Neoadjuvant Pembrolizumab in Patients With High Risk, Stage IIB/IIC Cutaneous Melanoma: a Single Arm Proof of Concept Phase IIA Study.

• Pembrolizumab neoadjuvant treatment (Drug): W1/D1: Pembrolizumab 200 mg W4/D21: Pembrolizumab 400 mg
• surgery (Procedure): between W5 and W8
• Adjuvant treatment (Drug): Pembrolizumab 400 mg every 6 weeks x 7 for a maximum of 1 year (since the initiation of neoadjuvant Pembro) within 3 months following surgery.

Primary outcomes

• Major Pathological Response (MPR) according to central review [up to Week 8]: Major Pathological Response (MPR) on the primary tumour surgical specimen in accordance with International Neoadjuvant Melanoma Consortium criteria \[(Tetzlaff et al. 2018; Amaria et al. 2019) including complete response (absence of viable tumour cells) and near-complete response (<10% tumoral viable cells)\]

Secondary outcomes

• toxicities [4 years]: incidence and grade for Adverse events (AEs), drug related AEs, drug related AE leading to discontinuation during neoadjuvant treatment, surgery related AEs, surgery related AE leading to delayed or cancellation of adjuvant treatment, SAE and SUSAR, according to NCI-CTCAE V5.0 until the end of treatment visit.
• Major Pathological Response (MPR) according to investigator assessment [at surgery]: Major Pathological Response (MPR) on the primary tumor surgical specimen in accordance with International Neoadjuvant Melanoma Consortium criteria \[(Tetzlaff et al. 2018) including complete response (absence of viable tumor cells) and near-complete response (<10% tumoral viable cells)\]
• Rate of micrometastatic sentinel lymph node (SLN) involvement [at surgery]: Proportion of patients undergoing a sentinel lymph node (SLN) biopsy who have a positive result in the SLN, the number of SLN identified and the number harvested, the proportion of patients with positive SLN who undergo complete lymph node dissection.
• Study feasibility [4 years]: The number of patients who complete in totality the neoadjuvant treatment, who undergo surgery and who start the adjuvant therapy divided by the number of patients who initiated the neoadjuvant treatment, The rate of patient included divided by the number of patients screened.
• Overall response rate (ORR) preoperatively [from enrollment to surgery]: Clinical response will be systematically assessed using clinical examination with standardized photographs of the primary tumor as the primary tumor will not be measured by CT scan. Complete response is defined as the disappearance of the lesion. Partial response is defined as the decrease in size of the lesion. Progression is defined as an increase in size of the lesion (>25% with at least 2 mm increase in size for lesion below 1cm).
• Event-free survival (EFS) [up to 4 years]: Event-free survival (EFS) defined as the time from neoadjuvant treatment initiation to the first of the following events: death of all causes, melanoma progression prior planned surgery leading to stage 3 or 4 disease or leading to unresectable disease, toxicity during the neoadjuvant treatment that preclude the surgery, local or distant recurrence after surgery, whichever occurred first Patients with no defined events observed during the follow-up will be censored at the date of last disease evaluation, which showed no evidence of relapse.
• Relapse-free survival (RFS) [up to 4 years]: Relapse-free survival (RFS) after surgery defined as the time from surgery to relapse or death, whichever occurred first. Secondary melanoma cancers will not be regarded as RFS events, nonmelanoma cancers will be disregarded in the analysis. Data for patients lost to follow-up will be censored.
• Distant metastasis-free survival (DMFS) [up to 4 years]: Distant metastasis-free survival (DMFS) as the time from surgery to relapse with distant metastasis or death, whichever occurred first. Data for patients lost to follow-up will be censored.
• Overall survival (OS) [up to 4 years]: Overall Survival (OS): defined as the time from the neoadjuvant treatment initiation to death from any cause. Alive patient will be censored at last date known to be alive either during study treatment period or during follow-up period
