Pembrolizumab and Radium Ra 223 Dichloride in Treating Patients with Metastatic Castration-Resistant Prostate Cancer

Status: Active

Description

This randomized phase II trial studies how well pembrolizumab and radium Ra 223 dichloride work in treating patients with castration-resistant prostate cancer that has spread to other places in the body. 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 tumor that has spread to the bones while limiting damage to the surrounding body tissues. Giving pembrolizumab and radium Ra 223 dichloride together may work better in treating patients with castration-resistant prostate cancer.

Eligibility Criteria

Inclusion Criteria

  • Histologically confirmed adenocarcinoma of the prostate
  • Castration-resistant prostate cancer requires the following 3 criteria: * Progression after surgical castration or on gonadotrophin releasing hormone (GnRH) agonist or antagonist * A castrate level of testosterone (< 50 ng/dL) * Prostate cancer progression documented by PSA rise or bone progression according to Prostate Cancer Clinical Trials Working Group (PCWG2)
  • There is no limit to number of prior therapies
  • Metastatic disease by bone scan
  • 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; if 2nd biopsy is non-diagnostic, the patient may enroll as good faith effort
  • 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)
  • Absolute neutrophil count (ANC) >= 1,500/mcL (within 42 days prior to treatment initiation)
  • Platelets >= 100,000/mcL (within 42 days prior to treatment initiation)
  • Hemoglobin >= 9 g/dL or >= 5.6 mmol/L; transfusions permitted (within 42 days prior to treatment initiation)
  • Serum creatinine =< 1.5 X institutional upper limit of normal (ULN) OR measured or calculated creatinine clearance >= 30 mL/min for subject with creatinine levels > 1.5 X institutional ULN (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) (within 42 days prior to treatment initiation) * Creatinine clearance should be calculated per institutional standard
  • Serum total bilirubin =< 1.5 X institutional ULN OR direct bilirubin =< institutional ULN for subjects with total bilirubin levels > 1.5 institutional ULN (within 42 days prior to treatment initiation)
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X institutional ULN (within 42 days prior to treatment initiation)
  • Albumin >= 2.5 mg/dL (within 42 days prior to treatment initiation)
  • International normalized ratio (INR) or prothrombin time (PT) =< 1.5 X institutional ULN unless subject is receiving anticoagulant therapy as long as PT or partial thromboplastin time (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 (within 42 days prior to treatment initiation)
  • 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 1.5-3 cm 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 > 10 mm 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 > 5 mm) 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 > 5 mm) are permitted
  • If present, primary disease in the prostate must be stable for > 6 months (defined as no growth > 5 mm)
  • Evidence of local recurrence in the prostate bed
  • Evidence of liver metastases or visceral disease
  • Has a diagnosis of immunodeficiency
  • Patients requiring systemic steroid therapy with > 10mg prednisone or its equivalent daily. Patients receiving systemic steroid therapy for non-autoimmune processes (e.g., chronic obstructive pulmonary disease [COPD], adrenal replacement therapy) are permitted if on stable dose and asymptomatic
  • Has a known history of active tuberculosis (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 or complications due to a previously administered systemic agent, radiation therapy, or major surgery * 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 cycle 1 day 1 (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 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 (e.g., 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
  • Has known active hepatitis B (e.g., hepatitis B virus surface antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [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 corrected QT (QTc) prolongation as defined as QTc using Fridericia's formula (QTcF) > 470 ms (per Fridericia’s formula)
  • Inability to comply with study and/or follow-up procedures

Locations & Contacts

Massachusetts

Boston
Beth Israel Deaconess Medical Center
Status: Active
Contact: Glenn J. Bubley
Phone: 617-735-6026
Email: gbubley@bidmc.harvard.edu
Brigham and Women's Hospital
Status: Active
Contact: Lauren Christine Harshman
Phone: 617-632-4524
Email: LaurenC_Harshman@dfci.harvard.edu
Dana-Farber Cancer Institute
Status: Active
Contact: Lauren Christine Harshman
Phone: 617-632-4524
Email: LaurenC_Harshman@dfci.harvard.edu

Trial Objectives and Outline

PRIMARY OBJECTIVES:

I. 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.

SECONDARY OBJECTIVES:

I. To assess the safety and tolerability of the combination therapy with pembrolizumab plus radium Ra 223 dichloride (radium-223).

II. To preliminarily investigate the efficacy of the combination of pembrolizumab plus radium-223 as evaluated by progression-free survival (PFS) and overall survival (OS).

EXPLORATORY OBJECTIVES:

I. To characterize changes in immune cell response and function elicited by radium-223 with or without pembrolizumab (PD-1 blockade).

II. To evaluate the prostate-specific antigen (PSA) response including change in PSA and time to PSA progression.

III. To assess the rate of symptomatic skeletal events (SSEs) and time to SSE in patients treated with radium-223 and pembrolizumab.

IV. To explore the use of quantitative single photon emission computed tomography/computed tomography (SPECT/CT) for evaluating changes in osteoblastic activity on bone scan after radium-223 and pembrolizumab.

V. To assess the effect of radium-223 and pembrolizumab on quality of life, pain, and analgesic use.

VI. To investigate the impact of genomic alterations including those in deoxyribonucleic acid (DNA) damage repair pathways on clinical outcomes in patients treated with radium-223 with or without pembrolizumab.

VII. To identify biomarkers of response and to investigate mechanisms of treatment resistance through targeted sequencing of cell free DNA at baseline, on therapy, and at the time of disease progression.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM A: Patients receive pembrolizumab intravenously (IV) over 30 minutes every 3 weeks for up to 35 doses or 24 months, whichever is later, in the absence of disease progression or unacceptable toxicity. Patients also receive radium Ra 223 dichloride IV over 1 minute or longer per institutional standards every 4 weeks. Patients with stable disease (SD) after 3 doses of radium Ra 223 dichloride discontinue treatment with radium Ra 223 dichloride until disease progression. Patients then receive radium Ra 223 dichloride IV every 4 weeks for 3 additional doses.

ARM B: Patients receive radium Ra 223 dichloride IV over 1 minute or longer per institutional standards every 4 weeks for 6 doses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days and then every 6 months for up to 2 years.

Trial Phase & Type

Trial Phase

Phase II

Trial Type

Treatment

Lead Organization

Lead Organization
Dana-Farber Harvard Cancer Center

Principal Investigator
Lauren Christine Harshman

Trial IDs

Primary ID 16-498
Secondary IDs NCI-2017-01181
Clinicaltrials.gov ID NCT03093428