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Fractionated dose radiolabeled antiprostate specific membrane antigen (PSMA) radioimmunotherapy (177Lu-J591) with or without docetaxel for metastatic castration-resistant prostate cancer (mCRPC).
Background: A phase II trial single-dose 177Lu-J591 was published. Dose fractionation offers theoretic advantages and 2 phase I dose-escalation studies of 177Lu-J591 have been performed to test the hypothesis that higher cumulative radiation doses can be administered with an acceptable toxicity profile. Methods: Pts with mCRPC and normal neutrophil and platelet counts were enrolled in 2 sequential phase I dose-escalation studies: (1) 177Lu-J591 administered as a single-agent 2 doses 2-weeks apart to determine the maximum tolerated dose (MTD) with expansion cohorts at the recommend phase II doses (RP2D) and (2) fractionated dose 177Lu-J591 in combination with docetaxel 75 mg/m2q3 weeks to determine the MTD. Results: 44 men with median age 75.4 (range 55.1-95.2) were enrolled in the single-agent fractionated dose escalation 177Lu-J591 trial and 15 men with median age 69.1 (49.3-80.8) were enrolled in 177Lu-J591 + docetaxel trial. The RP2D’s of fractionated 177Lu-J591 were 40 mCi/m2 x2 or 45 mCi/m2 x2 with the option for GCSF; at these doses (n=28), 8 (28.6%) with >50%, 11 (39.3%) >30%, and 16 (57%) of 28 pts with any PSA decline; pts at RP2D lived longer (p<0.0001). Predictable, reversible myelosuppression was seen. 18 (40.9%) received chemo prior to RIT and 24 (54.5%) received chemo post 177Lu-J591 [median of 7 cycles (range 1-20)]. In combination with docetaxel, the MTD/RP2D of 177Lu-J591 is 40 mCi/m2x2 doses (delivered with cycle 3), with 73.3% >50%, 80.0% >30%, and 86.7% with any PSA decline. Conclusions: Fractionated 177Lu-J591 is tolerated with subsequent PSA declines and reversible myelosuppression. The apparent dose-response of single-dose 177Lu-J591 appears confirmed with fractionated dosing (improved PSA declines and OS at higher doses). Despite predictable myelosuppression, chemotherapy is able to be delivered prior to 177Lu-J591, concurrently, or following radioimmuotherapy. Clinical trial information: NCT00538668, NCT00916123.
|Study||N||>30% PSA decline||Median OS (mo)|
|Fractionated dose 177Lu-J591||44||29.5%||24.9|
|Low dose sub-group||16||12.5%||14.6|
|Fractionated 177Lu-J591 + docetaxel||15||80.8%||18.1|