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A Study of Docetaxel + ARN-509 in Castration-Resistant Prostate Cancer

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: NCT03093272
Recruitment Status : Recruiting
First Posted : March 28, 2017
Last Update Posted : July 16, 2018
Janssen Pharmaceutica
Information provided by (Responsible Party):
Lauren C. Harshman, Dana-Farber Cancer Institute

Brief Summary:

This research study is studying a combination of drugs as a possible treatment for castration-resistant prostate cancer.

The interventions involved in this study are:

  • Docetaxel (a type of chemotherapy)
  • Apalutamide (the study medication, also known as ARN-509)
  • Prednisone (a corticosteroid given to prevent reactions to docetaxel).
  • Leuprolide acetate (also known as Lupron, a GnRH agonist or similar drug which is standard of care, causes chemical castration which greatly lowers the level of testosterone in the body)

Condition or disease Intervention/treatment Phase
Prostate Cancer Drug: Leuprolide Acetate Drug: Prednisone Drug: Docetaxel Drug: Apalutamide Phase 2

Detailed Description:

This research study is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of an investigational intervention to learn whether the intervention works in treating a specific disease. "Investigational" means that the intervention is being studied.

Apalutamide is considered an investigational product, which is believed to reduce the growth of prostate cancer cells. The FDA (the U.S. Food and Drug Administration) has not approved apalutamide as a treatment for any disease, but it is being studied in prostate cancer. Docetaxel is an approved therapy for this type of cancer. The FDA has not approved the combination of the two drugs in any use.

In this research study, the investigators are evaluating the combination of two drugs, docetaxel with apalutamide. The investigators will keep track of participants' prostate-specific antigen (PSA), scans, and overall health to determine how well this drug combination works at treating this type of cancer.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 33 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 2 Study of Docetaxel Plus Apalutamide in Castration-Resistant Prostate Cancer Patients Post Abiraterone Acetate
Actual Study Start Date : June 23, 2017
Estimated Primary Completion Date : August 31, 2020
Estimated Study Completion Date : August 31, 2024

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
Experimental: ARN-509 Combined With Docetaxel
  • Apalutamide (ARN-509) will be taken orally at home daily
  • Docetaxel will be administered every 3 weeks intravenously
  • Prednisone will be taken orally twice daily
  • Leuprolide Acetate will be administered at the specification of the physician
Drug: Leuprolide Acetate
a GnRH agonist
Other Name: Lupron Injection

Drug: Prednisone
Prednisone is a corticosteroid
Other Name: Deltasone

Drug: Docetaxel
Docetaxel is an antineoplastic agent that acts by disrupting the microtubular network in cells that is essential for mitotic and interphase cellular functions. Docetaxel binds to free tubulin and promotes the assembly of tubulin into stable microtubules while simultaneously inhibiting their disassembly.
Other Names:
  • Docefrez
  • Taxotere

Drug: Apalutamide
The apalutamide drug substance is an almost white to slightly brown powder. The tablet formulation of apalutamide is an immediate release oral tablet containing 60-mg of drug substance, with a non-functional green film coat
Other Name: ARN-509

Primary Outcome Measures :
  1. Progression Free Survival [ Time Frame: 4 months ]
    To evaluate progression-free survival on the combination of docetaxel plus apalutamide

Secondary Outcome Measures :
  1. Incidence of Treatment-Emergent Adverse Events according to NCI CTCAE v4.0 [ Time Frame: 2 years ]
    All adverse events recorded during the trial that are new or worsening from the time of first dose of treatment will be summarized for the safety population.

  2. Dose-Limiting Toxicities in the Safety Lead-in Group (first 6 patients) [ Time Frame: 6 months ]
    Specific adverse events will be recorded during the safety lead-in phase of 6 patients. Any toxicities considered unacceptable during this time will be considered a dose-limiting toxicity and will be summarized among all patients evaluable for a dose-limiting toxicity.

