Uveal MelanomaPhase 2GEM1402NCT02626962
Trial of Nivolumab in Combination With Ipilimumab in Subjects With Previously Untreated Metastatic Uveal Melanoma
A Phase 2 study testing ipilimumab and Nivolumab in people with Uveal Melanoma, run by Grupo Español Multidisciplinar de Melanoma at 10 sites in Spain.
Trial summary
This is a Phase 2, single-arm study of nivolumab combined with ipilimumab in subjects with previously untreated, unresectable or metastatic uveal melanoma. Previous studies with immunotherapy have shown promising results and this synergistic combination was very effective in other tumors. Read more about this study
- Who is it for?
- Ages 18 to 99 years
- Conditions the study is for
- Uveal Melanoma
- What is being tested?
- ipilimumab and Nivolumab
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 52 participants
- Where
- 10 sitesSpain
- Study dates
- Apr 2016to 22 Jul 2021
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 99 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Written informed consent must be provided;
- Patients must have a histological diagnosis of uveal melanoma;
- Progressive metastatic disease at baseline. Progressive disease is defined as new or progressive lesions on cross-sectional imaging;
- Age>18 years;
- Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 to 1;
- Measurable disease by CT or MRI per RECIST 1.1 criteria;
Who cannot join
- Prior systemic treatment for metastatic uveal melanoma.
- Prior malignancy active within the previous 3 years except for locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder cancer, carcinoma in situ of cervix or breast, or incidental prostate cancer.
- Autoimmune disease: 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). Subjects with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.
- Any underlying medical or psychiatric condition, which in the opinion of the investigator will make the administration of nivolumab and ipilimumab hazardous or obscure the interpretation of Advers Events (AEs), such as a condition associated with frequent diarrhea.
- Any non-oncology vaccine therapy used for prevention of infectious diseases (for up to 1 month before or after any dose of nivolumab and ipilimumab).
- A history of prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA4 antibody, or any other antibody or drug specifically targeting T-cell costimulation or immune checkpoint pathways.
Show all 12Show fewer
- Concomitant therapy with any of the following: Interleukin (IL) -2, interferon, or other non-study immunotherapy regimens; cytotoxic chemotherapy; immunosuppressive agents; other investigation therapies; or chronic use of systemic corticosteroids, defined as >10mg daily prednisone equivalents. Inhaled or topical steroids, and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
- Active brain metastases or leptomeningeal metastases. Subjects with brain metastases are eligible if these have been treated and there is no magnetic resonance imaging (MRI) evidence of progression for at least 8 weeks after treatment is complete and within 28 days prior to first dose of study drug administration. There must also be no requirement for immunosuppressive doses of systemic corticosteroids (> 10 mg/day prednisone equivalents) for at least 2 weeks prior to study drug administration.
- Women of childbearing potential (WOCBP) as defined below, who:
- are unwilling or unable to use an acceptable method of contraception to avoid pregnancy for their entire study period and for at least 8 weeks after cessation of study drug, or
- have a positive pregnancy test at baseline, or
- are pregnant or breastfeeding.
Trial locations and contacts
10 sites in 1 country.
10 sites in 1 country
Spain10 sites
ICO Hospitalet
L'Hospitalet de Llobregat
H. Insular de Canarias
Las Palmas de Gran Canaria
Hospital La Paz
Madrid
H. U. Virgen de la Victoria
Málaga
Hospital Son Espases
Palma de Mallorca, Balearic Islands
Clínica Universidad de Navarra
Pamplona
H. U. Clínico de Santiago
Santiago
H.U. Virgen Macarena
Seville
Hospital General Universitario de Valencia
Valencia
H. C. U. de Valladolid
Valladolid
About this study
Official title: Phase II Multicenter, Non Randomized, Open Label Trial of Nivolumab in Combination With Ipilimumab in Subjects With Previously Untreated Metastatic Uveal Melanoma
This is a Phase 2, single-arm study of nivolumab combined with ipilimumab in subjects with previously untreated, unresectable or metastatic uveal melanoma. Previous studies with immunotherapy have shown promising results and this synergistic combination was very effective in other tumors. This study will allow for further characterization of the safety and clinical activity of nivolumab combined with ipilimumab in subjects with uveal melanoma.
Read the detailed description
Uveal melanoma is a rare disease, accounting for 0.1% of all cancer deaths. This disease arises from melanocytes of the uveal tract and is the most common primary intraocular tumor in adults, with an incidence estimated at 0.6 per 100,000 persons/year in the Western population and seems to have remained stable over time.
