Stage IIIC Skin MelanomaPhase 1/2ipnivNCT02941744
A Clinical Trial: Adjuvant Low-dose Ipilimumab + Nivolumab After Resection of Melanoma Macrometastases
A Phase 1/2 study testing nivolumab and ipilimumab in people with Stage IIIC Skin Melanoma and Stage IV Skin Melanoma, run by Universitair Ziekenhuis Brussel at 1 site in Belgium.
Trial summary
Nivolumab (OpdivoTM, BMS), a human IgG-4 anti-PD-1 monoclonal antibody has demonstrated anti-tumor activity in patients with advanced melanoma. The investigators postulate that patients with melanoma nivolumab have a comparable tumor response rate at a dose range of 0.1 to 10 mg/kg q2wks. Read more about this study
- Who is it for?
- Ages 18 years and olderHealthy volunteers can take part
- Conditions the study is for
- Stage IIIC Skin Melanoma, Stage IV Skin Melanoma
- What is being tested?
- nivolumab and ipilimumab
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 56 participants
- Where
- 1 siteBelgium
- Study dates
- Mar 2016to Jan 2019
- Phase
- Phase 1/2
- 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 years and older
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- All subjects must be either Stage IIIb/c or Stage IV AJCC (7th edition) and have histologically confirmed melanoma that is completely surgically resected in order to be eligible. Subjects must have been surgically rendered free of disease with negative margins on resected specimens. Please refer to Appendix 1 or description of AJCC 7th editions of TNM and staging.
- If Stage III melanoma (whether Stage IIIb or IIIc) the subjects must have clinically detectable lymph nodes that are confirmed as malignant on the pathology report Clinically detectable lymph nodes are defined as:
- A palpable node (confirmed as malignant by pathology)
- A non-palpable but enlarged lymph node by CT (at least 15 mm in short axis) and confirmed as malignant by pathology
- A PET positive lymph node of any size confirmed by pathology
- Evidence of pathologically macrometastatic disease in one or more lymph nodes defined by one or more foci of melanoma at least 1cm in diameter
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- All melanomas, except ocular/uveal melanoma, regardless of primary site of disease will be allowed
- Complete resection of Stage III disease that is documented on the surgical and pathology reports or complete resection of Stage IV disease with margins negative that is documented on the pathology report.
- Complete resection must be performed within 16 weeks prior to recruitment
- Subjects must not have received systemic medical anti-cancer treatment (postsurgical local/locoregional radiation therapy applied according to local standard practice is allowed)
- All subjects must have disease-free status documented by a complete physical examination and total body PET/CT imaging within 4 weeks prior to recruitment.
- ECOG performance status score of 0 or 1 (Appendix 2)
- In order to be recruited, tumor tissue from the resected site of disease must be provided for biomarker analyses. If insufficient tumor tissue content is provided for analysis, acquisition of additional archived tumor tissue (block and /or slides) for the biomarker analysis is required.
- Prior treated central nervous system (CNS) metastases must be without MRI evidence of recurrence for at least 4 weeks after treatment, subjects must be off immunosuppressive doses of systemic steroids (> 10 mg/day or equivalent) for at least 14 days prior to study drug administration, and must have returned to neurologic baseline post-operatively. The 4-week period of stability is measured after the completion of the neurologic interventions, ie surgery and/or radiation
- In addition to neurosurgery to treat CNS metastases, adjuvant radiation after the resection of CNS metastasis is allowed. Immunosuppressive doses of systemic steroids (doses < 10 mg/day prednisone or equivalent) must be discontinued at least 14 days before study drug administration
- Prior surgery that required general anesthesia must be completed at least 4 weeks before study drug administration. Surgery requiring local/epidural anesthesia must be completed at least 72 hours before study drug administration.
