Trial Outcomes & Findings for GEM STUDY: Radiation And Yervoy in Patients With Melanoma and Brain Metastases (NCT NCT02115139)

NCT ID: NCT02115139

Last Updated: 2022-11-08

Results Overview

During treatment period, there will be assessments every cycle. After end of treatment every 3 month.

• Recruitment status: COMPLETED
• Study phase: PHASE2
• Target enrollment: 58 participants
• Primary outcome timeframe: From date of inclusion until the date of first documented date of death from any cause, assessed every 3 weeks during for the first 6 months, then every 3 months. Up to 1 year
• Results posted on: 2022-11-08

Participant Flow

58 patients were enrolled and fulfilled the inclusion criteria, analyzed for safety. During the trial 7 patients discontinued treatment before completion, so the total of patients for efficacy analysis was 51.

Participant milestones

Measure	Ipilimumab Ipilimumab 3mg/Kg iv q 3 weeks for 4 cycles Whole-brain radiotherapy (WBRT) 30 Gy in 10 fractions (or radiobiological equivalent schedule, after Sponsor approval), starting between Cycle 1 Day 2 and Cycle 2 Day 1 Ipilimumab: Ipilimumab 3mg/Kg iv q 3 weeks for 4 cycles
Overall Study STARTED	58
Overall Study COMPLETED	51
Overall Study NOT COMPLETED	7

Reasons for withdrawal

Measure	Ipilimumab Ipilimumab 3mg/Kg iv q 3 weeks for 4 cycles Whole-brain radiotherapy (WBRT) 30 Gy in 10 fractions (or radiobiological equivalent schedule, after Sponsor approval), starting between Cycle 1 Day 2 and Cycle 2 Day 1 Ipilimumab: Ipilimumab 3mg/Kg iv q 3 weeks for 4 cycles
Overall Study Protocol Violation	1
Overall Study treatment discontinuation	6

Baseline Characteristics

GEM STUDY: Radiation And Yervoy in Patients With Melanoma and Brain Metastases

Baseline characteristics by cohort

Measure	Ipilimumab n=58 Participants Ipilimumab 3mg/Kg iv q 3 weeks for 4 cycles Whole-brain radiotherapy (WBRT) 30 Gy in 10 fractions (or radiobiological equivalent schedule, after Sponsor approval), starting between Cycle 1 Day 2 and Cycle 2 Day 1 Ipilimumab: Ipilimumab 3mg/Kg iv q 3 weeks for 4 cycles
Age, Continuous	66 Years n=5 Participants
Sex: Female, Male Female	22 Participants n=5 Participants
Sex: Female, Male Male	36 Participants n=5 Participants
Region of Enrollment Spain	58 Participants n=5 Participants
Karnofsky performance status (KPS) 90-100	42 Participants n=5 Participants
Karnofsky performance status (KPS) 70-80	15 Participants n=5 Participants
Karnofsky performance status (KPS) Not evaluable (NE)	1 Participants n=5 Participants
Barthel index Lower than 15	2 Participants n=5 Participants
Barthel index 15-20	56 Participants n=5 Participants
BRAF mutational status Mutated	20 Participants n=5 Participants
BRAF mutational status Native	30 Participants n=5 Participants
BRAF mutational status Not evaluated (NE)	8 Participants n=5 Participants
Number of previous treatment lines No previous lines	29 Participants n=5 Participants
Number of previous treatment lines 1 previous line	20 Participants n=5 Participants
Number of previous treatment lines 2 or more previous lines	9 Participants n=5 Participants
Number of brain metastasis Single brain lesion	14 Participants n=5 Participants
Number of brain metastasis Multiple brain lesions	43 Participants n=5 Participants
Number of brain metastasis Not especified (NE)	1 Participants n=5 Participants
Corticoid use Yes	25 Participants n=5 Participants
Corticoid use No	33 Participants n=5 Participants
Lactate dehydrogenase (LDH) blood levels Levels higher than Upper limit normal (ULN) · Yes	24 Participants n=5 Participants
Lactate dehydrogenase (LDH) blood levels Levels higher than Upper limit normal (ULN) · No	34 Participants n=5 Participants
Lactate dehydrogenase (LDH) blood levels Levels higher than 1.5X Upper limit normal (ULN) · Yes	9 Participants n=5 Participants
Lactate dehydrogenase (LDH) blood levels Levels higher than 1.5X Upper limit normal (ULN) · No	49 Participants n=5 Participants

PRIMARY outcome

Timeframe: From date of inclusion until the date of first documented date of death from any cause, assessed every 3 weeks during for the first 6 months, then every 3 months. Up to 1 year

Population: Efficacy cohort, all patients that fulfill eligibility and completed the treatment with radiotherapy

During treatment period, there will be assessments every cycle. After end of treatment every 3 month.