Metastases in uveal melanoma appear in 6.5%-35% of the patients during the first decade. The clinical and metastatic behavior differs from cutaneous melanoma because of its initially purely hematogenous dissemination and its tendency to metastasize to the liver. Furthermore, the liver is almost a "sentinel lymph node" for uveal melanoma, because it is affected in 95% of patients and it is the sole site of metastasis in most cases. This specific ocular-hepatic tropism remains unexplained. When liver metastases develop, the prognosis is poor and life expectancy is reduced to less than 6 months in the absence of treatment. Only few prognostic factors for survival have been identified. Age, short time interval to metastases development, and tumor burden in the liver have shown a negative impact on survival, whereas patients diagnosed at regular follow-up survive significantly longer, probably due to the earlier diagnosis. Several loco-regional treatment options can be considered if metastases are confined to the liver, including partial hepatic resection or radiofrequency ablation. Curative resection is possible in only a small fraction of patients due to the number, location or size of the metastases.
Systemic chemotherapy is usually unsuccessful in metastatic uveal melanoma and results were recently reviewed showing an Overall Response Rate of 4,6 %with 95% CI 3.3-6.3%. There is no proof that conventional chemotherapy prolongs survival with most studies reporting OS between 5 and 12 months. Most therapies are derived from the experience extrapolated from cutaneous melanoma. Only few chemotherapeutic regimens have been studied in phase II trials such as bleomycin /vincristine/ lomustine /dacarbazine (BOLD), fotemustine,9-nitrocamptothecin, temozolomide, bendamustine, gemcitabine/treosulfan, cisplatin/gemcitabine/treosulfan, and dacarbazine/treosulfan with poor results that range from 0 to 15% response rate and less than 12 months overall survival with first line therapy. A phase III trial randomizing patients to chemotherapy or Best Suportive Care (BSC) is not expected to be performed because of difficulty in recruiting due to the low incidence of disease.
In the other hand, the best understanding of the biology of cancer disease has allowed us to identify pathways that are important in mechanisms of proliferation, survival or dissemination. Recently Guanine Nucleotide-Binding Protein G (GNAQ) gene oncogenic mutation has been identified in close to 50% of primary uveal melanomas. The emergence of newer agents that target this or other pathways (such as selumetinib, sunitinib, imatinib, vorinostat, antiangiogenics) have resulted in multiple small studies that up to date have failed to show a clear superiority against chemotherapy. To summarize, patients with metastatic uveal melanoma should be included in clinical trials evaluating other options with newer agents with potentially less toxicity and greater efficacy than conventional chemotherapy.
- Conditions
- Uveal Melanoma
- Being tested
- ipilimumab, Nivolumab
- Keywords
- melanoma
- Medical subject headings
- Uveal Melanoma, Melanoma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
ipilimumabDrug
Also called Yervoy
Ipilimumab every 3 weeks for a total of four doses (Cycles 1 and 2)
NivolumabDrug
Also called Opdivo
Nivolumab every 3 weeks for a total of four doses (Cycles 1 and 2) followed by Nivolumab every 2 weeks
| Study group | Role | What they receive |
|---|---|---|
| Nivolumab and Ipilimumab | Experimental | Nivolumab and Ipilimumab every 3 weeks for a total of four doses (Cycles 1 and 2) followed by Nivolumab every 2 weeks Receives: Drug: ipilimumab; Drug: Nivolumab |
What is being measured
The primary outcome is the main question the study is designed to answer.
Overall Survival at 12 months
Percentage of patients alive at 1-year from first dose of treatment.
Measured: 12 months after treatment start
Secondary outcomes (6)
Overall survival at 24 months.
Percentage of patients alive at 2-years from first dose of treatment.
Measured: 24 months
Progression Free Survival (PFS)
Percentage of patients without progression of disease at month 3, according RECIST 1.1 criteria.
Measured: 3 months
Global PFS according to RECIST 1.1 criteria.
Percentage of patients without progression of disease at month throughout follow-up, according RECIST 1.1 criteria.