- All baseline laboratory requirements will be assessed and should be obtained within 14 days of recruitment. Screening laboratory values must meet the following criteria:
- WBCs > 2000/μL ii. Neutrophils > 1500/μL iii. Lymphocytes > 1000/μL iv. Platelets > 100 x 10³/μL v. Hemoglobin > 9.0 g/dL vi. Creatinine Serum creatinine <1.5 x upper limit of normal (ULN) or creatinine clearance > 40 mL/minute (using Cockcroft/Gault formula) vii. AST < ULN viii. ALT < ULN ix. Total Bilirubin < 1 x ULN (except subjects with Gilbert Syndrome who must have total bilirubin < 3.0 mg/dL) x. LDH < 1,5x ULN xi. CRP < 2x ULN
Who cannot join
- Subjects with leptomeningeal metastases
- History of ocular/uveal melanoma
- Medical History and Concurrent Diseases
- Subjects with previous non-melanoma malignancies are excluded unless a complete remission was achieved at least 3 years prior to study entry and no additional therapy is required or anticipated to be required during the study period (exceptions include but are not limited to, non-melanoma skin cancers; in situ bladder cancer, in situ gastric cancer, or in situ colon cancers; in situ cervical cancers/dysplasia; or breast carcinoma in situ)
- Subjects with active, known, or suspected autoimmune disease. Subjects with type I diabetes mellitus, residual hypothyroidism due to autoimmune thyroiditis only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment are permitted to enroll. For any cases of uncertainty, it is recommended that a BMS medical monitor be consulted prior to signing informed consent.
- Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids are permitted in the absence of active autoimmune disease.
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- Prior therapy for melanoma except surgery for the melanoma lesion(s) and except adjuvant RT after neurosurgical resection for CNS lesions. Specifically subjects who received prior therapy with interferon, anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody (including ipilimumab or any other antibody or drug specifically targeting T cell co-stimulation or checkpoint pathways) are not eligible.
- Treatment directed against the resected melanoma (eg, chemotherapy, targeted agents, biotherapy, or limb perfusion) that is administered after the complete resection.
- Any serious or uncontrolled medical disorder or active infection that, in the opinion of the investigator, may increase the risk associated with study participation, study drug administration, or would impair the ability of the subject to receive protocol therapy.
- Physical and Laboratory Test Findings
- Positive test for hepatitis B virus surface antigen (HBVsAg) or hepatitis C virus ribonucleic acid (HCV RNA) indicating acute or chronic infection.
- Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).
- Allergies and Adverse Drug Reaction
- History of Grade ≥3 allergy to humanized monoclonal antibodies
- Other Exclusion Criteria
- Prisoners or subjects who are involuntarily incarcerated
- Subjects who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness
- Pregnant or nursing women
- Psychological, familial, sociological, or geographical conditions that potentially hamper compliance with the study protocol and follow-up schedule; those conditions should be discussed with the subject before registration in the trial
Trial locations and contacts
1 site in 1 country.
About this study
Official title: A Phase IB Clinical Trial on Adjuvant Low-dose Ipilimumab Plus Nivolumab Following the Resection of Melanoma Macrometastases
Nivolumab (OpdivoTM, BMS), a human IgG-4 anti-PD-1 monoclonal antibody has demonstrated anti-tumor activity in patients with advanced melanoma.
The investigators postulate that patients with melanoma nivolumab have a comparable tumor response rate at a dose range of 0.1 to 10 mg/kg q2wks.
Read more
Ipilimumab (YervoyTM, BMS), a human IgG-1 anti-CTLA-4 monoclonal antibody improves the survival of patients with advanced melanoma. Adjuvant therapy with ipilimumab improves the relapse-free survival after complete resection of high-risk stage III melanoma (EORTC 18071).
Combined treatment with ipilimumab plus nivolumab improves the tumor response rate and overall survival of patients with advanced melanoma but is associated with a higher incidence of immune related adverse events (CheckMate 067).Nivolumab and ipilimumab have distinct immunological mechanisms that can be revealed by analyzing TCR usage in blood lymphocytes.
