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

NCT03531827 | Terminated Phase 2 Results FDA Drug

• 2 other identifiers: 18009618-C-0096
• Study Type: interventional
• Target: 4
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Metastatic Castration Resistant Prostate Cancer; Prostate Neoplasms

Keywords

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

Outcome Measures

Primary Outcomes (1)

• Percentage of Participants With Anti-tumor Activity

  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).

  5 months

Secondary Outcomes (4)

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

  time of sustained >30% decline in prostate-specific antigen (PSA) from baseline, approximately >1 month

• Overall Survival (OS)

  time from the start of treatment to the time of death, up to 17.5 months

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

  Within 6 months

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

  Study end, approximately 6 months

Other Outcomes (1)

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

  Date treatment consent signed to date off study, approximately 26 months and 6 days.

Study Arms (2)

1/Lead-In Safety: CRLX101 with Enzalutamide

EXPERIMENTAL

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

Drug: enzalutamide; Drug: CRLX101

2/Efficacy: CRLX101 with Enzalutamide

EXPERIMENTAL

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

Drug: enzalutamide; Drug: CRLX101

Interventions

enzalutamide DRUG

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

Also known as: Xtandi

1/Lead-In Safety: CRLX101 with Enzalutamide; 2/Efficacy: CRLX101 with Enzalutamide

CRLX101 DRUG

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)

Also known as: IT-101

1/Lead-In Safety: CRLX101 with Enzalutamide; 2/Efficacy: CRLX101 with Enzalutamide

Eligibility Criteria

• Age: 18 Years+
• Sex: male
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

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

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

Location

Related Publications (3)

• Schmidt KT, Karzai F, Bilusic M, Cordes LM, Chau CH, Peer CJ, Wroblewski S, Huitema ADR, Schellens JHM, Gulley JL, Dahut WL, Figg WD, Madan RA. A Single-arm Phase II Study Combining NLG207, a Nanoparticle Camptothecin, with Enzalutamide in Advanced Metastatic Castration-resistant Prostate Cancer Post-Enzalutamide. Oncologist. 2022 Sep 2;27(9):718-e694. doi: 10.1093/oncolo/oyac100.

  PMID: 35640474 DERIVED

• Schmidt KT, Chau CH, Strope JD, Huitema ADR, Sissung TM, Price DK, Figg WD. Antitumor Activity of NLG207 (Formerly CRLX101) in Combination with Enzalutamide in Preclinical Prostate Cancer Models. Mol Cancer Ther. 2021 May;20(5):915-924. doi: 10.1158/1535-7163.MCT-20-0228. Epub 2021 Feb 25.

  PMID: 33632874 DERIVED

• Schmidt KT, Huitema ADR, Dorlo TPC, Peer CJ, Cordes LM, Sciuto L, Wroblewski S, Pommier Y, Madan RA, Thomas A, Figg WD. Population pharmacokinetic analysis of nanoparticle-bound and free camptothecin after administration of NLG207 in adults with advanced solid tumors. Cancer Chemother Pharmacol. 2020 Oct;86(4):475-486. doi: 10.1007/s00280-020-04134-9. Epub 2020 Sep 8.

  PMID: 32897402 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Prostatic Neoplasms

Interventions

enzalutamide; IT-101

Condition Hierarchy (Ancestors)

Genital Neoplasms, Male; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Genital Diseases, Male; Genital Diseases; Urogenital Diseases; Prostatic Diseases; Male Urogenital Diseases

Results Point of Contact

• Title: Dr. Ravi Madan
• Organization: National Cancer Institute

madanr@mail.nih.gov

301.480-7168

Study Officials

• Ravi A Madan, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: NIH
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: May 18, 2018
• First Posted: May 22, 2018
• Study Start: March 26, 2019
• Primary Completion: May 15, 2021
• Study Completion: June 1, 2021
• Last Updated: July 12, 2022
• Results First Posted: July 12, 2022

Record last verified: 2022-06

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Clinical data available during the study and indefinitely.
• Access Criteria: Clinical data will be made available via subscription to the Biomedical Translational Research Information System (BTRIS) and with the permission of the study principal investigator (PI).

Locations

US (1)