| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10049280 |
| E.1.2 | Term | Solid tumour |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
For Phase 1 -
•To determine the MTD as determined by incidence of DLTs and/or the RP2D of RP1
•To assess the safety and tolerability of RP1 alone and in combination with nivolumab as determined by the incidence of all TEAEs, ≥ Grade 3 TEAEs, SAEs and TEAEs requiring withdrawal from investigational product (IP)
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 |
|
| E.2.2 | Secondary objectives of the trial |
For Phase 1-
• To assess biological activity as determined by individual tumor responses (including changes in tumor sizes, inflammation, necrosis and erythema at injected and non-injected tumor sites)
• To assess incidence of RP1 detection in blood and urine during the treatment period
• To assess the rate of detection of RP1 in saliva/oral mucosa, at the injection sites, exterior of dressings and lesions that appear to be herpetic during the treatment period
• To assess the changes in levels of anti-HSV-1 antibodies during the treatment period compared to baseline
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
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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 (β-hCG) test with a minimum sensitivity of 25 IU/L or equivalent units of β-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 × 109/L
b. Absolute neutrophil count (ANC) ≥ 1.5 × 109/L
c. Platelet count ≥ 100 × 109/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 < 3.0 × ULN) or direct bilirubin ≤ ULN for a patient with total bilirubin level > 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 provided either a formalin-fixed, paraffin-embedded (FFPE) tissue block or unstained
tumor tissue sections, obtained within 6 months prior to enrollment, with an associated
pathology report, which must be submitted to the core laboratory for inclusion. Biopsy should be excisional, incisional or core needle. Fine needle aspiration is unacceptable for submission. A fresh biopsy is required at screening if an archival biopsy (within 6 months prior to enrollment) is not available.
14. Measurable disease as assessed by the local site based upon RECIST v1.1 as modified for
use in this study. Lesions situated in a previously irradiated area are considered measurable
if progression has been demonstrated in such lesions.
15. Life expectancy of at least 3 months
Patients with melanoma, Anti-PD1 failed cutaneous melanoma, Patients with MSI-H or dMMR, Patients with NMSC, Patients with anti-PD1/PD-L1 failed NSCLC:
Please see Protocol for additional inclusion criteria for each of the specific groups of patients
See protocol for inclusion criteria for each specific group of patients ( |
|
| E.4 | Principal 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), yellow fever, rabies, Bacille Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist®) are live attenuated vaccines and are not allowed.
16. Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis
17. Has a history or current evidence of any condition, therapy, or laboratory abnormality that will be unfavorable for the administration of study drug or affect the explanation of drug toxicity or AEs, or interfere with the patient’s participation for the full duration of the study, or is not in the best interest of the patient to participate, in the opinion of the treating Investigator.
18. Has serious or uncontrolled medical disorders
19. Has known psychiatric, alcohol abuse, or substance abuse disorders that would interfere with cooperating with the requirements of the study
20. Has clinically significant cardiovascular disease within 12 months from first dose of study drug, including New York Heart Association Class III or IV congestive heart failure, unstable angina, myocardial infarction, cerebral vascular accident, or cardiac arrhythmia associated with hemodynamic instability.
See protocol for additional exclusion criteria for all patients and for specific patients groups and for clarifications on exclusion criteria |
|
| E.5 End points |
| E.5.1 | 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 TEAEs and SAEs in all patients
• Incidence of TEAEs, using CTCAE v4.03, requiring withdrawal from the study treatment in all patients |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Phase 1
Dose Esclalation
The primary analysis for safety will occur when all cohorts have completed dosing, including analysis by administration method and had the opportunity to complete the follow-up visit and tumor assessments. The primary analysis clinical activity will be summarized at this time. The RP2D will be determined based upon the review of both safety and clinical activity data.
Dose Expansion
The primary analysis will occur when all expansion patients have completed dosing and had the opportunity to complete the follow-up visit and tumor assessments.
Response assessments will be carried out 30 days (+/-7) after last dose.
Phase 2
Response assessments will be carried out every 8 weeks (±7 days) after Day 1. |
|
| E.5.2 | 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
|
|
| E.5.2.1 | 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. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | Yes |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 7 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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