Ipilimumab Induction in Patients With Melanoma Brain Metastases Receiving Stereotactic Radiosurgery

• Sponsor: University of Michigan Rogel Cancer Center (Other)
• Overall Status: Terminated
• CT.gov ID: NCT02097732
• Collaborator: (none)
• Enrollment: 4
• Location: 1
• Arms: 2
• Duration (Months): 75
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This is a study to test the efficacy of using standard immune therapy for melanoma prior to stereotactic radiosurgery (ipilimumab induction), as compared to stereotactic radiosurgery followed by immune therapy. The study's hypothesis is that ipilimumab induction is as good as or better than controlling brain metastases as compared to stereotactic radiosurgery followed by immune therapy.

Condition or Disease	Intervention/Treatment	Phase
Metastatic Melanoma; Brain Metastases	Drug: Ipilimumab; Procedure: Stereotactic Radiosurgery	Phase 2

Detailed Description

This is a randomized Phase II selection study investigating the use of ipilimumab induction prior to stereotactic radiosurgery (SRS), versus no induction, for melanoma brain metastases. Participants will be randomized to Arm A "Induction" (two doses of ipilimumab prior to SRS, two doses of ipilimumab after SRS) versus Arm B "No induction" (SRS first, followed by 4 doses of ipilimumab). Participants will undergo multiple dynamic contrast-enhanced MRIs of the brain and submit blood samples for immune testing.

Study Design

• Study Type: Interventional
• Actual Enrollment: 4 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Ipilimumab Induction in Patients With Melanoma Brain Metastases Receiving Stereotactic Radiosurgery
• Study Start Date: Apr 1, 2014
• Actual Primary Completion Date: Aug 1, 2016
• Actual Study Completion Date: Jul 1, 2020

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: B: No induction Participants will undergo stereotactic radiosurgery (SRS) followed 2-3 weeks later by ipilimumab, which is given once every 3 weeks for a total of 4 doses.	Drug: Ipilimumab; Ipilimumab 3mg/kg given intravenously over 90 minutes, every 3 weeks for a total of 4 doses.; Procedure: Stereotactic Radiosurgery; Stereotactic radiosurgery is a type of focused radiation therapy. It requires the placement of a metal frame on the head for several hours.
Experimental: A: Induction Patients will receive 2 doses of ipilimumab, which is given once every 3 weeks, prior to stereotactic radiosurgery (SRS), followed by 2 more doses of ipilimumab, for a total of 4 doses.	Drug: Ipilimumab; Ipilimumab 3mg/kg given intravenously over 90 minutes, every 3 weeks for a total of 4 doses.; Procedure: Stereotactic Radiosurgery; Stereotactic radiosurgery is a type of focused radiation therapy. It requires the placement of a metal frame on the head for several hours.

Outcome Measures

Primary Outcome Measures

1. Local Control Rate [6 months]

   The number of patients in each arm who are free from progression in the index (radiated) lesions in the brain at 6 months. Immune related response criteria was used to assess response to treatment. Immune-related Progressive Disease (irPD) in this trial is defined as an increase in tumor burden ≥25% relative to nadir (minimum recorded tumor burden), with confirmation by a repeat, consecutive assessment no less than 4 weeks from the date first documented.

Secondary Outcome Measures

1. Overall Survival Rate [Up to 5 years]

   Number of participants alive at 5 years after enrollment.

2. Regional (Intracranial) Control Rate [6 months]

   The proportion of patients in each arm who are free from progression in the index (radiated) lesions and free from new brain metastases at 6 months.

3. Intracranial Response Rate [Up to 12 months]

   Response of treated (irradiated) brain metastases to combination therapy with ipilimumab and stereotactic radiosurgery using immune-related response criteria.

4. Time to Progression [From date of enrollment to up to 2 years]

   Time to progression in the brain due to treated metastases or new brain metastases. Immune-related Response Evaluation Criteria In Solid Tumors (irRECIST) was used to assess response. Progression was defined as an increase in tumor burden ≥25% relative to nadir (minimum recorded tumor burden), with confirmation by a repeat, consecutive assessment no less than 4 wk from the date first documented.

Other Outcome Measures

1. Imaging Correlates on Dynamic-contrast Enhanced MRI of the Brain [6 months]

   Exploratory endpoints: Interval changes in dynamic MRI parameters such as perfusion, blood volume, vascular permeability (Ktrans), and diffusion tensor imaging; the change in 3D tumor volume.

