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Study Evaluating the Addition of Pembrolizumab to Radium-223 in mCRPC

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. Read our disclaimer for details. Identifier: NCT03093428
Recruitment Status : Active, not recruiting
First Posted : March 28, 2017
Last Update Posted : July 21, 2020
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
Atish Choudhury, Dana-Farber Cancer Institute

Tracking Information
First Submitted Date  ICMJE March 15, 2017
First Posted Date  ICMJE March 28, 2017
Last Update Posted Date July 21, 2020
Actual Study Start Date  ICMJE June 9, 2017
Estimated Primary Completion Date February 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 22, 2017)
The Extent Of Immune Cell Infiltration [ Time Frame: 8 weeks ]
To compare differences in immune infiltrating cells (e.g., CD8+, CD4+, T cells) in bone biopsy specimens from baseline to 8 weeks on study therapy between the treatment arms.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: March 22, 2017)
  • Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability) [ Time Frame: 2 years ]
    Grade 3 or higher adverse events that are considered treatment related according to NCI CTCAE (version 4.0)
  • Progression Free Survival Rate [ Time Frame: 2 years ]
    Progression-free survival (PFS) is defined as the time from the first dose of study drug to the earlier of the first documentation of definitive disease progression [as defined by Response Evaluation Criteria in Solid Tumors (RECIST version 1.1)
  • Overall Survival Rate [ Time Frame: 2 years ]
    Overall Survival (OS) is defined as the time from randomization (or registration) to death due to any cause, or censored at date last known alive.
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 Study Evaluating the Addition of Pembrolizumab to Radium-223 in mCRPC
Official Title  ICMJE A Randomized, Phase II Study Evaluating the Addition of Pembrolizumab (MK-3475) to Radium-223 in Metastatic Castration Resistant Prostate Cancer (mCRPC)
Brief Summary

This research study is studying the safety and tolerability of an investigational combination of drugs, radium-223 plus pembrolizumab as a possible treatment for castration-resistant prostate cancer.

The interventions involved in this study are:

  • Radium-223
  • Pembrolizumab
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.

The FDA (the U.S. Food and Drug Administration) has approved radium-223 by itself as a treatment option for the participant's disease.

The FDA has not approved pembrolizumab for the participant's specific disease, but it has been approved for other uses, such as a type of skin cancer called melanoma.

In this research study, the investigators are evaluating the immune response, safety and tolerability of the combination of pembrolizumab (a type of immunotherapy drug) plus radium-223. Pembrolizumab works to block the PD-1 pathway, which plays an important role in lessening the activity of one's immune system to fight cancer. Pembrolizumab is therefore referred to as a PD-1 inhibitor, and acts by stimulating the patient's T cells, which are important immune cells, to attack tumors and treat cancer. Radium-223 targets cancer that exists in the bone directly. Radium-223 binds to minerals in the bone to deliver radiation directly to the cancer that has spread to the bones while limiting damage to the surrounding body tissues. Part of this study is to look at whether the investigators may more effectively control the participant's prostate cancer by combining these drugs. Radium-223 may kill cancer cells and release proteins specific to the tumor. The participant's immune system can then use those proteins to teach the T cells what the cancer looks like, and identify it for attack. Pembrolizumab can increase the number and activity of these immune cells, building a T cell "army" specialized to recognize and attack the cancer. The way these two drugs work on the cancer and the immune system may result in better control of the tumor than just radium-223 alone but needs to be investigated.

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: Radium-223
    Radium-223 is a calcium mimetic that hones in on bone metastases. It binds to new bone stroma and emits alpha particles, which induce double-stranded DNA breaks that result in tumor cell death.
    Other Name: Xofigo
  • Drug: Pembrolizumab
    Pembrolizumab is a PD-1 inhibitor
    Other Name: Keytruda
Study Arms  ICMJE
  • Experimental: Radium-223
    -Radium-223 will be administered intravenously every 4 weeks at a pre-determined dose
    Intervention: Drug: Radium-223
  • Experimental: Pembrolizumab Plus Radium-223
    • Radium-223 will be administered intravenously every 4 weeks at a pre-determined dose
    • Pembrolizumab will be administered intravenously every 3 weeks at a pre-determined dose
    • Drug: Radium-223
    • Drug: Pembrolizumab
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 Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: March 22, 2017)
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE June 2024
Estimated Primary Completion Date February 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Histologically confirmed adenocarcinoma of the prostate
  • Castration-resistant prostate cancer requires the following 3 criteria:

    • Progression after surgical castration or on GnRH agonist or antagonist
    • A castrate level of testosterone (<50ng/dL)
    • Prostate cancer progression documented by PSA rise or bone progression according to PCWG2
  • There is no limit to number of prior therapies
  • Metastatic disease by bone scan
  • Age ≥18 years
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
  • Be willing to undergo a core or excisional biopsy of a bone metastasis prior to study drug initiation for tumor tissue. Newly-obtained is defined as a specimen obtained up to 12 weeks (84 days) prior to initiation of treatment on Day 1. Bone biopsy can have been done prior to screening; archival specimens of bone metastasis are permitted if done for other purpose and available.

    --If biopsy is non-diagnostic, patient must undergo repeat biopsy as proof of tumor tissue by pathology review. Proof of tumor specimen is required for eligibility.

