Inclusion Criteria:
1. Age ≥ 18 years old.
2. ECOG performance status 0-1. 3. Subjects must have signed and dated an IRB/IEC approved written informed consent
form in accordance with regulatory and institutional guidelines. This must be
obtained before the performance of any protocol-related procedures that are not part
of normal subject care.
• Subjects must be willing and able to comply with scheduled visits, treatment
schedule, laboratory testing, and other requirements of the study.
4. Histologically confirmed unresectable stage III or stage IV malignant melanoma
(Stage IV).
5. At least one measurable target lesion according to RECIST 1.1. (Appendix 1), which
previously was not treated.
• Growth or change in a lesion previously irradiated will not be considered
measurable. Regrowth in cavity of previously excised lesion will not be considered
measurable. 6. Tumor tissue from an unresectable or metastatic site of disease must be available
for biomarker analyses. The biopsy should be a core biopsy, a punch biopsy, an
excisional biopsy, or a surgical specimen. Fine needle aspiration is unacceptable
for submission.
- - For Phase I participants: Pretreatment tissue must be available through either
an archival sample obtained within at most 6 months and submitted as an FFPE
tissue block or 30 unstained tumor tissue slides or a fresh pretreatment
biopsy.
Subsequent tumor biopsies will be optional.
- - For Phase IIa participants: Either an archival sample submitted as an FFPE
tissue block or unstained tumor tissue slides or a fresh pretreatment biopsy
from safely biopsiable lesion.
Note that if the patient has archival tissue
available from a biopsy within 90 days of C1D1 and there has been no systemic
treatment since that time then that tissue can be used in place of a fresh
pre-treatment biopsy. Patients must also agree to undergo post treatment, cycle
2, tumor biopsies for research purposes. Subsequent biopsies will be optional.
7. No prior systemic lines of treatment for metastatic melanoma. Prior adjuvant or
neo-adjuvant therapy will be permitted as long as it did not contain ipilimumab and
the last dose has been >6 months.
8. Prior radiation is allowed with a two week wash out period prior to initiation of
treatment.
9. Adequate organ function as described below.
Table 2. Evaluation of Organ Function Laboratory Value Hematological Absolute
neutrophil count (ANC) ≥ 1.5 X 109/L Platelets ≥ 100 X 109/L (≥ 60 for HCC)
Hemoglobin ≥ 8.0 g/dL Renal Creatinine OR ≤1.5 × ULN OR Measured or calculatedb
creatinine clearance ≥40 mL/min for participant with creatinine levels >1.5 ×
institutional (GFR can also be used in place of creatinine or ULN CRCl) Hepatic ≤1.5
×ULN OR direct bilirubin ≤ULN Total bilirubin for participants with total bilirubin
levels AST (SGOT) and ALT (SGPT) ≤3.0 × ULN (≤5 × ULN for participants with liver
metastases) Coagulation International normalized ratio (INR) OR ≤1.5 × ULN unless
participant is receiving prothrombin time (PTT) anticoagulant therapy as long as PT
or Activated partial thromboplastin time aPTT wi withing therapeutic range of
intended use of anticoagulants (aPTT) ALT (SGPT)=alanine aminotransferase (serum
glutamic pyruvic transaminase); AST (SGOT)=aspartate aminotransferase (serum
glutamic oxaloacetic transaminase); GFR=glomerular filtration rate; ULN=upper limit
of normal.
a Criteria must be met without erythropoietin dependency and without packed red
blood cell (pRBC) transfusion within last 2 weeks.
b Creatinine clearance (CrCl) should be calculated per institutional standard. NOTE:
This table includes eligibility-defining laboratory value requirements for
treatment; laboratory value requirements should be adapted according to local
regulations and guidelines for the administration of specific chemotherapies.
10. Women of child-bearing potential (WOCBP) must not be breastfeeding and must have a
negative pregnancy test within 3 days prior to initiation of dosing. She must agree
to use an acceptable method of birth control from the time of the negative pregnancy
test, through the duration of treatment with the study combination plus 5 half-lives
of study treatment for a total of 5 months post -treatment completion. WOCBP must
agree to adhere to the contraceptive guidance in Appendix 4. NOTE: A female
participant is eligible to participate if she is not a woman of childbearing
potential as defined Appendix 4.
11. All associated toxicity from previous or concurrent cancer therapy must be resolved
(to ≤ grade 1 or baseline) prior to study treatment administration. This excludes
low grade or non-serious toxicities. However, stable endocrinopathies requiring
replacement therapy will be allowed.
12. Steroids for physiological replacement are allowed as long as it does not exceed 10
mg/day prednisone equivalents.
