Ipilimumab and Nivolumab Followed by Adjuvant Nivolumab in Locally Advanced or Limited Metastatic Melanoma

August 21, 2024 updated by: European Institute of Oncology

Primary Ipilimumab and Nivolumab Combo-immunotherapy Followed by Adjuvant Nivolumab in Locally Advanced or Limited Metastatic Melanoma

This is open label, single arm study for pts with stage IIIB-IV melanoma, accordingly with AJCC staging criteria (8th ed.), with potentially resectable disease. Patients will receive every three weeks, four cycles of Nivolumab 3 mg/kg (over one 30 minutes infusion) and Ipilimumab 1 mg/kg (over 30 minutes infusion) with a 30 minute break between each infusion. Surgery will be performed after 4-6 weeks from the last dose. After 4-6 weeks from surgery, patients will receive Nivolumab 480 mg (over one 60 minutes infusion), every four weeks for six cycles.

The duration of the trial is expected to be 12 months of accrual and approximately 24 months of follow-up after the end of adjuvant therapy.

Study Overview

Status

Active, not recruiting

Conditions

Intervention / Treatment

Detailed Description

The study begins by establishing the patient's initial eligibility and signing of the ICF. Blood samples and tumor tissue obtained from core biopsy must be provided for biomarker analyses.

All patients will receive every three weeks cycles of combined Nivolumab 3 mg/kg and Ipilimumab 1 mg/kg (sequential) for a total of four doses. Nivolumab and Ipilimumab will be administered sequentially, as two separate infusions, one 30 minute Nivolumab infusion and one 30 minute Ipilimumab infusion with a 30 minute break between each infusion.

Surgery will be performed on Week 12-16 on known disease sites and in absence of G2-3-4 AE.

The Adjuvant treatment will be performed on Week 16-22 from surgery; it will consist in Nivolumab 480 mg (over one 60 minutes infusion), every four weeks for six cycles.

The Follow-up period will start 4 weeks after the end of adjuvant therapy. Patients will be followed for 24 months.

Study Type

Interventional

Enrollment (Actual)

35

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Italy
      • Milano, Italy, 20141
        • Istituto Europeo di Oncologia

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  1. Patients must have histologically or cytologically confirmed 8th ed. AJCC Stage IIIB/C/D or Stage IV oligometastatic resectable melanoma. Patients with cutaneous, mucosal, acral, ocular or unknown primary melanomas are eligible for enrollment. Oligometastatic melanoma is defined as three or fewer areas of resectable disease excluding central nervous system and bone involvement. In case of involvement of three areas, one must be superficial (cutaneous-subcutaneous). Resectable tumors are defined as having no significant vascular, neural or bony involvement. A multidisciplinary discussion within surgical oncologists, medical oncologists, and radiologist will assess if disease is resectable.
  2. Signed Written Informed Consent.
  3. Patients must be willing and able to comply with scheduled visits, treatment schedule, laboratory tests and all protocol procedures.
  4. Males and Females, ages ≥18 years of age.
  5. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
  6. Have measurable disease based on RECIST 1.1.
  7. Be willing to provide tissue from a newly obtained core or excisional biopsy of a tumor lesion at baseline and at the time points specified in the Study Procedure Tables.
  8. Known BRAF V600 mutation status as determined by local institutional standard. All BRAF statuses (BRAF wild type or BRAF 600 mutation positive) are eligible.
  9. Patients who have been previously treated in the adjuvant setting for melanoma will be eligible for treatment after a 28 day washout period.
  10. Patients must be medically fit enough to undergo surgery as determined by the treating medical and surgical oncology team.
  11. Demonstrate adequate organ function as defined below: Hematologic Absolute neutrophil count (ANC) >/= 1.5 X 10^9/L; Hemoglobin >/= 9.5 g/dL Platelets >/= 100 X 10^9/L PT/INR and PTT </= 1.5 X ULN. Hepatic Total bilirubin </= 1.5 X ULN (isolated bilirubin >1.5 X ULN is acceptable if bilirubin is fractionated and direct bilirubin <35%) AST and ALT Albumin </= 2.5 X ULN 1 >/=2.5 g/dL Renal Creatinine OR Calculated creatinine clearance OR 24-hour urine creatinine clearance </=1.5 X ULN 2 >/= 50 mL/min >/= 50 mL/min.
  12. Women are eligible to participate if: non-childbearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or postmenopausal defined as months of spontaneous amenorrhea [in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) > 40 MlU/mL and estradiol < 40 pg/mL (<140 pmol/L) is confirmatory]. Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the contraception methods if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrollment. For most forms of HRT, at least 2-4 weeks will elapse between the cessation of therapy and the blood draw; this interval depends on the type and dosage of HRT.
  13. The individual methods of contraception and duration should be determined in consultation with the investigator. Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of investigational product.
  14. Women must not be breastfeeding.
  15. Men who are sexually active must use any contraceptive method with a failure rate of less than 1% per year. The investigator shall review contraception methods and the time period that contraception must be followed.
  16. Women who are not of childbearing potential (i.e., who are postmenopausal or surgically sterile) and azoospermic men do not require contraception