• Correlation between pathological response (pR) and ORR [up to 4 years]: pR : Major Pathological Response (MPR) on the primary tumor surgical specimen in accordance with International Neoadjuvant Melanoma Consortium criteria \[(Tetzlaff et al. 2018) including complete response (absence of viable tumor cells) and near-complete response (<10% tumoral viable cells)\] ORR: Clinical response will be systematically assessed using clinical examination with standardized photographs of the primary tumor as the primary tumor will not be measured by CT scan. Complete response is defined as the disappearance of the lesion. Partial response is defined as the decrease in size of the lesion. Progression is defined as an increase in size of the lesion (>25% with at least 2 mm increase in size for lesion below 1cm).
• Correlation between pathological response and SLN positively [up to 4 years]: pR : Major Pathological Response (MPR) on the primary tumor surgical specimen in accordance with International Neoadjuvant Melanoma Consortium criteria \[(Tetzlaff et al. 2018) including complete response (absence of viable tumor cells) and near-complete response (<10% tumoral viable cells)\] Proportion of patients undergoing a sentinel lymph node (SLN) biopsy who have a positive result in the SLN
• Correlation between pathological response and EFS [up to 4 years]: pR : Major Pathological Response (MPR) on the primary tumor surgical specimen in accordance with International Neoadjuvant Melanoma Consortium criteria \[(Tetzlaff et al. 2018) including complete response (absence of viable tumor cells) and near-complete response (<10% tumoral viable cells)\] Event-free survival (EFS) defined as the time from neoadjuvant treatment initiation to the first of the following events: death of all causes, melanoma progression prior planned surgery leading to stage 3 or 4 disease or leading to unresectable disease, toxicity during the neoadjuvant treatment that preclude the surgery, local or distant recurrence after surgery, whichever occurred first Patients with no defined events observed during the follow-up will be censored at the date of last disease evaluation, which showed no evidence of relapse.
• Correlation between pathological response and RFS [up to 4 years]: pR : Major Pathological Response (MPR) on the primary tumor surgical specimen in accordance with International Neoadjuvant Melanoma Consortium criteria \[(Tetzlaff et al. 2018) including complete response (absence of viable tumor cells) and near-complete response (<10% tumoral viable cells)\] Relapse-free survival (RFS) after surgery defined as the time from surgery to relapse or death, whichever occurred first. Secondary melanoma cancers will not be regarded as RFS events, nonmelanoma cancers will be disregarded in the analysis. Data for patients lost to follow-up will be censored
• Correlation between pathological response and DMFS [up to 4 years]: pR : Major Pathological Response (MPR) on the primary tumor surgical specimen in accordance with International Neoadjuvant Melanoma Consortium criteria \[(Tetzlaff et al. 2018) including complete response (absence of viable tumor cells) and near-complete response (<10% tumoral viable cells)\] Distant metastasis-free survival (DMFS) as the time from surgery to relapse with distant metastasis or death, whichever occurred first. Data for patients lost to follow-up will be censored.
• Correlation between pathological response and OS [up to 4 years]: pR : Major Pathological Response (MPR) on the primary tumor surgical specimen in accordance with International Neoadjuvant Melanoma Consortium criteria \[(Tetzlaff et al. 2018) including complete response (absence of viable tumor cells) and near-complete response (<10% tumoral viable cells)\] Overall Survival (OS): defined as the time from the neoadjuvant treatment initiation to death from any cause. Alive patient will be censored at last date known to be alive either during study treatment period or during follow-up period
• Health-related quality of life [at baseline, week 6 and at the end of treatment]: Health-related quality of life measures by EORTC-QLQ C30 questionnaire

Sex: All, ages: 18 Years to any

Inclusion Criteria:

1. Age ≥ 18 years
2. Primary cutaneous melanoma. Primary acral melanoma are allowed up to 10% of the population (thus, a maximum of 2 patients will be included)
3. AJCC 8 melanoma stage IIB or IIC

   a. either T3b (Breslow >2mm and ulcerated) b. or T4a (>4mm non-ulcerated) or T4b (Breslow >4mm and ulcerated)
4. Diagnosis confirmed histologically on partial biopsy of lesion (thickest part of the primary tumor)
5. Operable primary tumor
6. Residual macroscopic primary tumor > 2mm, identifiable by photography or imaging
7. Performans status ECOG <2
8. Females must be using highly effective contraceptive measures, and have a negative pregnancy test prior to the start of dosing if of childbearing potential, or must have evidence of non-childbearing potential by fulfilling one of the following criteria at screening:

   \- a woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile.
   * Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. Of note: Women with documentation of irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation.
   * A postmenopausal state is defined as no menses for 12 months without an alternative medical cause, particularly if aged more than 50 years and amenorrhoeic for at least 12 months following cessation of all exogenous hormonal treatments.

   A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy.

   However in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient.

   \- Women under the age of 50 years would be considered postmenopausal if they have been amenorrhoeic for 12 months or more following cessation of exogenous hormonal treatments and with luteinizing hormone and follicle stimulating hormone levels in the post-menopausal range for the institution.

   Male patients with a female partner of childbearing potential should be willing to use barrier contraception during the study and for 6 months following discontinuation of study drug. Patients should refrain from donating sperm from the start of dosing until 6 months after discontinuing study treatment.
9. Patient affiliated to or beneficiary of French social security system
10. Ability to comply with the study protocol, in the Investigator's judgment.
11. Signed and date informed consent

Exclusion Criteria:

1. Non-cutaneous melanoma
2. Completely operated primary melanoma with no macroscopic residual tumor
3. Primary tumor which may become unresectable by the time of the surgery according to physician's opinion
4. Clinical or radiographic evidence of nodal, in-transit, satellite or microsatellite metastases or distant melanoma metastases.
5. Uncontrolled infection with HIV, HBC, or HCV infection; or diagnosis of immunodeficiency that is related to, or results in chronic infection.

   Notes :
   1. Patients with known HIV who have controlled infection (undetectable viral load and CD4 count above 350 either spontaneously or on a stable antiviral regimen) are permitted. For patients with controlled HIV infection, monitoring will be performed per local standard.
   2. Patients with known hepatitis B (HepBsAg+) who have controlled infection (serum hepatitis B virus DNA PCR that is below the limit of detection AND receiving antiviral therapy for hepatitis B) are permitted. Patients with controlled infections must undergo periodic monitoring of HBV DNA per local standards and must remain on anti-viral therapy for at least 6 months beyond the last dose of investigational study drug.
   3. Patients who are known HCV Ab+ who have controlled infection (undetectable HCV RNA by PCR either spontaneously or in response to a successful prior course of anti- HCV therapy) are permitted.
6. Women of childbearing potential (WOCP) who are unwilling to practice highly effective contraception prior to the initial dose/start of the first treatment, during the study, and for at least 6 months after the last dose.

   Highly effective contraceptive measures include:
   1. stable use of combined (estrogen and progestogen containing) hormonal contraception (oral, intravaginal, transdermal) or progestogen-only hormonal contraception (oral, injectable, implantable) associated with inhibition of ovulation initiated 2 or more menstrual cycles prior to screening;
   2. intrauterine device (IUD); intrauterine hormone-releasing system (IUS);
   3. bilateral tubal ligation (occlusion);
   4. vasectomized partner (provided that the male vasectomized partner is the sole sexual partner of the WOCBP study participant and that the vasectomized partner has obtained medical assessment of surgical success for the procedure); and/or
   5. sexual abstinence†, ‡.

      * Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study drugs. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the subject.

        * Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and lactational amenorrhea method (LAM) are not acceptable methods of contraception. Female condom and male condom shouldnot be used together.
7. Participants with a history of myocarditis
8. Troponin T (TnT) or troponin I (TnI) > 2x institutional ULN at baseline. Patients with TnT or TnI levels between > 1 to 2x ULN are permitted if repeat levels within 24 hours are ≤ 1x ULN. If TnT or TnI levels are > 1 to 2x ULN within 24 hours, the subject may undergo a cardiac evaluation and be considered for treatment by the investigator based on medical judgement in the patient's best interest.
9. History or current evidence of significant (CTCAE Grade ≥2) local or systemic infection (eg, cellulitis, pneumonia, septicemia) requiring systemic antibiotic treatment within 2 weeks prior to the first dose of pembrolizumab.
10. Cardiovascular disease, as defined below:

    a. New York Heart Association (NYHA) heart failure classifications of Class II, III, or IV; or b. Myocardial infarction (MI) or acute coronary syndrome (ACS) within 6 months; or c. Transient ischemic attack (TIA) or stroke within 1 year.
11. Received a live vaccine within 30 days of planned start of study medication. Note: Live or live attenuated vaccination with replicating potential. If a patient intends to receive a COVID-19 vaccine before the start of study drug, participation in the study shoul be delayed at least 1 week after any COVID-19 vaccination. During the treatment period, it is recommended to delay COVID-19 vaccination until patients are receiving and tolerating the study drug. A booster vaccine dose should not be less than 48 hours before or after study drug dosing.
12. Major surgical procedure (ie, requiring general anesthesia), or significant traumatic injury within 4 weeks prior to screening.

    Exception: Melanoma-related minor surgery/biopsy are allowed, provided that there is satisfactory wound healing before receiving study treatment.
13. A history of allergy or hypersensitivity to study treatment components.
14. Prior immunotherapy (anti-PD-(L)1, or other systemic treatment for primary melanoma IIB/IIC) 15. Immunosuppressive therapy (corticosteroids > 10 mg prednisone or prednisolone) within 14 days prior to start of study treatment or any other form of immunosuppressive therapy within 14 days prior to the first dose of study treatment. The following are permitted:

    1. Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc)
    2. Inhaled or intranasal corticosteroids (with minimal systemic absorption) may be continued if patient is on a stable dose
    3. Non-absorbed intra-articular steroid injections.

16\. active autoimmune disease with treatment within the last year

a. Has active autoimmune disease that has required systemic treatment in the past 12 months (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). The following are permitted: b. Vitiligo c. Type I diabetes mellitus d. Residual autoimmune hypothyroidism on stable hormone replacement e. Resolved childhood asthma or atopy f. Psoriasis not requiring systemic treatment g. Autoimmune conditions which are not expected to recur in the absence of an external trigger.

17\. Patients eligible for solid organ transplantation. Indeed, according to the Summary of Product Characteristics (SmPC) established within the framework of the Marketing Authorisation (MA) for Pembrolizumab, the drug may cause solid organ graft rejection among its adverse effects. Therefore, this population should be excluded in order to ensure the safety of patients who may be enrolled in the clinical study.

18\. Has a known additional malignancy that is progressing or has required active treatment within the past 3 years. The following malignancies, if undergone successful definitive resection or curative treatment, are permitted:

1. Basal cell carcinoma of the skin
2. Squamous cell carcinoma of the skin
3. Carcinoma in situ (e.g., breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy)
4. Prostatic intraepithelial neoplasia
5. Atypical melanocytic hyperplasia
6. Other malignancies for which the patient has been disease free for 1 year 19. Presence of a severe concurrent illness or other condition (eg, psychological, family, sociological, or geographical circumstances) that does not permit adequate follow-up and compliance with the protocol.

   20\. Patient with any medical or psychiatric condition or disease, which would make the patient inappropriate for entry into this study 21. Other usual contraindications 22. Current participation in a study of an investigational agent or in the period of exclusion 23. Pregnant or breast-feeding subjects, 24. Patient under guardianship, curatorship or under the protection of justice

• Charlée NARDIN, Dr, Principal investigator, Centre Hospitalier Universitaire de Besancon