Read the detailed description
Currently, there is no standard of care or no available treatment for subjects with AJCC Stage IIIb/c and Stage IV NED melanoma who are at high risk for recurrence following complete resection of their metastasis. Ipilimumab (10mg/kg), interferon, pegylated interferon therapy or observations alone are the typical options for the Stage III patients who achieve a complete resection and are Food and Drug Administration (FDA) approved. In the EU, high-dose interferon is the only approved drug for the adjuvant treatment of melanoma patients. Given the unexceptional benefit and high toxicity profile in a patient population that is free of disease, it is controversial whether ipilimumab and interferon can be considered standard of care for Stage III melanoma. Nivolumab, a PD1 blocking monoclonal antibody, has shown superior anti-tumor activity across a wide range of dose-levels (0,1 to 10 mg/kg every 2 weeks) in patients with advanced melanoma. Nivolumab (at a dose of 3 mg/kg every 3 weeks) demonstrated a survival benefit in treatment naive patients with BRAF Wild Type (WT), metastatic melanoma in a Phase 3, randomized clinical trial and a PFS benefit over ipilimumab as a first-line therapy for advanced melanoma. Combination therapy with ipilimumab and nivolumab results in a higher response rate and PFS as compared to the results obtained with monotherapy. Combination therapy however significantly increases the incidence of grade > 3 adverse events, to the extent that this regimen would probably be associated with unacceptable toxicity in the adjuvant setting. The toxicity seems to be driven by Ipilimumab. The adverse events seen on Ipilimumab are dose dependent.
Unlike PD-1 blockade, CTLA-4 blockade diversifies the peripheral T-cell pool, representing a pharmacodynamic effect that can be measured by a DNA-sequencing technology referred to as ImmunoSeq.
This phase IB study will investigate the effect of low-dose ipilimumab and low-dose nivolumab on the peripheral T-cell repertoire of patients who are free of disease following the resection of melanoma macrometastases.
Treatment with low-dose ipilimumab in combination with low-dose nivolumab will be safe and modify the peripheral T-cell repertoire in subjects with completely resected Stage IIIb/c and Stage IV melanoma who are at high risk for recurrence.
Ipilimumab (YervoyTM, BMS), a human IgG-1 anti-CTLA-4 monoclonal antibody improves the survival of patients with advanced melanoma .Adjuvant therapy with ipilimumab improves the relapse-free survival after complete resection of high-risk stage III melanoma .
Combined treatment with ipilimumab plus nivolumab improves the tumor response rate and overall survival of patients with advanced melanoma but is associated with a higher incidence of immune related adverse events.
Nivolumab and ipilimumab have distinct immunological mechanisms that can be revealed by analyzing TCR usage in blood lymphocytes.
- Conditions
- Stage IIIC Skin Melanoma, Stage IV Skin Melanoma
- Being tested
- nivolumab, ipilimumab
- Keywords
- nivolumab, ipilimumab, low fixed dose, adjuvant therapy, Melanoma
- Medical subject headings
- Melanoma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
nivolumabDrug
Also called Opdivo
low fixed dose ipilimumab in combination with nivolumab
ipilimumabDrug
Also called Yervoy
low fixed dose ipilimumab in combination with nivolumab
| Study group | Role | What they receive |
|---|---|---|
| IpNiv | Experimental | low fixed dose ipilimumab plus low fixed dose nivolumab Receives: Drug: nivolumab; Drug: ipilimumab |
What is being measured
The primary outcome is the main question the study is designed to answer.
Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
to evaluate the safety of the investigational regimen of adjuvant low-dose ipilimumab plus nivolumab
Measured: 2year
Secondary outcomes (1)
to measure t cell repertoire before and after treatment with low dose ipilimumab and nivolumab with immunoseq.
to evaluate the effect of the investigational regimen of adjuvant low-dose ipilimumab plus nivolumab on the T-cell repertoire in the blood of subjects with completely resected Stage IIIb/c or Stage IV NED melanoma who are at high risk for recurrence
Measured: 2years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted21 Oct 2016 (estimated)
- Study startMar 2016
- Primary completionDec 2018
- Study completionJan 2019
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Stage IIIC Skin MelanomaStudies of the same condition, open and under way.