Outcome measures

Measure	Ipilimumab n=51 Participants Ipilimumab 3mg/Kg iv q 3 weeks for 4 cycles Whole-brain radiotherapy (WBRT) 30 Gy in 10 fractions (or radiobiological equivalent schedule, after Sponsor approval), starting between Cycle 1 Day 2 and Cycle 2 Day 1 Ipilimumab: Ipilimumab 3mg/Kg iv q 3 weeks for 4 cycles
1-year Survival Rate	31.8 Percentage of patients alive at 1 year Interval 18.8 to 44.8

SECONDARY outcome

Timeframe: Within 4 weeks before start treatment, week 12, 17+/-1 and every 9 + / -1 weeks until progression up to 12 months after last patient treatment initiation.

Population: Efficacy population (patients that fulfill eligibility and completed the treatment with radiotherapy)

Median time from treatment initiation to progression of disease. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), 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

Outcome measures

Measure	Ipilimumab n=51 Participants Ipilimumab 3mg/Kg iv q 3 weeks for 4 cycles Whole-brain radiotherapy (WBRT) 30 Gy in 10 fractions (or radiobiological equivalent schedule, after Sponsor approval), starting between Cycle 1 Day 2 and Cycle 2 Day 1 Ipilimumab: Ipilimumab 3mg/Kg iv q 3 weeks for 4 cycles
Progression-Free Survival (PFS)	3.11 Months Interval 2.23 to 3.98

SECONDARY outcome

Timeframe: Within 4 weeks before start treatment, week 12, 17+/-1 and every 9 + / -1 weeks until progression up to 12 months after last patient treatment initiation.

Population: Data were not collected

median, 6-month PFS rate

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Within 4 weeks before start treatment, week 12, 17+/-1 and every 9 + / -1 weeks until progression up to 12 months after last patient treatment initiation.

Population: Data were not collected

median, 6-month PFS rate

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: From date of inclusion until the date of first documented date of death from any cause, assessed every 3 weeks during for the first 6 months, then every 3 months.

Population: Efficacy population (patients that comply with eligibility and completed radiotherapy treatment)

median value for OS estimated by kaplan meier method

Outcome measures

Measure	Ipilimumab n=51 Participants Ipilimumab 3mg/Kg iv q 3 weeks for 4 cycles Whole-brain radiotherapy (WBRT) 30 Gy in 10 fractions (or radiobiological equivalent schedule, after Sponsor approval), starting between Cycle 1 Day 2 and Cycle 2 Day 1 Ipilimumab: Ipilimumab 3mg/Kg iv q 3 weeks for 4 cycles
Overall Survival	4.73 Months Interval 3.59 to 5.87

SECONDARY outcome

Timeframe: Within 4 weeks before start treatment, week 12, 17+/-1 and every 9 + / -1 weeks until progression up to 12 months after last patient treatment initiation.

Population: Efficacy population

Measured according to Who response criteria and Immune-related response criteria.

Response for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.

Outcome measures

Measure	Ipilimumab n=51 Participants Ipilimumab 3mg/Kg iv q 3 weeks for 4 cycles Whole-brain radiotherapy (WBRT) 30 Gy in 10 fractions (or radiobiological equivalent schedule, after Sponsor approval), starting between Cycle 1 Day 2 and Cycle 2 Day 1 Ipilimumab: Ipilimumab 3mg/Kg iv q 3 weeks for 4 cycles
Response Rate Immun related response criteria (irRC) · Stable disease (SD)	12 Participants
Response Rate modified WHO criteria · Complete Response (CR)	2 Participants
Response Rate modified WHO criteria · Partial response (PR)	3 Participants
Response Rate modified WHO criteria · Stable disease (SD)	12 Participants
Response Rate modified WHO criteria · Progression disease (PD)	19 Participants
Response Rate modified WHO criteria · Not evaluable (NE)	15 Participants
Response Rate Immun related response criteria (irRC) · Complete Response (CR)	2 Participants
Response Rate Immun related response criteria (irRC) · Partial response (PR)	3 Participants
Response Rate Immun related response criteria (irRC) · Progression disease (PD)	17 Participants
Response Rate Immun related response criteria (irRC) · Not evaluable (NE)	17 Participants

SECONDARY outcome

Timeframe: From date of inclusion until the date of first documented date of death from any cause or end of study, assessed every 3 weeks during for the first 6 months, then every 3 months.

