COVID-19 is an emerging, rapidly evolving situation.
Get the latest public health information from CDC:

Get the latest research information from NIH: Menu

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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT03531827
Recruitment Status : Recruiting
First Posted : May 22, 2018
Last Update Posted : May 13, 2020
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

Tracking Information
First Submitted Date  ICMJE May 18, 2018
First Posted Date  ICMJE May 22, 2018
Last Update Posted Date May 13, 2020
Actual Study Start Date  ICMJE March 26, 2019
Estimated Primary Completion Date June 30, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 15, 2020)
Anti-tumor activity [ Time Frame: 5 months ]
>=50% PSA decline or stable disease on imaging following 5 months of treatment in patients with progressive mCRPC following enzalutamide treatment.
Original Primary Outcome Measures  ICMJE
 (submitted: May 19, 2018)
Anti-tumor activity [ Time Frame: 5 months ]
Greater than or equal to 50% PSA decline or stable disease on imaging following 5 months of treatment in patients with progressive mCRPC following enzalutamide treatment.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: April 15, 2020)
Duration of response [ Time Frame: Study end ]
Evaluate sustained >30% decline in PSA, overall survival, and changes in measurable disease as determined by RECIST and PCWG3.
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
Descriptive Information
Brief Title  ICMJE Combining CRLX101, a Nanoparticle Camptothecin, With Enzalutamide in People With Progressive Metastatic Castration Resistant Prostate Cancer Following Prior Enzalutamide Treatment
Official Title  ICMJE 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
Brief Summary


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 could make enzalutamide work again for people who have already had it.


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


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


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 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.

Detailed Description


  • Enzalutamide is established as first-line hormonal therapy in patients 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


-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.


  • 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


  • The study will be conducted using an optimal two stage Phase II design (8 patients, expandable to 21 patients total) aimed to determine the percentage of patients with a PSA decline of greater than 50% or stable disease at 5 months.
  • The first 3 to 6 patients 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 patients 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 patients.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Metastatic Castration Resistant Prostate Cancer
  • Prostate Neoplasms
Intervention  ICMJE
  • Drug: enzalutamide
    enzalutamide is an AR antagonist that is standard care therapy for metastatic prostate cancer
  • Drug: 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)
Study Arms  ICMJE
  • Experimental: 1/Lead-In Safety
    Combination treatment of increasing dose of CRLX101 with enzalutamide
    • Drug: enzalutamide
    • Drug: CRLX101
  • Experimental: 2/Efficacy
    Tolerable dose of CRLX101 in combination with enzalutamide (8 patients, expandable to 21 total patients)
    • Drug: enzalutamide
    • Drug: CRLX101
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: May 19, 2018)
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 30, 2021
Estimated Primary Completion Date June 30, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE
  • Patients must have histologically or cytologically confirmed prostate cancer confirmed by either the Laboratory of Pathology at the NIH Clinical Center or Walter Reed National Military Medical Center at Bethesda prior to starting this study. If no pathological specimen is available, patients may enroll with a pathologist s report showing a histological diagnosis of prostate cancer and clinical course consistent with the disease.
  • Patients must have progressive mCRPC. There must be radiographic evidence of disease progression or biochemically (rising PSA levels on successive measurements) recurring disease despite adequate testosterone suppression.
  • Progression must be evidenced and documented by any of the following parameters:

    • PSA progression defined by a minimum of two rising PSA levels with an interval of greater than or equal to 1 week between each determination
    • Appearance of one or more new lesions consistent with prostate cancer on bone scan
    • New or growing lesions on CT scan
  • Patients must have metastatic disease, per RECIST 1.1(64).
  • Patients must have received treatment with prior enzalutamide for two or more cycles and must have had evidence of disease progression while on enzalutamide.
  • Patients who have received antiandrogens such as flutamide, bicalutamide, or nilutamide for >6 months immediately before enrollment on this study must be off treatment for 4 weeks (6 weeks for bicalutamide) and demonstrate a continued rise in PSA. Patients on antiandrogens for <6 months must be off medication for 2 weeks.
  • Age greater than or equal to 18 years. Because no dosing or adverse event data are currently available on the use of enzalutamide and CRLX101 in patients <18 years of age and prostate cancer is not common in children <18 years of age, children are excluded from this study.
  • Patients must have adequate organ and marrow function as defined below:

    • leukocytes greater than or equal to 3,000/mcL
    • absolute neutrophil count greater than or equal to 1,500/mcL
    • platelets greater than or equal to 100,000/mcL
    • total bilirubin within normal institutional limits; for patients with Gilbert s syndrome, total bilirubin less than or equal to 3.0 mg/dL
    • hemoglobin greater than or equal to 9g/dL
    • serum albumin greater than or equal to 2.8 g/dL
    • AST(SGOT)/ALT(SGPT) less than or equal to 2.5 times institutional upper limit of normal (<5 times institutional ULN for liver metastases)
    • creatinine within 1.5 times normal institutional limits


--creatinine clearance greater than or equal to 60 mL/min/1.73 m(2) for patients with creatinine levels above institutional normal.