- More trials run by Universitair Ziekenhuis BrusselThe sponsor's other registered studies.
- 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 1/2
- Primary purpose
- Prevention
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 56 participants (actual)
Sponsor and investigators
- Lead sponsor
- Universitair Ziekenhuis Brussel
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Bart Neyns, MD Phd, Principal investigator, physician
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02941744
- Sponsor's protocol ID
- 2016-BN-001
- Acronym
- ipniv
- Status last verified
- Jan 2019
- First submitted
- 14 Sep 2016
- Last updated
- 24 Jan 2019
- Results posted
- No
- Data monitoring committee
- No
- Individual data sharing
- Yes: data wil be published in total and anonymous
Study at a glance
From the registry record, last updated by the sponsor on 24 Jan 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase IB Clinical Trial on Adjuvant Low-dose Ipilimumab Plus Nivolumab Following the Resection of Melanoma Macrometastases
- ClinicalTrials.gov ID
- NCT02941744
- Acronym / sponsor ID
- ipniv / 2016-BN-001
- Conditions
- Stage IIIC Skin Melanoma, Stage IV Skin Melanoma
- Keywords
- nivolumab, ipilimumab, low fixed dose, adjuvant therapy, Melanoma
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 56 participants (actual)
- Lead sponsor
- Universitair Ziekenhuis BrusselUniversity, hospital or other
- Study start
- Mar 2016
- Primary completion
- Dec 2018 (actual)
- Study completion
- Jan 2019 (actual)
- First posted
- 21 Oct 2016 (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.
Nivolumab (OpdivoTM, BMS), a human IgG-4 anti-PD-1 monoclonal antibody has demonstrated anti-tumor activity in patients with advanced melanoma.
The investigators postulate that patients with melanoma nivolumab have a comparable tumor response rate at a dose range of 0.1 to 10 mg/kg q2wks.
Ipilimumab (YervoyTM, BMS), a human IgG-1 anti-CTLA-4 monoclonal antibody improves the survival of patients with advanced melanoma. Adjuvant therapy with ipilimumab improves the relapse-free survival after complete resection of high-risk stage III melanoma (EORTC 18071).
Combined treatment with ipilimumab plus nivolumab improves the tumor response rate and overall survival of patients with advanced melanoma but is associated with a higher incidence of immune related adverse events (CheckMate 067).Nivolumab and ipilimumab have distinct immunological mechanisms that can be revealed by analyzing TCR usage in blood lymphocytes.
Detailed description
Currently, there is no standard of care or no available treatment for subjects with AJCC Stage IIIb/c and Stage IV NED melanoma who are at high risk for recurrence following complete resection of their metastasis. Ipilimumab (10mg/kg), interferon, pegylated interferon therapy or observations alone are the typical options for the Stage III patients who achieve a complete resection and are Food and Drug Administration (FDA) approved. In the EU, high-dose interferon is the only approved drug for the adjuvant treatment of melanoma patients. Given the unexceptional benefit and high toxicity profile in a patient population that is free of disease, it is controversial whether ipilimumab and interferon can be considered standard of care for Stage III melanoma. Nivolumab, a PD1 blocking monoclonal antibody, has shown superior anti-tumor activity across a wide range of dose-levels (0,1 to 10 mg/kg every 2 weeks) in patients with advanced melanoma. Nivolumab (at a dose of 3 mg/kg every 3 weeks) demonstrated a survival benefit in treatment naive patients with BRAF Wild Type (WT), metastatic melanoma in a Phase 3, randomized clinical trial and a PFS benefit over ipilimumab as a first-line therapy for advanced melanoma. Combination therapy with ipilimumab and nivolumab results in a higher response rate and PFS as compared to the results obtained with monotherapy. Combination therapy however significantly increases the incidence of grade > 3 adverse events, to the extent that this regimen would probably be associated with unacceptable toxicity in the adjuvant setting. The toxicity seems to be driven by Ipilimumab. The adverse events seen on Ipilimumab are dose dependent.
