| Eligibility |
Inclusion Criteria:
1. Signed and dated written ICF prior to performing any protocol-related procedures,
which are not part of normal standard care.
2. Patients must be willing and able to comply with scheduled visits, treatment schedule,
laboratory tests, tumour sample including core needle biopsy as required, and other
requirements of the study.
3. Male or female = 18 years of age at the time of informed consent.
4. Stage IIIB/IIIC/IIID or Stage IV AJCC (8th edition) (AJCC, 2018) before complete
resection.
Please note: If Stage III melanoma (whether Stage IIIB or IIIC or IIID) the patients
must have clinically detectable lymph nodes that are confirmed as malignant on the
pathology report and/or ulcerated primary lesions, and/or in transit metastasis. The
pathology report must be reviewed, signed and dated by the Investigator; this process
must be done prior to enrolling patients into the study. Clinically detectable lymph
nodes are defined as:
1. a palpable node (confirmed as malignant by pathology) after the CLND
2. a non-palpable but enlarged lymph node by CT scan (at least 15 mm in short axis)
and confirmed as malignant by pathology after the CLND
3. a PET scan positive lymph node of any size confirmed by pathology after CLND
4. evidence of pathologically macro metastatic disease in one or more lymph nodes
defined by one or more foci of melanoma at least 1 cm in diameter If Stage IV
melanoma, the pathology report confirming negative margins must be reviewed,
dated, and signed by the Investigator prior to randomisation.
5. Cutaneous Melanoma, with metastases to regional lymph nodes or distant metastases, or
in transit metastases, that can be surgically resected with negative margin on
resected specimens.
6. Specimen from the resected tumour tissue must be provided for evaluation by NGS.
7. ECOG performance status score of 0 or 1.
8. Screening laboratory values must meet the following criteria and must be reconfirmed
for eligibility within 72 hours prior to first dose of anti-PD-1 on Day 1:
i. WBCs = 2000/µL (2.0 x 109/L) ii. Neutrophils = 1500/µL (1.5 x109/L) iii. Platelets
= 100 x 10³/µL (100 x 109/L) iv. Haemoglobin = 9.0 g/dL (90 g/L) v. Creatinine Serum
creatinine = 1.5 x ULN or creatinine clearance > 40 mL/minute (using Cockcroft/Gault
formula) vi. AST = 3 x ULN vii. ALT = 3 x ULN viii. Total Bilirubin = 1.5 x ULN
(except patients with Gilbert Syndrome who must have total bilirubin < 3.0 mg/dL)
9. Life expectancy > 6 months at Screening.
10. WOCBP and men must agree to use adequate contraception (hormonal or barrier method of
birth control, abstinence) prior to study entry and for the duration of study
participation. Should a woman become pregnant or suspect she is pregnant while
participating in this study, she should inform her treating physician immediately.
11. 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 first dose of anti-PD-1 on Day
1.
12. WOCBP must agree to follow instructions for method(s) of contraception for the
duration of treatment with study drug (s) plus 5 half-lives of study drug plus 30 days
(duration of ovulatory cycle). The half-life of nivolumab is up to 25 days. WOCBP
should therefore use an adequate method to avoid pregnancy for a total of 23 weeks
post-treatment completion.
13. Men who are sexually active with a WOCBP must agree to follow instructions for
method(s) of contraception for the duration of treatment with study drug(s) plus 5
half-lives of the study drug(s) plus 90 days (duration of sperm turnover). The
half-life of nivolumab is up to 25 days, men should therefore use an adequate method
of contraception for a total of 31 weeks post-treatment completion.
14. Azoospermic males and WOCBP who are continuously not heterosexually active are exempt
from contraceptive requirements. However, WOCBP must still undergo pregnancy testing.
15. Disease-free at study enrolment (after surgery) based upon pathology report review by
the Investigator.
Exclusion Criteria:
1. Known or active other malignancies that have needed treatment (excluding palliative
radiation) within 2 years prior to Cycle 1 Day 1 are excluded except for the
following:
1. Curatively resected non-melanomatous skin cancer
2. Curatively treated cervical carcinoma in situ
3. Non-metastatic breast and prostate cancer patients with stable disease > 12
months
4. Other stable malignancies may be permitted based on case-by-case discussions with
Sponsor and Medical Monitor approval.
2. Patients with clinically occult lymph nodes (i.e. detected by SLN biopsy) stage N1a
and N2a.
3. Participated in any other investigational study, unless treatment in that study has
been discontinued at least 30 days or period of five half-lives prior to Screening.
4. Known or suspected allergy or hypersensitivity to any of the therapeutic agents to be
administered during the study.
5. Uncontrolled concurrent illness including, but not limited to, active infection,
symptomatic congestive heart failure or cardiac arrhythmia.
6. Has a history of clinically significant GI disease, renal, hepatic, neurologic,
haematologic, endocrine, oncologic, pulmonary, immunologic, or cardiovascular disease
or any other condition which, in the opinion of the Investigator, would jeopardise the
safety of the patient or impact the validity of the study results.
7. Uncontrolled mental disease or psychotic manifestation that, in the opinion of the
Investigator, would prohibit compliance with the protocol, the understanding of the
ICF, or the ability to withdraw from the study.
8. Known history of or positive test for HIV or known immunodeficiency syndrome (AIDS).
9. For patients with evidence of chronic HBV infection, the HBV viral load must be
undetectable on suppressive therapy, if indicated.
10. Patients with a history of HCV infection must have been treated and cured. For
patients with HCV infection who are currently on treatment, they are eligible if they
have an undetectable HCV viral load.
11. Pregnant or nursing women.
12. Ocular or uveal melanoma.
13. History of carcinomatosis meningitis.
14. History of Grade = 3 allergy to human monoclonal antibodies.
15. Active, known, or suspected autoimmune disease or immunosuppressive conditions with
the exception of vitiligo, type 1 diabetes, residual autoimmune-related hypothyroidism
requiring hormone replacement, or psoriasis not requiring systemic treatment.
16. Prior treatment with immune-modulatory agents including, but not limited to: IL-2,
CTLA-4 blockade, PD-1/PD-L1 blockade, CD40 stimulation, CD137 stimulation - with the
exception of IFN-a given as adjuvant treatment for high risk, surgically resected
melanoma (Note. IFN-a therapy must have been discontinued more than 4 weeks prior to
enrolment in the study).
17. Prior investigational melanoma-directed cancer vaccine therapy.
18. Prior chemotherapy, including targeted therapy such as BRAF or MEK inhibition.
19. Use of a non-oncology vaccine therapy for prevention of infectious diseases up to 4
weeks prior to enrolment in the study.
20. Patients with a condition requiring systemic treatment with either corticosteroids
(>10 mg daily prednisone equivalent) or other immunosuppressive medications within 14
days prior to first dose of anti-PD-1 on Day 1. Inhaled or topical steroids are
permitted in the absence of active autoimmune disease.
|