Population: Safety population

Number of patients with at least one treatment-related toxicity, classified by grade.

Outcome measures

Measure	Ipilimumab n=58 Participants Ipilimumab 3mg/Kg iv q 3 weeks for 4 cycles Whole-brain radiotherapy (WBRT) 30 Gy in 10 fractions (or radiobiological equivalent schedule, after Sponsor approval), starting between Cycle 1 Day 2 and Cycle 2 Day 1 Ipilimumab: Ipilimumab 3mg/Kg iv q 3 weeks for 4 cycles
Adverse Event Rates Any grade toxicity · Yes	37 Participants
Adverse Event Rates Any grade toxicity · No	21 Participants
Adverse Event Rates Grade 3 or higher toxicity · Yes	11 Participants
Adverse Event Rates Grade 3 or higher toxicity · No	47 Participants

SECONDARY outcome

Timeframe: Expected average of 3 weeks during for the first 6 months, then every 3 months.

Population: safety population

Treatment feasibility. Number of patients with treatment delays and reductions, categorized as function of the number of events (reductions/delays)

Outcome measures

Measure	Ipilimumab n=58 Participants Ipilimumab 3mg/Kg iv q 3 weeks for 4 cycles Whole-brain radiotherapy (WBRT) 30 Gy in 10 fractions (or radiobiological equivalent schedule, after Sponsor approval), starting between Cycle 1 Day 2 and Cycle 2 Day 1 Ipilimumab: Ipilimumab 3mg/Kg iv q 3 weeks for 4 cycles
Rate of Dose Delays/Reductions and Treatment Exposure. Ipilimumab delay · None	43 Participants
Rate of Dose Delays/Reductions and Treatment Exposure. Ipilimumab delay · 1 event	12 Participants
Rate of Dose Delays/Reductions and Treatment Exposure. Ipilimumab delay · 2 events	2 Participants
Rate of Dose Delays/Reductions and Treatment Exposure. Ipilimumab delay · 3 events	1 Participants
Rate of Dose Delays/Reductions and Treatment Exposure. Ipilimumab delay · 4 events	0 Participants
Rate of Dose Delays/Reductions and Treatment Exposure. Ipilimumab reductions · None	50 Participants
Rate of Dose Delays/Reductions and Treatment Exposure. Ipilimumab reductions · 1 event	5 Participants
Rate of Dose Delays/Reductions and Treatment Exposure. Ipilimumab reductions · 2 events	1 Participants
Rate of Dose Delays/Reductions and Treatment Exposure. Ipilimumab reductions · 3 events	1 Participants
Rate of Dose Delays/Reductions and Treatment Exposure. Ipilimumab reductions · 4 events	1 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: Within 28 days before start treatment, just before the start treatment, then expected average of 3 weeks for the first 12 weeks

Population: efficacy population

Translational study. PFS outcome reported by subgroups according to BRAF mutation status

Outcome measures

Measure	Ipilimumab n=51 Participants Ipilimumab 3mg/Kg iv q 3 weeks for 4 cycles Whole-brain radiotherapy (WBRT) 30 Gy in 10 fractions (or radiobiological equivalent schedule, after Sponsor approval), starting between Cycle 1 Day 2 and Cycle 2 Day 1 Ipilimumab: Ipilimumab 3mg/Kg iv q 3 weeks for 4 cycles
Correlation of Biomarker Expression and PFS. BRAF mutated · Progression disease	5 Participants
Correlation of Biomarker Expression and PFS. BRAF mutated · No progression	12 Participants
Correlation of Biomarker Expression and PFS. BRAF mutated · Not applicable	34 Participants
Correlation of Biomarker Expression and PFS. BRAF native · Progression disease	7 Participants
Correlation of Biomarker Expression and PFS. BRAF native · No progression	19 Participants
Correlation of Biomarker Expression and PFS. BRAF native · Not applicable	25 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline and 4 weeks after WBRT

