Clinical Trials /

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

NCT03531827

Description:

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 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 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.

Related Conditions:
  • Prostate Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: 180096
  • SECONDARY ID: 18-C-0096
  • NCT ID: NCT03531827

Conditions

  • Metastatic Castration Resistant Prostate Cancer
  • Prostate Neoplasms

Interventions

DrugSynonymsArms
enzalutamide1/Lead-In Safety
CRLX1011/Lead-In Safety

Purpose

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 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 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

      Background:

        -  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

      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 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.
    

Trial Arms

NameTypeDescriptionInterventions
1/Lead-In SafetyExperimentalCombination treatment of increasing dose of CRLX101 with enzalutamide
  • enzalutamide
  • CRLX101
2/EfficacyExperimentalTolerable dose of CRLX101 in combination with enzalutamide (8 patients, expandable to 21 total patients)
  • enzalutamide
  • CRLX101

Eligibility Criteria

        -  INCLUSION CRITERIA:

          -  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

        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 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.

        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 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

        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.
      
Maximum Eligible Age:100 Years
Minimum Eligible Age:18 Years
Eligible Gender:Male
Healthy Volunteers:No

Primary Outcome Measures

Measure:Anti-tumor activity
Time Frame:5 months
Safety Issue:
Description: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.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

Trial Keywords

  • Androgen Receptor Antagonist
  • PSA
  • Hormonal Therapy
  • Nanoparticle Drug
  • Antitumor

Last Updated

November 1, 2019