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GEM STUDY: Radiation And Yervoy in Patients With Melanoma and Brain Metastases (GRAY-B)

This study is currently recruiting participants. (see Contacts and Locations)
Verified April 2014 by Grupo Español Multidisciplinar de Melanoma
Sponsor:
Collaborator:
Bristol-Myers Squibb
Information provided by (Responsible Party):
Grupo Español Multidisciplinar de Melanoma
ClinicalTrials.gov Identifier:
NCT02115139
First received: April 10, 2014
Last updated: October 28, 2014
Last verified: April 2014
  Purpose

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.


Condition Intervention Phase
Melanoma
Brain Metastases
Drug: Ipilimumab
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Multicenter, Single Arm, Phase 2 Clinical Study on the Combination of Radiation Therapy and Ipilimumab, for the Treatment of Patients With Melanoma and Brain Metastases

Resource links provided by NLM:


Further study details as provided by Grupo Español Multidisciplinar de Melanoma:

Primary Outcome Measures:
  • 1-year survival rate [ Time Frame: Expected average of 3 weeks during for the first 6 months, then every 3 months. ] [ Designated as safety issue: No ]
    During treatment period, there will be assessments every cycle. After end of treatment every 3 month.


Secondary Outcome Measures:
  • Progression-Free survival (PFS) [ Time Frame: 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. ] [ Designated as safety issue: No ]
    median, 6-month PFS rate

  • Intracranial PFS [ Time Frame: 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. ] [ Designated as safety issue: No ]
    median, 6-month PFS rate

  • Extracranial PFS [ Time Frame: 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. ] [ Designated as safety issue: No ]
    median, 6-month PFS rate

  • Overall survival [ Time Frame: Expected average of 3 weeks during for the first 6 months, then every 3 months. ] [ Designated as safety issue: No ]
    median

  • Response rate [ Time Frame: 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. ] [ Designated as safety issue: No ]
    Global, intracranial, extracranial and Immune-related response criteria

  • Adverse Event rates [ Time Frame: Expected average of 3 weeks during for the first 6 months, then every 3 months. ] [ Designated as safety issue: Yes ]
  • Rate of dose delays/reductions and treatment exposure. [ Time Frame: Expected average of 3 weeks during for the first 6 months, then every 3 months. ] [ Designated as safety issue: No ]
    Treatment feasibility.


Other Outcome Measures:
  • Correlation of biomarker expression and PFS. [ Time Frame: Within 28 days before start treatment, just before the start treatment, then expected average of 3 weeks for the first 12 weeks ] [ Designated as safety issue: No ]
    Translational study.

  • Intrapatient variation of quantitative apparent diffusion coefficients of serial diffusion-weighted magnetic resonance imaging [ Time Frame: Baseline and 4 weeks after WBRT ] [ Designated as safety issue: No ]

Estimated Enrollment: 66
Study Start Date: April 2014
Estimated Study Completion Date: October 2016
Estimated Primary Completion Date: October 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 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
Drug: Ipilimumab
Ipilimumab 3mg/Kg iv q 3 weeks for 4 cycles
Other Name: Experimental

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Willing and able to give written informed consent.
  2. Histologic diagnosis of melanoma.
  3. First episode of radiological evidence of brain metastases
  4. Age less than 18 years.
  5. Radiation Therapy Oncology Group-recursive partitioning analysis (RTOG-RPA) class 2
  6. Karnofsky performance status (PS) more than 70%
  7. Barthel Index of Activities of Daily Living more than 10
  8. Measurable disease (mWHO criteria).
  9. 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.
    • Total bilirubin less or equal 2.0 x ULN, (except patients with Gilbert's Syndrome, who must have a total bilirubin less than 3.0 mg/dL)
  10. Persons of reproductive potential must agree to use an adequate method of contraception throughout treatment and for at least 26 weeks after ipilimumab is stopped

Exclusion Criteria:

  1. 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.
  2. 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.
  3. Uncontrolled diabetes mellitus (HbA1c more than 9 %)
  4. 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).
  5. Other chronic intestinal diseases associated with diarrhea.
  6. Active infection or other serious illness or medical condition.
  7. Known active or chronic infection with HIV, Hepatitis B, or Hepatitis C.
  8. 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.
  9. Any experimental therapy administered in the past 30 days prior to the beginning of the treatment.
  10. 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)
  11. Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) for treatment of either a psychiatric or physical (eg, infectious) illness.
  12. Any other general, medical or psychological conditions which in the opinion of the investigator will make the administration of ipilimumab hazardous, or that would preclude appropriate informed consent or compliance with the protocol, or obscure the interpretation of eventual adverse events (AEs).
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02115139

Contacts
Contact: Sonia Diez, Biothecnology +34934344412 ext 106 investigacion@mfar.net

Locations
Spain
ICO Badalona Active, not recruiting
Badalona, Spain
H. Clinic de Barcelona Recruiting
Barcelona, Spain
Principal Investigator: Ana Arance Fernández, MD         
Hospital Vall d'Hebron Active, not recruiting
Barcelona, Spain
H. Insular de Canarias Recruiting
Las Palmas de Gran Canaria, Spain
Principal Investigator: Delvys Rodríguez Abreu, MD         
H. U. Gregorio Marañón Recruiting
Madrid, Spain
Principal Investigator: Ivan Márquez Rodas, MD         
Hospital 12 de Octubre Active, not recruiting
Madrid, Spain
Clínica Universidad de Navarra Recruiting
Pamplona, Spain
Principal Investigator: Salvador Martín Algarra, MD         
H. Clínico de Santiago Recruiting
Santiago de Compostela, Spain
Principal Investigator: María Teresa Curiel García, MD         
H.U. Virgen Macarena Active, not recruiting
Sevilla, Spain
H. Virgen de la Salud Active, not recruiting
Toledo, Spain
H. General de Valencia Recruiting
Valencia, Spain
Principal Investigator: Alfonso Berrocal Jaime, MD         
Instituto Valenciano de Oncología Recruiting
Valencia, Spain
Principal Investigator: Virtudes Soriano Teruel, MD         
Sponsors and Collaborators
Grupo Español Multidisciplinar de Melanoma
Bristol-Myers Squibb
Investigators
Study Chair: José Antonio López-Martín, MD Hospital 12 de Octubre - GEM
  More Information

No publications provided

Responsible Party: Grupo Español Multidisciplinar de Melanoma
ClinicalTrials.gov Identifier: NCT02115139     History of Changes
Other Study ID Numbers: GEM 1202, 2013-001132-22
Study First Received: April 10, 2014
Last Updated: October 28, 2014
Health Authority: Spain: Spanish Agency of Medicines
Spain: Ethics Committee

Keywords provided by Grupo Español Multidisciplinar de Melanoma:
melanoma
brain
metastases
Patients with melanoma and brain metastases

Additional relevant MeSH terms:
Brain Neoplasms
Melanoma
Neoplasm Metastasis
Neoplasms, Second Primary
Brain Diseases
Central Nervous System Diseases
Central Nervous System Neoplasms
Neoplasms
Neoplasms by Histologic Type
Neoplasms by Site
Neoplasms, Germ Cell and Embryonal
Neoplasms, Nerve Tissue
Neoplastic Processes
Nervous System Diseases
Nervous System Neoplasms
Neuroectodermal Tumors
Neuroendocrine Tumors
Nevi and Melanomas
Pathologic Processes

ClinicalTrials.gov processed this record on November 25, 2014