Inclusion Criteria:
1. Signed ICF
2. Age ≥ 18 years
3. Histologically confirmed Stage IV (metastatic) or unresectable Stage IIIC (locally
advanced) melanoma, as defined by the AJCC, 7th revised edition
1. Naïve to prior systemic anti-cancer therapy for melanoma, with the following
exceptions: Adjuvant treatment with IFN, IL-2, or vaccine therapies, if
discontinued at least 28 days prior to initiation of study treatment
2. Adjuvant treatment with herbal therapies, if discontinued at least 7 days prior
to initiation of study treatment
4. Documentation of BRAFV600 mutation-positive status in melanoma tumor tissue (archival
or newly obtained) through use of a clinical mutation test approved by the local
health authority
5. ECOG of 0 or 1
6. Decision of eligibility for neoadjuvant combined vem+cobi+atezo treatment by
in-terdisciplinary tumor board. Patient with limited numbers of metastases and few
organ systems involved should be selected, making surgical resection after
neo-adjuvant treatment probable.
7. Measurable disease by RECIST V1.1 criteria (must be outside the CNS)
8. Adequate hematologic and end-organ function, defined by the following laboratory test
results, obtained within 14 days prior to initiation of study treatment, with the
exception of amylase, lipase, and LDH where up to 28 days is acceptable
- ANC ≥ 1.5 × 109/L without granulocyte colony-stimulating factor support
- WBC count ≥ 2.5 × 109/L
- Lymphocyte count ≥ 0.5 × 109/L
- Platelet count ≥ 100 × 109/L without transfusion
- Hemoglobin ≥ 9 g/dL without transfusion
- Serum albumin ≥ 2.5 g/dL
- Total bilirubin ≤ 1.5 × ULN
- AST and ALT ≤ 2.0 x ULN
- Amylase and lipase ≤ 1.5 x ULN
- ALP ≤ 2.5 × ULN or, for patients with documented liver or bone metastases, ALP ≤
5 × ULN
- Serum creatinine ≤ 1.5 × ULN or CrCl ≥ 40mL/min on the basis of measured CrCl
from a 24-hour urine collection or Crockcroft-Gault glomerular filtration rate
estimation:
- CrCL= ((140-age) x (weight in kg) x (72 x (serum creatinine in mg/dL)-1) (x 0.85
if female)
- For patients not receiving therapeutic anticoagulation: INR or aPTT ≤ 1.5 × ULN
within 28 days prior to initiation of study treatment
- For patients receiving therapeutic anticoagulation: stable anticoagulant regi-men
and stable INR during the 28 days immediately preceding initiation of study
treatment
9. For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use
contraceptive measures, and agreement to refrain from donating sperm, as defined
below:
1. With female partners of childbearing potential, men must remain abstinent or use
a condom plus an additional contraceptive method that together result in a
failure rate of < 1% per year during the treatment period and for at least 6
months after the last dose of study treatment. Men must refrain from donating
sperm during this same period.
2. With pregnant female partners, men must remain abstinent or use a condom during
the treatment period and for 6 months after the last dose of study treatment to
avoid exposing the embryo.
3. The reliability of sexual abstinence should be evaluated in relation to the
dura-tion of the clinical trial and the preferred and usual lifestyle of the
patient. Periodic abstinence and withdrawal are not acceptable methods of
contraception
10. For WOCBP: agreement to remain abstinent (refrain from heterosexual inter-course) or
use a contraceptive method with a failure rate of <1% per year during the treatment
period and for 6 months after the last dose of study treatment
1. A woman is considered to be of childbearing potential if she is postmenarcheal,
has not reached a postmenopausal state, and has not undergone surgical
sterilization
2. Examples of contraceptive methods with a failure rate of < 1% per year include
bilateral tubal ligation, male sterilization, hormonal contraceptives that
inhibit ovulation, hormone-releasing intrauterine devices (IUD), and copper IUDs.
3. Hormonal contraceptive methods must be supplemented by a barrier method. The
reliability of sexual abstinence should be evaluated in relation to the duration
of the clinical trial and the preferred and usual lifestyle of the patient.
