Assessment of Short Immunotherapy After Radical Surgery of High-risk Malignant Melanoma

NCT06488482 | Recruiting Phase 3

• 1 other identifier: 2023-509994-22-00
• Study Type: interventional
• Target: 1,792
• Locations: 3 countries
• Sites: 26

Brief Summary

1. 1.Rational Every year, around 5,000 people in Sweden are diagnosed with malignant skin melanoma. In the early stages of malignant skin melanoma, the chance of cure with surgery is very good. At a later stage, when the melanoma has become thick and/or has spread, the risk of recurrence is greater despite radical surgery. Therefore, in these cases (even in cases of recurrence after radical surgery), additional treatment with immunotherapy is often given, as it has been shown to reduce the risk of recurrence. Immunotherapy is given for one year based on previous research studies, but it has not been investigated whether a shorter treatment period has the same effect. The hypothesis is that six months of treatment is equally effective, which would have several advantages. The main advantage of a shorter treatment period is that the risk of severe side effects is reduced. A shorter treatment period also means fewer hospital visits for patients. In addition, significant drug costs and other healthcare resources could be saved.
2. 2.Aim/objective The aim of the study is to investigate whether 6 months of treatment with immunotherapy, in addition to radical surgery, for malignant skin melanoma at high risk of recurrence, is as effective in preventing recurrence as 12 months of treatment.
3. 3.Primary endpoints The two primary endpoints of the study are relapse-free survival (RFS) and distant metastatic-free survival (DMFS) and they will be analyzed for the first time in the interim analysis conducted after 2/3 of the estimated number of patients have been included in the study.
4. 4.Secondary outcome measures Overall survival will be analyzed for the first time in the interim analysis. Health economic calculations are planned only at the final stage of the study.
5. 5.Study design This is a randomised phase 3 study, with the aim of showing that treatment in the experimental arm (6 months of immunotherapy) is not inferior to the treatment in the standard arm (12 months of immunotherapy). Patients will be followed up to five years. The visits in the study follow clinical routine.
6. 6.Study population Patients aged ≥18 years undergoing radical surgery for stage IIb-c, III or IV cutaneous malignant melanoma, with a WHO general condition score of 0-1 and deemed tolerable to immunotherapy.
7. 7.Study treatment The study treatment consists of immunotherapy according to clinical routine, currently nivolumab or pembrolizumab given intravenously for either 6 months (experimental treatment) or 12 months (standard treatment). For patients receiving neoadjuvant treatment (additional treatment before surgery), the neoadjuvant treatment time is added to the adjuvant treatment time (additional treatment after surgery) to give a total treatment time of 6 or 12 months. Treatment is followed up according to routine, with imaging (CT or PET-CT) at baseline and after 6 months and at an additional time beyond clinical routine, after 36 months, as well as medical examination at baseline, 6, 12, 18, 24 and 36 months. In case of any signs of relapse, additional examinations are performed as needed. If relapse is detected, the patient is discussed at a local multidisciplinary conference to select the best available treatment for each patient. All study patients are followed for survival status for up to five years.
8. 8.Risk-benefit and ethical issues If this study shows that a shorter treatment period is as effective as the current one-year treatment, it would greatly benefit patients by reducing the risk of side effects and reducing the number of hospital visits. It would also save healthcare resources, which could then be used in other areas. The Swedish Melanoma Patient Association (Melanompatientföreningen) has been consulted and is positive about the study, however they expect that patients may be reluctant to participate for fear of receiving inferior treatment.

Conditions

High-risk Melanoma

Outcome Measures

Primary Outcomes (2)

• DMFS

  Distant Metastasis Free Survival

  At 2 years

• RFS

  Relapse Free Survival

  At 2 years

Secondary Outcomes (3)

• DMFS

  Up to 5 years

• RFS

  Up to 5 years

• OS

  Up to 5 years

Study Arms (2)

12 months of immunotherapy

ACTIVE COMPARATOR

Standard immunotherapy (adjuvant +/- neoadjuvant), currently monotherapy with PD-1 inhibitor administered intravenously for 12 months.

Drug: nivolumab or pembrolizumab

6 months of immunotherapy

EXPERIMENTAL

Standard immunotherapy (adjuvant +/- neoadjuvant), currently PD-1 inhibitor administered intravenously for 6 months.

