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

Prostate Neoplasms Clinical Trial

Official title: A Single Arm Phase II Study Combining CRLX101, a Nanoparticle Camptothecin, With Enzalutamide in Patients With Progressive Metastatic Castration Resistant Prostate Cancer Following Prior Enzalutamide Treatment

Status Terminated

Clinical Trial Summary

Background:

Some prostate cancer keeps growing even when testosterone in the body drops to very low levels. This is called castrate-resistant prostate cancer. One treatment is enzalutamide. This is a modern hormonal therapy. But it only works for a certain amount of time and then the cancer becomes resistant to it. Researchers want to see if adding the treatment CRLX101 (formerly IT-101) could make enzalutamide work again for people who have already had it.

Objective:

To test a new way of treating prostate cancer using CRLX101 plus enzalutamide in people with certain prostate cancer who already had enzalutamide treatment.

Eligibility:

Adults ages 18 years and older with metastatic, castration-resistant prostate cancer who have had enzalutamide treatment

Design:

Participants will be screened with a medical history and physical exam. They will have blood and urine tests. They will have a scan of the chest/abdomen/pelvis. They will have a bone scan.

Participants will get treatment in cycles. A cycle lasts 28 days. They will take enzalutamide by mouth once a day. They will get CRLX101 through an intravenous (IV) every 1 or 2 weeks.

Participants will repeat screening tests throughout the study.

Participants will have a follow-up visit 3-4 weeks after they stop taking the study drug. They will repeat most screening tests and have an electrocardiogram.

Clinical Trial 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., androgen receptor (AR) overexpression, androgen receptor variant 7 (AR-V7) could limit the durability of response to therapy

• Upregulation of Hypoxia-inducible factor 1-alpha (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 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

• Eastern Cooperative Oncology Group (ECOG) Performance Status less than or equal to 2

• Evaluable metastatic disease on bone scan or measurable disease on computed tomography (CT) Scan per PCWG3 and/or Response Evaluation Criteria in Solid Tumors (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 prostate-specific antigen (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 intravenous (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 pharmacokinetic (PK) and pharmacodynamic (PD0 analyses.

• Tumor assessments will be made using Technetium-99 (99Tc) bone scintigraphy 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. ;

Related Conditions & MeSH terms

• Metastatic Castration Resistant Prostate Cancer
• Prostate Neoplasms
• Prostatic Neoplasms

• NCT number: NCT03531827
• Study type: Interventional
• Source: National Institutes of Health Clinical Center (CC)
• Status: Terminated
• Phase: Phase 2
• Start date: March 26, 2019
• Completion date: June 1, 2021