  3. Maximum Blood Concentration (Cmax) for Docetaxel Pharmacokinetic Analysis [ Time Frame: 2 years ]
    Maximum blood concentration (Cmax) and time of maximum blood concentration (tmax) will be determined by visual inspection.

  4. Area Under the Curve (AUC) for Docetaxel Pharmacokinetic Analysis [ Time Frame: 2 years ]
    The area under the blood concentration-time curve (linear trapezoidal rule) will be determined between 0-24 hours (AUC0-24).

  5. Time to Progression [ Time Frame: 2 years ]
    Radiologic time to progression and PSA progression will be analyzed using the Kaplan-Meier Method.

  6. Time to Treatment Failure [ Time Frame: 2 years ]
    Time to treatment failure (including progression and intolerability) will be analyzed using the Kaplan-Meier Method.

  7. Objective Response Rate [ Time Frame: 2 years ]
    Objective Response Rate

  8. PSA Response [ Time Frame: 2 years ]
    Will be assessed according to Prostate Cancer Working Group 2 criteria

  9. Serum PSA Change From Baseline [ Time Frame: 12 weeks ]
    The maximum percent PSA change (rise or fall) from baseline to after 12 weeks on study. It will be summarized using box-whisker plots and waterfall plots for each treatment arm.

  10. Overall Survival [ Time Frame: 2 years ]
    Overall Survival

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Histologically confirmed adenocarcinoma of the prostate
  • Castration-resistant prostate cancer requires the following criteria:

    • A castrate level of testosterone (< 50ng/dL)
    • Prostate cancer progression on or since last treatment as documented by PSA rise or bone progression according to PCWG2 or soft tissue radiographic progression according to RECIST criteria Version 1.1
    • If on anti-androgen, will need to show no PSA decline after at least a 6 week withdrawal period from the last dose of bicalutamide or nilutamide or 4 weeks from last flutamide dose
    • Will require a 2 week washout period from last dose of ketoconazole, abiraterone acetate or radiation
  • Treatment with abiraterone acetate for CRPC in the past is required. Does not need to be the last treatment prior to enrollment.
  • There is no limit to number of prior therapies
  • Metastatic disease by bone scan or other nodal or visceral lesions on CT or MRI
  • Age ≥ 18 years
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (See Appendix A)
  • Adequate organ function as evaluated by the following laboratory criteria:

    • Hemoglobin ≥ 9g/dL; no transfusions and erythropoietin supplementation permitted within the last 3 months
    • Absolute neutrophil count (ANC) ≥ 1500/µL
    • Platelet count ≥ 100 x 10^9/L
    • Total bilirubin ≤ upper limit of normal (ULN, Note: In subjects with Gilbert's syndrome, if total bilirubin is ≥ 1.5 × ULN, measure direct and indirect bilirubin and if direct bilirubin is ≤ ULN, subject may be eligible)
    • AST and ALT < 2.5 x ULN or < 5x the ULN if liver metastasis
    • Serum creatinine < 2.0 × ULN or creatinine clearance > 30cc/min
    • Serum albumin ≥ 3.0 g/dL
    • Serum potassium ≥ 3.5 mmol/L (if < 3.5, can be repleted and reassess for eligibility as long as stable off potassium supplementation for > 48 hrs)
  • Ability to swallow the study drug as a whole tablet
  • The effects of apalutamide and docetaxel on the developing human fetus are unknown. For this reason and because chemotherapeutic agents are known to be teratogenic, men must agree to use adequate contraception. Specifically, they must agree to use a condom (even men with vasectomies) and another effective method of birth control if he is having sex with a woman of childbearing potential or agree to use a condom if he is having sex with a woman who is pregnant while on study drug and for 3 months following the last dose of study drug. They must also agree not to donate sperm during the study and for 3 months after receiving the last dose of study drug.
  • Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

