Study of RP2 Monotherapy and RP2 in Combination With Nivolumab in Patients With Solid Tumors

Inclusion Criteria:

• Willing and able to participate and comply with all trial requirements and able toprovide signed and dated informed consent prior to initiation of any trialprocedures

• Male or Female ≥ 18 years of age

• Patients with advanced or metastatic non-neurological solid tumors, who haveprogressed on standard therapy or cannot tolerate standard therapy, or for whichthere is no standard therapy preferred to enrolment in a clinical trial

• Consent to provide archival tumour biopsy samples within 6 months, or a fresh tumourbiopsy is needed. Patients must also consent to provide on-treatment biopsies as perprotocol

• At least one measurable and injectable tumor of ≥ 1 cm in longest diameter (orshorter diameter for lymph nodes).

• Women of child-bearing potential (WOCBP) must have a negative urine pregnancy testat screening and a negative urine pregnancy test prior to administration of eachdose of RP2 or nivolumab

• WOCBP must agree to use adequate birth control throughout their participation andfor 3 months after RP2 alone and 5 months after nivolumab last study treatment

• Males with partners of child-bearing potential must agree to use adequate birthcontrol throughout their participation and for 3 months for RP2 alone and 7 monthsafter nivolumab last study treatment

• Have laboratory values (obtained ≤ 28 days prior to first infusion day) inaccordance with the study protocol

• Have an Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1

Cohort 2a only:

• Baseline ECG that does not show abnormalities according to the protocol

• Baseline troponin < 0.06 ng/mL

• Baseline oxygen saturation levels that do not show abnormalities according to theprotocol

Cohort 2b and Part 3 only:

• Patients in Cohort 2b should have histologically or cytologically confirmeddiagnosis of advanced or metastatic uveal melanoma, lung cancer, breast cancer, orgastrointestinal cancers (including but not limited to colorectal cancer [CRC] [microsatellite stable], gastric cancer, gastroesophageal junction cancer, andoesophageal cancer) (n=30)

• Patients with HCC and a diagnosis of hepatitis B must be off antiviral therapy forat least 4 weeks prior to enrollment.

• Patients with acute or chronic hepatitis B or C must be expected to not requireantiviral therapy during the RP2 treatment period.

• Patients with HCC who have evidence of acute or chronic hepatitis C infection musthave completed treatment for hepatitis C at least 1 month prior to study enrollment

• Patients in Part 3 should have solid tumours (excluding skin cancers) that theinvestigator deems suitable for RP2 monotherapy, including at least 10 patients withliver metastases from prevalent tumour types (e.g. lung, breast [including recurrentchest wall], and gastrointestinal cancers [colorectal, gastric, and oesophagealcancers]) (n=15)

• Patient has progressed during or after one to three prior systemic anticancertherapies for advanced or metastatic disease or during or within six months ofreceiving adjuvant therapy. Patients who, in the opinion of the investigator, aredeemed not appropriate candidates for standard-of-care systemic anticancer therapyfor advanced or metastatic disease, or who, after documented consultation with theirtreating physician, refuse standard-of-care systemic anticancer therapy may beeligible after discussion with the medical monitor

Exclusion Criteria:

• Prior treatment with an oncolytic virus therapy

• History of viral infections according to the protocol

• Systemic infection requiring IV antibiotics within 14 days prior to dosing

• Prior complications with herpes infections

• Chronic use of anti-virals

• Systemic therapies for cancer within five half-lives or 4 weeks of first dose;whichever is shorter

• Conditions that require certain doses of steroids (some doses and types will bepermitted)

• Known active brain metastases - previously treated brain metastases may be permitted

• Major surgery ≤ 2 weeks prior to starting study drug

• Prior malignancy active with the previous 3 years; except for locally curablecancers that have apparently been cured

• Female who has a positive urine pregnancy test or is breast-feeding or planning tobecome pregnant during study treatment and 90 days for RP2 alone or 5 months for RP2and nivolumab after the last dose of treatment

• Participation in another clinical study within 4 weeks prior to the first dose

• History of myocarditis or congestive heart failure (as defined by the New York HeartAssociation Functional Classification III or IV), or unstable angina, seriousuncontrolled cardiac arrhythmia, uncontrolled infection, or myocardial infarctionwithin 6 months of randomization

• History of allergy or sensitivity to study drug components

• Has known psychiatric or substance abuse disorders that would interfere withcooperating with the requirements of the study

Part 2 patients only:

• Participants with history of life-threatening toxicity related to prior immunetherapy except those that are likely to re-occur with standard countermeasures

• Treatment with botanical preparations within 2 weeks prior to treatment

• Certain autoimmune diseases, some types will be permitted

• History of interstitial lung disease

• Severe hypersensitivity to another monoclonal antibody

• Has received radiotherapy within 2 weeks of start of study treatment

• Has received a live vaccine within 28 days prior to first dose of study drug

• History of non-infectious pneumonitis

• History or current evidence of any condition, therapy, or laboratory abnormalitythat might confound the results of the study

• Other serious or uncontrolled medical disorders

Cohort 2b and Part 3 (only for the subset of patients with liver metastases suitable and intended for injection)

• Presence of liver metastases that are estimated to invade more than one-third of theliver

• Macroscopic intravascular invasion into the main portal vein, hepatic vein or venacava

• Significant bleeding event within the last 12 months that places the patient at riskfor intrahepatic intratumoral injection procedure based on investigator assessment

• Prior chemoembolization, radioembolization, or other locoregional liver-directedprocedures to the lesion selected for intratumoral injection