  • Be willing to undergo a second core or excisional biopsy of a bone metastasis on therapy (approximately after 8 weeks of study therapy or after 2 doses of radium-223 if delays have occurred).
  • Demonstrate adequate organ function as defined below, all screening labs for eligibility should be performed within 30 days prior to treatment initiation.
  • Hematological

    • Absolute neutrophil count (ANC) ≥ 1,500 /mcL
    • Platelets ≥ 100,000 / mcL
    • Hemoglobin ≥ 9 g/dL or ≥ 5.6 mmol/L; transfusions permitted
  • Renal

    --Serum creatinine OR Measured or calculated creatinine clearance (GFR can also be used in place of creatinine or CrCl) ≤ 1.5 X institutional upper limit of normal (ULN) OR

    ≥30 mL/min for subject with creatinine levels > 1.5 X institutional ULN

  • Hepatic

    • Serum total bilirubin ≤ 1.5 X institutional ULN OR Direct bilirubin ≤ institutional ULN for subjects with total bilirubin levels > 1.5 institutional ULN
    • AST (SGOT) and ALT (SGPT) ≤ 2.5 X institutional ULN
    • Albumin > 2.5 mg/dL
  • Coagulation

    --International Normalized Ratio (INR) or Prothrombin Time (PT) ≤1.5 X institutional ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants

    • Activated Partial Thromboplastin Time (aPTT) ≤1.5 X institutional ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants
    • Creatinine clearance should be calculated per institutional standard.
  • The effects of radium-223 and pembrolizumab on the developing human fetus are unknown. For this reason, 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 120 days (4 months) following the last dose of study drug. They must also agree not to donate sperm during the study and for 4 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 other neuroendocrine features is acceptable).
  • Prior treatment with radium-223
  • Prior treatment with a PD-1, PD-L1, or PD-L2 blocking therapy
  • Evidence of nodal disease greater than or equal to 15 mm in short axis as these findings are concerning for metastases that would not be targeted with radium-223 alone (Arm B). However, lymph nodes with short axis measurements between 1.5-3cm that have not enlarged more than 5mm (to account for reader variability) over the last 6 months and which are not inducing symptoms, causing obstruction, or in the opinion of the investigator pose a risk of impending obstruction of any structures, will be allowed.
  • Pulmonary nodules >10 mm

    --Pulmonary nodules >10mm that have been stable for >6 months and are not clearly metastatic disease per the treating investigator are permitted

  • Soft tissue components of bone metastases ≥ 1.0 cm in longest axis

    --Soft tissue components of bone metastases < 1.0 cm that have been stable for >6 months (must not have enlarged > 5mm) are permitted

  • Soft tissue lesions ≥ 1.0 cm in longest axis

    --Soft tissue lesions < 1.0 cm that have been stable for > 6 months (must not have enlarged > 5mm) are permitted.

  • If present, primary disease in the prostate must be stable for > 6 months (defined as no growth > 5mm)
  • Evidence of local recurrence in the prostate bed
  • Evidence of liver metastases or visceral disease
  • Has a diagnosis of immunodeficiency
  • Receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment. Patients who have received acute, low-dose, systemic immunosuppressant medications (e.g., limited low-dose dexamethasone for nausea, multiple doses for contrast allergy) may be enrolled in the study and would not require a 7 day washout.
  • Has a known history of active TB (Bacillus Tuberculosis)
  • Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier.
  • Has had prior systemic therapy (exception: GnRH agonist or antagonist) or radiation therapy for prostate cancer within 2 weeks prior to study Day 1. There must be at least a 2 week washout period from last dose of any prior systemic or radiation therapy for prostate cancer prior to Day 1 of study treatment (including nonsteroidal antiandrogens). Screening may commence during this washout window.
  • Any patient who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a previously administered systemic agent or radiation therapy.

    • Exceptions: Subjects with ≤ Grade 2 neuropathy, hot flashes, or hypertension may qualify for the study if all other eligibility criteria met.
    • Other toxicity or complications that are deemed by the treating investigator as not clinically significant (e.g., urinary incontinence from past prostatectomy)
  • Diethylstilbestrol, estrogens, saw palmetto, or other preparations that are known to have possible endocrine effects on prostate cancer that have been started within the past 8 weeks, as they may affect PSA levels or response. These are allowed if the patient has been on a stable dose for at least 8 weeks prior to C1D1.
  • Receiving other investigational agents
  • History of allergic reactions to compounds with similar biologic or chemical composition to pembrolizumab or Radium-223
  • Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has is planned for curative therapy.
  • Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment. This exception does not include carcinomatous meningitis, which is excluded regardless of clinical stability.
  • Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment and is allowed.
  • Has known history of, or any evidence of active, non-infectious pneumonitis. A history of radiation pneumonitis which is asymptomatic with no signs of active process is allowed.
  • Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
  • Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
  • Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). HIV-positive participants on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with pembrolizumab. In addition, these participants are at increased risk of lethal infections when treated with marrow-suppressive therapy. Appropriate studies will be undertaken in participants receiving combination antiretroviral therapy when indicated.
  • Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA is detected).
  • Has received a live vaccine within 30 days of planned start of study therapy.
  • Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed.
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 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, cerebrovascular accident including transient ischemic attacks) or clinically significant ventricular arrhythmias within 6 months prior to randomization; or significant vascular disease (e.g., aortic aneurysm, aortic dissection), symptomatic peripheral vascular disease
  • Evidence of QTc prolongation as defined as QTcF > 470 ms
  • Inability to comply with study and/or follow-up procedures
Sex/Gender  ICMJE
Sexes Eligible for Study: Male
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
Administrative Information
NCT Number  ICMJE NCT03093428
Other Study ID Numbers  ICMJE 16-498
Has Data Monitoring Committee Yes
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: No
Responsible Party Atish Choudhury, Dana-Farber Cancer Institute
Study Sponsor  ICMJE Dana-Farber Cancer Institute
Collaborators  ICMJE Merck Sharp & Dohme Corp.
Investigators  ICMJE
Principal Investigator: Atish Choudhury, MD Dana-Farber Cancer Institute
PRS Account Dana-Farber Cancer Institute
Verification Date July 2020

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