Neoadjuvant Pembrolizumab in High-Risk Stage IIB/IIC Cutaneous Melanoma: A Phase IIA Single-Arm Study Assessing Major Pathological Response

Trial ID: 2024-519573-19-00
Protocol: 2024/880
Sponsor: Centre Hospitalier Regional Universitaire

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Diseases & Conditions

Malignant melanoma

Objectives

The primary objective of the NEOSTART Study is to evaluate the **Major Pathological Response (MPR)** rate in the primary tumor surgical specimen following neoadjuvant treatment with **pembrolizumab** in patients with resectable Stage IIB/IIC cutaneous melanoma. This assessment is conducted through a centralized review. The clinical relevance of this objective lies in determining the efficacy of pembrolizumab as a neoadjuvant therapy, which could potentially improve surgical outcomes and long-term prognosis for patients with high-risk melanoma.

Participants

The clinical trial involves participants diagnosed with **melanoma**, specifically targeting individuals with resectable IIB/IIC melanoma. The study population includes both male and female subjects aged 18 years and older. Participants are required to have a confirmed diagnosis of primary cutaneous melanoma, with a subset allowed to have primary acral melanoma, limited to 10% of the total population. The trial does not include a vulnerable population. Participants must have an operable primary tumor and a residual macroscopic primary tumor greater than 2mm. The trial population was selected based on their ability to comply with the study protocol, as judged by the investigator, and all participants must have signed an informed consent. Females of childbearing potential are required to use highly effective contraceptive measures and have a negative pregnancy test prior to the start of dosing. Male participants with a female partner of childbearing potential should use barrier contraception during the study and for six months following the discontinuation of the study drug. The sponsor has not provided information regarding the total number of participants in the trial.

Plans and Procedures

The clinical trial is designed to evaluate the **major pathological response** (MPR) rate induced by neoadjuvant treatment with **pembrolizumab** in patients with resectable stage IIB/IIC **melanoma**. This is a single-arm, proof-of-concept, Phase IIA study. The trial will involve the administration of pembrolizumab as a **solution for infusion**. The study is expected to commence recruitment on July 15, 2025, and conclude by July 15, 2029. Participants will be involved in the study for a maximum treatment period of 12 months.

The trial will include several study visits, beginning with a screening visit to confirm eligibility based on criteria such as age, diagnosis, and operability of the primary tumor. Participants must have a histologically confirmed diagnosis of melanoma and meet specific criteria regarding tumor characteristics and performance status. Females of childbearing potential must use effective contraceptive measures, and males with partners of childbearing potential must agree to use barrier contraception.

Following the screening, participants will undergo regular follow-up visits to monitor the response to treatment and assess any adverse events. The primary endpoint is the MPR on the primary tumor surgical specimen, evaluated according to the International Neoadjuvant Melanoma Consortium criteria. Secondary endpoints include the incidence and grade of adverse events, clinical response, and various survival metrics such as event-free survival and overall survival.

The end-of-study visit will occur after the completion of the treatment period or upon early termination. Conditions that may lead to early termination include significant adverse events, disease progression to an unresectable stage, or withdrawal of consent. Participants will be monitored for adverse events and treatment efficacy throughout the study, with data collected to assess both primary and secondary endpoints.

Treatment

The clinical trial involves the administration of **pembrolizumab**, marketed under the name KEYTRUDA, which is a **concentrate for solution for infusion**. This experimental medication is provided in a concentration of 25 mg/mL and is intended for use as a neoadjuvant treatment in patients with high-risk, stage IIB/IIC cutaneous melanoma. The pharmaceutical form is a solution for infusion, and the medication is administered via the infusion route. The maximum daily dose is 400 mg, with a total maximum dose of 3400 mg over the treatment period. The treatment is scheduled to last for a maximum of 12 weeks. Pembrolizumab is a protein-based therapeutic agent, specifically classified under the ATC code L01FF02, and is produced by Merck Sharp & Dohme B.V.