Measured: From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 48 months
Objective Response Rate (ORR)
Respose to treatment according to RECIST 1.1 criteria
Measured: 12 months
Disease Control Rate
Percentage of patients with disease control
Measured: From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 48 months
Duration of response
Length of time between date of evidenced response and progression of disease or death
Measured: From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 48 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted10 Dec 2015 (estimated)
- Study startApr 2016
- Primary completionMay 2017
- Study completion22 Jul 2021
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Uveal MelanomaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 52 participants (actual)
Sponsor and investigators
- Lead sponsor
- Grupo Español Multidisciplinar de Melanoma
- Sponsor type
- University, hospital or other
- Collaborators
- Bristol-Myers Squibb
- Responsible party
- Sponsor
- Investigators
- Josep Maria Piulats, MD, Study chair, ICO Hospitalet
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02626962
- Sponsor's protocol ID
- GEM-1402
- Other IDs
- 2015-004429-15, 2015
- Acronym
- GEM1402
- Status last verified
- Mar 2022
- First submitted
- 1 Dec 2015
- Last updated
- 22 Mar 2022
- Results posted
- No
- Data monitoring committee
- Yes
- Individual data sharing
- Undecided
Publications
Piulats JM, Espinosa E, de la Cruz Merino L, Varela M, Alonso Carrion L, Martin-Algarra S, Lopez Castro R, Curiel T, Rodriguez-Abreu D, Redrado M, Goma M, Rullan AJ, Calvo Gonzalez A, Berrocal-Jaime A. Nivolumab Plus Ipilimumab for Treatment-Naive Metastatic Uveal Melanoma: An Open-Label, Multicenter, Phase II Trial by the Spanish Multidisciplinary Melanoma Group (GEM-1402). J Clin Oncol. 2021 Feb 20;39(6):586-598. doi: 10.1200/JCO.20.00550. Epub 2021 Jan 8.
PubMed 33417511
Study at a glance
From the registry record, last updated by the sponsor on 22 Mar 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Phase II Multicenter, Non Randomized, Open Label Trial of Nivolumab in Combination With Ipilimumab in Subjects With Previously Untreated Metastatic Uveal Melanoma
- ClinicalTrials.gov ID
- NCT02626962
- Acronym / sponsor ID
- GEM1402 / GEM-1402
- Conditions
- Uveal Melanoma
- Keywords
- melanoma
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 52 participants (actual)
- Lead sponsor
- Grupo Español Multidisciplinar de MelanomaUniversity, hospital or other
- Collaborators
- Bristol-Myers Squibb
- Study start
- Apr 2016 (actual)
- Primary completion
- May 2017 (actual)
- Study completion
- 22 Jul 2021 (actual)
- First posted
- 10 Dec 2015 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This is a Phase 2, single-arm study of nivolumab combined with ipilimumab in subjects with previously untreated, unresectable or metastatic uveal melanoma. Previous studies with immunotherapy have shown promising results and this synergistic combination was very effective in other tumors. This study will allow for further characterization of the safety and clinical activity of nivolumab combined with ipilimumab in subjects with uveal melanoma.
Detailed description
Uveal melanoma is a rare disease, accounting for 0.1% of all cancer deaths. This disease arises from melanocytes of the uveal tract and is the most common primary intraocular tumor in adults, with an incidence estimated at 0.6 per 100,000 persons/year in the Western population and seems to have remained stable over time.
Metastases in uveal melanoma appear in 6.5%-35% of the patients during the first decade. The clinical and metastatic behavior differs from cutaneous melanoma because of its initially purely hematogenous dissemination and its tendency to metastasize to the liver. Furthermore, the liver is almost a "sentinel lymph node" for uveal melanoma, because it is affected in 95% of patients and it is the sole site of metastasis in most cases. This specific ocular-hepatic tropism remains unexplained. When liver metastases develop, the prognosis is poor and life expectancy is reduced to less than 6 months in the absence of treatment. Only few prognostic factors for survival have been identified. Age, short time interval to metastases development, and tumor burden in the liver have shown a negative impact on survival, whereas patients diagnosed at regular follow-up survive significantly longer, probably due to the earlier diagnosis. Several loco-regional treatment options can be considered if metastases are confined to the liver, including partial hepatic resection or radiofrequency ablation. Curative resection is possible in only a small fraction of patients due to the number, location or size of the metastases.
Systemic chemotherapy is usually unsuccessful in metastatic uveal melanoma and results were recently reviewed showing an Overall Response Rate of 4,6 %with 95% CI 3.3-6.3%. There is no proof that conventional chemotherapy prolongs survival with most studies reporting OS between 5 and 12 months. Most therapies are derived from the experience extrapolated from cutaneous melanoma. Only few chemotherapeutic regimens have been studied in phase II trials such as bleomycin /vincristine/ lomustine /dacarbazine (BOLD), fotemustine,9-nitrocamptothecin, temozolomide, bendamustine, gemcitabine/treosulfan, cisplatin/gemcitabine/treosulfan, and dacarbazine/treosulfan with poor results that range from 0 to 15% response rate and less than 12 months overall survival with first line therapy. A phase III trial randomizing patients to chemotherapy or Best Suportive Care (BSC) is not expected to be performed because of difficulty in recruiting due to the low incidence of disease.
