Advanced solid tumours MedDRA version: 21.0 Level: LLT Classification code 10049280 Term: Solid tumour System Organ Class: 100000004864
Conditions
Sponsors
Replimune Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: All patients: 1. Voluntary agreement to provide written informed consent prior to any study procedures and the willingness and ability to comply with all aspects of the protocol 2. Male or female = 18 years of age on the day of signed informed consent 3. At least one measurable (including use of image guided injection) tumor of = 1 cm in longest diameter or = 1.5 cm in shortest diameter for lymph nodes) and injectable lesions which in aggregate comprise = 1 cm in longest diameter 4. Females of childbearing potential must have a negative beta-human chorionic gonadotropin (ß-hCG) test with a minimum sensitivity of 25 IU/L or equivalent units of ß-hCG at screening within 72 hours before the first dose and a negative urine pregnancy test on Cycle 1 Day 1. For serum and urine pregnancy tests and instructions, see Section 9.6.8. 5. Female patients of reproductive potential must agree to avoid becoming pregnant and adhere to a highly effective contraception method until 90 days for RP1 alone or 150 days for RP1 and nivolumab after last dose of study agent. For a definition of highly effective contraceptive methods and instructions of patients and partners (see Section 9.6.8). 6. Male patients of reproductive potential must agree to avoid impregnating a partner and adhere to a highly effective contraception method until 90 days after last dose of RP1 and refrain from donating sperm during this period. For a definition of highly effective contraceptive methods and instructions of patients and partners (see Section 9.6.8). 7. Adequate hematologic function including: a. White blood cell count (WBC) = 2.0 × 10^9/L b. Absolute neutrophil count (ANC) = 1.5 × 10^9/L c. Platelet count = 100 × 10^9/L d. Hemoglobin = 9 g/dL or = 5.6 mmol/L (without erythropoietin dependency and without packed red blood cell (pRBC) transfusion within 2 weeks of dosing) 8. Adequate hepatic function including: a. Total bilirubin = 1.5 × upper limit of normal (ULN) (except patients with Gilbert Syndrome who must have a total bilirubin of 1.5 × ULN b. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) = 3.0 × ULN (or = 5.0 × ULN, if liver metastases) c. Alkaline phosphatase (ALP) = 2.5 × ULN (or = 5.0 × ULN, if liver or bone metastases) 9. Adequate renal function including: a. Blood creatinine = 1.5 × ULN or measured or calculated (using Cockcroft) creatinine clearance = 40 cc/minute for patients with creatinine levels > 1.5 × institutional ULN 10. Coagulation: a. Prothrombin time (PT) or international normalization ratio (INR) = 1.5 × ULN, unless the patient is receiving anticoagulant therapy, in which case PT and partial thromboplastin time (PTT)/activated PTT (aPTT) must be within therapeutic range of intended use of anticoagulants b. PTT or aPTT = 1.5 × ULN unless the patient is receiving anticoagulant therapy as long as PT and PTT/aPTT is within therapeutic range of intended use of anticoagulants 11. Patients must have an ECOG performance status (PS) = 1. Phase 1 patients only: 12. Patients with histologically or cytologically confirmed advanced or metastatic non-neurological solid tumors, who have progressed on standard therapy or cannot tolerate standard therapy, or for which there is no standard therapy preferred to enrollment in a clinical trial. Note: There is no limit to the number of prior treatment regimens. Phase 1 Expansion and Phase 2 patients only: 13. Have pro
Exclusion criteria
Exclusion criteria: All patients: 1. Prior treatment with an oncolytic therapy 2. Has acute or chronic active hepatitis B and C virus infection or known history of hepatitis B (defined as hepatitis B surface antigen [HBsAg] reactive) or known active hepatitis C virus (defined as HCV RNA [qualitative]) or HIV infection. 3. Had systemic infection requiring intravenous (IV) antibiotics or other serious infection within 14 days prior to dosing 4. With active significant herpetic infections or prior complications of HSV-1 infection (e.g., herpetic keratitis or encephalitis) 5. Systemic anticancer therapies, excluding PD1/PD-L1 directed therapy alone or in combination, within 4 weeks prior to enrollment or five half-lives, whichever is shorter, before the first administration of RP1 or has not recovered from all AEs due to previous therapies to CTCAE Grade 1 or baseline. 6. Conditions requiring treatment with immunosuppressive doses (> 10 mg daily prednisone or equivalent) of systemic corticosteroids other than for corticosteroid replacement therapy within 14 days of enrollment. For the definition of replacement therapy, see Section 7.3. 