Eligibility Details:
Inclusion Criteria:
1. Age ≥ 18 years
2. Written informed consent must be obtained from all patients prior to any study
procedures
3. Patients with advanced non-uveal melanoma defined as unresectable stage III or
metastatic stage IV disease. Patients with acral or mucosal melanoma are acceptable.
Patients with melanoma of unknown primary are acceptable for Phase Ib cohorts (Arms 1
to 4), but are excluded in Phase II cohorts. Patients with the diagnosis of UM are
excluded from all cohorts.
4. Phase 1b Arm 4 and Phase II: Patients with disease progression following initiation of
treatment with an approved PD-1 inhibitor. No prior cytotoxic therapy in the advanced
setting is permitted. Patients with BRAF mutations must be refractory to approved
BRAF-based therapy. CTLA-4-inhibition therapy is acceptable as a prior line of therapy
or in combination with anti-PD-1 therapy.
5. No longer applicable - (Phase II IMT naive cohorts: Patients have not received
systemic cytotoxic or immune-based therapy for advanced melanoma. BRAF and/or MEK
inhibition therapy is acceptable before immunotherapy where clinically indicated.
Other systemic cytotoxic or targeted therapy in the advanced setting is not permitted
in this subset)
6. Phase Ib Arms 1, 2, and 3: no restriction on prior therapy
7. HLA-A*0201 positive by Central Assay
8. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1
9. Life expectancy of at least 3 months
10. Phase II cohorts only: patients must have measurable disease according to RECIST v.1.1
criteria. Patients enrolled in Ph Ib cohorts must have evaluable disease
11. Phase 1b Arm 4 and Phase II cohorts only: Patients must have a site of disease
amenable to biopsy, that is not an index lesion, and be a candidate for tumor biopsy
according to the treating institution's guidelines. Phase Ib Arms 1-3 patients need
not have disease accessible to biopsy
12. Those receiving prior immunotherapy must meet all of the following conditions:
- Must not have experienced an immune-related adverse event (irAE) where the irAE
was the reason for permanent discontinuation of prior immunotherapy in the most
recent prior treatment regimen
- All irAEs while receiving prior immunotherapy must have resolved to ≤ grade 1 or
Baseline prior to Screening for this study. Must not have experienced a ≥ grade 3
immune-related AE within the past 16 weeks or any grade 4 life- threatening irAE
(regardless of duration) or neurologic or ocular AE of any grade while receiving
prior immunotherapy (NOTE: Subjects with endocrine AE of any grade are permitted
to enroll if they are stably maintained on appropriate replacement therapy, but
must have no history of adrenal crisis and be asymptomatic)
- Patients currently receiving chronic corticosteroid treatment (longer than 8
weeks duration) for management of pre-existing adverse events, or patients with a
history of chronic corticosteroid treatment longer than 8 weeks' duration for AEs
within 6 months of Screening are excluded
Exclusion Criteria:
1. Presence of untreated or symptomatic central nervous system metastases, or central
nervous system metastases that currently require local therapy (such as radiotherapy
or surgery), or require doses of corticosteroids within the prior 4 weeks
2. History of severe hypersensitivity reactions to other mAbs
3. History of treatment-related interstitial lung disease/pneumonitis
4. Patient with any out-of-range laboratory values defined as:
- Serum creatinine ≥ 1.5 x ULN and/or creatinine clearance (calculated using
Cockcroft-Gault formula, or measured) < 50 mL/min
- Total bilirubin > 1.5 x ULN, except for patients with Gilbert's syndrome who are
excluded if total bilirubin > 3.0 x ULN or direct bilirubin > 1.5 x ULN
- Alanine aminotransferase (ALT) > 3 x ULN
- Aspartate aminotransferase (AST) > 3 x ULN
- Absolute neutrophil count (ANC) < 1.0 x 10^9/L
- Absolute lymphocyte count < 0.5 x 10^9/L
- Platelet count < 75 x 10^9/L
- Hemoglobin (Hgb) < 8 g/dL
- Potassium, magnesium, corrected calcium or phosphate abnormality of National
Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) >
grade 1
5. Clinically significant cardiac disease or impaired cardiac function, including any of
the following:
- Clinically significant and/or uncontrolled heart disease such as congestive heart
failure (New York Heart Association [NYHA] grade ≥ 2), uncontrolled hypertension
or clinically significant arrhythmia currently requiring medical treatment
- QTcF >470 msec on screening ECG or congenital long QT syndrome
- Acute myocardial infarction or unstable angina pectoris < 6 months prior to
Screening
6. Active autoimmune disease or a documented history of autoimmune disease within 3 years
before Screening (or as indicated below), including the following:
- A documented history of inflammatory bowel disease (ulcerative colitis or Crohn's
disease, within three years)
- Patients with vitiligo, alopecia, managed hypothyroidism (on stable replacement
doses), psoriasis, resolved childhood asthma/atopy, well-controlled asthma and
type I diabetes mellitus are NOT excluded
7. Recent (< 12 months) active diverticulitis (PhIb combination arms and PhII only)
8. Active infection requiring systemic antibiotic therapy. Patients requiring systemic
antibiotics for infection must have completed therapy before Screening is initiated
9. Known history of human immunodeficiency virus (HIV) infection. Testing for HIV status