In the other hand, the best understanding of the biology of cancer disease has allowed us to identify pathways that are important in mechanisms of proliferation, survival or dissemination. Recently Guanine Nucleotide-Binding Protein G (GNAQ) gene oncogenic mutation has been identified in close to 50% of primary uveal melanomas. The emergence of newer agents that target this or other pathways (such as selumetinib, sunitinib, imatinib, vorinostat, antiangiogenics) have resulted in multiple small studies that up to date have failed to show a clear superiority against chemotherapy. To summarize, patients with metastatic uveal melanoma should be included in clinical trials evaluating other options with newer agents with potentially less toxicity and greater efficacy than conventional chemotherapy.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Nivolumab and Ipilimumab | Experimental | Drug: ipilimumab, Drug: NivolumabNivolumab and Ipilimumab every 3 weeks for a total of four doses (Cycles 1 and 2) followed by Nivolumab every 2 weeks |
Who may qualify
- Ages
- 18 to 99 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (6 listed)
- Written informed consent must be provided;
- Patients must have a histological diagnosis of uveal melanoma;
- Progressive metastatic disease at baseline. Progressive disease is defined as new or progressive lesions on cross-sectional imaging;
- Age>18 years;
- Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 to 1;
Key exclusion criteria (12 listed)
- Prior systemic treatment for metastatic uveal melanoma.
- Prior malignancy active within the previous 3 years except for locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder cancer, carcinoma in situ of cervix or breast, or incidental prostate cancer.
- Autoimmune disease: 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). Subjects with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.
- Any underlying medical or psychiatric condition, which in the opinion of the investigator will make the administration of nivolumab and ipilimumab hazardous or obscure the interpretation of Advers Events (AEs), such as a condition associated with frequent diarrhea.
- Any non-oncology vaccine therapy used for prevention of infectious diseases (for up to 1 month before or after any dose of nivolumab and ipilimumab).
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| ipilimumabAlso: YervoyIpilimumab every 3 weeks for a total of four doses (Cycles 1 and 2) | Drug | Nivolumab and Ipilimumab |
| NivolumabAlso: OpdivoNivolumab every 3 weeks for a total of four doses (Cycles 1 and 2) followed by Nivolumab every 2 weeks | Drug | Nivolumab and Ipilimumab |
Primary outcome
Overall Survival at 12 months
Time frame: 12 months after treatment start
Percentage of patients alive at 1-year from first dose of treatment.
6 secondary outcomes
Overall survival at 24 months.
Time frame: 24 months
Progression Free Survival (PFS)
Time frame: 3 months
Global PFS according to RECIST 1.1 criteria.
Time frame: From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 48 months
Objective Response Rate (ORR)
Time frame: 12 months
Disease Control Rate
Time frame: From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 48 months
Duration of response
Time frame: From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 48 months
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 22 Mar 2022.
- Derived from this study: PubMed 33417511Piulats JM, Espinosa E, de la Cruz Merino L, Varela M, Alonso Carrion L, Martin-Algarra S, Lopez Castro R, Curiel T, Rodriguez-Abreu D, Redrado M, Goma M, Rullan AJ, Calvo Gonzalez A, Berrocal-Jaime A. Nivolumab Plus Ipilimumab for Treatment-Naive Metastatic Uveal Melanoma: An Open-Label, Multicenter, Phase II Trial by the Spanish Multidisciplinary Melanoma Group (GEM-1402). J Clin Oncol. 2021 Feb 20;39(6):586-598. doi: 10.1200/JCO.20.00550. Epub 2021 Jan 8.
- Individual participant dataSharing planned: Undecided
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Josep Maria Piulats, MD study chair
ICO Hospitalet
10 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing ipilimumab and Nivolumab in people with Uveal Melanoma, run by Grupo Español Multidisciplinar de Melanoma at 10 sites in Spain.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 12 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 22 Mar 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 10 sites in Spain. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Overall Survival at 12 months (time frame: 12 months after treatment start). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02626962, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 22 Mar 2022.