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A Single-arm Phase II Study Combining NLG207, a Nanoparticle Camptothecin, with Enzalutamide in Advanced Metastatic
Keith T Schmidt1, Fatima Karzai2, Marijo Bilusic2
1Clinical Pharmacology Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Background:
Despite the clinical efficacy of enzalutamide monotherapy in patients with advanced prostate cancer, therapeutic resistance and disease progression are inevitable. We proposed a study to evaluate NLG207, a nanoparticle-drug conjugate (NDC) of the potent topoisomerase I inhibitor camptothecin, in combination with enzalutamide, in patients with metastatic castration-resistant prostate cancer (mCRPC) following progression on enzalutamide.
Methods:
This was a single-arm, optimal two-stage, phase II study to evaluate the efficacy of NLG207 in combination with enzalutamide in patients with mCRPC who received prior enzalutamide. A lead-in dose escalation evaluated the recommended phase 2 dose of NLG207 in combination with enzalutamide. Patients received NLG207 via IV infusion every 2 weeks and enzalutamide 160 mg orally once daily.
Results:
Between March 2019 and June 2021, four patients were accrued to the lead-in dose escalation. Two of the four patients were evaluable and both experienced DLTs at the NLG207 12 mg/m2 dose level; one DLT was related to a dose delay for noninfective cystitis and myelosuppression, the other a grade 3 noninfective cystitis. Further evaluation of NLG207 in combination with enzalutamide was halted and the study was ultimately terminated. PSA declines from baseline were observed in two patients.
Conclusion:
NLG207 12 mg/m2 in combination with enzalutamide was not well tolerated in patients with mCRPC following several lines of the standard of care therapy.
Clinicaltrials.Gov Identifier:
NCT03531827.
Insights
This study found that NLG207 combined with enzalutamide was not well tolerated in advanced prostate cancer patients. The combination therapy was halted due to dose-limiting toxicities observed in early trials.
Area of Science:
- Oncology
- Pharmacology
- Drug Development
Background:
- Advanced prostate cancer, including metastatic castration-resistant prostate cancer (mCRPC), often develops resistance to enzalutamide monotherapy.
- NLG207, a nanoparticle-drug conjugate (NDC) of camptothecin, targets topoisomerase I and was investigated for combination therapy.
- The study aimed to address treatment resistance in mCRPC patients progressing on enzalutamide.
Purpose of the Study:
- To evaluate the efficacy and tolerability of NLG207 in combination with enzalutamide.
- To determine the recommended phase 2 dose (RP2D) of NLG207 for combination therapy.
- To assess outcomes in patients with mCRPC who had previously progressed on enzalutamide.
Main Methods:
- A single-arm, optimal two-stage, phase II clinical trial (NCT03531827).
- Included a lead-in dose escalation phase to identify the RP2D of NLG207.
- Patients received NLG207 intravenously every two weeks and enzalutamide 160 mg orally daily.
Main Results:
- Four patients were enrolled in the dose escalation phase.
- Two evaluable patients experienced dose-limiting toxicities (DLTs) at the NLG207 12 mg/m2 dose.
- DLTs included noninfective cystitis and myelosuppression; the study was halted and terminated.
- Two patients showed prostate-specific antigen (PSA) declines from baseline.
Conclusions:
- The combination of NLG207 at 12 mg/m2 and enzalutamide was not well tolerated in mCRPC patients.
- The observed toxicities led to the termination of further investigation for this combination therapy.
- Further research may be needed to explore alternative dosing or combinations for NLG207.
