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Multi-arm Multi-modality Therapy for Very High Risk Localized and Low Volume Metastatic Prostatic Adenocarcinoma

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: NCT03436654
Recruitment Status : Recruiting
First Posted : February 19, 2018
Last Update Posted : November 17, 2020
Dana-Farber Cancer Institute
Information provided by (Responsible Party):
Memorial Sloan Kettering Cancer Center

Tracking Information
First Submitted Date  ICMJE February 7, 2018
First Posted Date  ICMJE February 19, 2018
Last Update Posted Date November 17, 2020
Actual Study Start Date  ICMJE June 21, 2018
Estimated Primary Completion Date February 14, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 22, 2018)
  • Pathologic complete response [ Time Frame: 24 months ]
    The primary efficacy measure of pathological complete response and minimal residual disease is defined as the less than or equal to 5 mm of morphologically identifiable carcinoma in the RP specimen.
  • Minimal residual disease (MRD) [ Time Frame: 24 months ]
    ≤ 5mm tumor
Original Primary Outcome Measures  ICMJE
 (submitted: February 12, 2018)
Pathologic complete response [ Time Frame: 24 months ]
The primary efficacy measure of pathological complete response and minimal residual disease is defined as the less than or equal to 5 mm of morphologically identifiable carcinoma in the RP specimen.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: February 12, 2018)
  • PSA Response Rate [ Time Frame: 10 months from randomization ]
    defined as percentage of patients with an undetectable PSA at 10 months from randomization (after completion of all protocol treatment)
  • Time to PSA Progression [ Time Frame: 24 months ]
    Time from the start of treatment to the date of first evidence of disease progression (serum PSA ≥0.2ng/mL, which is confirmed by a second determination with a PSA ≥0.2 ng/mL, according to the 2007 American Urological Association Prostate Guidelines). This will be estimated by the cumulative incidence function. For each arm, time to PSA progression will be presented for all patients as well as by metastatic status
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
Descriptive Information
Brief Title  ICMJE Multi-arm Multi-modality Therapy for Very High Risk Localized and Low Volume Metastatic Prostatic Adenocarcinoma
Official Title  ICMJE Multi-arm Multi-modality Therapy for Very High Risk Localized and Low Volume Metastatic Prostatic Adenocarcinoma
Brief Summary

The purpose of this study is to test if treatment with medications that reduce the male hormone level in the participant's body for a few months before surgery can shrink prostate cancer as much as possible, which might reduce the chances of the cancer coming back in the future. These treatments include a hormone injection given monthly or every three months and the study drugs, which include abiraterone acetate, prednisone, and apalutamide.

These medications are being used in combination with surgery and maybe radiotherapy because studies have shown that any single approach on its own is not sufficient to control or get rid of the cancer especially if they have high risk or aggressive features. The researchers hope to learn if combining the study drugs with surgery and radiation will get rid of the cancer from participants' prostates and reduce their prostate-specific antigen (PSA) to an undetectable level.

Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Prostate Cancer
Intervention  ICMJE
  • Drug: Apalutamide
    240mg daily orally
    Other Name: ARN-509, ERLEADA™
  • Drug: Abiraterone Acetate
    1000mg daily orally
    Other Name: ZYTIGA
  • Drug: Prednisone
    5mg BID orally
  • Procedure: Radical Prostatectomy
    A laparoscopic, robotic-assisted, or open approach to RP is permitted at the discretion of the operating surgeon.
  • Procedure: Extended Pelvic lymphadenectomy
    To be performed concurrently with prostatectomy. Bilateral pelvic lymphadenectomy should include complete removal of all pelvic lymph nodes within the broad template described and includes the external iliac, hypogastric, obturator, and pre-sacral lymph nodes
  • Drug: GnRH agonist/antagonist
    Physician's choice, for a total duration not to extend beyond the treatment phase of the protocol or 10 months from the start of investigational agent(s)
Study Arms  ICMJE
  • Experimental: ADT + Apalutamide
    • Drug: Apalutamide
    • Procedure: Radical Prostatectomy
    • Procedure: Extended Pelvic lymphadenectomy
    • Drug: GnRH agonist/antagonist
  • Experimental: ADT + Apalutamide + Abiraterone Acetate + Prednisone
    • Drug: Apalutamide
    • Drug: Abiraterone Acetate
    • Drug: Prednisone
    • Procedure: Radical Prostatectomy
    • Procedure: Extended Pelvic lymphadenectomy
    • Drug: GnRH agonist/antagonist
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: February 12, 2018)
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE February 14, 2022
Estimated Primary Completion Date February 14, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Willing and able to provide written informed consent and Authorization for Use and Release of Health and Research Study Information (HIPAA authorization) NOTE: HIPAA authorization may be either included in the informed consent or obtained separately
  • Male aged 18 years and above
  • Serum testosterone of ≥150 ng/dL (For cohorts A and B1, testosterone level requirement is exempted if they are already on ADT prior to treatment start. For cohort B2, patients will be considered eligible if their testosterone is currently ≥150 ng/dl).
  • Histologically confirmed adenocarcinoma of the prostate, who meet the following criteria:

Cohort A

  • Clinically localized disease with histologically confirmed adenocarcinoma of the prostate with either ≥3 positive cores or 2 positive cores if >1cm in length with at least 50% tumor content WITH
  • With Gleason score 8-10 OR
  • Gleason 4+3 with one of the following features:
  • PSA ≥ 20 mg/mL within 2 months prior to diagnostic biopsy
  • MRI suspicious for radiographic ≥T3 disease (as long as urologist deems tumor is resectable at baseline); defined as >75% probability of extracapsular extension or seminal vesicle invasion in the opinion of the reading radiologist.


  • Gleason 3+4 or 4+3 and Oncotype DX Genomic Prostate Score of >40
  • With or without clinical N1 (size >1.5cm in the short axis) (Gleason score requirement can be omitted if node positive)


Cohort B1

  • Newly diagnosed low-volume metastatic disease with either.
  • Bone metastases as documented by CT, MRI or radionuclide bone scan amenable to treatment with a maximum of 3 radiation isocenters*

    *(note: patients with PET scans that show osseous metastases that would not be amenable to 3-isocenter radiation treatment are still eligible as long as conventional imaging shows osseous disease that can be treated with 3 radiation isocenters) And/or

  • Retroperitoneal nodes up to the level of the renal hilum with/without pelvic nodal metastasis ≥1.5cm in the short axis


Cohort B2

  • Rising PSA after RP with:
  • Osseous or nodal metastases (up to the level of renal hila) as documented by FACBC or PSMA PET which are:
  • amenable to treatment with a maximum of 3 radiation isocenters* These lesions should have structural correlates on CT or MRI. Lesions without structural correlates will be viewed as equivocal and not need to be irradiated but will be followed.
  • With associated CT or MRI correlate
  • No evidence of local recurrence within prior radiation field on MRI or other imaging studies i.e. local recurrence is acceptable in patients without prior salvage radiation.
  • Prior salvage radiotherapy is permitted.

    * Multiple lesions within one isocenter may be permitted upon review by the sponsor's radiation oncologist;

  • ECOG performance status of ≤ 1
  • Adequate bone marrow, hepatic and renal function, as evidenced within 28 days prior to treatment start by:

    • ANC ≥ 1500/µl
    • Hemoglobin ≥ 9g/dL
    • Platelet count ≥ 100,000/µl
    • Serum Creatinine GFR >45 mL/min
    • Porassium within institutional normal range
    • Total Bilirubin ≤ 1.5 x ULN (Note: In subjects with Gilbert's syndrome, if total bilirubin is >1.5 x ULN, measure direct and indirect bilirubin and if direct bilirubin is ≤ 1.5 x ULN, subject may be eligible)
    • Albumin ≥ 3.0 g/dL
    • SGOT (AST) ≤ 2.5 x ULN
    • SGPT (ALT) ≤ 2.5 x ULN
  • Patients must have a clinical T stage documented by the treating urologist/medical oncologist within 90 days prior to treatment start using the 7th edition AJCC staging system, recorded as the urologist's/medical oncologist's best clinical assessment of extent of local disease by digital rectal examination and/or available imaging studies such as transrectral ultrasound, CT scan, and/or MRI. Applicable to Cohort A and B1.
  • The primary tumor must be considered unresectable by RP based on initial imaging with gross negative margins as determined by a urologist and documented as such. (applicable to cohorts A and B1 only)
  • Recovery of reversible effects of prior surgery (i.e., incisional pain, wound drainage) to Grade ≤1, and at least 4 weeks from prior surgery to treatment start. (biopsy excluded)
  • Able to swallow the study drug(s) whole as a tablet
  • Willing to take abiraterone acetate on an empty stomach; no food should be consumed at least one hour before and for at least two hours after the dose of abiraterone acetate is taken (Note: apalutamide does not have to be taken on an empty stomach.)
  • Agrees 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 agrees 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. Must also agree not to donate sperm during the study and for 3 months after receiving the last dose of study drug.
  • For Cohorts B1 and B2 only, biopsy confirmation of metastases (strongly encouraged; if safe and feasible at treating center)

Exclusion Criteria:

