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Combination treatment of increasing dose of CRLX101 (formerly IT-101) with enzalutamide

Tolerable dose of CRLX101 (formerly IT-101) in combination with enzalutamide (8 participants, expandable to 21 total participants)

enzalutamide is an androgen receptor (AR) antagonist that is standard care therapy for metastatic prostate cancer

enzalutamide

CRLX101 is a nanoparticle-drug conjugate (NDC) comprised of a linear cyclodextrin-polyethylene glycol-base polymer conjugated to multiple 2 (S)-camptothecin (CPT) molecules (Poly-CD-PEG-Camptothecin)

CRLX101

Ravi A Madan, M.D.

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.

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.

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

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

All individual participant data (IPD) recorded in the medical record will be shared with intramural investigators upon request.

All collected IPD will be shared with collaborators under the terms of collaborative agreements.

Here is the number of participants with serious and/or non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.

Anti-tumor activity is \>=50% prostate-specific antigen (PSA) decline or stable disease on imaging following 5 months of treatment in participants with progressive metastatic castration resistant prostate cancer (mCRPC) following enzalutamide treatment. Stable disease (SD) is neither sufficient shrinkage to qualify for partial response (at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters) nor sufficient increase to qualify for progressive disease (at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study).

Proportion of participants with a sustained \>30% decline in prostate-specific antigen (PSA) from baseline based on all evaluable participants.

OS is defined as the duration of time from the start of treatment to the time of death estimated based on all evaluable participants.

Number of participants with a change in measurable disease as determined by RECIST. Complete response (CR) is disappearance of all target lesions. Partial response (PR) is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters. Progressive disease (PD) is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study. Stable disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of diameters while on study.

Number of participants with a change in measurable disease as determined by the Prostate Cancer Working Group 3 (PCWG3). PSA values will be captured at each visit and PSA declines and progression (by radiographic evidence or clinical symptoms) will be followed. Radiographic disease progression is considered if a minimum of two new lesions is observed on bone scan. Clinical disease progression is the need for chemotherapy or other change in therapy based on increased cancer related symptoms.

National Cancer Institute (NCI)

Principal Investigator

Lead-in Dosing: CRLX101 (formerly IT-101) 12mg/m\^2 every (q) 2 weeks x 2 cycles; CRLX101 15mg/m\^2 (q) 2 weeks cycle 3+; enzalutamide 160 mg every day (QD) cycle 1 day 2+

1/Lead-In Safety: CRLX101 With Enzalutamide

Age, Categorical

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Normal PSA is variable. Higher above the normal range often means more cancer.

Median Prostate-Specific Antigen (PSA)

Prior lines of therapy refers to the multiple lines of treatment given to a participant for their disease. First treatment, second treatment, third treatment, and so forth.

Median Prior Lines of Therapy

Dr. Ravi Madan

>=50% prostate-specific antigen (PSA) decline

Stable Disease

Percentage of Participants With Anti-tumor Activity

Proportion of Participants With a Sustained >30% Decline in Prostate-specific Antigen (PSA)

3/4 participants were analyzed because one participant was lost to follow-up.

Overall Survival (OS)

Lead-in Dosing: CRLX101 12mg/m\^2 every (q) 2 weeks x 2 cycles; CRLX101 15mg/m\^2 (q) 2 weeks cycle 3+; enzalutamide 160 mg every day (QD) cycle 1 day 2+

Number of Participants With a Change in Measurable Disease From Baseline as Determined by Response Evaluation Criteria in Solid Tumors (RECIST)

Number of Participants With a Change in Measurable Disease as Determined by the Prostate Cancer Working Group 3 (PCWG3)

Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0)

Tolerable dose of CRLX101 (formerly IT-101) in combination with enzalutamide (8 participants, expandable to 21 total participants)

enzalutamide: enzalutamide is an androgen receptor (AR) antagonist that is standard care therapy for metastatic prostate cancer

CRLX101: CRLX101 is a nanoparticle-drug conjugate (NDC) comprised of a linear cyclodextrin-polyethylene glycol-base polymer conjugated to multiple 2 (S)-camptothecin (CPT) molecules (Poly-CD-PEG-Camptothecin)

Spots Global Cancer Trial Database for androgen receptor antagonist