| Eligibility |
Inclusion Criteria
All patients must meet the following criteria for inclusion:
1. Patient has provided informed consent prior to initiation of any study-specific
activities/procedures.
2. Male or female age = 18 years at the time of informed consent.
3. Willingness to provide pre-and post-treatment fresh tumor biopsy specimens as
specified in the Schedule of Study Procedures and Assessments (Table 1).
4. Histologically confirmed diagnosis of malignant melanoma (except for uveal melanoma).
5. Patient with stage IIIB to IV advanced malignant melanoma (as defined by American
Joint Committee on Cancer [AJCC] staging manual version 8.0) that is not surgically
resectable, failed for standard of care (SOC) therapy or in the opinion of the
investigator not suitable for SOC therapy. SOC may include, but not be limited to
chemotherapy, targeted therapy or immunotherapy.
6. BRAF V600E/V600K mutation-positive (applied to part 1 and part 2 cohort 1) or RAS
mutation-positive (applied to part 1 and part 2 cohort 2). BRAF V600E/V600K and RAS
mutation status result from diagnosis of tumor histopathology should be provided
during Screening. If the patient is unable to provide, testing will be required during
the Screening period in local laboratory.
7. Measurable disease defined as one or both of the following:
(1) At least 1 melanoma lesion that can be accurately and serially measured in at least 2
dimensions sand for which the longest diameter is = 10 mm and with perpendicular diameter =
5 mm as measured by contrast-enhanced or spiral CT scan for visceral or nodal/soft tissue
disease. Lymph nodes must measure > 15 mm in their short axis to be considered measurable
by CT scan.
(2) At least 1 superficial cutaneous or subcutaneous melanoma lesion that can be accurately
and serially measured in at least 2 dimensions and for which the short axis is = 5 mm as
measured by calipers.
(3) Previously irradiated lesions can be considered as measurable disease only if
progressive disease has been unequivocally documented at that lesion since radiation.
8. Injectable disease (i.e., suitable for direct injection or through the use of ultrasound
[US] or CT guidance) defined as follows:
1. At least 1 injectable melanoma lesion = 5 mm in longest diameter, or in the opinion of
the investigator the lesion can be injected.
9. Eastern Cooperative Oncology Group (ECOG) performance status 0-1.
10. Life expectancy = 12 weeks.
11. Adequate bone marrow function defined by ANC of = 1.5 × 109/L, platelet count of = 100
× 109/L, and hemoglobin (Hb) of = 8.5 g/dL.
12. Adequate hepatic function defined as AST/ALT = 3 × ULN and total bilirubin = 1.5 × ULN
(except patients with Gilbert's Syndrome, wherein total bilirubin < 3.0 mg/dL is
acceptable; patients with hepatic metastases: AST and/or ALT = 5 × ULN is acceptable;
patients with hepatic or bone metastases: ALP = 5 × ULN is acceptable).
13. Adequate renal function defined as creatinine clearance > 50 mL/min as determined by
the Cockcroft-Gault equation.
14. Adequate coagulation function defined as international normalization ratio
(INR)/prothrombin time (PT) = 1.5 × ULN, and partial thromboplastin time (PTT)/ activated
PTT (aPTT) = 1.5 × ULN, unless the patient is receiving anticoagulant therapy, in which
case PT and PTT/aPTT must be within therapeutic range of intended use of anticoagulants.
15. Resolution of all prior anti-tumor therapy toxicities (except for alopecia) to = NCI
CTCAE version 5.0 Grade 1.
Note: patients with immune-mediated endocrinopathies on replacement therapy are eligible.
Patients with endocrine-related AE who can recover to = NCI CTCAE version 5.0 Grade 1 after
hormone replacement therapy, in the judgment of the investigator, have no impact on the
safety and efficacy of this study can also be enrolled. Patients with toxicities attributed
to the prior anti-tumor therapy and not expected to resolve, such as neuropathy or
ototoxicity after platinum-based therapy, are permitted to enroll. Patients with other
toxicities > NCI CTCAE version 5.0 Grade 1 may be enrolled with approval from the sponsor.