Periodic abstinence and withdrawal are not acceptable methods of contraception.
11. Female subjects who are lactating have to discontinue nursing prior to the first dose
of study drug and must refrain from nursing throughout the treatment period and for 14
days following the last dose of study drug.
Exclusion Criteria:
1. Candidates for direct surgery: patients with single site easily resectable metasta-sis
2. Major surgical procedure or significant traumatic injury within 2 weeks prior to first
dose of study drug treatment
3. Palliative radiotherapy within 14 days prior to initiation of study treatment
4. Active malignancy (other than BRAFV600 mutation-positive melanoma) or malig-nancy
within 3 years prior to screening are excluded, with the exception of resected
melanoma, resected BCC, resected cuSCC, resected carcinoma in situ of the cervix,
resected carcinoma in situ of the breast, in situ prostate cancer, limited-stage
bladder cancer, or any other curatively treated malignancies from which the patient
has been disease-free for at least 3 years
a. Patients with a history of isolated elevation in prostate-specific antigen in the
absence of radiographic evidence of metastatic prostate cancer are eligible for the
study.
5. A history of or evidence of retinal pathology on ophthalmologic examination that is
considered a risk factor for neurosensory retinal detachment, CSCR, RVO, or
ne-ovascular macular degeneration
a. Patients will be excluded from study participation if they currently are known to
have any of the following risk factors for RVO: i. History of serous retinopathy ii.
History of RVO iii. Evidence of ongoing serous retinopathy or RVO at baseline
6. History of clinically significant cardiac dysfunction, including the following:
1. Poorly controlled hypertension, defined as sustained, uncontrolled, non-episodic
baseline hypertension consistently above 159/99mmHg despite opti-mal medical
management
2. Unstable angina, or new-onset angina within 3 months prior to initiation of study
treatment
3. Symptomatic congestive heart failure, defined as NYHA Class II or higher
4. Myocardial infarction within 3 months prior to initiation of study treatment
5. Unstable arrhythmia
6. History of congenital long QT syndrome
7. QTcF ≥480 ms at screening, or uncorrectable abnormalities in serum electro-lytes
8. LVEF below the institutional lower limit of normal or below 50%, whichever is
lower
7. Untreated or actively progressing CNS lesions (carcinomatous meningitis)
8. Patients with a history of CNS lesions are eligible, provided that all of the
following criteria are met:
1. Measurable disease, per RECIST v1.1, must be present outside the CNS
2. All known CNS lesions have been treated with radiotherapy or surgery
3. CNS lesions have not been treated with whole-brain radiotherapy, except in
patients who underwent definitive resection of or stereotactic therapy for all
radiologically detectable parenchymal brain lesions
4. Absence of interim progression must be confirmed by radiographic study within 4
weeks prior to initiation of study treatment. If new CNS metastases are suspected
during the screening period, a confirmatory radiographic study is required prior
to initiation of study treatment
5. Any radiotherapy or surgery must be completed ≥ 4 weeks prior to initiation of
study treatment
6. There is no ongoing requirement for corticosteroids, and any prior corticosteroid
treatment must be discontinued ≥ 2 weeks prior to initiation of study treatment.
Treatment with an anticonvulsant at a stable dose is allowed
7. No history of intracranial hemorrhage from CNS lesions
9. History of metastases to brain stem, midbrain, pons, or medulla, or within 10 mm of
the optic apparatus
10. History of leptomeningeal metastatic disease
11. Anticipated use of any concomitant medication during or within 7 days prior to
initiation of study treatment that is known to cause QT prolongation. Patients with
regular amiodaron intake in the last 365 days cannot be included.
12. Uncontrolled diabetes or symptomatic hyperglycemia
13. History of malabsorption or other clinically significant metabolic dysfunction that
may interfere with absorption of oral study treatment
14. Pregnancy or lactation period or intention to become pregnant during the study.
a. WOCBP must have a negative serum pregnancy test result within 7 days prior to
initiation of study treatment
15. Prior allogeneic stem cell or solid organ transplantation
16. History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced
pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening
chest CT scan
a. History of radiation pneumonitis in the radiation field (fibrosis) is permitted.
