| Eligibility |
Inclusion Criteria:
1. Has histologically or cytologically confirmed melanoma.
2. Has unresectable Stage III or Stage IV melanoma, per AJCC 8th Edition Staging
Criteria, not amenable to local therapy.
3. Male or female participants who are at least 18 years of age on the day of signing
informed consent
4. Male participants must agree to use a reliable method of contraception (refer to
Section 6.4.1) during the treatment period and for at least 120 days after the last
dose of study drug and must refrain from donating sperm during this period.
5. Female participants must not be pregnant or breast feeding and meet at least one of
the following conditions:
1. Not a woman of childbearing potential (WOCBP)
2. A WOCBP must agree to use a reliable method of contraception (refer to Section
6.4.1) during the treatment period and for at least 120 days after the last dose
of study treatment.
6. Participants must have received an anti-PD-1/PD-L1 mAb as part of their most recent
line of therapy prior to enrollment in the study.
7. Participants must have progressed on or after treatment with an anti-PD-1/PD-L1 mAb
administered either as monotherapy or in combination with other checkpoint inhibitors
or other therapies in their most recent line of therapy. PD 1 treatment progression is
defined by meeting all of the following criteria:
1. Has received at least 8 weeks of an anti-PD-1/PD-L1 mAb
2. Has demonstrated progression after anti-PD-1/PD-L1 mAb therapy as defined by
RECIST v.1.1. The initial evidence of progressive disease (PD) is to be confirmed
by a second assessment no less than 4 weeks from the date of the first documented
PD, in the absence of rapid clinical progression (as defined in 7.c)
3. Progressive disease has been documented within 6 months from the last dose of
anti-PD-1/L1 mAb.
i. Progressive disease must be determined according to iRECIST ii. This determination
is made by the investigator. Once PD is confirmed, the initial date of PD
documentation will be considered the date of disease progression.
d. Patients who progress while receiving or within 6 months of receiving the last dose
of anti-PD-1/L1 mAb in the neoadjuvant or adjuvant setting will be included. Inclusion
of patients who progress within 6 months of stopping neoadjuvant or adjuvant
anti-PD-1/L1 mAb will be capped at 20% of the total study population. Inclusion of
patients who progress while still receiving neoadjuvant or adjuvant anti-PD-1/L1 mAB
will not be capped.
8. The participant provides written informed consent for the trial
9. Measurable disease based on RECIST v.1.1. Lesions situated in a previously irradiated
area are considered measurable if progression has been demonstrated in such lesions
1. Multiple target lesions will be allowed and will be selected based on standard
RECIST criteria.
2. The following cutaneous lesions will be considered measurable lesions: lesions =
10 mm in longest diameter or multiple melanoma lesions which in aggregate have a
longest diameter of = 10 mm, when measured by caliper.
10. Have available archival tumor tissue sample or newly obtained core or excisional
biopsy of a tumor lesion. Formalin-fixed, paraffin embedded (FFPE) tissue blocks are
preferred to slides.
1. Newly obtained biopsies are preferred to archived tissue, but archived sample can
be used at baseline provided that the patient has only had anti-PD-1/L1 based
regimen since obtaining the sample.
2. Biopsies may be taken from any amenable lesion, but it is preferable to use the
same lesion throughout.
3. Biopsy may be taken from previously irradiated lesions only if they have
progressed since radiation therapy.
4. Patient may still be eligible for study if tumor is not amenable to safe biopsy
or biopsy is judged by patient or treating physician to not be in their best
interest.
11. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2. Evaluation
of ECOG must be performed within 7 days prior to C1D1.