Drug: nivolumab or pembrolizumab

Interventions

nivolumab or pembrolizumab DRUG

See above

Also known as: Opdivo and Keytruda

12 months of immunotherapy; 6 months of immunotherapy

Eligibility Criteria

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

You may qualify if:

• Provision of written informed consent for participation.
• ≥ 18 years of age.
• Performance status ECOG/WHO 0-1.
• Adequate organ functions as per standards for immunotherapy.
• Radical surgery for CMM (including acral) stage IIb-c, III (including in transit) and IV. Stage III CMM patients with unknown primary and stage IIb-c CMM patients who have not undergone sentinel node procedure are eligible.
• A complete physical examination within 28 days prior to randomization
• Previous adjuvant treatment with BRAF + MEK inhibitors is allowed.
• Neoadjuvant treatment with immunotherapy for two months (currently pembrolizumab every third weeks three times or nivolumab every fourth week two times) is allowed providing that a complete or near complete pathological response was not achieved and patients with clear progressive disease according to the pathology report are not eligible.
• All participants who have not received neo-adjuvant treatment must have disease-free status documented by radiological assessment within 28 days prior to randomization while 6 weeks is sufficient for neo-adjuvant treated patients.
• Participants must be off immunosuppressive doses of systemic steroids (\>10 mg/day prednisone or equivalent) for a minimum of 14 days prior to study drug administration.
• Sufficient renal function for radiological assessments with i.v. contrast.
• Peri-operative radiation therapy is allowed.
• Patients who experience a locoregional lymph node relapse, i.e. stage III disease or operable stage IV at a time-point later than primary diagnosis are welcome to participate.

You may not qualify if:

• The patient is, in the opinion of the investigator, assessed as unfit to receive systemic adjuvant treatment.
• Serious and/or uncontrolled medical disorder that in the opinion of the investigator is contraindicated.
• An active, known, or suspected autoimmune disease. Participants with type I diabetes mellitus, hypothyroidism requiring hormone replacement only and skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment are eligible.
• Life-expectancy less than 2 years due to concurrent disease (e.g., cardiac disease and liver cirrhosis).
• Inability to provide informed consent or refusal to do so.
• Inability to comply with the study protocol.
• Participation in other clinical trials interfering with the current study protocol.
• Existing or previous malignancies within the past 5 years (except for in situ breast and in situ cervical cancer, melanoma in situ, malignant melanoma, non-melanoma skin cancer and low risk prostate cancer).
• Pregnancy or planned pregnancy.
• Ocular and mucosal melanoma.

Sponsors & Collaborators

• Karolinska University Hospital: collaborator
• Skane University Hospital: collaborator
• Sahlgrenska University Hospital: collaborator
• Norrlands University Hospital: collaborator
• Region Örebro County: collaborator
• University Hospital, Linkoeping: collaborator
• Karlstad Central Hospital: collaborator
• Västmanland County Council, Sweden: collaborator
• Gävle Hospital: collaborator
• Falu Hospital: collaborator
• Uppsala University: lead

Study Sites (26)

Helsinki University Hospital

Helsinki, Finland

RECRUITING

Kuopio University Hospital

Kuopio, Finland

RECRUITING

Tampere University Hospital

Tampere, Finland

RECRUITING

Turku University Hospital

Turku, Finland

RECRUITING

Ålesund Hospital

Ålesund, Norway

RECRUITING

Haukeland University Hospital

Bergen, Norway

RECRUITING

Sorlandet Hospital

Kristiansand, Norway

RECRUITING

Akershus University Hospital

Oslo, Norway

RECRUITING

Oslo University Hospital

Oslo, Norway

RECRUITING

Stavanger University Hospital

Stavanger, Norway

RECRUITING

North Norway University Hospital

Tromsø, Norway

RECRUITING

Trondheim University Hospital

Trondheim, Norway

RECRUITING

Eskilstuna Hospital

Eskilstuna, Sweden

RECRUITING

Falu Hospital

Falun, Sweden

RECRUITING

Gävle Hospital

Gävle, Sweden

RECRUITING

Sahlgrenska University Hospital

Gothenburg, Sweden

RECRUITING

Ryhov Hospital

Jönköping, Sweden

RECRUITING

Kalmar Hospital

Kalmar, Sweden

RECRUITING

Karlstad Hospital

Karlstad, Sweden

RECRUITING

Linköping University Hospital

Linköping, Sweden

RECRUITING

Skåne University Hospital

Lund, Sweden

RECRUITING

Örebro University Hospital

Örebro, Sweden

RECRUITING

Karolinska University Hospital

Stockholm, Sweden

RECRUITING

Sundsvall Hospital

Sundsvall, Sweden

RECRUITING

Växjö Hospital

Vaxjo, Sweden

RECRUITING

Västmanland Hospital

Västerås, Sweden

RECRUITING

Related Publications (5)

• Ascierto PA, Del Vecchio M, Mandala M, Gogas H, Arance AM, Dalle S, Cowey CL, Schenker M, Grob JJ, Chiarion-Sileni V, Marquez-Rodas I, Butler MO, Maio M, Middleton MR, de la Cruz-Merino L, Arenberger P, Atkinson V, Hill A, Fecher LA, Millward M, Khushalani NI, Queirolo P, Lobo M, de Pril V, Loffredo J, Larkin J, Weber J. Adjuvant nivolumab versus ipilimumab in resected stage IIIB-C and stage IV melanoma (CheckMate 238): 4-year results from a multicentre, double-blind, randomised, controlled, phase 3 trial. Lancet Oncol. 2020 Nov;21(11):1465-1477. doi: 10.1016/S1470-2045(20)30494-0. Epub 2020 Sep 19.

