A Study of Tilsotolimod in Combo With Ipilimumab vs Ipilimumab Alone in Subjects With Anti-PD-1 Refractory Melanoma

Study Overview
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Brief Summary
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A Phase 3 comparison of ipilimumab with and without IMO-2125 in advanced melanoma

Detailed Description
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A Phase 3 global, multi-center, open-label comparison of ipilimumab with and without intratumoral IMO-2125 in subjects with advanced melanoma who had confirmed disease progression while on anti-PD-1

Official Title
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A Randomized Phase 3 Comparison of IMO-2125 With Ipilimumab Versus Ipilimumab Alone in Subjects With Anti-PD-1 Refractory Melanoma (ILLUMINATE-301)

Conditions
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Metastatic Melanoma

Intervention / Treatment
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* Drug: Ipilimumab
* Drug: Tilsotolimod with Ipilimumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects must be willing and able to sign the informed consent and comply with the study protocol. Subjects must be ≥18 years of age. Subjects must have histologically confirmed metastatic melanoma with measurable (by RECIST v1.1), stage III (lymph node or in transit lesions) or stage IVA, IVB, or IVC disease that is accessible for injection. Patients must have confirmed progression during or after treatment with a PD-1 inhibitor (cannot be part of a bi-specific antibody) e.g. nivolumab or pembrolizumab. Confirmed progression is defined as: Radiological progression (confirmed at least 4 weeks after the initial scan showing PD); or (For progression based solely on worsening of non-target or new, non-measurable disease) confirmation by an additional scan at least 4 weeks after the initial scan unless it is accompanied by correlative symptoms. In addition, all the following must hold: No intervening anti-cancer therapy between the last course of PD-1 inhibitor treatment and the first dose of study treatment is allowed except for local measures (e.g., surgical excision or biopsy, focal radiation therapy). The interval between last PD-1 inhibitor and start of study treatment should be at least 21 days with no residual anti-PD-1-related immune toxicities in excess of Grade 1 severity. If BRAF mutation status is unknown, before randomization the subject must have BRAF testing performed using an approved assay method. Patients with BRAF-positive tumor(s) are eligible for the study if they received prior treatment with a BRAF inhibitor (alone of in combination with a MEK inhibitor) or declined targeted therapy. Patients must have Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 1. Patients must meet the following laboratory criteria: Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L (1500/mm3) Platelet count ≥ 75 x 10^9/L (75,000/mm3) Hemoglobin ≥ 8.0 g/dL (4.96 mmol/L) Serum creatinine ≤ 1.5 x upper limit of normal (ULN) or calculated creatinine clearance ≥ 60 mL/minute Aspartate aminotransferase (AST) ≤ 2.5 x ULN; alanine aminotransferase (ALT) ≤ 2.5 x ULN; AST/ALT < 5 x ULN if liver involvement Serum bilirubin ≤ 1.5 x ULN, except in subjects with Gilbert's Syndrome who must have a total bilirubin < 3 mg/dL Women of childbearing potential (WOCBP) and men must agree to use effective contraceptive methods from Screening throughout the study treatment period and until at least 90 days after the last dose of either ipilimumab or IMO-2125, whichever is later. WOCBP must have a negative pregnancy test (serum or urine). Exclusion Criteria: Ocular melanoma. Prior therapy with a toll-like receptor (TLR) agonist, excluding topical agents. Prior ipilimumab treatment with the exception of adjuvant treatment completed ≥6 months prior to enrollment Systemic treatment with interferon (IFN)-α within the previous 6 months. Known hypersensitivity to any oligodeoxynucleotide. Active autoimmune disease requiring disease-modifying therapy at the time of Screening. Subjects requiring systemic steroid therapy receiving >10 mg/day of prednisone (or equivalent) for the 2 weeks preceding start of study. Subjects with another primary malignancy that has not been in remission for at least 3 years, with the exception of non-melanoma skin cancer, curatively treated localized prostate cancer with non-detectable prostate-specific antigen, cervical carcinoma in situ on biopsy or a squamous intraepithelial lesion on Papanicolaou (Pap) smear, and thyroid cancer (except anaplastic). Active systemic infections requiring antibiotics Active hepatitis A, B, or C infection. Known diagnosis of human immunodeficiency virus (HIV) infection. Women who are pregnant or breastfeeding. Prior severe reaction to treatment with a human antibody that cannot be managed with standard supportive measures. Presence of known central nervous system, meningeal, or epidural metastatic disease. However, subjects with known brain metastases are allowed if the brain metastases are stable for ≥4 weeks before the first dose of study treatment. Stable is defined as neurological symptoms not present or resolved to baseline, no radiologic evidence of progression, and steroid requirement of prednisone ≤10 mg/day or equivalent Impaired cardiac function or clinically significant cardiac disease.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A: ipilimumab<br>ipilimumab 3 mg/kg intravenous | Drug: Ipilimumab<br>* Arm A: 4 doses administered intravenously at a dose of 3 mg/kg over 90 minutes on Weeks 1, 4, 7, and 10.<br>* Other names: Yervoy®;|
| Experimental: Arm B: IMO-2125 plus ipilimumab<br>IMO-2125 by intratumoral injection plus ipilimumab 3 mg/kg intravenous | Drug: Tilsotolimod with Ipilimumab<br>* IMO-2125 intratumoral injection administered as 9 doses on Weeks 1, 2, 3, 5, 8, 11, 16, 20, and 24. WITH (Arm B): Ipilimumab administered as 4 doses on Weeks 2, 5, 8, and 11. in combination with tilsotolimod<br>* Other names: IMO-2125 with Yervoy;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Summary of Independent Reviewer-Assessed Objective Response Rate (ORR) by RECIST v1.1 | The ORR for evaluable participants was calculated using the participant's best overall response (BOR). Per Response Evaluation Criteria in Solid Tumors (RECIST v1.1) for target lesions as assessed by MRI, CT or X-ray: Complete Response (CR) - disappearance of all target lesions; Partial Response (PR) - >=30% decrease from baseline of the sum of diameters of all target lesions; Stable Disease (SD) - does not qualify for CR, PR or Progression; Progressive Disease (PD) - 20% increase in the sum of diameters of target lesions. The calculation is derived from measuring the diameter (mm) of the target lesion at baseline and comparing target lesion diameter (mm) at intervals during treatment and/or post-treatment. Based on the percent of tumor decrease or increase, the appropriate category is assigned. | Response is measured from the date of randomization, until disease progression, death, or start of new anti-cancer therapy (up to 36 months). | 
| Summary of Overall Survival | Efficacy measured by overall survival (OS) was defined as the number of participants alive compared to the number of participants that died by treatment group. | OS is measured from the date of randomization to the date of death from any cause (up to 36 months). | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Melanoma, PD1, PD-1, refractory, metastatic, IMO-2125, illuminate 301, TLR9 agonist, advanced melanoma, CTLA4, CTLA-4, immunotherapy, skin cancer, ILLUMINATE-301