Cutaneous Melanoma, Stage III, Mucosal Melanoma
Conditions
Keywords
Neo-adjuvant Immunotherapy, Localized Cancers, Intra-tumoral treatment, Melanoma, Immune-checkpoint blockade
Brief summary
The success of anti-PD-1 and anti-CTLA-4 therapies has initiated a paradigm shift in oncology, with drugs now targeting the immune system rather than cancer cells to stimulate the antitumor immune response. Intratumoral (IT) delivery of immunostimulating agents reduces the systemic toxicity associated with monoclonal antibodies (mAbs) targeting immune checkpoints. Notably, IT injections of immune checkpoint blockade (ICB) have been shown to induce immune-mediated tumor responses both at the injected site and at distant, non-injected tumor sites. While surgery has traditionally been the preferred treatment for stage III and IV melanoma patients, neoadjuvant therapy with anti-CTLA-4 and anti-PD-1 agents has shown promising efficacy. In patients with localized melanoma, it is hypothesized that IT administration of ipilimumab (anti-CTLA-4 Ab) combined with nivolumab (anti-PD-1 Ab) will provide the most effective and safe treatment combination. The NEO-1 study is a proof-of-concept clinical trial designed as a sub-protocol of NEOREM master protocol (NCT07262489) to validate the intratumoral immunotherapy approach, aiming to maximize the dose/efficacy ratio of combined ipilimumab and nivolumab treatment while minimizing systemic adverse events. This is an academic, open-label, multicentric, phase II clinical trial evaluating the efficacy and safety of intratumoral injections of ipilimumab and nivolumab combination as neoadjuvant treatment in localized stage III resectable cutaneous or mucosal melanoma patients. Baseline and on-treatment PORTRAIT profiling, as described in the NEOREM Master Protocol (NCT07262489), will be performed using fresh blood and tumor samples. This profiling will reveal the immune status of patients and support biomarker-driven preselection for future trials.
Detailed description
The combination of ipilimumab + nivolumab injected intravenously before resection of resectable stage III melanoma is more effective than adjuvant immunotherapy as recently demonstrated in a large phase III randomized controlled trial. However, the dual systemic immunotherapy gives rise to severe AEs (30% of patients had \> grade 3 related AEs versus 14% in the adjuvant arm). NEO-1, a prospective, multicenter, phase II sub-protocol of the NEOREM master protocol (NCT07262489) focuses on evaluating the efficacy and safety of intratumoral neo-adjuvant treatment with ipilimumab and nivolumab in patients with resectable stage III melanoma. NEO-1 is a proof-of-concept study designed to validate human intratumoral immunotherapy (HIT-IT) approach, which could maximize its dose/efficacy ratio of combined ipilimumab and nivolumab treatment while preventing systemic AEs. Image guided drug administration directly into tumor will increase the drug concentration at the tumor site leading to targeted drug action. While evaluating the efficacy of intratumoral administration of ipilimumab in combination with nivolumab in melanoma patients, the NEO-1 study employs PORTRAIT profiling to analyze fresh blood and tumor samples collected at baseline and throughout treatment. This approach will reveal the features of the tumor microenvironment both before and after surgery, facilitating the identification of biomarkers that predict the efficacy of the proposed immunotherapy. The NEOREM master protocol (NCT07262489) allows the rapid analyses of the fresh samples collected, which enables an actual characterization of the immune landscape in patients prior to and during treatment.
Interventions
The 25 mg flat dose of the Ipilimumab will be administered by intra-tumoral injection. Injections will be performed under image guidance (the most adequate according to investigators preference). Ultrasound guidance will be privileged, as it is not using radiation. A maximum of 3 intratumoral procedures may occur with 3 weeks intervals prior to surgery.
The 30 mg flat dose of the Nivolumab will be administered by intra-tumoral injection. Injections will be performed under image guidance (the most adequate according to investigators preference). Ultrasound guidance will be privileged, as it is not using radiation. A maximum of 3 intratumoral procedures may occur with 3 weeks intervals prior to surgery.
Sponsors
UNICANCER
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
NEO-1 is an academic, non-comparative, non-randomized, multicenter Phase II clinical trial evaluating the effectiveness and safety of intratumoral injections of ipilimumab combined with nivolumab as a neoadjuvant treatment for patients with operable, localized stage III cutaneous or mucosal melanoma. Eligible patients in the NEOREM master protocol and its therapeutic sub-protocol i.e. NEO-1 trial will receive three injections of the ipilimumab and nivolumab combination, one injection every three weeks over six weeks prior to surgery. Surgery will take place between 6 and 8 weeks after the last intratumoral injection. If deemed necessary by the doctor, some patients may receive standard adjuvant treatment after surgery. Patient participation in the trial will not exceed 65 months from their selection into NEOREM and inclusion in NEO-1 including the treatment, surgery and post-surgery follow-up.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
In addition to NEOREM Master Protocol inclusion and
Exclusion criteria
, the following inclusion and
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The primary objective is to evaluate the efficacy of the intratumoral combination of ipilimumab and nivolumab in terms of pCR or MPR in patients with resectable stage III cutaneous or mucosal melanoma. | Between 6 and 8 weeks upon end of the treatment | The primary efficacy endpoint is defined as a pathological complete response (pCR) rate defined as the percentage of patients with pCR defined as the complete absence of viable tumor cells, or the major pathologic response (MPR) defined as less than 10% of surviving tumor cells in tumor biopsy of the surgical specimen. |
| The primary objective is to evaluate the tolerability of the intratumoral combination of ipilimumab and nivolumab in patients with resectable stage III cutaneous or mucosal melanoma. | Between 6 and 8 weeks upon end of the treatment | The primary safety endpoint defined as the percentage of patients whose surgery was delayed by more than 2 weeks beyond the planned timeline, due to treatment-related adverse events. |
Countries
France
Contacts
CONTACTPriyanka DEVI-MARULKAR, PhD, MBA
Outcome results
None listed