Phase II trial of SM-88, a cancer metabolism based therapy, in non-metastatic biochemical recurrent prostate cancer
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PHASE II STUDIES
Phase II trial of SM-88, a cancer metabolism based therapy, in non-metastatic biochemical recurrent prostate cancer Benjamin A. Gartrell 1 & Mack Roach III 2 & Avi Retter 3 & Gerald H. Sokol 4,5,6 & Giuseppe Del Priore 6 & Howard I. Scher 7,8 Received: 28 July 2020 / Accepted: 21 August 2020 # The Author(s) 2020
Summary Background Androgen deprivation therapy (ADT) is a standard treatment for high-risk biochemically-recurrent, nonmetastatic prostate cancer (BRPC) but is not curative and associated with toxicity. Racemetyrosine (SM-88) is an amino-acid analogue used with methoxsalen, phenytoin, and sirolimus (MPS) to enhance SM-88 activity. Method A phase 1b/2, open-label trial in BRPC and rising PSA. Patients were given daily SM-88 (230 mg BID), methoxsalen (10 mg), phenytoin (50 mg), and sirolimus (0.5 mg)). Outcome measures included changes in PSA, circulating tumor cells (CTCs) and imaging. Results 34 subjects were screened, 23 treated and 21 remained on study for ≥12 weeks. The median PSA was 6.4 ng/ml (range 1.7–80.1); doubling-time 6.2 months (range 1.4–36.6) and baseline testosterone 319.1 ng/ml (range 2.5– 913.7). Median duration of therapy was 6.5 months (2.6–14.0). CTCs (median 48.5 cells/4 ml (range 15–268) at baseline) decreased a median of 65.3% in 18 of 19 patients. For patients who achieved an absolute CTC nadir count of 2 ng/ml); and local or metastatic progression by CT and bone scan mandated at study end (6 months after SM-88 start) or earlier if clinically indicated as determined by the local investigator. Additional outcomes included evaluations of adverse events commonly ascribed to androgen deprivation. The sample size was based on a single stage design using the exact binomial distribution to allow testing the hypotheses that the approximate overall clinical benefit rate (OCBR) of SM-88 was >25%. The OCBR was defined by PSA level or CTC enumeration, and no imaging worsening after initiation of therapy. For comparison, the assumed spontaneous OCBR was set at 10%. Therefore 33 subjects would yield a type I and type II error rate of 80%, respectively.
Results As of September 2019, 34 subjects were screened, with 23 subjects enrolled. 21 subjects remained on study for ≥12 weeks. Per protocol, 4 subjects who received the same regimen from Phase 1b portion of the trial were included in the 21 patient overall phase 2 cohort. Table 1 presents the demographic and disease characteristics of the cohort. The population is typical for this disease except for the inclusion of several co-morbid conditions often excluded in clinical trials of hormone based therapy (see Table 2). Median duration of therapy was 6.5 months (range 2.6 to 14.0 months). The cumulative exposure of the entire cohort was >149 months of daily dosing (See Fig. 1). Because of the observed outcomes, the trial was terminated early after clinical experts determined the results justified consideration of moving forward with later stage clinical testing in a randomized trial design. All subjects had PSA values >2 ng/dL at
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