Anti-PD(L)1 and SBRT in the Treatment of Advanced, Platinum-Refractory Urothelial Carcinoma

• ClinicalTrials.gov Identifier: NCT03287050
• Recruitment Status: Terminated
• First Posted: September 19, 2017
• Results First Posted: December 15, 2021
• Last Update Posted: December 15, 2021
• Sponsor: University of Michigan Rogel Cancer Center
• Information provided by (Responsible Party): University of Michigan Rogel Cancer Center

• Study Type: Interventional
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Urothelial Carcinoma
• Interventions: Drug: Pembrolizumab; Radiation: SBRT
• Enrollment: 6

Participant Flow

Recruitment Details
Pre-assignment Details

Arm/Group Title	Pembrolizumab + SBRT
Arm/Group Description	Pembrolizumab: 200 mg IV q 21 days SBRT: Stereotactic body radiation therapy (SBRT) that will commence not later than the initiation of the second cycle of pembrolizumab. SBRT dose and fractionation will be at the discretion of the treating radiation oncologist, and will be selected to respect the normal tissue tolerance of adjacent organs at risk.
Period Title: Overall Study
Started	6
Completed	6
Not Completed	0

Baseline Characteristics

Arm/Group Title		Pembrolizumab + SBRT
Arm/Group Description		Pembrolizumab: 200 mg IV q 21 days SBRT: Stereotactic body radiation therapy (SBRT) that will commence not later than the initiation of the second cycle of pembrolizumab. SBRT dose and fractionation will be at the discretion of the treating radiation oncologist, and will be selected to respect the normal tissue tolerance of adjacent organs at risk.
Overall Number of Baseline Participants		6
Baseline Analysis Population Description		[Not Specified]
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	6 participants
		64 (8)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	6 participants
	Female	1 16.7%
	Male	5 83.3%
Ethnicity (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	6 participants
	Hispanic or Latino	0 0.0%
	Not Hispanic or Latino	6 100.0%
	Unknown or Not Reported	0 0.0%
Race (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	6 participants
	American Indian or Alaska Native	0 0.0%
	Asian	0 0.0%
	Native Hawaiian or Other Pacific Islander	0 0.0%
	Black or African American	0 0.0%
	White	6 100.0%
	More than one race	0 0.0%
	Unknown or Not Reported	0 0.0%
Region of Enrollment; Measure Type: Number; Unit of measure: Participants
United States	Number Analyzed	6 participants
		6

Outcome Measures

1. Primary Outcome

Title	The Percentage of Subjects Who Receive 4 Doses of Pembrolizumab and at Least One Session of Treatment of SBRT
Description	Feasibility will be determined by the percentage of subjects who receive 4 doses of pembrolizumab and at least one session of treatment of SBRT (Stereotactic Body Radiation Therapy) within 15 weeks from the first dose of pembrolizumab.
Time Frame	15 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pembrolizumab + SBRT
Arm/Group Description:	Pembrolizumab: 200 mg IV q 21 days SBRT: Stereotactic body radiation therapy (SBRT) that will commence not later than the initiation of the second cycle of pembrolizumab. SBRT dose and fractionation will be at the discretion of the treating radiation oncologist, and will be selected to respect the normal tissue tolerance of adjacent organs at risk.
Overall Number of Participants Analyzed	6
Measure Type: Number; Unit of Measure: percentage of participants
	83

2. Secondary Outcome

Title	The Number of Grades 3-5 Drug Related Adverse Events (AEs)
Description	The number of grades 3-5 drug related adverse events (AEs) will be recorded. AEs will be graded using the CTCAE v4.03
Time Frame	30 days post last dose

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pembrolizumab + SBRT
Arm/Group Description:	Pembrolizumab: 200 mg IV q 21 days SBRT: Stereotactic body radiation therapy (SBRT) that will commence not later than the initiation of the second cycle of pembrolizumab. SBRT dose and fractionation will be at the discretion of the treating radiation oncologist, and will be selected to respect the normal tissue tolerance of adjacent organs at risk.
Overall Number of Participants Analyzed	6
Measure Type: Number; Unit of Measure: events
	0

3. Secondary Outcome

Title	The Percentage of Patients That Respond to Treatment
Description	The percentage of patients that achieve either a complete response (CR) or partial response (PR). Response will be reported separately using RECIST and irRECIST criteria. CR (RECIST): Disappearance of all target lesions, determined by two separate observations conducted not less than 4 weeks apart. There can be no appearance of new lesions CR (irRECIST): Disappearance of all lesions in two consecutive observations not less than 4 wk apart PR (RECIST): At least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD. There can be no appearance of new lesions PR (irRECIST): ≥50% decrease in tumor burden compared with baseline in two observations at least 4 wk apart
Time Frame	51 weeks (up to 17, 3 week doses)

Outcome Measure Data

Analysis Population Description

One patient who did not have non-radiated measurable disease is not included.

