Combining CRLX101, a Nanoparticle Camptothecin, With Enzalutamide in People With Progressive Metastatic Castration Resistant Prostate Cancer Following Prior Enzalutamide Treatment

Summary

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Description

Background: Enzalutamide is established as first-line hormonal therapy in participants with metastatic castration resistant prostate cancer (mCRPC). However, it is increasingly recognized that acquired resistance to therapy (e.g. AR overexpression, AR-V7) could limit the durability of response to th...

Background: Enzalutamide is established as first-line hormonal therapy in participants with metastatic castration resistant prostate cancer (mCRPC). However, it is increasingly recognized that acquired resistance to therapy (e.g. AR overexpression, AR-V7) could limit the durability of response to therapy Upregulation of HIF-1Alpha in hypoxic tumor cells provides a mechanism of acquired resistance to current hormonal therapies and chemotherapies. Acquired resistance increases angiogenesis and metastasis, leading to disease progression Targeting the hypoxia driven tumor microenvironment (e.g. down-regulation of HIF-1Alpha) in addition to the androgen receptor (e.g. enzalutamide) has synergistic activity against prostate cancer cell line models (e.g. LNCaP, 22Rv1). CRLX101 is a nanoparticle drug conjugate composed of 20(S)-camptothecin (a potent and highly selective topoisomerase I inhibitor with anti-HIF-1Alpha properties) conjugated to a linear, cyclodextrin-polyethylene glycol-based polymer CRLX101 has been to shown to be safe, tolerable, and efficacious in numerous Phase II clinical investigations in a variety of tumor subtypes. Preclinical and clinical studies have shown CRLX101 significantly down-regulates HIF-1alpha, impacting tumor-driven angiogenesis. The treatment combination of CRLX101 and enzalutamide provides a reasonable approach to re-sensitizing prostate cancer cells to hormonal therapy via synergistic antitumor activity and inhibition of acquired resistance Objectives: -Primary Objective: To evaluate the anti-tumor activity of CRLX101 at the recommended phase II dose (RP2D) in combination with enzalutamide with respect to treatment response, defined as greater than or equal to 50% PSA decline or stable disease on imaging following 5 months of treatment. Eligibility: Patients must have progressive mCRPC per Prostate Cancer Working Group 3(PCWG3) Patients must be at least 18 years of age and able to give informed consent ECOG Performance Status less than or equal to 2 Evaluable metastatic disease on bone scan or measurable disease on CT Scan per PCWG3 and/or RECIST Patients must have had disease progression while receiving prior enzalutamide treatment Design: The study will be conducted using an optimal two stage Phase II design (8 participants, expandable to 21 participants total) aimed to determine the percentage of participants with a PSA decline of greater than 50% or stable disease at 5 months. The first 3 to 6 participants enrolled on study will follow a lead-in dosing scheme to confirm the safety of the combination (CRLX101 12 mg/m(2) every 2 weeks for the first two cycles, followed by CRLX101 15 mg/m(2) every 2 weeks at the start of cycle 3, with enzalutamide 160 mg administered once daily starting on cycle 1 day 2) prior to initiation of the optimal two stage study design. For participants enrolled on study following the lead-in, the confirmed tolerable dose of CRLX101 will be administered via IV infusion every 2 weeks. Enzalutamide 160 mg will be administered orally once daily beginning on cycle 1 day 2. Blood and urine will be collected at multiple time points for PK and PD analyses. Tumor assessments will be made using 99Tc bone scintography and/or CT scan (chest, abdomen, and pelvis) at baseline, prior to Cycle 3 and every 3 cycles thereafter. The accrual ceiling for the study is set at 30 participants.

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