2. Immune Correlates [6 months]

   Exploratory endpoints: Interval changes in immune markers in the blood

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Patients with a histologically-confirmed diagnosis of melanoma who have imaging findings suggestive of 1 to 4 brain metastases

• At least one lesion in the brain that is measurable, which is defined as ≥5 x 5mm (Prior craniotomy and surgical resection is allowed, as long as there is at least one remaining measurable lesion in the brain)

• Patients must be candidates for stereotactic radiosurgery (SRS) and planning to undergo SRS

• Patients must be candidates for ipilimumab as determined by the treating physician

• Patients must be neurologically asymptomatic, or very minimally symptomatic, as judged by the treating physicians

• At least 3 weeks has elapsed from any prior therapy, and the patient has recovered from side effects to ≤ grade 1 toxicities per Common Terminology Criteria (CTC) for Adverse Events

• Age > or = 18 years old

• Performance status of ECOG of 0 or 1 (ECOG is the Eastern Oncology Cooperative Group Scoring system used to quantify cancer patients' general well-being and activities of daily life; scores range from 0 to 5 where 0 is perfect health and 5 is death)

• Adequate organ and marrow function: alanine aminotransferase (ALT ) < 2.5x's upper limit of normal (ULN) of the institutional normal reference range, aspartate aminotransferase (AST) < 2.5x's ULN of the institutional normal reference range, Bilirubin < 1.5x's ULN of the institutional normal reference range, Creatinine < 2.0 milligrams per deciliter, Platelets > 50,000 per microliter

• Women of child-bearing potential must agree to use adequate contraception, defined as complete abstinence from intercourse with men or two methods

• Ability to understand and the willingness to sign a written informed consent

Exclusion Criteria:

• Previous radiotherapy to the lesion(s) of interest, including prior treatment with whole brain radiation therapy (WBRT). Prior treatment with SRS is allowed if the index lesion(s) is in a different, non-contiguous location than the previously treated lesion.

• Patients who have previously received ipilimumab, PD-1 inhibitors or PD-L1 inhibitors are excluded due to the potential of effects on primary outcome

• Patients who require WBRT or surgery at the time of enrollment

• Neurologic symptoms or imaging findings that necessitate the use of steroids on the day of enrollment or in the prior 7 days

• Highly suspicious magnetic resonance imaging (MRI) or cerebrospinal fluid evidence of leptomeningeal metastases, unless all measurable disease is localized and SRS is considered the treatment of choice

• Concurrent treatment with any other anti-neoplastic drug or concurrent participation in another therapeutic clinical trial

• Patients unable to undergo or tolerate MRI scans (presence of cardiac pacemaker, implanted cardiac defibrillator, aneurysm clips, history of allergic reaction/hypersensitivity to gadolinium)

• Women who are pregnant or are nursing

• Patients with absolute lymphocyte count of <500 cells/microliter, who are known to be HIV positive, who have clinically significant active autoimmune disease, or are receiving immunosuppression following solid organ or stem cell transplant

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Michigan Hospital	Ann Arbor	Michigan	United States	48109

Sponsors and Collaborators

• University of Michigan Rogel Cancer Center

Investigators

• Principal Investigator: Christopher Lao, M.D., University of Michigan Rogel Cancer Center

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: University of Michigan Rogel Cancer Center
• ClinicalTrials.gov Identifier: NCT02097732
• Other Study ID Numbers: UMCC 2013.114; HUM00082134
• First Posted: Mar 27, 2014
• Last Update Posted: May 12, 2021
• Last Verified: Apr 1, 2021

• Keywords provided by University of Michigan Rogel Cancer Center: Metastatic melanoma; Brain metastases; Radiation therapy; Immune therapy
• Additional relevant MeSH terms: Melanoma; Neoplasm Metastasis; Neoplasms, Second Primary; Brain Neoplasms; Ipilimumab

