Phase I/II Study of AloCelyvir in Patients With Metastatic Uveal Melanoma

Inclusion Criteria:

* Patients must have histologically confirmed metastatic uveal melanoma with measurable disease not eligible for curative therapy.
* Participants must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for nonnodal lesions and short axis for nodal lesions) as ≥20 mm with conventional techniques or as ≥10 mm with spiral CT scan, PET/CT, MRI, or calipers by clinical exam. Patients must have at least 1 biopsiable liver metastasis.
* Patients can have received prior therapy for metastatic disease, excepting for treatments listed in exclusion criteria.
* Patients must be 18 years of age or older at time of study entry.
* Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1.
* Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. Written informed consent and any locally required authorization obtained from the patient/legal representative prior to performing any protocol-related procedures, including screening evaluations not performed according to normal practice. Patient must consent for liver metastasis biopsies donation at day 0 and day +28 since treatment initiation.
* Adequate normal organ and marrow function as defined below:

  * Haemoglobin ≥9.0 g/dL
  * Absolute neutrophil count (ANC) \> 1.5 x 109/L (\> 1500 per mm3)
  * Platelet count ≥ 100 x 109/L (\>100,000 per mm3)
  * Serum bilirubin ≤1.5 x institutional upper limit of normal (ULN). This will not apply to patients with confirmed Gilbert's syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis or hepatic pathology), who will be allowed only in consultation with Coordinating Investigator.
  * Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) ≤3 x ULN.
  * Creatinine clearance ≤1.5 x ULN or a calculated by Cockcroft-Gault \>60 ml/min/1,73.
* Female participant has a negative serum pregnancy test prior to revieving study treatment if of childbearing potential and agrees to abstain from activities that could result in pregnancy from screening through 150 days after the last dose of study treatment, or is of non-childbearing potential.
* Postmenopausal or evidence of non-childbearing status for women of childbearing potential as confirmed by a negative urine or serum pregnancy test within 7 days prior to inclusion. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply:

  * Amenorrheic for ≥1 year in the absence of chemotherapy and/or hormonal treatments,
  * Luteinizing hormone (LH) and/or follicle stimulating hormone and/or estradiol levels in the post-menopausal range,
  * Radiation induced oophorectomy with last menses \>1 year ago,
  * Chemotherapy induced menopause with \>1 year interval since last menses,
  * Surgical sterilization (bilateral oophorectomy or hysterectomy).
* Women \<50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy).
* Women ≥50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses \>1 year ago, had chemotherapy-induced menopause with last menses \>1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy).
* Contraceptive use by men should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. Male participants are eligible to participate if they agree to the following during the intervention period and for at least 120 days after the last dose of study intervention:

  * Refrain from donating sperm, PLUS either:
  * Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent, OR
  * Must agree to use contraception, unless confirmed to be azoospermic (vasectomized or secondary to medical cause ), as detailed below:
  * Agree to use a male condom plus partner use of an additional contraceptive method when having penile-vaginal intercourse with a WOCBP who is not currently pregnant. Note: Men with a pregnant or breastfeeding partner must agree to remain abstinent from penile-vaginal intercourse or use a male condom during each episode of penile-vaginal penetration.
  * Male participants must agree to use male condom when engaging in any activity that allows for passage of ejaculate to another person of any sex.
* Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up.
* Must have a life expectancy of at least 12 weeks.

Exclusion Criteria:

* Prior treatment with Celyvir or AloCelyvir. Previous treatment with immune checkpoint blockaders (E.g. anti-PD1/PDL1 or anti CTLA4) are permitted.
* Prior malignancy except for any of the following:

  * Carcinoma in situ or non melanoma skin cancer.
  * Any prior malignancies ≥3 years before randomization with no subsequent evidence of recurrence or progression regardless of the stage.
  * Stage 0 or Stage 1 cancer \<3 years before randomization that has a remote probability of recurrence or progression in the opinion of the investigator.
* Patients with brain or leptomeningeal involvement should be clinically stable with unchanged or descendant steroids (≤10mg/day of prednisone or its equivalent) for at least 2 weeks.
* Patients weighing \<30kg will be excluded from enrollment.
* Participation in another clinical study with an investigational product during the last 4 weeks.
* Concurrent enrolment in another clinical study, unless it is an observational (noninterventional) clinical study or during the follow-up period of an interventional study.
* Receipt of the last dose of anticancer therapy (chemotherapy, immunotherapy, endocrine therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal antibodies) ≤28 days prior to the first dose of study drug If sufficient wash-out time has not occurred due to the schedule or PK properties of an agent, a longer wash-out period will be required, as agreed by Sponsor designated Coordinating Investigator and Principal Investigator.
* Any unresolved acute toxicity NCI CTCAE Grade ≥3 from previous anticancer therapy.
* Any concurrent chemotherapy, IMP, biologic, or hormonal therapy for cancer treatment different to AloCelyvir. Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., hormone replacement therapy) is acceptable.
* Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation within 4 weeks of the first dose of study drug.
* Major surgery within a minimum of 2 weeks prior to inclusion; patients must have recovered from any effects of any major surgery prior to inclusion. Note: Local surgery of isolated lesions for palliative intent and minor surgeries performed to obtain biological material for the study (i.e. liver biopsy) are acceptable.
* History of allogeneic organ transplantation.
* Active and prior serious documented autoimmune or inflammatory disorders that suppose an unacceptable risk according to investigators criteria.
* Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent.
* History of active primary immunodeficiency.
* Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice), hepatitis B (known positive HBV surface antigen (HBsAg) result), hepatitis C, or human immunodeficiency virus (positive HIV 1/2 antibodies). Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody \[anti-HBc\] and absence of HBsAg) are eligible. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
* Current or prior use of immunosuppressive medication within 14 days before the first dose of AloCelyvir. The following are exceptions to this criterion:

  * Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection)
  * Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent
  * Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication).
* Receipt of live attenuated vaccine within 30 days prior to the first dose of AloCelyvir. Note: Patients, if enrolled, should not receive live vaccine whilst receiving AloCelyvir and up to 30 days after the last dose of AloCelyvr.
* Female patients who are pregnant (confirmed with positive pregnancy test) or breastfeeding or male or female patients of reproductive potential who are not willing to employ effective birth control from screening to 90 days after the last dose AloCelyvir.
* History of severe allergic reaction attributed to Celyvir or known hypersensitivity to any component of AloCelyvir dose composition.
* Resting ECG with clinically significant abnormal findings.
* Subjects with any one or more of the following:

  * History of myocardial infarction within 6 months prior to inclusion; patients with a history of myocardial infarction within 6 to 12 months prior to inclusion may be allowed following assessment
  * Unstable angina within 6 months prior to inclusion
  * Known significant cardiac disease (New York Heart Association \[NYHA\] classification of III or IV).
* History of stroke or transient ischemic attack within 6 months prior to inclusion.
* Evidence of any other disease, physical examination or laboratory finding giving reasonable suspicion of a disease or condition that puts the subject at high risk for treatment-related complication.
* Prior enrollment or treatment in a previous Alocelyvir clinical study regardless of treatment arm assignment.