3 fever, transient (≤24h) G3 chills or flu-like symptoms, or G3 fatigue lasting ≤7 days (Ds). Treatment with ISIS EIF4ERx beyond Cycle (C)10, Ad: “During these additional Cs, all applicable procedures listed under Cs1-10 in the Schedule of Procedures will be followed except for docetaxel administration.” Tumor assessments at 28-D posttreatment follow (F)-up visit for subjects without prior disease progression, Ad: “If the duration between patient’s last treatment cycle-associated tumor assessment and F-up visit is too short to warrant performance of radiological procedures (e.g., ≤27Ds), performance of an unscheduled tumor assessment at 1-3 weeks after visit should be considered rather than waiting until first of every-8-week F-up visits.” Ad denosumab to Exclusion Criteria 13. Ad recommended use of Dubois and Dubois formula for body surface area calculation. Permitted omission, reduction, or lengthening of 1h interval between EIF4E Rx and docetaxel infusions on drug administration Ds other than P1, C1, D1. Ad time windows for dexamethasone dosing schedule and allow for changes to schedule on Ds other than P1, C1, D1. Transaminase elevation to >5x upper limit of normal (ULN) and bilirubin >1xULN, dose adjustment changed from “Remove from protocol treatment” to “Hold both docetaxel and ISIS EIF4ERx. Consult with Isis Medical Monitor, or designee, to determine conditions under which treatment may be resumed.” Immunogenicity evaluation Ad to P1 and P2, Arm B schedules. Ad coagulation panel to Screen procedures. Reduced circulating tumor cells sampling to C0–D1–predose, C1–D1–predose, C2–D22, and C4–D22.

Added “(i.e., 1000 mg)” to end of statement “Arm B: docetaxel and prednisone plus ISIS 183750 at dosing regimen identified in Part 1”. Revised inclusion criteria #10 subpart “g” to PT <1.3 x ULN (<15 sec) and INR <1.2 x ULN. Added “Serum albumin ≥3.0 g/dL” to inclusion criteria #10 as subpart “I”. Clarified: “… delays dosing >7 days …” changed to “… delays in initiating treatment cycle >7 days …” “If treatment cannot be initiated ≤21 days, the patient ….” changed to “If a new treatment cycle cannot be initiated ≤21 days from Day 22 of the previous treatment cycle (i.e., the duration between the Days 1 of sequential cycles > 42 days), the patient ….” Changed limit for ISIS EIF4E Rx dose reductions to 400 mg and allow for continued treatment with chemotherapeutics in absence of continued ISIS EIF4E Rx dosing. Added reduction of ISIS EIF4E Rx at lower transaminase criteria (i.e., >3.0 to 5.0 x ULN). Added clarification to conditions for resumption of dosing. Section number for section on dose modifications for Grade 3 or 4 or Prolonged Grade 2 Toxicities changed from 7.2.10 to 7.2.11. Introduced new guidance for dose modification in response to albumin reductions.

Addition of the statement “Once all patients have discontinued from treatment with study drug, the Sponsor may terminate further assessments for disease progression when sufficient events have occurred to support estimation of the effect of study drug on time to disease progression.