Exclusion Criteria:

  1. Currently receiving cancer therapy (chemotherapy, radiation therapy, immunotherapy, or biologic therapy) or investigational anti-cancer drug.
  2. Any major surgery within the last 3 weeks.
  3. Brain metastases, leptomeningeal disease or bone metastases.
  4. Pregnant or lactating female.
  5. Unwillingness or inability to follow the procedures required in the protocol.
  6. Any serious or uncontrolled medical disorder that, in the opinion of the investigator, may increase the risk associated with study participation or study drug administration, impair the ability of the subject to receive protocol therapy, or interfere with the interpretation of study results.
  7. Prior malignancy active within the previous 2 years except for patient's prior diagnosis of melanoma and locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast with local control measures (surgery, radiation).
  8. Patients with active, known or suspected autoimmune disease. Patients 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.
  9. Patients with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
  10. Prior treatment with an anti-PD-1, anti-PD-L1 or anti-CTLA-4 antibody.
  11. Any positive test result for hepatitis B or C virus indicating acute or chronic infection.
  12. Known history of testing positive for human immunodeficiency virus or known acquired immunodeficiency syndrome.
  13. History of severe hypersensitivity reaction to any monoclonal antibody.
  14. Prisoners or patients who are involuntarily incarcerated.
  15. Patients who are compulsorily detained for treatment of either a psychiatric or physical (infection disease) illness.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Ipilimumab + Nivolumab followed by Nivolumab
Neoadjuvant therapy: Ipilimumab 1 mg/kg + Nivolumab 3mg/kg every 3 weeks for 4 cycles; Adjuvant therapy: Nivolumab 480 mg every 4 weeks for 6 cycles
Drug: Ipilimumab
Nivolumab and Ipilimumab (sequential) for a total of four doses followed by Nivolumab
Other Names:
  • Nivolumab

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Percentage of pathological complete response (Efficacy)
Time Frame: 12-16 weeks after Neoadjuvant therapy
Efficacy assessment is pathological complete remission rate, documented after neoadjuvant therapy.
12-16 weeks after Neoadjuvant therapy

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Rates of 3-4 AEs
Time Frame: 24 months
Rates of grade 3-4 AE rates (immune related or not) of neoadjuvant and adjuvant regimen
24 months
Overall AE rates
Time Frame: up to 24 months after the end of adjuvant therapy
Overall AE rates (immune related or not)
up to 24 months after the end of adjuvant therapy
Patients completing treatment schedule.
Time Frame: up to 24 months after the end of adjuvant therapy
Rates of pts completing treatment schedule.
up to 24 months after the end of adjuvant therapy
Overall Response Rate (ORR)
Time Frame: 12-14 weeks
Overall Response Rate (ORR), according to RECIST 1.1 criteria.
12-14 weeks
Overall Survival (OS)
Time Frame: 12-14 weeks
Overall Survival (OS), according to RECIST 1.1 criteria
12-14 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

European Institute of Oncology

Collaborators

Bristol-Myers Squibb

Investigators

  • Principal Investigator: Luigi Nezi, PhD, Istituto Europeo di Oncologia

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

March 5, 2019

Primary Completion (Estimated)

December 31, 2024

Study Completion (Estimated)

December 31, 2024

Study Registration Dates

First Submitted

August 20, 2024

First Submitted That Met QC Criteria

August 21, 2024

First Posted (Actual)

August 22, 2024

Study Record Updates

Last Update Posted (Actual)

August 22, 2024

Last Update Submitted That Met QC Criteria

August 21, 2024

Last Verified

February 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • IEO 838

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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