Study Results

Participant Flow

Arm/Group Title	B: No Induction	A: Induction
Arm/Group Description	Participants will undergo stereotactic radiosurgery (SRS) followed 2-3 weeks later by ipilimumab, which is given once every 3 weeks for a total of 4 doses. Ipilimumab: Ipilimumab 3mg/kg given intravenously over 90 minutes, every 3 weeks for a total of 4 doses. Stereotactic Radiosurgery: Stereotactic radiosurgery is a type of focused radiation therapy. It requires the placement of a metal frame on the head for several hours.	Patients will receive 2 doses of ipilimumab, which is given once every 3 weeks, prior to stereotactic radiosurgery (SRS), followed by 2 more doses of ipilimumab, for a total of 4 doses. Ipilimumab: Ipilimumab 3mg/kg given intravenously over 90 minutes, every 3 weeks for a total of 4 doses. Stereotactic Radiosurgery: Stereotactic radiosurgery is a type of focused radiation therapy. It requires the placement of a metal frame on the head for several hours.
Period Title: Overall Study
STARTED	1	3
COMPLETED	1	3
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	B: No Induction	A: Induction	Total
Arm/Group Description	Participants will undergo stereotactic radiosurgery (SRS) followed 2-3 weeks later by ipilimumab, which is given once every 3 weeks for a total of 4 doses. Ipilimumab: Ipilimumab 3mg/kg given intravenously over 90 minutes, every 3 weeks for a total of 4 doses. Stereotactic Radiosurgery: Stereotactic radiosurgery is a type of focused radiation therapy. It requires the placement of a metal frame on the head for several hours.	Patients will receive 2 doses of ipilimumab, which is given once every 3 weeks, prior to stereotactic radiosurgery (SRS), followed by 2 more doses of ipilimumab, for a total of 4 doses. Ipilimumab: Ipilimumab 3mg/kg given intravenously over 90 minutes, every 3 weeks for a total of 4 doses. Stereotactic Radiosurgery: Stereotactic radiosurgery is a type of focused radiation therapy. It requires the placement of a metal frame on the head for several hours.	Total of all reporting groups
Overall Participants	1	3	4
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	69	55	58
Sex: Female, Male (Count of Participants)
Female	0 0%	1 33.3%	1 25%
Male	1 100%	2 66.7%	3 75%

Outcome Measures

1. Primary Outcome

Title	Local Control Rate
Description	The number of patients in each arm who are free from progression in the index (radiated) lesions in the brain at 6 months. Immune related response criteria was used to assess response to treatment. Immune-related Progressive Disease (irPD) in this trial is defined as an increase in tumor burden ≥25% relative to nadir (minimum recorded tumor burden), with confirmation by a repeat, consecutive assessment no less than 4 weeks from the date first documented.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	B: No Induction	A: Induction
Arm/Group Description	Participants will undergo stereotactic radiosurgery (SRS) followed 2-3 weeks later by ipilimumab, which is given once every 3 weeks for a total of 4 doses. Ipilimumab: Ipilimumab 3mg/kg given intravenously over 90 minutes, every 3 weeks for a total of 4 doses. Stereotactic Radiosurgery: Stereotactic radiosurgery is a type of focused radiation therapy. It requires the placement of a metal frame on the head for several hours.	Patients will receive 2 doses of ipilimumab, which is given once every 3 weeks, prior to stereotactic radiosurgery (SRS), followed by 2 more doses of ipilimumab, for a total of 4 doses. Ipilimumab: Ipilimumab 3mg/kg given intravenously over 90 minutes, every 3 weeks for a total of 4 doses. Stereotactic Radiosurgery: Stereotactic radiosurgery is a type of focused radiation therapy. It requires the placement of a metal frame on the head for several hours.
Measure Participants	1	3
Count of Participants [Participants]	1 100%	3 100%

2. Secondary Outcome

Title	Overall Survival Rate
Description	Number of participants alive at 5 years after enrollment.
Time Frame	Up to 5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	B: No Induction	A: Induction
Arm/Group Description	Participants will undergo stereotactic radiosurgery (SRS) followed 2-3 weeks later by ipilimumab, which is given once every 3 weeks for a total of 4 doses. Ipilimumab: Ipilimumab 3mg/kg given intravenously over 90 minutes, every 3 weeks for a total of 4 doses. Stereotactic Radiosurgery: Stereotactic radiosurgery is a type of focused radiation therapy. It requires the placement of a metal frame on the head for several hours.	Patients will receive 2 doses of ipilimumab, which is given once every 3 weeks, prior to stereotactic radiosurgery (SRS), followed by 2 more doses of ipilimumab, for a total of 4 doses. Ipilimumab: Ipilimumab 3mg/kg given intravenously over 90 minutes, every 3 weeks for a total of 4 doses. Stereotactic Radiosurgery: Stereotactic radiosurgery is a type of focused radiation therapy. It requires the placement of a metal frame on the head for several hours.
Measure Participants	1	3
Number [participants]	1 100%	2 66.7%

