Combining CRLX101, a Nanoparticle Camptothecin, With Enzalutamide in People With Progressive Metastatic Castration Resistant Prostate Cancer Following Prior Enzalutamide Treatment
Condition: Metastatic Castration Resistant Prostate Cancer; Prostate Neoplasms
MeSH terms: Prostatic Neoplasms
Intervention: enzalutamide; CRLX101
Intervention description: enzalutamide is an androgen receptor (AR) antagonist that is standard care therapy for metastatic prostate cancer; 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)
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Sequential Assignment
Masking: None (Open Label)
Enrollment: 4.0
Sex: Male
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Androgen Receptor Antagonist; PSA; Hormonal Therapy; Nanoparticle Drug; Antitumor

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.
    

Eligibility criteria:

        -  INCLUSION CRITERIA:

          -  Patients must have histologically or cytologically confirmed prostate cancer confirmed
             by either the Laboratory of Pathology at the national Institutes of Health (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 metastatic castration-resistant prostate cancer mCRPC.
             There must be radiographic evidence of disease progression or biochemically (rising
             prostate-specific antigen (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 computed tomography (CT) scan

          -  Patients must have metastatic disease, per Response Evaluation Criteria in Solid
             Tumors (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 Gilberts
                  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

               -  Aspartate aminotransferase (AST) Serum glutamic oxaloacetic transaminase
                  (SGOT)/alanine aminotransferase (ALT)Serum glutamic-pyruvic transaminase (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

        OR

        --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
             gonadotropin-releasing hormone (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 (formerly IT-101) 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.

          -  Eastern Cooperative Oncology Group (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.

        EXCLUSION CRITERIA:

          -  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 androgen receptor
             variant 7 (AR-V7) splice variants.

        This includes but is not limited to Ralaniten (EPI-002) and AZD5312 (IONIS-AR-2.5Rx).
        (Note: patients previously treated with abiraterone, orteronel (TAK-700), apalutamide
        (ARN-509), galeterone, or VT-464 (formerly INO-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 a recent (within 1 year) history of seizure or any condition that, in
             the opinion of the investigator, significantly increases seizure risk. 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 (systolic blood pressure (SBP)>170/diastolic
             blood pressure (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 Common Terminology Criteria for Adverse Events (CTCAE) less than or
             equal to Grade 1 from toxicity due to all prior therapies, including surgery, except
             alopecia and other non-clinically significant adverse events (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 prostate-specific antigen (PSA) levels
             (e.g., saw palmetto).

          -  Patients with microscopic hematuria (defined as >100 red blood cells (RBCs) on
             urinalysis) or worsening urinary symptoms within 7 days prior to the initiation of
             study treatment.

          -  Known human immunodeficiency virus (HIV)-positive patients on antiretroviral therapy
             are ineligible because of potential pharmacokinetic interactions with study drugs.
             However, patients with long-standing (>5 years) HIV on antiretroviral therapy >1 month
             (undetectable HIV viral load and cluster of differentiation 4 (CD4) count > 150
             cells/micro L) may be eligible if the Principal Investigator or designee determines no
             anticipated clinically significant drug-drug

        interactions.

        INCLUSION OF MINORITIES AND WOMEN:

        -Men of all races and ethnic groups are eligible for this trial. Women are excluded as
        prostate cancer does not exist in this population.