12. Adequate organ function as defined below. Specimens must have been collected within 7
days prior to the start of study treatment:
1. Absolute neutrophil count (ANC) =1500/µL
2. Platelets =100,000/µL
3. Hemoglobin =9.0 g/dL or =5.6 mmol/La
4. Creatinine OR measured or calculated creatinine clearance (GFR can be used in
place of CrCl) =1.5 x ULN OR =45 mL/min for participant with creatinine levels
>1.5 x institutional ULN
5. Total bilirubin =1.5 x ULN OR direct bilirubin =ULN for participants with total
bilirubin levels > 1.5 x ULN
6. AST (SGOT) and ALT (SGPT) =2.5 x ULN (=5 x ULN for participants with liver
metastases)
7. International normalized ratio (INR) OR prothrombin time (PT) =1.5 x ULN unless
participant is receiving anticoagulant therapy as long as PT or aPTT is within
therapeutic range of intended use of anticoagulants
8. Activated partial thromboplastin time (aPTT) =1.5 x ULN unless participant is
receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range
of intended use of anticoagulants NOTE: Criteria must be met without
erythropoietin dependency and without packed red blood cell (pRBC) transfusion
within the last 2 weeks NOTE: Creatinine clearance (CrCl) should be calculated
per institutional standard
13. Prior adverse events from anticancer therapy must be resolved to = grade 1, with the
exception of alopecia or endocrinopathies, which may be on replacement therapy.
Prednisone equivalent of = 10 mg is allowed.
Exclusion Criteria:
1. Ocular or mucosal melanoma
2. A WOCBP who is pregnant or breastfeeding or has a positive pregnancy test within 72
hours prior to receiving study treatment
3. Has received prior systemic anti-cancer therapy including investigational agents
within 4 weeks prior to starting study treatment
4. Has received prior radiotherapy within 2 weeks of start of study intervention.
Participants must have recovered from all radiation-related toxicities, not require
corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted
for palliative radiation (=2 weeks of radiotherapy) to non-CNS disease
5. Has received cytotoxic chemotherapy for melanoma at any point prior to study
enrollment
6. Is currently participating in or has participated in a study of an investigational
agent or has used an investigational device within 4 weeks prior to the first dose of
study intervention
7. Has received an additional line of therapy after the PD-1/PD-L1 therapy prior to
starting on this study.
8. Diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in
dosing exceeding 10 mg daily of prednisone equivalent) or any other form of
immunosuppressive therapy within 14 days prior to the first dose of study drug
9. History of a second malignancy, unless potentially curative treatment has been
completed with no evidence of malignancy for 2 years
a. Exception: time requirement does not apply to patients who underwent successful
definitive resection of basal cell carcinoma of the skin, squamous cell carcinoma of
the skin, superficial bladder cancer, in situ cervical cancer, or other in situ
cancers
10. Known active CNS metastases and/or carcinomatous meningitis. Participants with
previously treated brain metastases may participate, provided the patient is
clinically stable and without requirement of steroid treatment for at least 14 days
prior to first dose of study intervention
11. Severe hypersensitivity (=Grade 3) to pembrolizumab and/or any of its excipients
12. Active autoimmune disease that has required systemic treatment in the past 2 years
(i.e., with use of disease modifying agents, corticosteroids or immunosuppressive
drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
form of systemic treatment and is allowed
13. History of (non-infectious) pneumonitis/ interstitial lung disease that required
steroids or has current pneumonitis/ interstitial lung disease
14. Active infection requiring systemic therapy
15. Known history of Human Immunodeficiency Virus (HIV) infection
16. Known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive)
or known active Hepatitis C virus (defined as HCV RNA [qualitative] is detected)
infection. Note: no testing for Hepatitis B and Hepatitis C is required
17. Has a known history of active TB (Bacillus Tuberculosis)
18. History or current evidence of any condition, therapy, or laboratory abnormality that
might confound the results of the study, interfere with the subject's participation
for the full duration of the study, or is not in the best interest of the subject to
participate, in the opinion of the treating investigator
19. Known psychiatric or substance abuse disorders that would interfere with cooperation
with the requirements of the trial
20. Expecting to conceive or father children within the projected duration of study
participation, starting with the screening visit through 120 days after the last dose
of trial treatment
21. History of allogenic tissue/solid organ transplant
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