3. Secondary Outcome

Title	Regional (Intracranial) Control Rate
Description	The proportion of patients in each arm who are free from progression in the index (radiated) lesions and free from new brain metastases at 6 months.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	B: No Induction	A: Induction
Arm/Group Description	Participants will undergo stereotactic radiosurgery (SRS) followed 2-3 weeks later by ipilimumab, which is given once every 3 weeks for a total of 4 doses. Ipilimumab: Ipilimumab 3mg/kg given intravenously over 90 minutes, every 3 weeks for a total of 4 doses. Stereotactic Radiosurgery: Stereotactic radiosurgery is a type of focused radiation therapy. It requires the placement of a metal frame on the head for several hours.	Patients will receive 2 doses of ipilimumab, which is given once every 3 weeks, prior to stereotactic radiosurgery (SRS), followed by 2 more doses of ipilimumab, for a total of 4 doses. Ipilimumab: Ipilimumab 3mg/kg given intravenously over 90 minutes, every 3 weeks for a total of 4 doses. Stereotactic Radiosurgery: Stereotactic radiosurgery is a type of focused radiation therapy. It requires the placement of a metal frame on the head for several hours.
Measure Participants	1	3
Count of Participants [Participants]	1 100%	3 100%

4. Secondary Outcome

Title	Intracranial Response Rate
Description	Response of treated (irradiated) brain metastases to combination therapy with ipilimumab and stereotactic radiosurgery using immune-related response criteria.
Time Frame	Up to 12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	B: No Induction	A: Induction
Arm/Group Description	Participants will undergo stereotactic radiosurgery (SRS) followed 2-3 weeks later by ipilimumab, which is given once every 3 weeks for a total of 4 doses. Ipilimumab: Ipilimumab 3mg/kg given intravenously over 90 minutes, every 3 weeks for a total of 4 doses. Stereotactic Radiosurgery: Stereotactic radiosurgery is a type of focused radiation therapy. It requires the placement of a metal frame on the head for several hours.	Patients will receive 2 doses of ipilimumab, which is given once every 3 weeks, prior to stereotactic radiosurgery (SRS), followed by 2 more doses of ipilimumab, for a total of 4 doses. Ipilimumab: Ipilimumab 3mg/kg given intravenously over 90 minutes, every 3 weeks for a total of 4 doses. Stereotactic Radiosurgery: Stereotactic radiosurgery is a type of focused radiation therapy. It requires the placement of a metal frame on the head for several hours.
Measure Participants	1	3
Count of Participants [Participants]	1 100%	3 100%

5. Secondary Outcome

Title	Time to Progression
Description	Time to progression in the brain due to treated metastases or new brain metastases. Immune-related Response Evaluation Criteria In Solid Tumors (irRECIST) was used to assess response. Progression was defined as an increase in tumor burden ≥25% relative to nadir (minimum recorded tumor burden), with confirmation by a repeat, consecutive assessment no less than 4 wk from the date first documented.
Time Frame	From date of enrollment to up to 2 years

Outcome Measure Data

Analysis Population Description

Of the 4 patients, 2 patients remained progression-free throughout the 2-year time frame for data collection for this outcome measure.

Arm/Group Title	B: No Induction	A: Induction
Arm/Group Description	Participants will undergo stereotactic radiosurgery (SRS) followed 2-3 weeks later by ipilimumab, which is given once every 3 weeks for a total of 4 doses. Ipilimumab: Ipilimumab 3mg/kg given intravenously over 90 minutes, every 3 weeks for a total of 4 doses. Stereotactic Radiosurgery: Stereotactic radiosurgery is a type of focused radiation therapy. It requires the placement of a metal frame on the head for several hours.	Patients will receive 2 doses of ipilimumab, which is given once every 3 weeks, prior to stereotactic radiosurgery (SRS), followed by 2 more doses of ipilimumab, for a total of 4 doses. Ipilimumab: Ipilimumab 3mg/kg given intravenously over 90 minutes, every 3 weeks for a total of 4 doses. Stereotactic Radiosurgery: Stereotactic radiosurgery is a type of focused radiation therapy. It requires the placement of a metal frame on the head for several hours.
Measure Participants	1	3
5 months, 27 days	0 0%	1 33.3%
19 months, 3 days	1 100%	0 0%