  PMID: 32961119 RESULT

• Eggermont AMM, Blank CU, Mandala M, Long GV, Atkinson V, Dalle S, Haydon A, Lichinitser M, Khattak A, Carlino MS, Sandhu S, Larkin J, Puig S, Ascierto PA, Rutkowski P, Schadendorf D, Koornstra R, Hernandez-Aya L, Maio M, van den Eertwegh AJM, Grob JJ, Gutzmer R, Jamal R, Lorigan P, Ibrahim N, Marreaud S, van Akkooi ACJ, Suciu S, Robert C. Adjuvant Pembrolizumab versus Placebo in Resected Stage III Melanoma. N Engl J Med. 2018 May 10;378(19):1789-1801. doi: 10.1056/NEJMoa1802357. Epub 2018 Apr 15.

  PMID: 29658430 RESULT

• Luke JJ, Rutkowski P, Queirolo P, Del Vecchio M, Mackiewicz J, Chiarion-Sileni V, de la Cruz Merino L, Khattak MA, Schadendorf D, Long GV, Ascierto PA, Mandala M, De Galitiis F, Haydon A, Dummer R, Grob JJ, Robert C, Carlino MS, Mohr P, Poklepovic A, Sondak VK, Scolyer RA, Kirkwood JM, Chen K, Diede SJ, Ahsan S, Ibrahim N, Eggermont AMM; KEYNOTE-716 Investigators. Pembrolizumab versus placebo as adjuvant therapy in completely resected stage IIB or IIC melanoma (KEYNOTE-716): a randomised, double-blind, phase 3 trial. Lancet. 2022 Apr 30;399(10336):1718-1729. doi: 10.1016/S0140-6736(22)00562-1. Epub 2022 Apr 1.

  PMID: 35367007 RESULT

• Patel SP, Othus M, Chen Y, Wright GP Jr, Yost KJ, Hyngstrom JR, Hu-Lieskovan S, Lao CD, Fecher LA, Truong TG, Eisenstein JL, Chandra S, Sosman JA, Kendra KL, Wu RC, Devoe CE, Deutsch GB, Hegde A, Khalil M, Mangla A, Reese AM, Ross MI, Poklepovic AS, Phan GQ, Onitilo AA, Yasar DG, Powers BC, Doolittle GC, In GK, Kokot N, Gibney GT, Atkins MB, Shaheen M, Warneke JA, Ikeguchi A, Najera JE, Chmielowski B, Crompton JG, Floyd JD, Hsueh E, Margolin KA, Chow WA, Grossmann KF, Dietrich E, Prieto VG, Lowe MC, Buchbinder EI, Kirkwood JM, Korde L, Moon J, Sharon E, Sondak VK, Ribas A. Neoadjuvant-Adjuvant or Adjuvant-Only Pembrolizumab in Advanced Melanoma. N Engl J Med. 2023 Mar 2;388(9):813-823. doi: 10.1056/NEJMoa2211437.

  PMID: 36856617 RESULT

• Togo K, Iwasaki M. Optimal timing for interim analyses in clinical trials. J Biopharm Stat. 2013;23(5):1067-80. doi: 10.1080/10543406.2013.813522.

  PMID: 23957516 RESULT

MeSH Terms

Interventions

Nivolumab; pembrolizumab

Intervention Hierarchy (Ancestors)

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

Study Officials

• Gustav J Ullenhag, professor

  Uppsala University Hospital

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Gustav J Ullenhag, professor

CONTACT

+46-18-6110000; Gustav.Ullenhag@IGP.uu.se

Leila Boukharta, MSc

CONTACT

+46-18-6110000; Leila.Boukharta@Akademiska.se

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 1:1 randomization

Study Record Dates

• First Submitted: June 10, 2024
• First Posted: July 5, 2024
• Study Start: December 19, 2024
• Primary Completion (Estimated): September 1, 2030
• Study Completion (Estimated): September 1, 2033
• Last Updated: March 9, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will not share

Locations

NO (8); SE (14); FI (4)