Study of RP1 Monotherapy and RP1 in Combination With Nivolumab (IGNYTE)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Replimune Group Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

26 Aug 2021 → 16 May 2026

Decision date (initial)

2024-10-01

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Replimune, Inc.

External identifiers

EU CT number

2024-511728-15-00

EudraCT number

2016-004548-12

ClinicalTrials.gov

NCT03767348

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy

Phase 1:
• To determine the maximum tolerated dose (MTD) as determined by incidence of dose limiting toxicities (DLTs) and/or the recommended Phase 2 dose (RP2D) of RP1
• To assess the safety and tolerability of RP1 alone and in combination with nivolumab as determined by the incidence of all treatment-emergent adverse events (TEAEs), ≥ Grade 3 TEAEs, serious adverse events (SAEs), and TEAEs requiring withdrawal from investigational product (IP) treatment

Phase 2:
Primary:
• To assess the safety and tolerability of RP1 in combination with nivolumab as determined using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 (v5.0) by the incidence of all TEAEs, ≥ Grade 3 TEAEs, SAEs, and TEAEs requiring withdrawal from RP1 treatment
• To assess the efficacy of RP1 in combination with nivolumab as determined by ORR 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 as determined by ORR according to independent review

Secondary objectives 6

1. Phase 1 To assess the biological activity as determined by individual tumor responses (including changes in tumor size, inflammation, necrosis, and erythema at injected and non-injected tumor sites)
2. Phase 1 To assess the incidence of RP1 detection in blood and urine during the treatment period
3. Phase 1 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
4. Phase 1 To assess the changes in levels of anti-herpes simplex virus 1 (anti-HSV-1) antibodies during treatment compared to baseline
5. Phase 2: To assess the efficacy of RP1 in combination with nivolumab as determined by duration of response (DOR), CR rate, disease control rate (DCR), progression-free survival (PFS), and 1-year and 2-year overall survival (OS) according to Investigator review
6. Phase 2: • To assess the efficacy of RP1 in combination with nivolumab in the anti-PD1 failed melanoma cohort as determined by DOR, CR rate, DCR, and PFS according to independent review

