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

NCT02115139 | Completed Phase 2 Results

• 2 other identifiers: GEM 12022013-001132-22
• Study Type: interventional
• Target: 58
• Locations: 1 country
• Sites: 12

Brief Summary

Ipilimumab adds a clinical benefit to radiation therapy in patients with melanoma metastatic to the brain. Melanoma is the third most common cancer causing brain metastases, after cancers of the lung and breast, which appears to reflect the relative propensity of melanoma to metastasize to the central nervous system (CNS). Brain metastases are responsible for 20 to 54 percent of deaths in patients with melanoma, and among those with documented brain metastases, these lesions contribute to death in up to 95 percent of cases, with an estimated median overall survival ranging between 1.8 and 10.5 months, depending upon other prognostic factors. Ipilimumab is an anti-Cytotoxic T-Lymphocyte Antigen 4 (anti-CTLA4) monoclonal antibody that has demonstrated a clinically relevant and statistically significant improvement in overall survival, either alone (second line) or in combination with dacarbazine (DTIC) in 1st line. Ipilimumab has shown activity against brain metastases. According to the European Medicines Agency (EMA) approved label for Yervoy®, the use of glucocorticoids at baseline (commonly prescribed when brain metastases are diagnosed) should be avoided before the administration of ipilimumab. Data show that the use of even high doses of glucocorticoids for the management of immune-related adverse events do not decrease the efficacy of Yervoy®. There is no documented experience on the efficacy of Yervoy® when given concomitantly with radiation therapy and glucocorticoids. In experimental models, radiation therapy is synergistic to anti-Cytotoxic T-Lymphocyte Antigen 4 (anti-CTLA4) strategies (abscopal effect). There are no published results from clinical trials on the interaction between radiation therapy and ipilimumab.

Conditions

Melanoma; Brain Metastases

Keywords

melanoma; brain; metastases; Patients with melanoma and brain metastases

Outcome Measures

Primary Outcomes (1)

• 1-year Survival Rate

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

  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

Secondary Outcomes (7)

• Progression-Free Survival (PFS)

  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.

• Intracranial PFS

  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.

• Extracranial PFS

  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.

• Overall Survival

  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.

• Response Rate

  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.

Other Outcomes (2)

• Correlation of Biomarker Expression and PFS.

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

• Intrapatient Variation of Quantitative Apparent Diffusion Coefficients of Serial Diffusion-weighted Magnetic Resonance Imaging

  Baseline and 4 weeks after WBRT

Study Arms (1)

Ipilimumab

EXPERIMENTAL

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

Drug: Ipilimumab

Interventions

Ipilimumab DRUG

Ipilimumab 3mg/Kg iv q 3 weeks for 4 cycles

Also known as: Experimental

Ipilimumab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Willing and able to give written informed consent.
• Histologic diagnosis of melanoma.
• First episode of radiological evidence of brain metastases
• Be over the age of 18 years old
• Radiation Therapy Oncology Group-recursive partitioning analysis (RTOG-RPA) class 2
• Karnofsky performance status (PS) more than 70%
• Barthel Index of Activities of Daily Living more than 10
• Measurable disease (mWHO criteria).
• Adequate organ function as determine by the following criteria:
• White blood count (WBC) more or equal to 2000/ microliter (uL)
• Absolute neutrophil count (ANC) more than 1.5 x 109/L.
• Platelet count more than 75 x 109/L.
• Hemoglobin more than 9 g/dL. If the patient received a red blood count (RBC) transfusion, the required value of hemoglobin should be met at least 1 week after the most recent transfusion.
• Serum creatinine less or equal to 2.0 x upper limit of normal (ULN).
• Serum aspartate aminotransferase (AST) and serum alanine aminotransferase (ALT) less or equal to 2.5 x ULN for patients without liver metastasis, or less or equal to 5 times for liver metastases.

