Promising Results: Enzalutamide and CC-115 Combination Shows Potential in Treating mCRPC
A recent Phase 1b multicenter trial has shown promising results for the combination of enzalutamide and CC-115 in the treatment of metastatic castration-resistant prostate cancer (mCRPC). The trial, which focused on patients with progressive mCRPC and certain eligibility criteria, aimed to determine the safety, tolerability, and preliminary effectiveness of this combination therapy.
The study enrolled patients aged 18 and above with a life expectancy of at least 6 months, documented progressive mCRPC, and a serum testosterone level below 50 ng/dl. Eligible patients also had an ECOG performance status of 0-1 and were required to provide a tumor sample or adequate archival tissue from a metastatic site for analysis. Prior exposure to certain therapies was not permitted, and patients with central nervous system metastases or significant medical comorbidities were excluded.
Enzalutamide, a standard approved dose of 160 mg QD, was combined with escalating doses of oral CC-115 (5 mg, 10 mg, and later amended to include 7.5 mg BID) using a dose escalation design. The starting dose for CC-115 was reduced to 5 mg BID due to concerns about potential drug-drug interactions and overlapping toxicity with enzalutamide.
The trial included a dose escalation phase to establish the recommended phase 2 dose (RP2D) and an expansion phase to further assess safety, tolerability, and preliminary evidence of anti-tumor activity.
During the expansion phase, an interim analysis of 17 subjects was conducted and evaluated by a Data Monitoring Committee. The trial protocol was amended due to an unacceptable rate of grade 3 rash toxicities observed at higher doses of CC-115. The dose of CC-115 was ultimately reduced to 5 mg BID. Adverse events were recorded and graded per the NCI-CTCAE version 4.0.
The trial also evaluated pharmacokinetic parameters to assess potential drug-drug interactions between enzalutamide and CC-115. Blood or plasma concentration versus time data were used to derive these parameters.
PSA response, time to PSA progression, and radiographic progression-free survival were calculated and evaluated according to predefined criteria. Biomarker analyses, including genomic profiling and evaluation of circulating tumor cells, were conducted on available specimens.
According to the preliminary results, the combination of enzalutamide and CC-115 showed promising anti-tumor activity in patients with mCRPC. The trial aimed to establish the RP2D, assess safety, and evaluate preliminary efficacy, with a focus on PSA response rates.
The trial design included a stopping boundary in case of excessive dose-limiting toxicities, and the expansion phase used a Simon two-stage design to assess treatment efficacy based on PSA response rates.
While the trial did not recruit the intended number of patients at the RP2D for CC-115, the reduction in the frequency of grade 3 rash toxicities was encouraging.
In addition to evaluating the efficacy of the combination therapy, the trial explored the association of PI3K/mTOR pathway activations with PSA response and time to PSA progression.
In vitro studies using prostate cancer cell lines were also conducted to evaluate the effects of CC-115, NU-7441 (a DNA-PK inhibitor), and INK128 (an mTORC1/2 inhibitor) on DNA-PK and PI3K/AKT/mTOR pathway activation.
Although further research is needed, these preliminary findings suggest that the combination of enzalutamide and CC-115 holds promise in the treatment of mCRPC. The study provides valuable insights into the safety, tolerability, and potential efficacy of this combination therapy, highlighting the importance of ongoing research in the field of prostate cancer treatment.
Sources:
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