Arm/Group Title	Pembrolizumab + SBRT
Arm/Group Description:	Pembrolizumab: 200 mg IV q 21 days SBRT: Stereotactic body radiation therapy (SBRT) that will commence not later than the initiation of the second cycle of pembrolizumab. SBRT dose and fractionation will be at the discretion of the treating radiation oncologist, and will be selected to respect the normal tissue tolerance of adjacent organs at risk.
Overall Number of Participants Analyzed	5
Measure Type: Number; Unit of Measure: percentage of participants
RECIST	40
irRECIST	40

4. Secondary Outcome

Title	Progression Free Survival (PFS) Time
Description	Progression-free survival (PFS) is defined as the duration of time from start of treatment to time of progressive disease (PD), or death, whichever occurs first, up to 24 months. PD (RECIST): At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started, or the appearance of one or more new lesions PD (irRECIST): At least 25% increase in tumor burden compared with nadir (at any single time point) in two consecutive observations at least 4 wk apart
Time Frame	24 months

Outcome Measure Data

Analysis Population Description

One patient who did not have non-radiated measurable disease is not included in the results table.

Arm/Group Title	Pembrolizumab + SBRT
Arm/Group Description:	Pembrolizumab: 200 mg IV q 21 days SBRT: Stereotactic body radiation therapy (SBRT) that will commence not later than the initiation of the second cycle of pembrolizumab. SBRT dose and fractionation will be at the discretion of the treating radiation oncologist, and will be selected to respect the normal tissue tolerance of adjacent organs at risk.
Overall Number of Participants Analyzed	5
Measure Type: Number; Unit of Measure: months
Patient 1	23
Patient 2	10
Patient 3	2
Patient 4	NA [1]
Patient 5	6

[1]

This patient was continuing treatment without progression at the time of study completion/data cut-off.

