A phase I dose-escalation study of oral BR-DIM (BioResponse 3,3'- Diindolylmethane) in castrate-resistant, non-metastatic prostate cancer

Abstract

3, 3'-diindolylmethane (DIM) modulates estrogen metabolism and acts as an anti-androgen which down-regulates the androgen receptor and prostate specific antigen (PSA). We conducted a dose-escalation, phase I study of BioResponse (BR)-DIM with objectives to determine the maximum tolerated dose (MTD), toxicity profile, and phar-macokinetics (PK) of BR-DIM, and to assess its effects on serum PSA and quality of life (QoL).

Patients and methods: Cohorts of 3-6 patients received escalating doses of twice daily oral BR-DIM providing DIM at 75 mg, then 150 mg, 225 mg, and 300 mg. Toxicity was evaluated monthly. Serum PSA and QoL were measured at baseline, monthly during treatment, and at end of study.

Results: 12 patients with castrate-resistant, non-metastatic, PSA relapse prostate cancer were treated over 4 dose cohorts; 2 patients (at 150 mg and 225 mg, respectively) underwent intra-patient dose escalation, by one dose level. After oral administration of the first dose of BR-DIM, the plasma exposure to DIM appeared dose proportional at doses ranging from 75 to 300 mg, with the mean C(max) and mean AUC(last) increasing from 41.6 to 236.4 ng/ml and from 192.0 to 899.0 ng/ml*h, respectively. Continued relatively stable systemic exposure to DIM was achieved following twice daily oral administration of BR-DIM. Minimal toxicity was observed. Two of the four patients treated at 300 mg had grade 3 asymptomatic hyponatremia (AH) discovered on routine blood work. The other 2 patients at this dose had no AH. Therefore, the maximum tolerated dose (MTD) was deemed to be 300 mgand the recommended phase II dose (RP2D) of BR-DIM was 225 mg twice daily. One patient without AH at 225 mg experienced a 50% PSA decline. One patient with BR-DIM dose of 225 mg had PSA stabilization. The other 10 patients had an initial deceleration of their PSA rise (decrease in slope), but eventually progressed based on continual PSA rise or evidence of metastatic disease. Ten patients completed monthly QoL reports for a mean of 6 months (range: 1-13). QoL measures emotional functioning may have held up somewhat better over time than their physical functioning.

Conclusion: BR-DIM was well tolerated. Increasing systemic exposure to DIM was achieved with the increase of BR-DIM dose. Modest efficacy was demonstrated. Patients' QoL varied over time with length of treatment. Phase II studies are recommended at the dose of 225 mg orally twice daily.

Keywords: BR-DIM; DIM; PSA relapse; clinical trial; diindolylmethane; indole-3-carbinol; phase I.

Figure 1

DIM maximum plasma concentration (C_max) (a) and area under the plasma concentration-time curve (AUC_0-t) as a function of BR-DIM dose. The symbols (▴ and Δ) represent the individual values for C_max and AUC_0-t; the dash lines represent the mean value at each dose level.

Figure 2

PSA Response Curves for 7 patients. The actual PSA values are plotted overtime for each of the 7 patients who ended their BR-DIM treatment at the RP2D of 225 mg twice daily. The different line types identify three time periods: pre-, during, and post-therapy with BR-DIM. The upper graph is for the 2 patients (ID # 4, 5) who started at 150 mg twice daily; the middle graph is for the 2 patients (# 7, 8) who started at 225 mg twice daily; and the lower graph is for the 3 patients (# 10, 11, 12) who started at 300 mg twice daily. Patient ID numbers in Figure 2 match those in Table 3. To accommodate the high variability in PSA values while still providing adequate visibility in their lower range, and to keep PSA in its original units for easier visual interpretation, different scalings on each of the three Y-axes were utilized.

Figure 3

QoL scores over time. Median scores over time for Emotional Functioning and for Physical Functioning are shown for patients who completed QoL questionnaires.