16. Female patients must be surgically sterile (or have a monogamous partner who is
surgically sterile), or be at least 2 years postmenopausal, or commit to using 2 acceptable
forms of birth control (defined as the use of an intrauterine device, a barrier method with
spermicide, condoms, any form of hormonal contraceptives, or abstinence) for the duration
of the study and for 6 months following the last dose of study treatment. Male patients
must be sterile (biologically or surgically) or commit to the use of a reliable method of
birth control (condoms with spermicide) for the duration of the study and for 6 months
following the last dose of study treatment.
17. Women of childbearing potential (WCBP) must have a negative serum pregnancy test at
Screening within 14 days before the first dose of study treatment on W1D1 and a negative
urine pregnancy test pre-dose on W1D1 (assessment not required at W1D1 if completed within
the previous 7 days of W1D1).
Note: A woman is considered to be of childbearing potential if she is postmenarchal, has
not reached a postmenopausal state (= 12 continuous months of amenorrhea with no identified
cause other than menopause), and is not permanently infertile due to surgery (i.e., removal
of ovaries, fallopian tubes, and/or uterus) or another cause as determined by the
investigator (e.g., Müllerian agenesis).
Exclusion Criteria
Patients are to be excluded from the study if they meet any of the following criteria:
1. Prior treatment with other Oncolytic virus (OV) (including but not be limited to
T-VEC), tumor vaccines, cellular therapy or gene therapy.
2. Prior local anti-tumor therapy < 21 days prior to the first dose of study treatment;
prior systemic targeted therapy (including but not be limited to MEK inhibitors) < 21
days or last dose of therapy with MEK inhibitors < 5 times the half-life prior to
first dose of study treatment; prior other anti-tumor therapy (including but not be
limited to PD-1/programmed cell death ligand 1[PD-L1]) < 21 days prior to the first
dose of study treatment, prior major surgery < 21 days prior to the first dose of
study treatment.
3. Prior treatment with anti-PD-(L)1 monoclonal Ab in combination with IL-12.
4. Previous intolerance to anti-PD-(L)1 monoclonal Ab or previous history of
immunotherapy induced = NCI CTCAE version 5.0 Grade 3 non-infectious
pneumonitis/interstitial lung disease.
5. The following foods/supplements are used within 7 days before the study treatment or
the following foods/supplements are planned to be used during the study treatment:
(1) St. John's wort or hyperforin (potent cytochrome P450 CYP3A4 enzyme inducer).
(2) Grapefruit juice (potent cytochrome P450 CYP3A4 enzyme inhibitor).
6. Refractory nausea and vomiting, chronic gastrointestinal diseases or previous
significant bowel resection that would interfere with absorption of study drugs, inability
or unwillingness to swallow the formulated product.
7. A history of metastasis to the brain stem, midbrain, pons/medulla oblongata, or within
10 mm of optic nerve organs (optic nerve and optic chiasma); Or a history of leptomeningeal
metastasis.
8. Patients with rapidly disease progression, defined as patients who cannot tolerate
interruption of systemic anti-tumor therapy for at least 8 weeks, according to the
investigator's judgment.
9. Primary or acquired immunodeficient status (leukemia, lymphoma, human immunodeficiency
virus [HIV]/acquired immunodeficiency syndrome [AIDS]).
10. History or evidence of active autoimmune disease that requires systemic treatment
(i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs)
within 4 weeks prior to first dose of study treatment. Replacement therapy (e.g.,
thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or
pituitary insufficiency, etc.) is not considered a form of systemic treatment.
11. History or evidence of active primary immunodeficiency. 12. Current or prior use of
immunosuppressive medication within 14 days before the first dose of study drug. The
following are exceptions to this criterion:
1. Intranasal, inhaled, topical steroids, or local steroid injections (e.g.,
intra-articular injection).
2. Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or
its equivalent.
3. Steroids as premedication for hypersensitivity reactions (e.g., CT scan
premedication).
13. Requires continued concurrent systemic therapy with any drug active against herpes
simplex virus (HSV) (acyclovir, valaciclovir, penciclovir, famciclovir, ganciclovir,
foscarnet, cidofovir). Topical use of drugs against HSV are allowed.