is not necessary unless clinically indicated or if required by local regulation
10. Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection, currently
requiring medical intervention, per institutional protocol. Testing for HBV or HCV
status is not necessary unless clinically indicated or the patient has a history of
HBV or HCV infection requiring treatment with currently an unknown status. History of
treated hepatitis is not exclusionary
11. Malignant disease, other than that being treated in this study. Exceptions to this
exclusion include the following: malignancies that were treated curatively and have
not recurred within 2 years after completion of treatment; completely resected basal
cell and squamous cell skin cancers; any malignancy considered to be indolent and that
has never required therapy; and completely resected carcinoma in situ of any type
12. Any medical condition that would, in the investigator's judgment, prevent the
patient's participation in the clinical study due to safety concerns, compliance with
clinical study procedures or interpretation of study results
13. Systemic anti-cancer therapy within 2 weeks of the first dose of study treatment. For
cytotoxic agents that have major delayed toxicity and any prior immunotherapy
approach, 4 weeks is indicated as washout period
14. Presence of National Cancer Institute Common Terminology Criteria for Adverse Events
(NCI CTCAE) ≥ grade 2 toxicity (except alopecia, peripheral neuropathy and
ototoxicity, which are excluded if ≥ NCI CTCAE grade 3) due to prior cancer therapy
15. Patients currently requiring chronic, systemic corticosteroid therapy at any dose for
longer than 2 weeks. Local steroid therapies (eg, otic, ophthalmic, intra-articular or
inhaled medications) are acceptable
16. Use of any live vaccines against infectious diseases within 4 weeks of initiation of
study treatment. Non-live vaccination (eg, influenza) are permitted anytime during
treatment
17. Major surgery as defined by the investigator within 2 weeks of the first dose of study
treatment (minimally invasive procedures such as bronchoscopy, tumor biopsy, insertion
of a central venous access device, and insertion of a feeding tube are not considered
major surgery)
18. Radiotherapy within 2 weeks of the first dose of study drug, with the exception of
palliative radiotherapy to a limited field, such as for the treatment of bone pain or
a focally painful tumor mass
19. Use of hematopoietic colony-stimulating growth factors (eg, G-CSF, GMCSF, M-CSF) ≤ 2
weeks prior start or study drug. Patients must have completed therapy at least 2 weeks
before the screening period begins with any hematopoietic colony-stimulating growth
factors. An erythroid stimulating agent is allowed as long as it was initiated at
least 2 weeks prior to the first dose of study treatment and the patient is not red
blood cell transfusion dependent
20. Pregnant or lactating women, where pregnancy is defined as the state of a female after
conception and until the termination of gestation, confirmed by a positive hCG
laboratory test
21. Women of child-bearing potential who are sexually active with a non-sterilized male
partner, defined as all women physiologically capable of becoming pregnant, unless
they are using highly effective contraception from screening throughout study
treatment, and must agree to continue using such precautions for 6 months after the
final dose of investigational product; cessation of birth control after this point
should be discussed with a responsible physician. Highly effective methods include the
following:
- Total abstinence from sexual relations for the duration of the treatment when
applicable to the lifestyle of the patient. Periodic abstinence (eg, calendar,
ovulation, symptothermal, post-ovulation methods) and withdrawal are not
acceptable methods of contraception
- Female sterilization (have had surgical bilateral oophorectomy with or without
hysterectomy) or tubal ligation at least 6 weeks before taking study treatment.
In case of oophorectomy alone, this applies only when the reproductive status of
the woman has been confirmed by follow up hormone level assessment
- Male sterilization (at least 6 months prior to Screening). For female patients on
the study the vasectomized male partner should be the sole partner for that
patient
- The combination of any 2 of the following methods when both are used
simultaneously:
1. Use of oral, injected, or implanted hormonal methods of contraception or
other forms of hormonal contraception that have comparable efficacy (failure
rate <1%), for example hormone vaginal ring or transdermal hormone
contraception
2. Placement of an intrauterine device or intrauterine system
3. Barrier methods of contraception: condom or occlusive cap (diaphragm or
cervical/vault caps) when used with spermicidal foam, gel, film, cream, or
used of a spermicidal vaginal suppository Women of child-bearing potential
must have a negative serum pregnancy test at Screening. Otherwise, female
patients must be post-menopausal (no menstrual period for at least 12 months
prior to Screening), or surgically sterile.
22. Male patients must be surgically sterile or use double barrier contraception method
from enrollment through treatment and for 6 months following administration of the
last dose of study drug.
common.study.methods.has-drugs-yes
common.study.methods.is-healthy-yes