Outcome measures

Outcome data not reported

Adverse Events

Ipilimumab

Serious events: 33 serious events

Other events: 57 other events

Deaths: 40 deaths

Serious adverse events

Measure	Ipilimumab n=58 participants at risk Ipilimumab 3mg/Kg iv q 3 weeks for 4 cycles Whole-brain radiotherapy (WBRT) 30 Gy in 10 fractions (or radiobiological equivalent schedule, after Sponsor approval), starting between Cycle 1 Day 2 and Cycle 2 Day 1 Ipilimumab: Ipilimumab 3mg/Kg iv q 3 weeks for 4 cycles
Blood and lymphatic system disorders Anemia	1.7% 1/58 • Throughout the study period, from inclusion to 30 days after treatment has ended. Approximately 1 year
Nervous system disorders Ataxia	1.7% 1/58 • Throughout the study period, from inclusion to 30 days after treatment has ended. Approximately 1 year
Investigations Blood bilirrubin increase	1.7% 1/58 • Throughout the study period, from inclusion to 30 days after treatment has ended. Approximately 1 year
Nervous system disorders Cognitive disturbance	3.4% 2/58 • Throughout the study period, from inclusion to 30 days after treatment has ended. Approximately 1 year
Psychiatric disorders Confusion	1.7% 1/58 • Throughout the study period, from inclusion to 30 days after treatment has ended. Approximately 1 year
Gastrointestinal disorders Diarrhoea	10.3% 6/58 • Throughout the study period, from inclusion to 30 days after treatment has ended. Approximately 1 year
Nervous system disorders Dizziness	1.7% 1/58 • Throughout the study period, from inclusion to 30 days after treatment has ended. Approximately 1 year
Nervous system disorders Dysphasia	1.7% 1/58 • Throughout the study period, from inclusion to 30 days after treatment has ended. Approximately 1 year
Eye disorders Hemianopsia	1.7% 1/58 • Throughout the study period, from inclusion to 30 days after treatment has ended. Approximately 1 year
General disorders Fever	3.4% 2/58 • Throughout the study period, from inclusion to 30 days after treatment has ended. Approximately 1 year
Gastrointestinal disorders Gastric Hemorrage	1.7% 1/58 • Throughout the study period, from inclusion to 30 days after treatment has ended. Approximately 1 year
Nervous system disorders Headache	5.2% 3/58 • Throughout the study period, from inclusion to 30 days after treatment has ended. Approximately 1 year
Metabolism and nutrition disorders Hypercalcemia	1.7% 1/58 • Throughout the study period, from inclusion to 30 days after treatment has ended. Approximately 1 year
Metabolism and nutrition disorders Hyperglycemia	1.7% 1/58 • Throughout the study period, from inclusion to 30 days after treatment has ended. Approximately 1 year
Metabolism and nutrition disorders Hypokalemia	1.7% 1/58 • Throughout the study period, from inclusion to 30 days after treatment has ended. Approximately 1 year
Infections and infestations Candidiasis	1.7% 1/58 • Throughout the study period, from inclusion to 30 days after treatment has ended. Approximately 1 year
Nervous system disorders Intracranial hemorrage	1.7% 1/58 • Throughout the study period, from inclusion to 30 days after treatment has ended. Approximately 1 year
Infections and infestations Lung infection	3.4% 2/58 • Throughout the study period, from inclusion to 30 days after treatment has ended. Approximately 1 year
General disorders Malaise	6.9% 4/58 • Throughout the study period, from inclusion to 30 days after treatment has ended. Approximately 1 year
Musculoskeletal and connective tissue disorders Muscle weakness	1.7% 1/58 • Throughout the study period, from inclusion to 30 days after treatment has ended. Approximately 1 year
Respiratory, thoracic and mediastinal disorders Pleural effussion	1.7% 1/58 • Throughout the study period, from inclusion to 30 days after treatment has ended. Approximately 1 year
Respiratory, thoracic and mediastinal disorders Hemoptysis	1.7% 1/58 • Throughout the study period, from inclusion to 30 days after treatment has ended. Approximately 1 year
Nervous system disorders Seizures	3.4% 2/58 • Throughout the study period, from inclusion to 30 days after treatment has ended. Approximately 1 year
Infections and infestations Sepsis	1.7% 1/58 • Throughout the study period, from inclusion to 30 days after treatment has ended. Approximately 1 year
Nervous system disorders somnolence	1.7% 1/58 • Throughout the study period, from inclusion to 30 days after treatment has ended. Approximately 1 year
Reproductive system and breast disorders Testicular disorder	1.7% 1/58 • Throughout the study period, from inclusion to 30 days after treatment has ended. Approximately 1 year
Vascular disorders Thromboembolic event	3.4% 2/58 • Throughout the study period, from inclusion to 30 days after treatment has ended. Approximately 1 year
Infections and infestations Upper respiratory infection	1.7% 1/58 • Throughout the study period, from inclusion to 30 days after treatment has ended. Approximately 1 year
Infections and infestations Urinary tract infection	3.4% 2/58 • Throughout the study period, from inclusion to 30 days after treatment has ended. Approximately 1 year
Gastrointestinal disorders Vomiting	3.4% 2/58 • Throughout the study period, from inclusion to 30 days after treatment has ended. Approximately 1 year
Hepatobiliary disorders Hepatotoxicity	1.7% 1/58 • Throughout the study period, from inclusion to 30 days after treatment has ended. Approximately 1 year
Psychiatric disorders Depression	1.7% 1/58 • Throughout the study period, from inclusion to 30 days after treatment has ended. Approximately 1 year
Gastrointestinal disorders Duodenal perforation	1.7% 1/58 • Throughout the study period, from inclusion to 30 days after treatment has ended. Approximately 1 year
Investigations ALT increased	1.7% 1/58 • Throughout the study period, from inclusion to 30 days after treatment has ended. Approximately 1 year
Investigations GPT increased	1.7% 1/58 • Throughout the study period, from inclusion to 30 days after treatment has ended. Approximately 1 year