Conditions and MedDRA coding

Solid tumors

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 28

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 1 measurable 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 9.6.9).
5. Female patients of reproductive potential must agree to avoid becoming pregnant and adhere to a highly effective contraception method until 90 days after the last dose of RP1 alone or 150 days after the last dose of RP1 and nivolumab. For a definition of highly effective contraceptive methods and instructions of patients and partners (see Section 9.6.9).
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 9.6.9).
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. If total bilirubin is > 1.5 × ULN but ≤ 3 × ULN, both aminotransferase (AST and ALT) levels must be ≤ 3 × ULN. b. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3.0 × ULN (or ≤ 5.0 × ULN, if liver metastases). Note: If aminotransferase levels (AST and/or ALT) are > 3 × ULN but ≤ 5 × ULN, total bilirubin must be ≤ 1.5 × ULN. c. Alkaline phosphatase (ALP) ≤ 2.5 × ULN (or ≤ 5.0 × ULN, if liver or bone metastases).
9. Adequate renal function: Blood creatinine ≤ 1.5 × ULN or measured or calculated (using Cockcroft) creatinine clearance ≥ 30 mL/minute for patients with creatinine levels > 1.5 × institutional ULN.
10. Coagulation: a. Prothrombin time (PT) or international normalization ratio (INR) ≤ 1.5 × ULN, and partial thromboplastin time (PTT) or activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN. Note: Patients who are on chronic anticoagulant therapy may be enrolled if pretreatment INR < 2.5 × ULN. (Guidance for the peri-procedural management of anticoagulants is provided in Appendix E).
11. Patients must have an ECOG performance status (PS) ≤ 1.
12. Phase 1 patients only: 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.
13. Phase 1 Expansion and Phase 2 patients only: 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. Phase 1 Expansion and Phase 2 patients only: Measurable disease based upon RECIST v1.1. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.
15. Phase 1 Expansion and Phase 2 Patients only: Life expectancy of at least 3 months.
16. Melanoma cohort: Diagnosis of Stage IIIb-IV melanoma (ocular and mucosal allowed).
17. Melanoma cohort: Patients for whom PD1 directed therapy is indicated according to a current approved label or who have previously received a PD1/PD-L1 directed therapy, or have exhausted or become intolerant to, or refuse, currently available therapies for melanoma. Note: Only 1 line of prior systemic therapy for metastatic disease (combination ipilimumab/nivolumab is considered 1 line of therapy for the purposes of determining eligibility), other than adjuvant, is allowed.
18. Anti-PD1 failed cutaneous melanoma cohort: Diagnosis of unresectable Stage IIIb-IV cutaneous melanoma.
19. Anti-PD1 failed cutaneous melanoma cohort: Disease progression must have been confirmed and documented using clinical or radiological assessment by 2 assessments at least 4 weeks apart while being treated with an anti-PD1 antibody (e.g., nivolumab or pembrolizumab), administered either as monotherapy or in combination with anti-cytotoxic T-lymphocyte antigen-4 (anti–CTLA-4) (e.g., ipilimumab), targeted therapies, chemotherapy, or investigational agents (oncolytic virus [OV] therapy excluded) for at least 8 consecutive weeks.
20. Anti-PD1 failed cutaneous melanoma cohort: Treatment with prior anti-PD1 therapy must have continued from the time of initial tumor progression until confirmation of progressive disease (PD) (i.e., such that no doses of anti-PD1 therapy are missed). Radiological confirmation o-f PD can occur during the screening period for this study. Note: If radiographic progression at the initial scan where progression was documented is accompanied by clear clinical progression, defined as a decline in performance status directly attributed to disease or increased disease related symptoms, anti-PD1 therapy does not need to continue.
21. Anti-PD1 failed cutaneous melanoma cohort:Patients must have known and documented BRAF mutation status. If BRAFV600 mutation-positive, a BRAF inhibitor alone or BRAF/MEK directed therapy (at Investigator’s discretion) is also allowed prior to anti-PD1 therapy.
22. Anti-PD1 failed cutaneous melanoma cohort: Patients treated with anti-PD1 in the adjuvant setting with documented disease progression while on adjuvant therapy may enroll. In this setting, a confirmatory biopsy can be used in place of a confirmatory scan. Germany-specific IC #22: Patients with known and documented BRAF mutation status should have received appropriate standard of care unless they have refused such therapy or are intolerant to such therapy.
23. Anti-PD1 failed cutaneous melanoma cohort: Lactate dehydrogenase (LDH) < 2.0 × ULN. Up to 20% of patients with LDH ≥ 2 × ULN may enroll provided all other eligibility criteria are met.
24. MSI-H or dMMR cohort: Diagnosis of metastatic MSI-H or metastatic dMMR who have progressed on prior anti-PD-1/PD-L1 therapy. France-specific IC #24: Diagnosis of metastatic MSI-H or metastatic dMMR who have progressed on prior anti-PD1 therapy and have exhausted, become intolerant to, or in the opinion of the Investigator are not candidates for any other currently available therapies for their cancer. Note: Anti-PD-1 therapy must be the immediate prior therapy.
25. NMSC cohort: Histologic diagnosis of locally advanced or metastatic NMSC that are not considered treatable with surgical excision; including patients with basal cell carcinoma (BCC), cutaneous squamous cell carcinoma (CSCC), basosquamous carcinoma (BSC), Merkel cell carcinoma (MCC), high grade dermatofibrosarcoma protuberans (DFSP), angiosarcoma of the skin, non-human immunodeficiency virus (non-HIV)-related Kaposi’s sarcoma, sebaceous gland carcinoma, and eccrine carcinomas including eccrine porocarcinoma, hidradenocarcinoma, mucinous eccrine carcinoma, and microcystic adnexal carcinoma; cutaneous T-cell lymphoma (CTCL) is excluded. a. Anti-PD1/PD-L1 naïve NMSC patients: patients for whom PD1/PD-L1 directed therapy is indicated according to a current approved label or have exhausted or become intolerant to, or refuse, currently available therapies for their cancer. France-specific IC #25: Anti-PD-L1 naïve NMSC patients: patients for whom PD1/PD-L1 directed therapy is indicated according to a current approved label or have exhausted or become intolerant to currently available therapies for their cancer. b. Anti-PD1/PD-L1 failed NMSC patients: Patients must have received at least 8 weeks of anti-PD1/PD-L1 as their last line of therapy and progressed while on treatment. For CSCC, mixed histology may be allowed, provided that the major histological component is SCC, after consultation with the Medical Monitor. Note: Patients with CSCC may have received prior chemotherapy or epidermal growth factor receptor (EGFR) inhibitor therapy. Patients with NMSC and co-existing chronic
26. Anti-PD1/PD-L1 failed NSCLC cohort: Histologically confirmed diagnosis of squamous or non-squamous NSCLC.
27. Anti-PD1/PD-L1 failed NSCLC cohort: Must have failed prior treatment, including PD1/PD-L1 directed therapy administered either as monotherapy or in combination with platinum-based chemotherapy or anti-CTLA-4. The most recent treatment regimen must have included an anti-PD1/PD-L1 directed therapy with radiologic disease progression on or after treatment. Note: Patients with documented, known genomic tumor aberrations such as EGFR, ALK, ROS1, or BRAF V600E should also have received appropriate standard of care targeted therapy. France-specific IC #27: Must have failed prior standard-of-care treatment, including PD1/PD-L1 directed therapy administered either as monotherapy or in combination with platinum-based chemotherapy or anti-CTLA-4 and chemotherapy, when appropriate. The most recent treatment regimen must have included an anti-PD1/PD-L1 directed therapy with radiologic disease progression on or after treatment. Note: Patients with documented, known genomic tumor aberrations such as EGFR, ALK, ROS1, or BRAF V600E should also have received appropriate standard of care targeted therapy.
28. Anti-PD1/PD-L1 failed NSCLC cohort: Has measurable disease per RECIST v.1.1 with no tumor exceeding 7 cm in longest diameter. Notes: (a) A minimum of 30% of patients should have liver metastases that are suitable and intended for IT injection with RP1. (b) Patients who only exhibit disease that may be invading the heart, great vessels, or other critical structures, and no other injectable lesions, are not eligible.