Adverse Events

Time Frame	All adverse event data (serious and non-serious) collected from the time of the initial study treatment administration through 30 days after the last dose of study treatment; additionally, any serious adverse event occurring more than 30 days after the last study treatment if considered to be related to the study treatment. Data was collected during a 16 month period.
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	Pembrolizumab + SBRT
Arm/Group Description	Pembrolizumab: 200 mg IV q 21 days SBRT: Stereotactic body radiation therapy (SBRT) that will commence not later than the initiation of the second cycle of pembrolizumab. SBRT dose and fractionation will be at the discretion of the treating radiation oncologist, and will be selected to respect the normal tissue tolerance of adjacent organs at risk.
All-Cause Mortality
	Pembrolizumab + SBRT
	Affected / at Risk (%)
Total	3/6 (50.00%)
Serious Adverse Events
	Pembrolizumab + SBRT
	Affected / at Risk (%)	# Events
Total	1/6 (16.67%)
Injury, poisoning and procedural complications
Spinal fracture † 1	1/6 (16.67%)	1
Musculoskeletal and connective tissue disorders
Bone pain † 1	1/6 (16.67%)	1
1 Term from vocabulary, CTCAE (4.0); † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	0%
	Pembrolizumab + SBRT
	Affected / at Risk (%)	# Events
Total	6/6 (100.00%)
Blood and lymphatic system disorders
Anemia † 1	3/6 (50.00%)
Blood and lymphatic system disorders - Other † 1	1/6 (16.67%)
Cardiac disorders
Palpitations † 1	1/6 (16.67%)
Ear and labyrinth disorders
Ear pain † 1	1/6 (16.67%)
Endocrine disorders
Hyperthyroidism † 1	1/6 (16.67%)
Hypothyroidism † 1	1/6 (16.67%)
Gastrointestinal disorders
Abdominal pain † 1	2/6 (33.33%)
Constipation † 1	2/6 (33.33%)
Diarrhea † 1	3/6 (50.00%)
Dry mouth † 1	1/6 (16.67%)
Gastroesophageal reflux disease † 1	1/6 (16.67%)
Nausea † 1	3/6 (50.00%)
Vomiting † 1	3/6 (50.00%)
General disorders
Edema limbs † 1	2/6 (33.33%)
Fatigue † 1	2/6 (33.33%)
Fever † 1	2/6 (33.33%)
General disorders and administration site conditions - Other † 1	1/6 (16.67%)
Pain † 1	2/6 (33.33%)
Infections and infestations
Infections and infestations - Other † 1	1/6 (16.67%)
Papulopustular rash † 1	2/6 (33.33%)
Rash pustular † 1	1/6 (16.67%)
Urinary tract infection † 1	2/6 (33.33%)
Injury, poisoning and procedural complications
Fall † 1	1/6 (16.67%)
Investigations
Alanine aminotransferase increased † 1	1/6 (16.67%)
Alkaline phosphatase increased † 1	1/6 (16.67%)
Aspartate aminotransferase increased † 1	2/6 (33.33%)
Creatinine increased † 1	3/6 (50.00%)
Lymphocyte count decreased † 1	1/6 (16.67%)
Platelet count decreased † 1	1/6 (16.67%)
Serum amylase increased † 1	1/6 (16.67%)
Weight loss † 1	1/6 (16.67%)
Metabolism and nutrition disorders
Hyperglycemia † 1	2/6 (33.33%)
Hypocalcemia † 1	1/6 (16.67%)
Hyponatremia † 1	2/6 (33.33%)
Musculoskeletal and connective tissue disorders
Arthralgia † 1	1/6 (16.67%)
Back pain † 1	1/6 (16.67%)
Bone pain † 1	1/6 (16.67%)
Flank pain † 1	1/6 (16.67%)
Generalized muscle weakness † 1	1/6 (16.67%)
Musculoskeletal and connective tissue disorder - Other † 1	1/6 (16.67%)
Pain in extremity † 1	1/6 (16.67%)
Nervous system disorders
Dizziness † 1	1/6 (16.67%)
Dysgeusia † 1	2/6 (33.33%)
Paresthesia † 1	2/6 (33.33%)
Peripheral sensory neuropathy † 1	2/6 (33.33%)
Somnolence † 1	1/6 (16.67%)
Psychiatric disorders
Anxiety † 1	2/6 (33.33%)
Confusion † 1	2/6 (33.33%)
Depression † 1	1/6 (16.67%)
Insomnia † 1	2/6 (33.33%)
Personality change † 1	1/6 (16.67%)
Renal and urinary disorders
Acute kidney injury † 1	1/6 (16.67%)
Renal and urinary disorders - Other † 1	2/6 (33.33%)
Urinary urgency † 1	1/6 (16.67%)
Urine discoloration † 1	1/6 (16.67%)
Reproductive system and breast disorders
Pelvic pain † 1	1/6 (16.67%)
Penile pain † 1	1/6 (16.67%)
Respiratory, thoracic and mediastinal disorders
Cough † 1	2/6 (33.33%)
Hoarseness † 1	1/6 (16.67%)
Pneumonitis † 1	1/6 (16.67%)
Productive cough † 1	1/6 (16.67%)
Respiratory, thoracic and mediastinal disorders - Other † 1	1/6 (16.67%)
Skin and subcutaneous tissue disorders
Pruritus † 1	3/6 (50.00%)
Rash acneiform † 1	1/6 (16.67%)
Skin and subcutaneous tissue disorders - Other † 1	1/6 (16.67%)
Vascular disorders
Hematoma † 1	1/6 (16.67%)
Hot flashes † 1	2/6 (33.33%)
1 Term from vocabulary, CTCAE (4.0); † Indicates events were collected by systematic assessment

Limitations and Caveats

This study was closed early (at 6 patients) due to changing therapeutic landscape in metastatic bladder cancer and lack of radiation/immunotherapy systemic synergy in other malignancies.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

Results Point of Contact

• Name/Title: Zachery Reichert
• Organization: University of Michigan
• Phone: 764-3066
• EMail: zreiche@med.umich.edu

• Responsible Party: University of Michigan Rogel Cancer Center
• ClinicalTrials.gov Identifier: NCT03287050
• Other Study ID Numbers: UMCC 2017.069; HUM00135161 ( Other Identifier: University of Michigan )
• First Submitted: September 15, 2017
• First Posted: September 19, 2017
• Results First Submitted: September 21, 2021
• Results First Posted: December 15, 2021
• Last Update Posted: December 15, 2021