14. Live, attenuated vaccines within 4 weeks prior to initiation of study treatment
(patients vaccinated with inactivated vaccines can be enrolled).
15. Active infection requiring systemic treatment. 16. Hepatic diseases known to be
clinically significant include alcoholism, cirrhosis, fatty hepatic disease, and other
hereditary hepatic diseases, or positive serological test of hepatitis B virus (HBV) or
hepatitis C virus (HCV) at Screening.
1. Patients who test positive for anti-hepatitis C Ab (anti-HCV) but negative for HCV
ribonucleic acid (RNA) are considered eligible to participate in the study.
2. Patients with infection of hepatitis B (positive hepatitis B surface antigen [HBsAg]
result) will be excluded. Patients with a past or resolved HBV infection (defined as
the presence of hepatitis B core Ab [HBcAb] and absence of HBsAg) are eligible.
17. Female patient is pregnant or breast-feeding, or planning to become pregnant during
study treatment and through 6 months after the last dose of study treatment.
18. History of or evidence of retinal pathology on ophthalmologic examination that is
considered a risk factor for neurosensory retinal detachment, central serous
chorioretinopathy, retinal vein occlusion (RVO), or neovascular macular degeneration.
Patients will be excluded from study participation if they currently are known to have any
of the following risk factors for RVO:
1. History of serous retinopathy;
2. History of retinal vein occlusion;
3. Evidence of ongoing serous retinopathy or RVO at baseline.
19. Patients with active central nervous system (CNS) lesions (i.e., those with
radiographically unstable, symptomatic lesions, including but not limited to carcinomatous
meningitis) and history of intracranial hemorrhage are excluded. However, patients are
eligible if:
1. Patients with all known CNS lesions have been treated with stereotactic therapy or
surgery, whose disease is stable without using corticosteroids; AND
2. There has been no evidence of clinical and radiographic disease progression in the CNS
for = 3 weeks after radiotherapy or surgery.
20. History of another primary malignant tumor, except the following: 1) the patient has
undergone potentially curative therapy with no evidence of that disease and recurrence for
3 years prior to the first dose of study treatment; 2) Adequately treated non-melanoma skin
cancer or lentigo with no evidence of malignancy; 3) Adequately treated carcinoma in situ
without evidence of disease.
21. Patients with moderate to large amount of pleural effusion, ascites or pericardial
effusion who need drug or medical intervention. Patient may be eligible to participate
following discussion with investigator and approval from the sponsor.
22. Unexplained > 38.5? fever (If the fever is caused by the tumor according to the
investigator's judgment, the patient can be enrolled) occurs during the Screening period or
on the day of administration, which in the judgment of investigator, would interfere with
patient participation in the study or evaluation of patient's efficacy.
23. History of seizure disorders within 6 months prior to Screening. 24. Active oral or
skin herpes lesion at Screening. 25. Plan to receive any other anti-tumor therapy
(including herbal therapy that has anti-tumor effects) during treatment with study drug.
26. History of congestive heart failure (> New York Heart Association Class II), active
coronary artery disease, unevaluated new onset angina within 3 months or unstable angina
(angina symptoms at rest), LVEF below institutional lower limit of normal or below 50%,
whichever is lower, poorly controlled hypertension, defined as sustained, uncontrolled,
nonepisodic baseline hypertension consistently above 159/99 mmHg despite optimal medical
management, or clinically significant cardiac arrhythmias.
27. Uncontrolled diabetes or symptomatic hyperglycemia. 28. History of allergic reactions
attributed to compounds of similar biological composition to HSV-1, IL-12, or anti-PD-1
monoclonal Ab or their excipients.
29. History of psychiatric disorders that would interfere with cooperation with the
requirements of the trial or is still requiring for medication control.
30. History of substance abuse (including alcohol) within 6 months prior to signing
informed consent.
31. Other systemic conditions or organ abnormalities that, in the opinion of the
investigator, may interfere with the conduct and/or interpretation of the current study.
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