Exclusion criteria 26

1. Prior treatment with an oncolytic therapy.
2. With active significant herpetic infections or prior complications of HSV-1 infection (e.g., herpetic keratitis or encephalitis).
3. Systemic anticancer therapies, excluding PD1/PD-L1 directed therapy alone or in combination, within 4 weeks prior to enrollment or 5 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. Note: Patients with toxicities after prior anticancer therapies that are not considered a likely safety risk such as Grade ≤ 2 neuropathy or alopecia, or immune mediated AEs that are unlikely to recur with standard countermeasures (e.g., hormone replacement after adrenal crisis, stable endocrine insufficiencies such as thyroid and adrenal insufficiency), are an exception to this criterion and may qualify for the study in discussion with the Medical Monitor.
4. 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.
5. Active leptomeningeal disease or uncontrolled, untreated brain metastasis: Patients with a history of treated brain metastasis and, at the time of screening, asymptomatic stable 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 first dose of study drug.
6. Major surgery ≤ 2 weeks prior to starting study drug. Note: Patients who undergo major surgery must have recovered prior to starting study treatment.
7. 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).
8. Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis
9. 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.
10. Has serious or uncontrolled medical disorders
11. Has known psychiatric, alcohol abuse, or substance abuse disorders that would interfere with cooperating with the requirements of the study.
12. 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.
13. 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.
14. 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. Note: Patients who have entered the follow-up phase of an investigational study may participate as long as it has been at least 4 weeks since the last dose of the previous investigational agent.
15. History of interstitial lung disease.
16. History of documented allergic reactions or acute hypersensitivity reactions attributed to RP1 or nivolumab or any of its excipients
17. 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. A one-week washout is permitted for palliative radiation (≤ 2 weeks of radiotherapy) to non-CNS disease.
18. 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. Note: Available COVID-19 vaccines do not contain live virus (see Section 7.0).
19. 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 (HCV) (defined as HCV RNA [qualitative]) or HIV infection. Note: No testing for hepatitis B, hepatitis C, or HIV is required unless mandated by local health authority or clinically indicated
20. Had systemic infection requiring intravenous (IV) antibiotics or other serious infection within 14 days prior to dosing.
21. Is a person deprived of their liberty by a judicial or administrative decision, or an adult person subject to a legal protection measure.
22. Germany-specific additions: Patients requiring chronic use of systemic (oral or IV) antiviral medication with known antiherpetic activity (e.g., acyclovir).
23. Germany-specific additions: Has known hypersensitivity to contrast agent and its excipients or inability to undergo contrast-mediated imaging.
24. Phase 1 Expansion and Phase 2 patients only: 22. Treatment with botanical preparations (e.g., herbal supplements or traditional Chinese medicines) intended for general health support or to treat the disease under study within 2 weeks prior to first dose and throughout the study.
25. Phase 1 Expansion and Phase 2 patients only: Patients with an active, known, or suspected autoimmune disease. Patients with Type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.
26. Phase 1 Expansion and Phase 2 patients only: May not have a history of life-threatening toxicity related to prior immune therapy except those that are unlikely to recur with standard countermeasures (e.g., hormone replacement after adrenal crisis).

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 6

1. Phase 1: The primary endpoint for determination of MTD is the incidence of AEs and clinical laboratory abnormalities defined as DLT
2. Phase 1: 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, SAEs, events requiring withdrawal from IP treatment
3. Phase 2: Primary 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
4. Phase 2: Primary Efficacy Endpoint: 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 coh
5. Phase 2: Primary Safety Endpoints • Incidence of TEAEs, using CTCAE v5.0, ≥ Grade 3 TEAEs and SAEs in all patients
6. Phase 2: Primary Safety Endpoint: Incidence of TEAEs, using CTCAE v5.0, requiring withdrawal from the study treatment in all patients

Secondary endpoints 16

1. Phase 1: Incidence of changes in individual tumor sizes, inflammation, necrosis and erythema in injected and noninjected tumor
2. Phase 1: Incidence of clearance of RP1 from blood and urine before and after each injection
3. Phase 1:Rate of RP1 detection on exterior of the dressing, injected lesions, saliva/oral mucosa and lesions that are herpetic in appearance
4. Phase 1: Changes in HSV-1 antibody levels during treatment compared to baseline
5. Phase 1: Overall ORR as assessed by modified RECIST v1.1
6. Phase 1: Dose Expansion Phase only: Incidence of positive PD-L1 expression, CD8+ T cell infiltration and positive interferon-gamma gene signature by Nanostring analysis
7. Phase 1:Duration of clinical benefit defined as duration of CR, PR, or SD according to modified RECIST v1.1
8. Phase 2: Secondary Efficacy Endpoints: ORR, DOR, CR rate, DCR, PFS, and OS according to Investigator review
9. Phase 2: Secondary Efficacy Endoints: ORR, DOR, CR rate, DCR, PFS, and OS will also be assessed by independent central review for the anti-PD1 failed cutaneous melanoma cohort
10. Phase 2: Secondary Efficacy Endoints: Time to next therapy
11. Phase 2:To assess the incidence of clearance of RP1 from blood and urine overall, by baseline HSV1 serostatus, and by route of injection (superficial vs deep)
12. Phase 2: To assess rate of detection of RP1 from the injection site, exterior of the injection site dressing, oral mucosa/saliva, and any lesions that appear herpetic during the study
13. Phase 2: To assess evidence of immune response through biomarker analysis of tumor biopsy and peripheral blood specimens in select patients
14. Phase 2: To assess the changes in levels of anti–HSV-1 antibodies during RP1 treatment compared to baseline
15. Phase 2: To explore the response rates in lesions that were never injected
16. Phase 2: To assess health-related quality of life for patients in the anti-PD1 failed cutaneous melanoma cohort using the EORTC QLQ-C30

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 6

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Replimune Group Inc.

Sponsor organisation

Replimune Group Inc.

Address

500 Unicorn Park Drive Floor Third

City

Woburn

Postcode

01801-3377

Country

United States

Scientific contact point

Organisation

Replimune Group Inc.

Contact name

Kari Jeschke, SVP Regulatory Affairs

Public contact point

Organisation

Replimune Group Inc.

Contact name

Kari Jeschke, SVP Regulatory Affairs

Third parties 11

Locations

3 EU/EEA countries · 9 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 19 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

3 submissions — initial application plus substantial / non-substantial modifications