  • Prior treatment for prostate cancer including prior surgery (excluding TURP and patients with rising PSA after RP), pelvic lymph node dissection, radiation therapy unless the patient is eligible for Cohort B2.
  • Prior cytotoxic chemotherapy or biologic therapy for prostate cancer
  • More than 2 months of prior ADT with GnRH antagonist/agonist at time of treatment start. Bicalutamide given for < 2 months at the time of registration as flare prevention is allowed. For Cohort B2, prior ADT and/or first generation anti-androgen treatment in the (neo)adjuvant and/or salvage setting in conjunction with radiation or surgery is allowed provided last effective dose of ADT and/or first generation anti-androgen is > 12 months prior to the date of randomization and total duration of prior therapy is 12 months or lesser, and their testosterone is currently >150ng/dL.
  • Prior exposure to ketoconazole (systemic), abiraterone acetate, enzalutamide or other agents targeting the AR signaling pathway
  • Concomitant therapy with any other experimental drug
  • Known brain, liver, lung or other visceral metastasis (with the exception of retroperitoneal and / or pelvic nodal metastases as per inclusion criteria)
  • Prior prostate cancer metastasis-directed therapies
  • Currently active second malignancy or past history of malignancies diagnosed within the last 5 years that require active therapy and/or in remission with life expectancy of < 5 years, with the exception of resected non-melanoma skin cancers, non-muscle invasive bladder cancer, state I head and neck cancer, or stage I colorectal cancer
  • Significant medical condition other than cancer, that would prevent consistent and compliant participation in the study that would, in the opinion of the investigator, make this protocol unreasonably hazardous including but not limited to:

    • Any medical condition requiring a higher dose of corticosteroid than 10mg prednisone/prednisolone once daily
    • History of gastrointestinal disordered (medical disorders or extensive surgery) that may interfere with the absorption of the study agents
    • Uncontrolled hypertension (systolic BP ≥ 160 mmHg or diastolic BP ≥ 95 mmHg); patients with a history of hypertension are allowed provided blood pressure is controlled by anti-hypertensive treatment (systolic BP < 160 mmHg or diastolic BP <95 mmHg)
    • Active or symptomatic viral hepatitis of chronic liver disease
    • Known active HIV, Hepatitis B or Hepatitis C infection. (HIV testing is not mandatory)
    • History of pituitary or adrenal dysfunction
    • History of hypogonadism
    • Clinically significant heart disease as evidenced by myocardial infarction, or arterial thrombotic events in the past 6 months, severe or unstable angina, or New York Heart Association (NYHA) Class III or IV heart disease or cardiac ejection fraction measurement of <50% at baseline, or clinically significant ventricular arrhythmias within 6 months prior to treatment start.
    • History of seizure or any condition that may predispose to seizure (including, but not limited to prior stroke, transient ischemic attack or loss of consciousness </= 1 year prior to treatment start; brain arteriovenous malformation; or intracranial masses such as schawnnomas and meningiomas that are causing edema or mass effect)
    • Uncontrolled diabetes mellitus
    • History of inflammatory bowel disease
    • Baseline moderate and severe hepatic impairment (Child Pugh Class B & C)
  • Use of any prohibited concomitant medications within 14 days prior to treatment start, or use of prohibited concomitant medication listed in section 7.9.1 within the outlined windows NOTE: Medications known to lower the seizure threshold must be discontinued or substituted at least 4 weeks prior to treatment start
  • Pre-existing condition that warrants long-term corticosteroid use in excess of 10 mg prednisone/prednisolone daily
  • Known allergies, hypersensitivity or intolerance to apalutamide, abiraterone acetate, prednisone, or GBRH agonist or GNRH antagonist
  • Administration of an investigational therapeutic within 30 days of treatment start
  • Patients that cannot tolerate MRI
  • Any condition which, in the opinion of the investigator, would preclude participation in this trial
Sex/Gender  ICMJE
Sexes Eligible for Study: Male
Gender Based Eligibility: Yes
Gender Eligibility Description: Prostate
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Howard Scher, MD 646-422-4323
Contact: James Eastham, MD 646-422-4322
Listed Location Countries  ICMJE United States
Removed Location Countries  
Administrative Information
NCT Number  ICMJE NCT03436654
Other Study ID Numbers  ICMJE 17-646
PCCTC #: c16-183 ( Other Identifier: Prostate Cancer Clinical Trials Consortium, LLC (PCCTC) )
Has Data Monitoring Committee No
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
Plan to Share IPD: Undecided
Responsible Party Memorial Sloan Kettering Cancer Center
Study Sponsor  ICMJE Memorial Sloan Kettering Cancer Center
Collaborators  ICMJE Dana-Farber Cancer Institute
Investigators  ICMJE
Principal Investigator: Howard Scher, MD Memorial Sloan Kettering Cancer Center
PRS Account Memorial Sloan Kettering Cancer Center
Verification Date November 2020

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