  • Patients must have castrate levels of testosterone (<50 ng/dL [1.74 nmol/L]).
  • Patients must have undergone bilateral surgical castration or must continue on GnRH agonists/antagonists for the duration of the study.
  • Patients on 5-alpha reductase inhibitors such as finasteride or dutasteride must stop medication at least 28 days prior to study entry.
  • The effects of enzalutamide and CRLX101 on the developing human fetus are unknown. For this reason and because androgen receptor antagonists and topoisomerase I inhibitors as well as other therapeutic agents used in this trial are known to be teratogenic, all study subjects must agree to use a condom during the study treatment period and for 120 days following the last dose of study drug. Should a woman become pregnant or suspect she is pregnant while her partner is participating in this study, she should inform her treating physician immediately.
  • ECOG performance status less than or equal to 2 (Karnofsky greater than or equal to 60%).
  • Ability of subject to understand and the willingness to sign a written informed consent document.


  • Patients who are receiving any other investigational agents. A minimum washout period of 28 days is required prior to the initiation of on study treatment unless the patient is receiving immunotherapy, for which the minimum washout period will be 14 days. This is because Immune-related toxicities are distinct and unlikely to synergize with this protocol therapy, a shorter washout period is reasonable and customary in clinical trials.
  • Patients who have been treated with prior secondary hormonal manipulations with proposed investigational rationale for having efficacy against AR-V7 splice variants.

This includes but is not limited to EPI-002 and AZD5312. (Note: patients previously treated with abiraterone, orteronel (TAK-700), apalutamide (ARN-509), galeterone, or VT-464 will be eligible for this study. Patients who have received prior chemotherapy will also be eligible for this study).

  • Patients with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events.
  • Patients with history of seizure as an adult including febrile seizure or any condition that may predispose to seizure (e.g., prior stroke, brain arteriovenous malformation, head trauma with loss of consciousness requiring hospitalization). Also current or prior treatment with anti-epileptic medications for the treatment of seizures. Transient ischemic attack within 12 months prior to study enrollment will not be permitted.
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to enzalutamide, CRLX101, or other agents used in study.
  • Patients with a history within the last 3 years of another invasive malignancy (localized non-melanoma skin and bladder cancers are allowed).
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, uncontrolled hypertension (SBP>170/DBP>105), or psychiatric illness/social situations within 6 months that would limit compliance with study requirements.
  • Patients who have received palliative radiotherapy within 2 weeks of study entry and have not recovered to Grade 1 or baseline from associated toxicities. Note: Patients may receive palliative radiation once enrolled on study. The subject has not recovered to baseline or CTCAE less than or equal to Grade 1 from toxicity due to all prior therapies, including surgery, except alopecia and other non-clinically significant AEs.
  • Patients who are unable to swallow tablets or have a gastrointestinal disease that could hinder the absorption of enzalutamide
  • The use of any herbal products that may lower PSA levels (e.g. saw palmetto).
  • Patients with microscopic hematuria (defined as >100 RBCs on urinalysis) or worsening urinary symptoms within 7 days prior to the initiation of study treatment.
  • Known HIV-positive patients on antiretroviral therapy are ineligible because of potential pharmacokinetic interations with study drugs. However, patients with long-standing (>5 years) HIV on antiretroviral therapy >1 month (undetectable HIV viral load and CD4 count > 150 cells/micro L) may be eligible if the Principal Investigator or designee determines no anticipated clinically significant drug-drug



-Men of all races and ethnic groups are eligible for this trial. Women are excluded as prostate cancer does not exist in this population.

Sex/Gender  ICMJE
Sexes Eligible for Study: Male
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Susan G Wroblewski, R.N. (240) 858-3217
Listed Location Countries  ICMJE United States
Removed Location Countries  
Administrative Information
NCT Number  ICMJE NCT03531827
Other Study ID Numbers  ICMJE 180096
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
Study Sponsor  ICMJE National Cancer Institute (NCI)
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Ravi A Madan, M.D. National Cancer Institute (NCI)
PRS Account National Institutes of Health Clinical Center (CC)
Verification Date May 7, 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP