Pembrolizumab and Cryosurgery in Treating Patients With Newly Diagnosed, Oligo-metastatic Prostate Cancer

• Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins (Other)
• Overall Status: Completed
• CT.gov ID: NCT02489357
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 12
• Location: 1
• Arm: 1
• Actual Duration (Months): 23.7
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief Summary

This pilot phase II trial studies the side effects and how well pembrolizumab and cryosurgery work with short term androgen ablation to treat patients with prostate cancer that has traveled from the original tumor, through the body, and formed a small number of new tumors in other parts of the body (oligo-metastatic). Cryosurgery, also known as cryoablation or cryotherapy, kills tumor cells by freezing them. The process also incites an immune response within the ablated tumor. Giving monoclonal antibodies such as pembrolizumab which enhance a systemic anti-cancer immune response, may augment the effects of cryosurgery and increase tumor killing at distant (metastatic) sites.

Condition or Disease	Intervention/Treatment	Phase
Stage IV Prostate Cancer	Procedure: Cryosurgery; Drug: Degarelix; Other: Laboratory Biomarker Analysis; Biological: Pembrolizumab	N/A

Detailed Description

PRIMARY OBJECTIVES:

1. Assess feasibility via the proportion of men reaching a low prostate-specific antigen (PSA) nadir (< 0.6 ng/ml) at 1 year.

2. Evaluate the safety of cryotherapy to the prostate combined with pembrolizumab.

TERTIARY OBJECTIVES:

1. To evaluate the effects of combination cryotherapy / pembrolizumab on programmed cell death 1 (PD-1) and programmed cell death 1 ligand 1 (PD-L1) expression in the prostate as assessed by biopsy performed 6 months post treatment.

OUTLINE:

Patients receive standard of care androgen ablation with degarelix subcutaneously (SC) once a month for 8 months. Within 1 month of receiving degarelix, patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1. Treatment repeats every 3 weeks for up to 6 courses in the absence of disease progression or unacceptable toxicity. Within 3 days of receiving the first dose of pembrolizumab, patients undergo whole gland cryoablation of the prostate.

After completion of study treatment, patients are followed up at 30 days and then every 12 weeks for up to 1 year.

Study Design

• Study Type: Interventional
• Actual Enrollment: 12 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Pilot Study of MK-3475 With Cryotherapy for Men With Newly Diagnosed Oligo-metastatic Prostate Cancer
• Actual Study Start Date: Dec 11, 2015
• Actual Primary Completion Date: Nov 30, 2017
• Actual Study Completion Date: Nov 30, 2017

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Treatment (pembrolizumab, cryosurgery) Patients receive standard of care degarelix SC once a month for 8 months. Within 1 month of receiving degarelix, patients receive pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 3 weeks for up to 6 courses in the absence of disease progression or unacceptable toxicity. Within 3 days of receiving pembrolizumab, patients undergo whole gland cryoablation of the prostate.

Procedure: Cryosurgery; Undergo whole gland cryoablation; Other Names: CRYOABLATION cryosurgical ablation ; Drug: Degarelix; Given SC; Other Names: FE200486 Firmagon ; Other: Laboratory Biomarker Analysis; Correlative studies; Biological: Pembrolizumab; Given IV; Other Names: Keytruda Lambrolizumab MK-3475 SCH 900475

Outcome Measures

Primary Outcome Measures

1. Number of Participants With PSA < 0.6 ng/mL [At 1 year]

Other Outcome Measures

1. Expression of PD-1 [Baseline]

   Number of participants with PD-1 expression in tumor tissue.

2. Expression of PD-L1 [Baseline]

   Number of participants with PD-L1 expression in tumor tissue.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Have histologically or cytologically diagnosed oligo-metastatic prostate cancer; oligo-metastatic disease is defined to reflect men with low volume disease; specifically, oligo-metastatic disease is defined as less than 5 extra-pelvic metastases; metastatic lesions may be lymph nodes

• Be willing and able to provide written informed consent/assent for the trial

• Have available tissue from an archival tissue sample or newly obtained core or excisional biopsy of a tumor lesion

• Eastern Cooperative Oncology Group (ECOG) performance scale status of 0 or 1

• Demonstrate adequate organ function, all screening labs should be performed within 14 days of treatment initiation

• Absolute neutrophil count (ANC) >= 1,500/mcL

• Platelets >= 100,000/mcL

• Hemoglobin >= 9 g/dL or >= 5.6 mmol/L

• Serum creatinine OR measured or calculated creatinine clearance (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) =< 1.5 X upper limit of normal (ULN) OR >= 60 mL/min for subject with creatinine levels > 1.5 X institutional upper limit of normal (ULN)

• Serum total bilirubin =< 1.5 X ULN OR direct bilirubin =< ULN for subjects with total bilirubin levels > 1.5 ULN

• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X ULN OR =< 5 X ULN for subjects with liver metastases

• International normalized ratio (INR) or prothrombin time (PT) =< 1.5 X 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 ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulant

• Have testosterone greater than 50 ng/dl

• Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy

Exclusion Criteria:

• Is currently participating in or has participated in a study of an investigational agent or using an investigational device within 4 weeks of the first dose of treatment

• Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment

• Has had a prior monoclonal antibody 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 chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to a previously administered agent; Note: subjects with =< grade 2 neuropathy are an exception to this criterion and may qualify for the study; Note: if subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy

• Has a known additional malignancy that is progressing or requires active treatment; exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially 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

• Has an active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents; subjects with vitiligo or resolved childhood asthma/atopy would be an exception to this rule; subjects that require intermittent use of bronchodilators or local steroid injections would not be excluded from the study; subjects with hypothyroidism stable on hormone replacement or Sjorgen's syndrome will not be excluded from the study

• Has evidence of interstitial lung disease or active, non-infectious pneumonitis

• Has an active infection requiring systemic therapy

• 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

• Is expecting to father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment

• Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-cluster of differentiation (CD)137, or anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways)

• Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)

• Has known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or hepatitis c (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] (qualitative) is detected)

• Has received a live vaccine within 30 days prior to the first dose of trial treatment

• Has severe voiding symptoms (International Prognostic Scoring System [IPSS] > 20) or urinary retention requiring a catheter

• Has contraindications to cryotherapy of the prostate, including: previous transurethral prostatic resection (TURP) with persistent transurethral resection (TUR) defect, existing peri-anal or recto-urethral fistula, previous external beam radiation therapy or brachytherapy, coagulopathy, inability to tolerate anesthesia (spinal or general), inability to tolerate transrectal ultrasound (i.e. history of previous abdominal perineal resection)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Johns Hopkins University/Sidney Kimmel Cancer Center	Baltimore	Maryland	United States	21287

Sponsors and Collaborators

• Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Emmanuel Antonarakis, MD, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Feb 2, 2017

More Information

Publications

None provided.

• Responsible Party: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• ClinicalTrials.gov Identifier: NCT02489357
• Other Study ID Numbers: J1534; NCI-2015-00981; IRB00045444; MK-3475; P30CA006973
• First Posted: Jul 3, 2015
• Last Update Posted: Nov 12, 2021
• Last Verified: Nov 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Additional relevant MeSH terms: Prostatic Neoplasms; Pembrolizumab

Study Results

Participant Flow

Arm/Group Title	Treatment (Pembrolizumab, Cryosurgery)
Arm/Group Description	Patients receive standard of care degarelix SC once a month for 8 months. Within 1 month of receiving degarelix, patients receive pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 3 weeks for up to 6 courses in the absence of disease progression or unacceptable toxicity. Within 3 days of receiving pembrolizumab, patients undergo whole gland cryoablation of the prostate. Cryosurgery: Undergo whole gland cryoablation Degarelix: Given SC Laboratory Biomarker Analysis: Correlative studies Pembrolizumab: Given IV
Period Title: Overall Study
STARTED	12
COMPLETED	12
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Treatment (Pembrolizumab, Cryosurgery)
Arm/Group Description	Patients receive standard of care degarelix SC once a month for 8 months. Within 1 month of receiving degarelix, patients receive pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 3 weeks for up to 6 courses in the absence of disease progression or unacceptable toxicity. Within 3 days of receiving pembrolizumab, patients undergo whole gland cryoablation of the prostate. Cryosurgery: Undergo whole gland cryoablation Degarelix: Given SC Laboratory Biomarker Analysis: Correlative studies Pembrolizumab: Given IV
Overall Participants	12
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	6 50%
>=65 years	6 50%
Sex: Female, Male (Count of Participants)
Female	0 0%
Male	12 100%
Race and Ethnicity Not Collected (Count of Participants)
Region of Enrollment (Count of Participants)
United States	12 100%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With PSA < 0.6 ng/mL
Time Frame	At 1 year

Outcome Measure Data

Analysis Population Description

Data was not collected in 1/12 participants due to lost to follow up before one year.

Arm/Group Title	Treatment (Pembrolizumab, Cryosurgery)
Arm/Group Description	Patients receive standard of care degarelix SC once a month for 8 months. Within 1 month of receiving degarelix, patients receive pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 3 weeks for up to 6 courses in the absence of disease progression or unacceptable toxicity. Within 3 days of receiving pembrolizumab, patients undergo whole gland cryoablation of the prostate. Cryosurgery: Undergo whole gland cryoablation Degarelix: Given SC Laboratory Biomarker Analysis: Correlative studies Pembrolizumab: Given IV
Measure Participants	11
Count of Participants [Participants]	5 41.7%

2. Other Pre-specified Outcome

Title	Expression of PD-1
Description	Number of participants with PD-1 expression in tumor tissue.
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

1 participant refused biopsy. Only 2/11 samples were evaluable for this outcome measure.

Arm/Group Title	Treatment (Pembrolizumab, Cryosurgery)
Arm/Group Description	Patients receive standard of care degarelix SC once a month for 8 months. Within 1 month of receiving degarelix, patients receive pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 3 weeks for up to 6 courses in the absence of disease progression or unacceptable toxicity. Within 3 days of receiving pembrolizumab, patients undergo whole gland cryoablation of the prostate. Cryosurgery: Undergo whole gland cryoablation Degarelix: Given SC Laboratory Biomarker Analysis: Correlative studies Pembrolizumab: Given IV
Measure Participants	2
Count of Participants [Participants]	1 8.3%

3. Other Pre-specified Outcome

Title	Expression of PD-L1
Description	Number of participants with PD-L1 expression in tumor tissue.
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

1 participant refused biopsy. Only 2/11 samples were evaluable for this outcome measure.

Arm/Group Title	Treatment (Pembrolizumab, Cryosurgery)
Arm/Group Description	Patients receive standard of care degarelix SC once a month for 8 months. Within 1 month of receiving degarelix, patients receive pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 3 weeks for up to 6 courses in the absence of disease progression or unacceptable toxicity. Within 3 days of receiving pembrolizumab, patients undergo whole gland cryoablation of the prostate. Cryosurgery: Undergo whole gland cryoablation Degarelix: Given SC Laboratory Biomarker Analysis: Correlative studies Pembrolizumab: Given IV
Measure Participants	2
Count of Participants [Participants]	0 0%

Adverse Events

Time Frame	up to 2 years
Arm/Group Title	Treatment (Pembrolizumab, Cryosurgery)
Arm/Group Description	Patients receive standard of care degarelix SC once a month for 8 months. Within 1 month of receiving degarelix, patients receive pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 3 weeks for up to 6 courses in the absence of disease progression or unacceptable toxicity. Within 3 days of receiving pembrolizumab, patients undergo whole gland cryoablation of the prostate. Cryosurgery: Undergo whole gland cryoablation Degarelix: Given SC Laboratory Biomarker Analysis: Correlative studies Pembrolizumab: Given IV
All Cause Mortality
	Treatment (Pembrolizumab, Cryosurgery)
	Affected / at Risk (%)	# Events
Total	0/12 (0%)
Serious Adverse Events
	Treatment (Pembrolizumab, Cryosurgery)
	Affected / at Risk (%)	# Events
Total	0/12 (0%)
Other (Not Including Serious) Adverse Events
	Treatment (Pembrolizumab, Cryosurgery)
	Affected / at Risk (%)	# Events
Total	12/12 (100%)
Blood and lymphatic system disorders
Edema	3/12 (25%)	3
Anemia	1/12 (8.3%)	1
Gastrointestinal disorders
Nausea	1/12 (8.3%)	1
Oral pain	1/12 (8.3%)	1
Constipation	2/12 (16.7%)	2
Mucositis	1/12 (8.3%)	2
Dry mouth	1/12 (8.3%)	1
Abdominal Pain	1/12 (8.3%)	1
Groin Pain	3/12 (25%)	3
General disorders
Fatigue	8/12 (66.7%)	8
Injection site reaction	3/12 (25%)	3
Chills	1/12 (8.3%)	1
Metabolism and nutrition disorders
Night sweats	1/12 (8.3%)	1
Musculoskeletal and connective tissue disorders
Pain	4/12 (33.3%)	5
Pain, extremities	2/12 (16.7%)	2
Nervous system disorders
Dysgeusia	2/12 (16.7%)	2
Headache	2/12 (16.7%)	2
Psychiatric disorders
Depression	2/12 (16.7%)	2
Insomnia	1/12 (8.3%)	1
Agitation	1/12 (8.3%)	1
Renal and urinary disorders
Urinary incontinence	2/12 (16.7%)	2
Urinary urgency	3/12 (25%)	3
Bladder spasm	1/12 (8.3%)	1
Urinary frequency	3/12 (25%)	3
Nocturia	1/12 (8.3%)	1
Hematuria	2/12 (16.7%)	2
Reproductive system and breast disorders
Erectile Dysfunction	1/12 (8.3%)	1
Penile pain	1/12 (8.3%)	1
Respiratory, thoracic and mediastinal disorders
Voice alteration	1/12 (8.3%)	1
Skin and subcutaneous tissue disorders
Pruritis	2/12 (16.7%)	3
Maculo-papular Rash	2/12 (16.7%)	3
Skin induration	1/12 (8.3%)	1
Vascular disorders
Hot flashes	6/12 (50%)	6

Limitations/Caveats

[Not Specified]

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.