You may not qualify if:

• Patients with melanoma and brain metastases with any of the following disease-specific characteristics:
• Documented evidence of prior progression of melanoma to an ipilimumab-containing regimen (i.e. received at least 2 doses of ipilimumab for either advanced disease or in the adjuvant setting and the disease progressed/relapsed (according to mWHO criteria) within 24 weeks since the first dose of ipilimumab)
• Prior radiation therapy to the brain
• Other prior antineoplastic therapies for brain metastases.
• Patients with cerebral metastases as the only location of the disease, for which local therapy (neurosurgery, radiosurgery) could achieve a disease-free status
• Patients with a rapid clinical deterioration, or with risk of herniation, or who require unstable ascending dosing of supportive medication in the last week -including anti-convulsivants, steroids and analgesics-, or who require dexamethasone more than 16 mg/d (or other glucocorticoid at an equipotent dose), or with a high lactate dehydrogenase (LDH) more than 2 x ULN.
• Any other malignancy form which the patient has been disease-free for less than 5 years, with the exception of adequately treated and cured basal or squamous cell skin cancer, superficial bladder cancer or carcinoma in situ of the cervix, or incidental prostate cancer.
• Uncontrolled diabetes mellitus (HbA1c more than 9 %)
• Autoimmune disease other than vitiligo or past thyroiditis under substitutive hormone therapy: Patients with a history of inflammatory bowel disease, including ulcerative colitis and Crohn's Disease, are excluded from this study, as are patients with a history of symptomatic disease (eg, rheumatoid arthritis, systemic progressive sclerosis \[scleroderma\], systemic lupus erythematosus, autoimmune vasculitis \[eg, Wegener's Granulomatosis\]); motor neuropathy considered of autoimmune origin (e.g. Guillain-Barre Syndrome and Myasthenia Gravis).
• Other chronic intestinal diseases associated with diarrhea.
• Active infection or other serious illness or medical condition.
• Known active or chronic infection with HIV, Hepatitis B, or Hepatitis C.
• Concomitant therapy with any of the following: interleukin-2 (IL-2), interferon, or other non-study immunotherapy regimens; cytotoxic chemotherapy; immunosuppressive agents; other investigation therapies; or chronic use of systemic corticosteroids (used for the management of non-cancer related illnesses), either concomitantly or during the last 30 days prior to the beginning of the treatment.
• Any experimental therapy administered in the past 30 days prior to the beginning of the treatment.
• Any non-oncology vaccine therapy used for the prevention of infectious diseases (for up to 4 weeks prior to or after any dose of blinded study drug) (see definitions in protocol text)

Sponsors & Collaborators

• Grupo Español Multidisciplinar de Melanoma: lead
• Bristol-Myers Squibb: collaborator

Study Sites (12)

ICO Badalona

Badalona, Spain

Location

H. Clinic de Barcelona

Barcelona, Spain

Location

Hospital Vall d'Hebron

Barcelona, Spain

Location

H. Insular de Canarias

Las Palmas de Gran Canaria, Spain

Location

H. U. Gregorio Marañón

Madrid, Spain

Location

Hospital Universitario 12 de Octubre

Madrid, Spain

Location

Clínica Universidad de Navarra

Pamplona, Spain

Location

H. Clínico de Santiago

Santiago de Compostela, Spain

Location

H.U. Virgen Macarena

Seville, Spain

Location

H. Virgen de la Salud

Toledo, Spain

Location

H. General de Valencia

Valencia, Spain

Location

Instituto Valenciano de Oncología

Valencia, Spain

Location

MeSH Terms

Conditions

Melanoma; Brain Neoplasms; Neoplasm Metastasis

Interventions

Ipilimumab

Condition Hierarchy (Ancestors)

Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases; Central Nervous System Neoplasms; Nervous System Neoplasms; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neoplastic Processes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Results Point of Contact

• Title: Pau Doñate
• Organization: MFAR Clinical Research

investigacion@mfar.net

Study Officials

• José A López-Martín, MD

  Hospital Universitario 12 de Octubre - GEM

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 10, 2014
• First Posted: April 15, 2014
• Study Start: April 4, 2014
• Primary Completion: December 31, 2016
• Study Completion: July 31, 2018
• Last Updated: November 8, 2022
• Results First Posted: July 1, 2021

Record last verified: 2022-10

Locations

ES (12)