Study Evaluating the Addition of Pembrolizumab to Radium-223 in mCRPC
Study Details
Study Description
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
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| 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.
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 Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| 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 Radium-223 will be halted after 3 doses. Once radiographic progressive disease occurs, the last 3 doses of radium will be given. |
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 Names:
Drug: Pembrolizumab
Pembrolizumab is a PD-1 inhibitor. Pembrolizumab binds to human PD-1 and blocks the interaction between PD1 and its ligands.
Other Names:
|
| Experimental: Radium-223 - Radium-223 will be administered intravenously every 4 weeks at a pre-determined dose |
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 Names:
|
Outcome Measures
Primary Outcome Measures
- Number of Participants With Increased Immune Cell Infiltration Across Arms [2 months]
Differences in immune infiltrating cells (CD8+ T-cells and CD4+ T-cells) in bone biopsy specimens were compared from baseline to 8 weeks on study therapy between the treatment arms.
Secondary Outcome Measures
- Number of Participants With Grade 3 or Higher Treatment Related Adverse Events [Toxicity was assessed every cycle and up to 22.4 months.]
Adverse events were assessed using NCI CTCAE (version 4.0). Treatment related adverse events were those that were deemed as "Definitely", "Probably" and "Possibly" related to the study treatment.
- Median Progression-Free Survival [Imaging was performed every 12 weeks and up to 25 months.]
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 by RECIST v 1.1 for soft tissue disease and PCWG2 guidelines for bone disease or death due to any cause, or censored at last imaging date. Per RECIST, progression is defined as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. For the bone per PCWG2 criteria, appearance of at least 2 new lesions within 12 weeks and confirmed by a second scan >=6 weeks. Median PFS is estimated using Kaplan-Meier method.
- Median Overall Survival [Participants were followed up for ~36 months.]
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. Median OS is estimated using Kaplan-Meier method.
Eligibility Criteria
Criteria
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
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Beth Israel Deaconess Medical Center | Boston | Massachusetts | United States | 02115 |
| 2 | Dana Farber Cancer Institute | Boston | Massachusetts | United States | 02115 |
Sponsors and Collaborators
- Dana-Farber Cancer Institute
- Merck Sharp & Dohme LLC
Investigators
- Principal Investigator: Atish Choudhury, MD, Dana-Farber Cancer Institute
Study Documents (Full-Text)
More Information
Publications
None provided.- 16-498
Study Results
Participant Flow
| Recruitment Details | |
|---|---|
| Pre-assignment Detail | Participants were enrolled and underwent bone biopsy prior to randomization. |
| Arm/Group Title | Pembrolizumab Plus Radium-223 | Radium-223 |
|---|---|---|
| Arm/Group Description | 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 Radium-223 will be halted after 3 doses. Once radiographic progressive disease occurs, the last 3 doses of radium will be given. 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. Pembrolizumab: Pembrolizumab is a PD-1 inhibitor. Pembrolizumab binds to human PD-1 and blocks the interaction between PD1 and its ligands. | - Radium-223 will be administered intravenously every 4 weeks at a pre-determined dose 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. |
| Period Title: Overall Study | ||
| STARTED | 31 | 14 |
| COMPLETED | 12 | 8 |
| NOT COMPLETED | 19 | 6 |
Baseline Characteristics
| Arm/Group Title | Pembrolizumab Plus Radium-223 | Radium-223 | Total |
|---|---|---|---|
| Arm/Group Description | 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 Radium-223 will be halted after 3 doses. Once radiographic progressive disease occurs, the last 3 doses of radium will be given. 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. Pembrolizumab: Pembrolizumab is a PD-1 inhibitor. Pembrolizumab binds to human PD-1 and blocks the interaction between PD1 and its ligands. | - Radium-223 will be administered intravenously every 4 weeks at a pre-determined dose 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. | Total of all reporting groups |
| Overall Participants | 29 | 13 | 42 |
| Age (years) [Median (Full Range) ] | |||
| Median (Full Range) [years] |
69
|
71
|
70
|
| Sex: Female, Male (Count of Participants) | |||
| Female |
0
0%
|
0
0%
|
0
0%
|
| Male |
29
100%
|
13
100%
|
42
100%
|
| Race (NIH/OMB) (Count of Participants) | |||
| American Indian or Alaska Native |
0
0%
|
0
0%
|
0
0%
|
| Asian |
1
3.4%
|
0
0%
|
1
2.4%
|
| Native Hawaiian or Other Pacific Islander |
0
0%
|
0
0%
|
0
0%
|
| Black or African American |
0
0%
|
0
0%
|
0
0%
|
| White |
27
93.1%
|
12
92.3%
|
39
92.9%
|
| More than one race |
0
0%
|
0
0%
|
0
0%
|
| Unknown or Not Reported |
1
3.4%
|
1
7.7%
|
2
4.8%
|
| Volume of bone metastases (Count of Participants) | |||
| < 4 bone metastases |
4
13.8%
|
1
7.7%
|
5
11.9%
|
| ≥ 4 bone metastases |
25
86.2%
|
12
92.3%
|
37
88.1%
|
| Alkaline phosphatase (Count of Participants) | |||
| < 220U/L |
21
72.4%
|
11
84.6%
|
32
76.2%
|
| ≥ 220 U/L |
8
27.6%
|
2
15.4%
|
10
23.8%
|
Outcome Measures
| Title | Number of Participants With Increased Immune Cell Infiltration Across Arms |
|---|---|
| Description | Differences in immune infiltrating cells (CD8+ T-cells and CD4+ T-cells) in bone biopsy specimens were compared from baseline to 8 weeks on study therapy between the treatment arms. |
| Time Frame | 2 months |
Outcome Measure Data
| Analysis Population Description |
|---|
| Participants who initiated at least one dose of study treatment and available bone biopsy data on baseline and 8-week on treatment. |
| Arm/Group Title | Pembrolizumab Plus Radium-223 | Radium-223 |
|---|---|---|
| Arm/Group Description | 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 Radium-223 will be halted after 3 doses. Once radiographic progressive disease occurs, the last 3 doses of radium will be given. 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. Pembrolizumab: Pembrolizumab is a PD-1 inhibitor. Pembrolizumab binds to human PD-1 and blocks the interaction between PD1 and its ligands. | - Radium-223 will be administered intravenously every 4 weeks at a pre-determined dose 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. |
| Measure Participants | 21 | 5 |
| Increase |
7
24.1%
|
2
15.4%
|
| No increase |
14
48.3%
|
3
23.1%
|
| Increase |
3
10.3%
|
1
7.7%
|
| No increase |
18
62.1%
|
4
30.8%
|
| Title | Number of Participants With Grade 3 or Higher Treatment Related Adverse Events |
|---|---|
| Description | Adverse events were assessed using NCI CTCAE (version 4.0). Treatment related adverse events were those that were deemed as "Definitely", "Probably" and "Possibly" related to the study treatment. |
| Time Frame | Toxicity was assessed every cycle and up to 22.4 months. |
Outcome Measure Data
| Analysis Population Description |
|---|
| Participants who initiated at least one dose of study treatment |
| Arm/Group Title | Pembrolizumab Plus Radium-223 | Radium-223 |
|---|---|---|
| Arm/Group Description | 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 Radium-223 will be halted after 3 doses. Once radiographic progressive disease occurs, the last 3 doses of radium will be given. 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. Pembrolizumab: Pembrolizumab is a PD-1 inhibitor. Pembrolizumab binds to human PD-1 and blocks the interaction between PD1 and its ligands. | - Radium-223 will be administered intravenously every 4 weeks at a pre-determined dose 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. |
| Measure Participants | 29 | 13 |
| Count of Participants [Participants] |
13
44.8%
|
5
38.5%
|
| Title | Median Progression-Free Survival |
|---|---|
| Description | 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 by RECIST v 1.1 for soft tissue disease and PCWG2 guidelines for bone disease or death due to any cause, or censored at last imaging date. Per RECIST, progression is defined as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. For the bone per PCWG2 criteria, appearance of at least 2 new lesions within 12 weeks and confirmed by a second scan >=6 weeks. Median PFS is estimated using Kaplan-Meier method. |
| Time Frame | Imaging was performed every 12 weeks and up to 25 months. |
Outcome Measure Data
| Analysis Population Description |
|---|
| Participants who initiated at least one dose of study treatment |
| Arm/Group Title | Pembrolizumab Plus Radium-223 | Radium-223 |
|---|---|---|
| Arm/Group Description | 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 Radium-223 will be halted after 3 doses. Once radiographic progressive disease occurs, the last 3 doses of radium will be given. 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. Pembrolizumab: Pembrolizumab is a PD-1 inhibitor. Pembrolizumab binds to human PD-1 and blocks the interaction between PD1 and its ligands. | - Radium-223 will be administered intravenously every 4 weeks at a pre-determined dose 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. |
| Measure Participants | 29 | 13 |
| Median (Full Range) [Months] |
6.1
|
5.7
|
| Title | Median Overall Survival |
|---|---|
| Description | 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. Median OS is estimated using Kaplan-Meier method. |
| Time Frame | Participants were followed up for ~36 months. |
Outcome Measure Data
| Analysis Population Description |
|---|
| Participants who initiated at least one dose of study treatment |
| Arm/Group Title | Pembrolizumab Plus Radium-223 | Radium-223 |
|---|---|---|
| Arm/Group Description | 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 Radium-223 will be halted after 3 doses. Once radiographic progressive disease occurs, the last 3 doses of radium will be given. 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. Pembrolizumab: Pembrolizumab is a PD-1 inhibitor. Pembrolizumab binds to human PD-1 and blocks the interaction between PD1 and its ligands. | - Radium-223 will be administered intravenously every 4 weeks at a pre-determined dose 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. |
| Measure Participants | 29 | 13 |
| Median (Full Range) [Months] |
16.9
|
16.0
|
Adverse Events
| Time Frame | AE was measured from baseline to end of treatment. Participants were on study up to 35 and 27months for combination and monotherapy arms, respectively. | |||
|---|---|---|---|---|
| Adverse Event Reporting Description | A serious adverse event is classified using physician's discretion. All adverse events resulting in death, life threatening events, significant disability, prolonged hospitalization, congenital abnormality/birth defect, or new cancer will be considered a serious adverse event. | |||
| Arm/Group Title | Pembrolizumab Plus Radium-223 | Radium-223 | ||
| Arm/Group Description | 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 Radium-223 will be halted after 3 doses. Once radiographic progressive disease occurs, the last 3 doses of radium will be given. 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. Pembrolizumab: Pembrolizumab is a PD-1 inhibitor. Pembrolizumab binds to human PD-1 and blocks the interaction between PD1 and its ligands. | - Radium-223 will be administered intravenously every 4 weeks at a pre-determined dose 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. | ||
All Cause Mortality |
||||
| Pembrolizumab Plus Radium-223 | Radium-223 | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 15/31 (48.4%) | 7/14 (50%) | ||
Serious Adverse Events |
||||
| Pembrolizumab Plus Radium-223 | Radium-223 | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 9/31 (29%) | 3/14 (21.4%) | ||
| Blood and lymphatic system disorders | ||||
| Anemia | 1/31 (3.2%) | 0/14 (0%) | ||
| Cardiac disorders | ||||
| Acute coronary syndrome | 0/31 (0%) | 1/14 (7.1%) | ||
| Endocrine disorders | ||||
| Adrenal insufficiency | 2/31 (6.5%) | 0/14 (0%) | ||
| Gastrointestinal disorders | ||||
| Diarrhea | 1/31 (3.2%) | 0/14 (0%) | ||
| General disorders | ||||
| Fever | 1/31 (3.2%) | 0/14 (0%) | ||
| Pain | 0/31 (0%) | 1/14 (7.1%) | ||
| Infections and infestations | ||||
| Lung infection | 1/31 (3.2%) | 0/14 (0%) | ||
| Sepsis | 1/31 (3.2%) | 0/14 (0%) | ||
| Urinary tract infection | 2/31 (6.5%) | 0/14 (0%) | ||
| Investigations | ||||
| Aspartate aminotransferase increased | 1/31 (3.2%) | 0/14 (0%) | ||
| Platelet count decreased | 1/31 (3.2%) | 0/14 (0%) | ||
| White blood cell decreased | 1/31 (3.2%) | 0/14 (0%) | ||
| Metabolism and nutrition disorders | ||||
| Dehydration | 1/31 (3.2%) | 0/14 (0%) | ||
| Musculoskeletal and connective tissue disorders | ||||
| Back pain | 2/31 (6.5%) | 0/14 (0%) | ||
| Nervous system disorders | ||||
| Abducens nerve disorder | 0/31 (0%) | 1/14 (7.1%) | ||
| Oculomotor nerve disorder | 0/31 (0%) | 1/14 (7.1%) | ||
| Stroke | 1/31 (3.2%) | 0/14 (0%) | ||
| Renal and urinary disorders | ||||
| Renal calculi | 1/31 (3.2%) | 0/14 (0%) | ||
| Urinary tract obstruction | 1/31 (3.2%) | 0/14 (0%) | ||
| Respiratory, thoracic and mediastinal disorders | ||||
| Pneumonitis | 2/31 (6.5%) | 0/14 (0%) | ||
Other (Not Including Serious) Adverse Events |
||||
| Pembrolizumab Plus Radium-223 | Radium-223 | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 30/31 (96.8%) | 13/14 (92.9%) | ||
| Blood and lymphatic system disorders | ||||
| Anemia | 14/31 (45.2%) | 4/14 (28.6%) | ||
| Leukocytosis | 1/31 (3.2%) | 0/14 (0%) | ||
| Thrombotic thrombocytopenic purpura | 1/31 (3.2%) | 1/14 (7.1%) | ||
| Cardiac disorders | ||||
| Atrial fibrillation | 2/31 (6.5%) | 0/14 (0%) | ||
| Sinus tachycardia | 1/31 (3.2%) | 0/14 (0%) | ||
| Ear and labyrinth disorders | ||||
| Hearing impaired | 1/31 (3.2%) | 0/14 (0%) | ||
| Middle ear inflammation | 1/31 (3.2%) | 0/14 (0%) | ||
| Tinnitus | 1/31 (3.2%) | 0/14 (0%) | ||
| Endocrine disorders | ||||
| Adrenal insufficiency | 1/31 (3.2%) | 0/14 (0%) | ||
| Hyperthyroidism | 4/31 (12.9%) | 0/14 (0%) | ||
| Hypothyroidism | 10/31 (32.3%) | 3/14 (21.4%) | ||
| Eye disorders | ||||
| Blurred vision | 1/31 (3.2%) | 0/14 (0%) | ||
| Dry eye | 1/31 (3.2%) | 0/14 (0%) | ||
| Eye disorders - Other, specify | 1/31 (3.2%) | 0/14 (0%) | ||
| Gastrointestinal disorders | ||||
| Abdominal pain | 2/31 (6.5%) | 0/14 (0%) | ||
| Bloating | 0/31 (0%) | 1/14 (7.1%) | ||
| Constipation | 12/31 (38.7%) | 4/14 (28.6%) | ||
| Diarrhea | 11/31 (35.5%) | 5/14 (35.7%) | ||
| Dry mouth | 2/31 (6.5%) | 1/14 (7.1%) | ||
| Dyspepsia | 1/31 (3.2%) | 0/14 (0%) | ||
| Dysphagia | 1/31 (3.2%) | 0/14 (0%) | ||
| Gastroesophageal reflux disease | 2/31 (6.5%) | 0/14 (0%) | ||
| Gastrointestinal disorders - Other, specify | 2/31 (6.5%) | 0/14 (0%) | ||
| Hemorrhoids | 2/31 (6.5%) | 0/14 (0%) | ||
| Nausea | 14/31 (45.2%) | 3/14 (21.4%) | ||
| Periodontal disease | 1/31 (3.2%) | 0/14 (0%) | ||
| Vomiting | 2/31 (6.5%) | 0/14 (0%) | ||
| General disorders | ||||
| Chills | 0/31 (0%) | 1/14 (7.1%) | ||
| Edema limbs | 4/31 (12.9%) | 2/14 (14.3%) | ||
| Fatigue | 26/31 (83.9%) | 10/14 (71.4%) | ||
| Fever | 2/31 (6.5%) | 0/14 (0%) | ||
| Flu like symptoms | 2/31 (6.5%) | 0/14 (0%) | ||
| Gait disturbance | 1/31 (3.2%) | 0/14 (0%) | ||
| Injection site reaction | 1/31 (3.2%) | 0/14 (0%) | ||
| Localized edema | 0/31 (0%) | 1/14 (7.1%) | ||
| Non-cardiac chest pain | 2/31 (6.5%) | 0/14 (0%) | ||
| Pain | 13/31 (41.9%) | 6/14 (42.9%) | ||
| Infections and infestations | ||||
| Lung infection | 1/31 (3.2%) | 0/14 (0%) | ||
| Skin infection | 4/31 (12.9%) | 0/14 (0%) | ||
| Upper respiratory infection | 1/31 (3.2%) | 0/14 (0%) | ||
| Urinary tract infection | 2/31 (6.5%) | 0/14 (0%) | ||
| Injury, poisoning and procedural complications | ||||
| Bruising | 1/31 (3.2%) | 0/14 (0%) | ||
| Fall | 1/31 (3.2%) | 1/14 (7.1%) | ||
| Fracture | 3/31 (9.7%) | 0/14 (0%) | ||
| Hip fracture | 1/31 (3.2%) | 0/14 (0%) | ||
| Spinal fracture | 0/31 (0%) | 2/14 (14.3%) | ||
| Investigations | ||||
| Alanine aminotransferase increased | 4/31 (12.9%) | 0/14 (0%) | ||
| Alkaline phosphatase increased | 9/31 (29%) | 2/14 (14.3%) | ||
| Aspartate aminotransferase increased | 11/31 (35.5%) | 2/14 (14.3%) | ||
| Blood bilirubin increased | 3/31 (9.7%) | 0/14 (0%) | ||
| CD4 lymphocytes decreased | 1/31 (3.2%) | 2/14 (14.3%) | ||
| Cholesterol high | 1/31 (3.2%) | 0/14 (0%) | ||
| Creatinine increased | 1/31 (3.2%) | 1/14 (7.1%) | ||
| INR increased | 1/31 (3.2%) | 0/14 (0%) | ||
| Lymphocyte count decreased | 1/31 (3.2%) | 0/14 (0%) | ||
| Neutrophil count decreased | 5/31 (16.1%) | 1/14 (7.1%) | ||
| Platelet count decreased | 7/31 (22.6%) | 3/14 (21.4%) | ||
| Weight loss | 2/31 (6.5%) | 1/14 (7.1%) | ||
| White blood cell decreased | 2/31 (6.5%) | 1/14 (7.1%) | ||
| Metabolism and nutrition disorders | ||||
| Anorexia | 8/31 (25.8%) | 1/14 (7.1%) | ||
| Dehydration | 2/31 (6.5%) | 0/14 (0%) | ||
| Hyperglycemia | 5/31 (16.1%) | 3/14 (21.4%) | ||
| Hypernatremia | 1/31 (3.2%) | 0/14 (0%) | ||
| Hypoalbuminemia | 1/31 (3.2%) | 0/14 (0%) | ||
| Hypocalcemia | 3/31 (9.7%) | 0/14 (0%) | ||
| Hypokalemia | 1/31 (3.2%) | 3/14 (21.4%) | ||
| Hypomagnesemia | 1/31 (3.2%) | 0/14 (0%) | ||
| Hyponatremia | 4/31 (12.9%) | 0/14 (0%) | ||
| Hypophosphatemia | 1/31 (3.2%) | 0/14 (0%) | ||
| Metabolism and nutrition disorders - Other, specify | 1/31 (3.2%) | 0/14 (0%) | ||
| Musculoskeletal and connective tissue disorders | ||||
| Arthralgia | 4/31 (12.9%) | 2/14 (14.3%) | ||
| Arthritis | 3/31 (9.7%) | 0/14 (0%) | ||
| Back pain | 16/31 (51.6%) | 5/14 (35.7%) | ||
| Bone pain | 5/31 (16.1%) | 3/14 (21.4%) | ||
| Flank pain | 2/31 (6.5%) | 0/14 (0%) | ||
| Generalized muscle weakness | 3/31 (9.7%) | 1/14 (7.1%) | ||
| Musculoskeletal and connective tissue disorder - Other, specify | 2/31 (6.5%) | 0/14 (0%) | ||
| Myalgia | 1/31 (3.2%) | 0/14 (0%) | ||
| Myalgia | 0/31 (0%) | 1/14 (7.1%) | ||
| Pain in extremity | 6/31 (19.4%) | 1/14 (7.1%) | ||
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, specify | 1/31 (3.2%) | 0/14 (0%) | ||
| Tumor pain | 1/31 (3.2%) | 0/14 (0%) | ||
| Nervous system disorders | ||||
| Concentration impairment | 0/31 (0%) | 1/14 (7.1%) | ||
| Dizziness | 3/31 (9.7%) | 0/14 (0%) | ||
| Dysgeusia | 3/31 (9.7%) | 1/14 (7.1%) | ||
| Headache | 4/31 (12.9%) | 1/14 (7.1%) | ||
| Neuralgia | 1/31 (3.2%) | 0/14 (0%) | ||
| Paresthesia | 3/31 (9.7%) | 0/14 (0%) | ||
| Peripheral motor neuropathy | 1/31 (3.2%) | 0/14 (0%) | ||
| Peripheral sensory neuropathy | 5/31 (16.1%) | 2/14 (14.3%) | ||
| Seizure | 1/31 (3.2%) | 0/14 (0%) | ||
| Tremor | 1/31 (3.2%) | 0/14 (0%) | ||
| Psychiatric disorders | ||||
| Anxiety | 7/31 (22.6%) | 0/14 (0%) | ||
| Depression | 2/31 (6.5%) | 0/14 (0%) | ||
| Insomnia | 4/31 (12.9%) | 0/14 (0%) | ||
| Libido decreased | 2/31 (6.5%) | 0/14 (0%) | ||
| Personality change | 1/31 (3.2%) | 0/14 (0%) | ||
| Renal and urinary disorders | ||||
| Renal and urinary disorders - Other, specify | 1/31 (3.2%) | 1/14 (7.1%) | ||
| Urinary frequency | 7/31 (22.6%) | 4/14 (28.6%) | ||
| Urinary incontinence | 5/31 (16.1%) | 1/14 (7.1%) | ||
| Urinary retention | 1/31 (3.2%) | 0/14 (0%) | ||
| Urinary tract obstruction | 1/31 (3.2%) | 0/14 (0%) | ||
| Reproductive system and breast disorders | ||||
| Breast pain | 1/31 (3.2%) | 0/14 (0%) | ||
| Erectile dysfunction | 2/31 (6.5%) | 0/14 (0%) | ||
| Gynecomastia | 1/31 (3.2%) | 2/14 (14.3%) | ||
| Respiratory, thoracic and mediastinal disorders | ||||
| Allergic rhinitis | 4/31 (12.9%) | 0/14 (0%) | ||
| Bronchospasm | 1/31 (3.2%) | 0/14 (0%) | ||
| Cough | 6/31 (19.4%) | 1/14 (7.1%) | ||
| Dyspnea | 12/31 (38.7%) | 1/14 (7.1%) | ||
| Epistaxis | 1/31 (3.2%) | 0/14 (0%) | ||
| Hypoxia | 1/31 (3.2%) | 0/14 (0%) | ||
| Nasal congestion | 3/31 (9.7%) | 0/14 (0%) | ||
| Pneumonitis | 3/31 (9.7%) | 0/14 (0%) | ||
| Productive cough | 1/31 (3.2%) | 0/14 (0%) | ||
| Sinus disorder | 1/31 (3.2%) | 1/14 (7.1%) | ||
| Sleep apnea | 1/31 (3.2%) | 0/14 (0%) | ||
| Tracheal fistula | 1/31 (3.2%) | 0/14 (0%) | ||
| Wheezing | 1/31 (3.2%) | 0/14 (0%) | ||
| Skin and subcutaneous tissue disorders | ||||
| Dry skin | 2/31 (6.5%) | 0/14 (0%) | ||
| Nail discoloration | 1/31 (3.2%) | 1/14 (7.1%) | ||
| Pruritus | 6/31 (19.4%) | 1/14 (7.1%) | ||
| Purpura | 1/31 (3.2%) | 0/14 (0%) | ||
| Rash acneiform | 4/31 (12.9%) | 0/14 (0%) | ||
| Rash maculo-papular | 12/31 (38.7%) | 0/14 (0%) | ||
| Skin and subcutaneous tissue disorders - Other, specify | 2/31 (6.5%) | 0/14 (0%) | ||
| Vascular disorders | ||||
| Hematoma | 0/31 (0%) | 1/14 (7.1%) | ||
| Hot flashes | 13/31 (41.9%) | 5/14 (35.7%) | ||
| Hypertension | 7/31 (22.6%) | 6/14 (42.9%) | ||
| Hypotension | 2/31 (6.5%) | 0/14 (0%) | ||
| Thromboembolic event | 4/31 (12.9%) | 0/14 (0%) | ||
Limitations/Caveats
More Information
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
| Name/Title | Atish Choudhury |
|---|---|
| Organization | Dana Farber Cancer Institute |
| Phone | 617-632-6328 |
| achoudhury@partners.org |
- 16-498