Unlike PD-1 blockade, CTLA-4 blockade diversifies the peripheral T-cell pool, representing a pharmacodynamic effect that can be measured by a DNA-sequencing technology referred to as ImmunoSeq.
This phase IB study will investigate the effect of low-dose ipilimumab and low-dose nivolumab on the peripheral T-cell repertoire of patients who are free of disease following the resection of melanoma macrometastases.
Treatment with low-dose ipilimumab in combination with low-dose nivolumab will be safe and modify the peripheral T-cell repertoire in subjects with completely resected Stage IIIb/c and Stage IV melanoma who are at high risk for recurrence.
Ipilimumab (YervoyTM, BMS), a human IgG-1 anti-CTLA-4 monoclonal antibody improves the survival of patients with advanced melanoma .Adjuvant therapy with ipilimumab improves the relapse-free survival after complete resection of high-risk stage III melanoma .
Combined treatment with ipilimumab plus nivolumab improves the tumor response rate and overall survival of patients with advanced melanoma but is associated with a higher incidence of immune related adverse events.
Nivolumab and ipilimumab have distinct immunological mechanisms that can be revealed by analyzing TCR usage in blood lymphocytes.
Study design
- Primary purpose
- Prevention
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| IpNiv | Experimental | Drug: nivolumab, Drug: ipilimumablow fixed dose ipilimumab plus low fixed dose nivolumab |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (18 listed)
- All subjects must be either Stage IIIb/c or Stage IV AJCC (7th edition) and have histologically confirmed melanoma that is completely surgically resected in order to be eligible. Subjects must have been surgically rendered free of disease with negative margins on resected specimens. Please refer to Appendix 1 or description of AJCC 7th editions of TNM and staging.
- If Stage III melanoma (whether Stage IIIb or IIIc) the subjects must have clinically detectable lymph nodes that are confirmed as malignant on the pathology report Clinically detectable lymph nodes are defined as:
Key exclusion criteria (19 listed)
- Subjects with leptomeningeal metastases
- History of ocular/uveal melanoma
- Medical History and Concurrent Diseases
- Physical and Laboratory Test Findings
- Allergies and Adverse Drug Reaction
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 |
|---|---|---|
| nivolumabAlso: Opdivolow fixed dose ipilimumab in combination with nivolumab | Drug | IpNiv |
| ipilimumabAlso: Yervoylow fixed dose ipilimumab in combination with nivolumab | Drug | IpNiv |
Primary outcome
Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
Time frame: 2year
to evaluate the safety of the investigational regimen of adjuvant low-dose ipilimumab plus nivolumab
1 secondary outcome
to measure t cell repertoire before and after treatment with low dose ipilimumab and nivolumab with immunoseq.
Time frame: 2years
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 24 Jan 2019.
- Individual participant dataSharing planned: Yes. data wil be published in total and anonymous
Related trials for Stage IIIC Skin Melanoma
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Tacrolimus, Nivolumab, and Ipilimumab in Treating Kidney Transplant Recipients With Selected Unresectable or Metastatic Cancers
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Genetically Modified T-Cells Followed by Aldesleukin in Treating Patients With Stage III-IV Melanoma
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Active, not recruitingPhase 2
Ipilimumab With or Without Sargramostim in Treating Patients With Stage III or Stage IV Melanoma That Cannot Be Removed by Surgery
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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.
Bart Neyns, MD Phd principal investigator
physician
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing nivolumab and ipilimumab in people with Stage IIIC Skin Melanoma and Stage IV Skin Melanoma, run by Universitair Ziekenhuis Brussel at 1 site in Belgium.
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 18 inclusion and 19 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 24 Jan 2019. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Belgium. 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 combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
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?
Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 (time frame: 2year). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
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 24 Jan 2019.