  • Pathology consistent with majority of specimen having small cell carcinoma of the prostate (prostate cancer with neuroendocrine features is acceptable).
  • Prior treatment with enzalutamide for CPRC; non-CRPC use allowed (e.g., neoadjuvant, combined with radiation for localized disease and didn't progress while on it in those settings)
  • Prior treatment with docetaxel chemotherapy except if > 12 months since it was given in either the neoadjuvant or adjuvant setting or for hormone sensitive disease (e.g., CHAARTED population)
  • Presence of untreated brain metastasis
  • Seizure or known condition that may pre-dispose to seizure (including but not limited to prior stroke, transient ischemic attack within 1 year prior to randomization, brain arteriovenous malformation; or intracranial masses such as schwannomas and meningiomas that are causing edema or mass effect). Loss of consciousness within 12 months may be permitted upon discussion with study PI.
  • Medications known to lower the seizure threshold must be discontinued or substituted at least 4 weeks prior to study entry.
  • Current, recent (within 4 weeks of the first dose of this study), or planned participation in an experimental drug study
  • Persistent grade > 1 (NCI CTCAE v4.0) AEs due to investigational drugs that were administered more than 14 days before study enrollment.
  • Radiation within 2 weeks prior to entering the study
  • Peripheral neuropathy ≥ Grade 2.
  • Current evidence of any of the following:

    • Uncontrolled hypertension
    • Gastrointestinal disorder affecting absorption
    • Active infection (e.g., human immunodeficiency virus [HIV] or viral hepatitis) or other medical condition that would make prednisone/prednisolone (corticosteroid) use contraindicated
  • Uncontrolled intercurrent illness including, but not limited to, severe or unstable angina, myocardial infarction, symptomatic congestive heart failure (defined as New York Heart Association Grade II or greater), arterial or venous thromboembolic events (e.g., pulmonary embolism), or clinically significant ventricular arrhythmias, significant vascular disease (e.g. aortic aneurysm, aortic dissection), or symptomatic peripheral vascular disease within 6 months prior to randomization.
  • Psychiatric illness/social situations that would limit compliance with study requirements.
  • Any condition that in the opinion of the investigator, would preclude participation in this study
  • History of allergic reactions or severe hypersensitivity reactions to drugs formulated with polysorbate 80 or antisense oligonucleotides.
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to apalutamide or docetaxel
  • Participants receiving any medications or substances that are strong inhibitors or inducers of CYP3A4 are ineligible. Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated list such as; medical reference texts such as the Physicians' Desk Reference may also provide this information. As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product.
  • Inability to comply with study and/or follow-up procedures

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT03093272

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Contact: Lauren C Harshman, MD 617-632-4524

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United States, Massachusetts
Beth Israel Deaconess Medical Center Recruiting
Boston, Massachusetts, United States, 02215
Contact: Glenn Bubley, MD    617-735-2062      
Principal Investigator: Glenn Bubley, MD         
Dana Farber Cancer Institute Recruiting
Boston, Massachusetts, United States, 02215
Contact: Lauren C Harshman, MD    617-632-4524   
Principal Investigator: Lauren C Harshman, MD         
Sponsors and Collaborators
Dana-Farber Cancer Institute
Janssen Pharmaceutica
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Principal Investigator: Lauren C Harshman, MD Dana-Farber Cancer Institute

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Responsible Party: Lauren C. Harshman, Assistant Professor of Medicine, Dana-Farber Cancer Institute Identifier: NCT03093272     History of Changes
Other Study ID Numbers: 16-485
First Posted: March 28, 2017    Key Record Dates
Last Update Posted: July 16, 2018
Last Verified: July 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Lauren C. Harshman, Dana-Farber Cancer Institute:
Prostate Cancer

Additional relevant MeSH terms:
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Prostatic Neoplasms
Genital Neoplasms, Male
Urogenital Neoplasms
Neoplasms by Site
Genital Diseases, Male
Prostatic Diseases
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Anti-Inflammatory Agents
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Antineoplastic Agents, Hormonal
Fertility Agents, Female
Fertility Agents
Reproductive Control Agents