13. Participants must have known BRAF V600 mutation status or consent to BRAF V600
mutation testing per local institutional standards during the screening period. BRAF
V600 results need not be available at the time of study start.
14. Participants with asymptomatic brain metastases are eligible. There must also be no
requirement for immunosuppressive doses of systemic corticosteroids (> 10 mg/day
prednisone equivalents) for at least 10 days prior to study treatment
administration. Patients with brain metastases treated with SRS will be allowed, as
long as last radiation therapy is >1 week.
Exclusion Criteria:
1. Patients with ocular melanoma.
2. Patients with symptomatic CNS metastases and/or requiring corticosteroid treatment.
3. History of known leptomeningeal involvement (lumbar puncture not required).
4. Patients who experienced Grade 3/4 immune-related adverse events with checkpoint
inhibitor therapy, except those that are unlikely to re-occur with standard
countermeasures (e.g. hypothyroidism) 5. Subjects with an active, known or suspected
autoimmune disease. Subjects with type I diabetes mellitus, hypothyroidism only
requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or
alopecia) not requiring systemic treatment, or conditions not expected to recur in
the absence of an external trigger are permitted to enroll.
6. Subjects with major medical, neurologic or psychiatric condition who are judged as
unable to fully comply with study therapy or assessments should not be enrolled.
7. Subject has a history of a second malignancy, unless potentially curative treatment
has been completed with no evidence of malignancy for 2 years. Note: The time
requirement does not apply to participants who underwent successful treatment of
superficial bladder cancer, in situ cervical cancer, or other in-situ cancers.
Subjects with a completely treated prior malignancy and no evidence of disease for ≥
2 years are eligible.
a. Skin Cancer Exclusion: Please note that basal cell carcinoma and squamous cell
carcinoma is exempt from needing resection prior to treatment. (Resection can be
completed after the start of treatment).
8. History of or is positive for hepatitis B (hepatitis B surface antigen [HBsAg]
reactive) or hepatitis C (hepatitis C virus [HCV] RNA [qualitative] is detected).
a. NOTE: Without known history, testing needs to be performed to determine eligibility.
Hepatitis C antibody (Ab) testing is allowed for screening purposes in countries where
HCV RNA is not part of standard of care.
9. History of human immunodeficiency virus (HIV) infection. No HIV testing is required
unless mandated by local health authority.
10. The use of corticosteroids is not allowed for 14 days prior to initiation of therapy
(based upon 5 times the expected half-life of dexamethasone) except patients who are
taking steroids for physiological replacement or in the case of Inhaled or topical
steroids or other immunosuppressive medications. If alternative corticosteroid
therapy has been used, consultation with the PI is required to determine the washout
period prior to initiating study treatment.
11. Major surgical procedure, open biopsy (excluding skin cancer resection), or
significant traumatic injury within 14 days of initiating study drug (unless the
wound has healed) or anticipation of the need for major surgery during the study.
12. Non-healing wound, ulcer, or bone fracture. 13. Women who are breast-feeding or
pregnant. 14. Uncontrolled intercurrent illness (i.e., active infection ≥ grade 2)
or concurrent condition that, in the opinion of the Investigator, would interfere
with the study endpoints or the subject's ability to participate.
15. History of clinically significant cardiac disease or congestive heart failure > New
York Heart Association (NYHA) class 2. Subjects must not have unstable angina
(anginal symptoms at rest) or new-onset angina within the last 3 months or
myocardial infarction within the past 6 months or a history of myocarditis. Also, •
prior myocarditis of any etiology. • Left ventricular ejection fraction (LVEF)
assessment with documented LVEF < 50% by either transthoracic echocardiogram (TTE)
or multigated acquisition scan (TTE preferred test) within 6 months prior to the
start of study treatment.
16. Troponin T (TnT) or I (TnI) > 2 × institutional ULN. Participants with TnT or TnI
levels between > 1 to 2 × ULN will be permitted if repeat levels within 24 hours are
≤ 1 ULN. If TnT or TnI levels are between >1 to 2 × ULN within 24 hours, the
participant may undergo a cardiac consultation and be considered for treatment,
following cardiologist recommendation. When repeat levels within 24 hours are not
available, a repeat test should be conducted as soon as possible. If TnT or TnI
repeat levels beyond 24 hours are < 2 × ULN, the participant may undergo a cardiac
consultation and be considered for treatment, following cardiologist recommendation.
Notification of the decision to enroll the participant following cardiologist
recommendation has to be made to the principal investigator.
17. Investigational drug use within 14 days (or 5 half-lives, whichever is shorter) of
the first dose of the triplet therapy.
18. The use of herbal supplements within 7 days. 19. History of non-infectious
pneumonitis that required steroids or current pneumonitis.