In this study, pembrolizumab is the sole experimental treatment, and no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are utilized. The trial aims to assess the Major Pathological Response (MPR) rate on the primary tumor surgical specimen induced by the neoadjuvant treatment with pembrolizumab. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the treatment protocol. The study is designed as a single-arm proof of concept phase IIA study, focusing on the efficacy of pembrolizumab in the specified patient population.

Efficacy

Efficacy in the clinical trial titled "NEOSTART Study - Neoadjuvant Pembrolizumab in Patients with High Risk, Stage IIB/IIC Cutaneous Melanoma: A Single Arm Proof of Concept Phase IIA Study" will be assessed primarily through the evaluation of the **Major Pathological Response (MPR)** on the primary tumor surgical specimen. This assessment will be conducted in accordance with the International Neoadjuvant Melanoma Consortium criteria, which include complete response (absence of viable tumor cells) and near-complete response (less than 10% tumoral viable cells).

Secondary endpoints for efficacy include the clinical response, which will be systematically assessed using clinical examination with standardized photographs of the primary tumor. Complete response is defined as the disappearance of the lesion, partial response as a decrease in size, and progression as an increase in size of the lesion by more than 25% with at least a 2 mm increase for lesions below 1 cm. Additional secondary endpoints include event-free survival (EFS), relapse-free survival (RFS), distant metastasis-free survival (DMFS), and overall survival (OS). These parameters will be measured from specific time points such as the initiation of neoadjuvant treatment or surgery to the occurrence of defined events like death, progression, or relapse.

Health-related quality of life will also be evaluated using the EORTC-QLQ C30 questionnaire. The incidence and grade of toxicities, including adverse events (AEs) and serious adverse events (SAEs), will be monitored according to NCI-CTCAE V5.0. The proportion of patients undergoing sentinel lymph node biopsy and the outcomes of these procedures will also be recorded. The trial is designed to provide comprehensive data on the efficacy of pembrolizumab as a neoadjuvant treatment in this patient population.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Age ≥ 18 years
Primary cutaneous melanoma. Primary acral melanoma are allowed up to 10% of the population (thus, a maximum of 2 patients will be included)
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)
Diagnosis confirmed histologically on partial biopsy of lesion
Operable primary tumor
Residual macroscopic primary tumor > 2mm, identifiable by photography or imaging
Performans status ECOG <2
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.
Patient affiliated to or beneficiary of French social security system
Ability to comply with the study protocol, in the Investigator’s judgment
Signed and date informed consent

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Exclusion Criteria

Non-cutaneous melanoma
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.
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.
A history of allergy or hypersensitivity to study treatment components
Prior immunotherapy (anti-PD-(L)1, or other systemic treatment for primary melanoma IIB/IIC)
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: a. Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc) b. Inhaled or intranasal corticosteroids (with minimal systemic absorption) may be continued if patient is on a stable dose c. Non-absorbed intra-articular steroid injections.
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.
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: a. Basal cell carcinoma of the skin b. Squamous cell carcinoma of the skin c. Carcinoma in situ (e.g., breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy) d. Prostatic intraepithelial neoplasia e. Atypical melanocytic hyperplasia f. Other malignancies for which the patient has been disease free for 1 year
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.
Patient with any medical or psychiatric condition or disease, which would make the patient inappropriate for entry into this study
Other usual contraindications
Completely operated primary melanoma with no macroscopic residual tumor
Current participation in a study of an investigational agent or in the period of exclusion
Pregnant or breast-feeding subjects
Patient under guardianship, curatorship or under the protection of justice
Clinical or radiographic evidence of nodal, in-transit, satellite or microsatellite metastases or distant melanoma metastases
Uncontrolled infection with HIV, HBC, or HCV infection; or diagnosis of immunodeficiency that is related to, or results in chronic infection. Notes : a. 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. DRCI NEOSTART Version : 1 Date : 03/12/2024 PROTOCOLE EC MED - Anglais Page 21 / 75 b. 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. c. 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.
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: a. 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; b. intrauterine device (IUD); intrauterine hormone-releasing system (IUS); c. bilateral tubal ligation (occlusion); d. 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 e. 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.
Participants with a history of myocarditis
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.
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.
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.
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.