6. Other Pre-specified Outcome

Title	Imaging Correlates on Dynamic-contrast Enhanced MRI of the Brain
Description	Exploratory endpoints: Interval changes in dynamic MRI parameters such as perfusion, blood volume, vascular permeability (Ktrans), and diffusion tensor imaging; the change in 3D tumor volume.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

7. Other Pre-specified Outcome

Title	Immune Correlates
Description	Exploratory endpoints: Interval changes in immune markers in the blood
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	Adverse events were collected up to 6 months after study start. All-cause mortality is observed up to 5 years.
Adverse Event Reporting Description	Both arms were combined in the reporting of Adverse Events because both arms received the same two interventions.
Arm/Group Title	Ipilimumab and SRS
Arm/Group Description	(Induction) Patients will receive 2 doses of ipilimumab, which is given once every 3 weeks, prior to stereotactic radiosurgery (SRS), followed by 2 more doses of ipilimumab, for a total of 4 doses. OR (No Induction) Participants will undergo stereotactic radiosurgery (SRS) followed 2-3 weeks later by ipilimumab, which is given once every 3 weeks for a total of 4 doses. Ipilimumab: Ipilimumab 3mg/kg given intravenously over 90 minutes, every 3 weeks for a total of 4 doses. Stereotactic Radiosurgery: Stereotactic radiosurgery is a type of focused radiation therapy. It requires the placement of a metal frame on the head for several hours.
All Cause Mortality
	Ipilimumab and SRS
	Affected / at Risk (%)	# Events
Total	1/4 (25%)
Serious Adverse Events
	Ipilimumab and SRS
	Affected / at Risk (%)	# Events
Total	0/4 (0%)
Other (Not Including Serious) Adverse Events
	Ipilimumab and SRS
	Affected / at Risk (%)	# Events
Total	4/4 (100%)
Blood and lymphatic system disorders
Lymphocyte count decreased	1/4 (25%)	2
Platelet count decreased	1/4 (25%)	1
Gastrointestinal disorders
Constipation	2/4 (50%)	2
Diarrhea	2/4 (50%)	2
Nausea	1/4 (25%)	2
Vomiting	1/4 (25%)	1
General disorders
Fatigue	3/4 (75%)	3
Fever	1/4 (25%)	1
Infections and infestations
Flu like symptoms	1/4 (25%)	1
Investigations
Alanine aminotransferase increased	1/4 (25%)	1
Creatinine increased	1/4 (25%)	1
Decreased T4	1/4 (25%)	1
Vitamin D Deficiency	1/4 (25%)	1
Low Testosterone	1/4 (25%)	2
Elevated LDH	1/4 (25%)	2
Metabolism and nutrition disorders
Hyperglycemia	1/4 (25%)	2
Musculoskeletal and connective tissue disorders
Muscle weakness left-sided	1/4 (25%)	1
Myalgia	1/4 (25%)	1
Neck pain	1/4 (25%)	1
Pain in extremity	1/4 (25%)	1
Nervous system disorders
Dizziness	2/4 (50%)	2
Headache	2/4 (50%)	2
Hot flashes	1/4 (25%)	1
Tremor	1/4 (25%)	1
Vertigo	1/4 (25%)	1
Psychiatric disorders
Concentration impairment	1/4 (25%)	1
Depression	1/4 (25%)	1
Respiratory, thoracic and mediastinal disorders
Upper respiratory infection	1/4 (25%)	1
Skin and subcutaneous tissue disorders
Nail discoloration	1/4 (25%)	1
Pruritus	1/4 (25%)	1
Rash acneiform	1/4 (25%)	1
Rash maculo-papular	2/4 (50%)	2
Vascular disorders
Edema limbs	1/4 (25%)	1
Periorbital edema	1/4 (25%)	1

Limitations/Caveats

Study halted prematurely due to a change in the standard of care treatment.

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.