17. Active or history of autoimmune disease or immune deficiency, including, but not
limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus
ery-thematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid
antibody syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome,
or multiple sclerosis, with the following exceptions:
a. Patients with a history of autoimmune-related hypothyroidism on a stable dose of
thyroid-replacement hormone may be eligible for the study after discussion with and
approval by the Medical Monitor b. Patients with controlled Type 1 diabetes mellitus
on a stable insulin regimen may be eligible for the study after discussion with and
approval by the Medical Monitor c. Patients with eczema, psoriasis, lichen simplex
chronicus, or vitiligo with der-matologic manifestations only are eligible for the
study provided all of following conditions are met: i. Rash must cover < 10% of body
surface area ii. Disease is well controlled at baseline and requires only low-potency
topical corticosteroids iii. No occurrence of acute exacerbations of the underlying
condition requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids,
biologic agents, oral calcineurin inhibitors, or high-potency or oral cor-ticosteroids
within the previous 12 months
18. Known clinically significant liver disease, including alcoholism, cirrhosis, fatty
liver, and other inherited liver disease as well as active viral disease including:
1. Positive HIV test at screening
2. Active HBV infection, defined as having a positive HBsAg test at screening
Patients with a past or resolved HBV infection, defined as having a negative
HBsAg test and a positive total HBcAb test at screening, are eligible for the
study
3. Active HCV infection, defined as having a positive HCV antibody test and a
positive HCV RNA test at screening
19. Active tuberculosis
20. Severe infection within 4 weeks prior to initiation of study treatment, including, but
not limited to, hospitalization for complications of infection, bacteremia, or severe
pneumonia
21. Any Grade ≥ 3 hemorrhage or bleeding event within 4 weeks prior to initiation of study
treatment
22. History of stroke, reversible ischemic neurological defect, or transient ischemic
at-tack within 6 months prior to initiation of study treatment
23. Current severe, uncontrolled systemic disease or any other disease, metabolic
dysfunction, physical examination finding, or clinical laboratory finding that
contraindicates the use of an investigational drug, may affect the interpretation of
the results, or could jeopardize the safety of the patient and their compliance in the
study
24. Signs or symptoms of clinically relevant infection and/or treatment with therapeutic
systemic antibiotics within 2 weeks prior to initiation of study treatment
a. Patients receiving prophylactic antibiotics are eligible for the study
25. Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study
treatment, or anticipation of need for such a vaccine during the course of the study
26. Treatment with systemic immunosuppressive medication within 2 weeks prior to
initiation of study treatment, or anticipation of need for systemic immunosuppressive
medication during the study
1. Patients who have received acute, low-dose systemic immunosuppressant medication
≥ 4 weeks prior to ini-tiation of study treatment or a one-time pulse dose of
systemic immunosup-pressant medication are eligible for the study.
2. The use of inhaled corticosteroids for chronic obstructive pulmonary disease or
asthma, mineralocorticoids , or low-dose corticosteroids for patients with
orthostatic hypotension or adrenocortical insufficiency is allowed.
27. Known hypersensitivity to biopharmaceutical agents produced in Chinese hamster ovary
cells
28. Known hypersensitivity to any component of the atezo, cobi, or vem formulations
29. History of severe allergic, anaphylactic or other hypersensitivity reactions to
chi-meric or humanized antibodies or fusion proteins
30. Treatment with any other investigational agent or participation in another clinical
study with therapeutic intent within 4 weeks of the start of study treatment.
31. Inability or unwillingness to swallow pills
32. Any psychological, familial, sociological, or geographical conditions that may hamper
compliance with the protocol and follow-up after treatment discontinuation
33. Requirement for concomitant therapy or food that is prohibited during the study, as
described in Sections 10.10 and 10.11.
34. Patient is unable to comply with the study protocol for any other reason