7. Active leptomeningeal disease or uncontrolled, untreated brain metastasis: Patients with a history of treated brain metastasis and, at the time of screening, asymptomatic stable central nervous system (CNS) metastases are eligible, provided they meet all the following: a. Brain imaging at screening shows no evidence of interim progression for at least 4 weeks by repeat imaging, and clinically stable for at least 2 weeks b. Have measurable disease outside the CNS c. Only supratentorial metastases allowed d. No ongoing requirement for corticosteroids as therapy for CNS disease; anticonvulsants at a stable dose allowed e. No stereotactic or whole-brain radiation within 14 days prior to enrollment 8. Major surgery = 2 weeks prior to starting study drug. Note: If patient received major surgery, he or she must have recovered adequately from the toxicity and/or complications from the intervention prior to starting study treatment. 9. Any active malignancy = 3 years before enrollment except for the specific cancer under investigation in this study and locally recurring cancer that has been treated curatively (e.g., resected basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast) 10. Female who has a positive serum pregnancy test (at screening within 72 hours before dosing) or urine pregnancy test (Cycle 1 Day1) or is breastfeeding or planning to become pregnant during study treatment or within 90 days (RP1 alone) or 150 days (RP1 and nivolumab) after the last dose of study treatment 11. Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment. 12. History of interstitial lung disease 13. History of documented allergic reactions or acute hypersensitivity reaction attributed to RP1 or nivolumab or any of its excipients. 14. Has received prior radiotherapy within 2 weeks of start of study treatment. Patients must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. 15. Has received a live vaccine within 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox)
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Please see protocol for Phase 1 For Phase 2 •To assess the safety and tolerability of RP1 in combination with nivolumab as determined using CTCAE v4.03 by the incidence of all TEAEs, = Grade 3 TEAEs, SAEs, and TEAEs requiring withdrawal from IP treatment •To assess efficacy of RP1 in combination with nivolumab as determined by ORR according to RECIST 1.1 criteria, as modified for use in this study according to investigator review •To assess the efficacy of RP1 in combination with nivolumab in the anti–programmed cell death protein 1 (anti-PD1) failed cutaneous melanoma cohort using RECIST v1.1 as modified for use in this study as determined by ORR according to independent review;Secondary Objective: Please see the protocol for Phase 1 For Phase 2 •To assess efficacy of RP1 in combination with nivolumab as determined by DOR, complete response (CR) rate, disease control rate (DCR), PFS and 1-year and 2- year OS • To assess the efficacy of RP1 in combination with nivolumab in the anti-PD1 failed melanoma cohort using RECIST v1.1 as modified for use in this study as determined by DOR, CR rate, DCR, and PFS according to independent review;Primary end point(s): Phase 1 • The primary endpoint for determination of MTD is the incidence of AEs and clinical laboratory abnormalities defined as DLT, and • The primary endpoints for determination the safety and tolerability of RP1 alone and in combination with nivolumab will be determined by the incidence of all TEAEs, = Grade 3 TEAEs, serious adverse events (SAEs), events requiring withdrawal from the study Phase 2 Efficacy Endpoints: • ORR for RP1 in combination with nivolumab using RECIST v1.1 as modified for use in this study as determined by investigator review • ORR for RP1 in combination with nivolumab using RECIST v1.1 as modified for use in this study assessed by independent review for the anti-PD1 failed cutaneous melanoma cohort. Safety Endpoints: • Incidence of TEAEs, using CTCAE v4.03, = Grade 3 | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Phase 1 • Incidence of changes in individual tumor sizes, inflammation, necrosis and erythema in injected and uninjected tumors • Incidence of clearance of RP1 from blood and urine before and after each injection • Rate of RP1 detection on: exterior of the dressing, injected lesions, saliva/oral mucosa and lesions that are herpetic in appearance • Changes in HSV-1 antibody levels during treatment compared to baseline Phase 2 Efficacy Endpoints • ORR, DOR, CR rate, DCR, PFS, and 1-year and 2-year survival rates according to investigator review • ORR, DOR, CR rate, DCR, and PFS will also be assessed by independent central review for the anti-PD1 failed cutaneous melanoma cohort • Time to next therapy;Timepoint(s) of evaluation of this end point: Response assessments will be carried out every 8 weeks (±7 days) after Day 1 OS assessed at 1 year and 2 year timepoints RP1 detection for the first three doses at pre-dose, 6 (± 2hr) hours, 21 hours (±3 hr) and 48 hours (± 6hr) and also immediately prior to dosing at the fourth dose and at both the 30 day and 60 day follow-up visits. In the anti-PD1 refractory cutaneous melanoma cohort, patients will be followed for a total of 60 months from the start of study treatment. | — |
Countries
Australia, Spain, United Kingdom, United States
Contacts
Public ContactRegulatory Affairs
Replimune Inc
Outcome results
None listed