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)
4
Enrollment
1
Location
2
Arms
75
Duration (Months)
0.1
Patients Per Site Per Month

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 DiseaseIntervention/TreatmentPhase
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

ArmIntervention/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

SiteCityStateCountryPostal Code
1University of Michigan HospitalAnn ArborMichiganUnited States48109

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
Additional relevant MeSH terms:

Study Results

Participant Flow

Recruitment Details
Pre-assignment Detail
Arm/Group TitleB: No InductionA: Induction
Arm/Group DescriptionParticipants 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
STARTED13
COMPLETED13
NOT COMPLETED00

Baseline Characteristics

Arm/Group TitleB: No InductionA: InductionTotal
Arm/Group DescriptionParticipants 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 Participants134
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
TitleLocal Control Rate
DescriptionThe 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 Frame6 months

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group TitleB: No InductionA: Induction
Arm/Group DescriptionParticipants 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 Participants13
Count of Participants [Participants]
1
100%
3
100%
2. Secondary Outcome
TitleOverall Survival Rate
DescriptionNumber of participants alive at 5 years after enrollment.
Time FrameUp to 5 years

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group TitleB: No InductionA: Induction
Arm/Group DescriptionParticipants 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 Participants13
Number [participants]
1
100%
2
66.7%
3. Secondary Outcome
TitleRegional (Intracranial) Control Rate
DescriptionThe 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 Frame6 months

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group TitleB: No InductionA: Induction
Arm/Group DescriptionParticipants 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 Participants13
Count of Participants [Participants]
1
100%
3
100%
4. Secondary Outcome
TitleIntracranial Response Rate
DescriptionResponse of treated (irradiated) brain metastases to combination therapy with ipilimumab and stereotactic radiosurgery using immune-related response criteria.
Time FrameUp to 12 months

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group TitleB: No InductionA: Induction
Arm/Group DescriptionParticipants 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 Participants13
Count of Participants [Participants]
1
100%
3
100%
5. Secondary Outcome
TitleTime to Progression
DescriptionTime 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 FrameFrom 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 TitleB: No InductionA: Induction
Arm/Group DescriptionParticipants 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 Participants13
5 months, 27 days
0
0%
1
33.3%
19 months, 3 days
1
100%
0
0%
6. Other Pre-specified Outcome
TitleImaging Correlates on Dynamic-contrast Enhanced MRI of the Brain
DescriptionExploratory 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 Frame6 months

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group Title
Arm/Group Description
7. Other Pre-specified Outcome
TitleImmune Correlates
DescriptionExploratory endpoints: Interval changes in immune markers in the blood
Time Frame6 months

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group Title
Arm/Group Description

Adverse Events

Time FrameAdverse 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 TitleIpilimumab 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
Total1/4 (25%)
Serious Adverse Events
Ipilimumab and SRS
Affected / at Risk (%)# Events
Total0/4 (0%)
Other (Not Including Serious) Adverse Events
Ipilimumab and SRS
Affected / at Risk (%)# Events
Total4/4 (100%)
Blood and lymphatic system disorders
Lymphocyte count decreased1/4 (25%) 2
Platelet count decreased1/4 (25%) 1
Gastrointestinal disorders
Constipation2/4 (50%) 2
Diarrhea2/4 (50%) 2
Nausea1/4 (25%) 2
Vomiting1/4 (25%) 1
General disorders
Fatigue3/4 (75%) 3
Fever1/4 (25%) 1
Infections and infestations
Flu like symptoms1/4 (25%) 1
Investigations
Alanine aminotransferase increased1/4 (25%) 1
Creatinine increased1/4 (25%) 1
Decreased T41/4 (25%) 1
Vitamin D Deficiency1/4 (25%) 1
Low Testosterone1/4 (25%) 2
Elevated LDH1/4 (25%) 2
Metabolism and nutrition disorders
Hyperglycemia1/4 (25%) 2
Musculoskeletal and connective tissue disorders
Muscle weakness left-sided1/4 (25%) 1
Myalgia1/4 (25%) 1
Neck pain1/4 (25%) 1
Pain in extremity1/4 (25%) 1
Nervous system disorders
Dizziness2/4 (50%) 2
Headache2/4 (50%) 2
Hot flashes1/4 (25%) 1
Tremor1/4 (25%) 1
Vertigo1/4 (25%) 1
Psychiatric disorders
Concentration impairment1/4 (25%) 1
Depression1/4 (25%) 1
Respiratory, thoracic and mediastinal disorders
Upper respiratory infection1/4 (25%) 1
Skin and subcutaneous tissue disorders
Nail discoloration1/4 (25%) 1
Pruritus1/4 (25%) 1
Rash acneiform1/4 (25%) 1
Rash maculo-papular2/4 (50%) 2
Vascular disorders
Edema limbs1/4 (25%) 1
Periorbital edema1/4 (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.

Results Point of Contact

Name/TitleDr. Christopher Lao, MD, MPH
OrganizationUniversity of Michigan Comprehensive Cancer Center
Phone(734) 936-4498
Emailclao@med.umich.edu
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