Other adverse events

Measure	Ipilimumab n=58 participants at risk Ipilimumab 3mg/Kg iv q 3 weeks for 4 cycles Whole-brain radiotherapy (WBRT) 30 Gy in 10 fractions (or radiobiological equivalent schedule, after Sponsor approval), starting between Cycle 1 Day 2 and Cycle 2 Day 1 Ipilimumab: Ipilimumab 3mg/Kg iv q 3 weeks for 4 cycles
Skin and subcutaneous tissue disorders Alopecia	15.5% 9/58 • Throughout the study period, from inclusion to 30 days after treatment has ended. Approximately 1 year
Metabolism and nutrition disorders Anorexia	25.9% 15/58 • Throughout the study period, from inclusion to 30 days after treatment has ended. Approximately 1 year
Gastrointestinal disorders Diarrhoea	24.1% 14/58 • Throughout the study period, from inclusion to 30 days after treatment has ended. Approximately 1 year
Nervous system disorders Dizziness	12.1% 7/58 • Throughout the study period, from inclusion to 30 days after treatment has ended. Approximately 1 year
Blood and lymphatic system disorders Edema	10.3% 6/58 • Throughout the study period, from inclusion to 30 days after treatment has ended. Approximately 1 year
General disorders Fatigue	48.3% 28/58 • Throughout the study period, from inclusion to 30 days after treatment has ended. Approximately 1 year
General disorders Fever	12.1% 7/58 • Throughout the study period, from inclusion to 30 days after treatment has ended. Approximately 1 year
Nervous system disorders Headache	39.7% 23/58 • Throughout the study period, from inclusion to 30 days after treatment has ended. Approximately 1 year
Metabolism and nutrition disorders Hyperglycemia	10.3% 6/58 • Throughout the study period, from inclusion to 30 days after treatment has ended. Approximately 1 year
Gastrointestinal disorders Nausea	27.6% 16/58 • Throughout the study period, from inclusion to 30 days after treatment has ended. Approximately 1 year
Skin and subcutaneous tissue disorders Pruritus	22.4% 13/58 • Throughout the study period, from inclusion to 30 days after treatment has ended. Approximately 1 year
Skin and subcutaneous tissue disorders Rash	8.6% 5/58 • Throughout the study period, from inclusion to 30 days after treatment has ended. Approximately 1 year
Gastrointestinal disorders Vomiting	15.5% 9/58 • Throughout the study period, from inclusion to 30 days after treatment has ended. Approximately 1 year

Additional Information

Pau Doñate

MFAR Clinical Research

Email: investigacion@mfar.net

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place

Restriction type: LTE60