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Published on: March 6, 2018
A Phase II Study of sEphB4-HSA in Metastatic Castration-Resistant Prostate Cancer
David J VanderWeele1, Masha Kocherginsky2, Sabah Munir3
1Robert H. Lurie Comprehensive Cancer Center at Northwestern University, Chicago, IL; Division of Hematology Oncology, Department of Medicine, Northwestern University, Chicago, IL.
Introduction:
Ephrin receptors and their membrane-localized ligands induce bidirectional signaling and facilitate tumor-stroma interactions. Blocking the EphB4-EphrinB2 pathway, which can be accomplished by soluble EphB4 conjugated to human serum albumin (sEphB4-HSA), promotes cell death in preclinical models of aggressive prostate cancer. We hypothesized that targeting the EphB4-EphrinB2 pathway may serve as a therapeutic target in the treatment of metastatic castration resistant prostate cancer (mCRPC).
Patients And Methods:
We conducted a single arm, phase II trial in patients with progressive mCRPC who had received no more than 3 prior therapies for mCRPC. sEphB4-HSA 1000 mg IV was administered every 2 weeks, extending to 3 weeks starting from cycle 7. The primary endpoint was confirmed prostate specific antigen (PSA) response rate. We employed a Simon 2-stage Minimax design with 15 patients in the first stage and 10 additional patients in the second stage.
Results:
Fourteen eligible patients enrolled in the study with median age of 73.5 years (range: 52-83) and median baseline PSA of 65.11 ng/mL (range: 7.77-2850 ng/mL). Most patients received 3 prior therapies for mCRPC. The median treatment duration with sEphB4-HSA was 6.5 weeks (range: 2-35 weeks). Three patients experienced a serious adverse event potentially related to therapy, including 1 patient with a grade 5 event (cerebral vascular accident) possibly related to the study drug. No patient had a confirmed PSA response, and the study was stopped for futility. Thirteen patients had PSA progression. The median time to PSA progression was 28 days (90% CI: 28-42 days), and median time to radiologic progression was 55 days (90% CI: 54-72 days). Of 3 patients with measurable disease, 2 had stable disease and one had progressive disease.
Conclusion:
In patients with mCRPC who progressed on prior second generation AR-targeted therapy, sEphB4-HSA monotherapy had no discernable anti-tumor activity.
Insights
Soluble EphB4 conjugated to human serum albumin (sEphB4-HSA) did not show anti-tumor activity in metastatic castration-resistant prostate cancer (mCRPC) patients. The phase II trial was stopped early due to futility, with no patients achieving a prostate-specific antigen (PSA) response.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Ephrin receptors and ligands mediate tumor-stroma interactions via bidirectional signaling.
- Blocking the EphB4-EphrinB2 pathway shows promise in preclinical models of aggressive prostate cancer.
- Targeting the EphB4-EphrinB2 pathway is a potential therapeutic strategy for metastatic castration-resistant prostate cancer (mCRPC).
Purpose of the Study:
- To evaluate the efficacy of soluble EphB4 conjugated to human serum albumin (sEphB4-HSA) as a monotherapy for patients with progressive mCRPC.
- To determine the prostate-specific antigen (PSA) response rate in patients treated with sEphB4-HSA.
- To assess the safety and tolerability of sEphB4-HSA in this patient population.
Main Methods:
- A single-arm, phase II clinical trial was conducted.
- Patients with progressive mCRPC received sEphB4-HSA 1000 mg intravenously every 2 weeks.
- A Simon 2-stage Minimax design was employed to assess the primary endpoint of confirmed PSA response rate.
Main Results:
- Fourteen patients were enrolled; median age was 73.5 years, and median baseline PSA was 65.11 ng/mL.
- No confirmed PSA response was observed in any patient.
- The study was terminated early for futility, with 13 patients experiencing PSA progression and a median time to PSA progression of 28 days.
Conclusions:
- sEphB4-HSA monotherapy demonstrated no discernible anti-tumor activity in patients with mCRPC who had progressed on prior therapies.
- The EphB4-EphrinB2 pathway may not be a viable therapeutic target for mCRPC when targeted with sEphB4-HSA in this setting.
- Further investigation into alternative therapeutic strategies targeting this pathway or patient populations may be warranted.
