A Study of ONCOS-102 in Combination With Other Novel Immune-therapies in Advanced Treatment-resistant Melanoma Patients

Study Overview
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Brief Summary
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A Phase 2 study investigating the efficacy and safety of ONCOS-102 alone or in combination with balstilimab (a programmed death receptor-1 [PD-1] inhibitor).

Detailed Description
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This study will test ONCOS-102 in combination with novel immune-targeted anti-cancer agents in patients with unresectable or metastatic cutaneous melanoma resistant to anti-PD (L)1 treatment. The purpose of this study is to further evaluate safety and tolerability, as well as anti-tumour activity of ONCOS-102 (both as monotherapy and in combination with anti-PD-1 balstilimab) in the target population. Following a safety run-in period, up to approximately 63 participants with cutaneous melanoma who previously progressed on anti-PD-1/L1-based therapy will be allocated 1:1 to receive either ONCOS-102 alone or ONCOS-102 plus balstilimab. Part 1 - Dose Exploration Run-in: Part 1 of the study will evaluate and further optimise the dose of ONCOS-102; a recommended phase 2 dose (RP2D) for ONCOS-102 will be identified. Part 2 - Multiple Expansion: In the expansion phase, ONCOS-102 alone or in combination with balstilimab will be further evaluated in Cohorts 1 and 2 using the RP2D identified in Part 1. The study is structured to allow for additional combination cohorts to be added to the study following a protocol amendment.

Official Title
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An Open-Label, Two-Part, Dose-Exploration and Multiple Expansion, Phase 2 Study of ONCOS-102 in Combination With Novel Immune-Targeted Anti-Cancer Agents in Patients With Unresectable or Metastatic Cutaneous Melanoma Resistant to Anti-PD-(L)1 Treatment

Conditions
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Melanoma

Intervention / Treatment
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* Biological: ONCOS-102
* Biological: Balstilimab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Be willing and able to provide written informed consent for the study. Be ≥ 18 years of age on the day of signing the informed consent form (ICF). Eastern Co-operative Oncology Group (ECOG) performance status 0 or 1. Histologically confirmed diagnosis of metastatic or unresectable malignant melanoma at screening with measurable disease (by RECIST v1.1) that is accessible for IT injection into cutaneous or subcutaneous lesions. Resistant to PD-(L)1 blockade (primary or secondary resistance in the advanced setting or relapse after adjuvant therapy) either as monotherapy or in combination with other therapies, as defined by the following criteria: Received at least 1 prior anti-PD-[L]1 immunotherapy regimen for a minimum of 6 weeks. Prior progression must be either on treatment with anti-PD-(L)1 or ≤ 12 weeks from last dose in metastatic setting or relapse ≤ 24 weeks from completion of therapy in adjuvant setting. Has demonstrated disease progression (PD) after anti-PD-(L)1 as defined by RECIST v1.1. The initial evidence of PD is to be confirmed by a second assessment (i.e., a confirmatory scan no less than 4 weeks from the date of the first documented PD), in the absence of clear clinical progression. Has recovered from all adverse events (AEs) due to previous therapies to ≤ Grade 1 or baseline. Patients with ≤ Grade 2 endocrinopathies stable on mediation, stable neuropathy, and alopecia are eligible. Exclusion Criteria: Uveal or mucosal melanoma. Any history of National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Grade ≥ 3 immune-mediated toxicity (excluding endocrinopathies and non-necrotising/bullous rash) from prior checkpoint inhibition. • If prior severe toxicity occurred during combination treatment with anti-PD-(L)1 + anti-cytotoxic lymphocyte associated antigen 4 (CTLA-4) but subsequent treatment with anti-PD-(L)1 as monotherapy was tolerated, the patient may be eligible for inclusion after discussion with the medical monitor. Has known (current or previously treated) central nervous system metastases and/or carcinomatous meningitis.

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
Interventional Model Description: 2 part dose escalation and multiple expansion phase 2 trial.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ONCOS-102<br>ONCOS-102 will be administered by intratumoral (IT) injection at 1.0×10^12 VP/dose with the potential to de-escalate dosing to 3.0×10^11 VP/dose. | Biological: ONCOS-102<br>* Oncolytic virus<br>|
| Experimental: ONCOS-102 and balstilimab<br>ONCOS-102 will be administered by IT injection at 3.0×10^11 VP/dose with planned dose escalation to 1.0×10^12 VP/dose. Balsitilmab will be administered at a fixed dose of 300 mg by intravenous (IV) injection. | Biological: ONCOS-102<br>* Oncolytic virus<br>Biological: Balstilimab<br>* Anti PD-1<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of treatment-emergent adverse events [safety and tolerability] of ONCOS-102 monotherapy and ONCOS-102 plus balstilimab. | To determine the incidence of treatment emergent adverse events including treatment emergent serious adverse events assessed by CTCAE v5.0, treatment interruptions and discontinuations. | 90 days after last treatment | 
| To evaluate the objective response rate (ORR) in individual cohorts using RECIST v1.1 | The proportion of patients achieving confirmed complete (CR) or partial response (PR) per RECIST v1.1 criteria | Up to 27 months after the last patient first dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To evaluate the duration of response (DoR) in individual cohorts | Time from observed objective response to first occurrence of disease progression or death based on Investigator assessment according to RECIST v1.1 | Up to 27 months after the last patient first dose | 
| To evaluate progression-free survival (PFS) in the individual cohorts using the Kaplan-Meier method | Time from treatment initiation to first occurrence of disease progression or death based on Investigator assessment according to RECIST v1.1 | Up to 27 months after last patient recruited per cohort | 
| To evaluate overall survival (OS) in individual cohorts using the Kaplan-Meier method | Time from treatment initiation to death that occurred up to 24 months after the last patient recruited per cohort | Up to 27 months after last patient recruited per cohort | 
| To evaluate PFS rate estimates at 3, 6 and 12 months in individual cohorts | Proportion of patients with a partial or complete response to treatment observed at Month 3 (Month 6 and Month 12) based on RECIST v1.1 | 3, 6 and 12 months after last patient recruited per cohort | 
| To evaluate systemic exposure of ONCOS-102 | Concentration of virus particles in blood and non-compartmental PK parameters as data allow. | Up to 24 months after last patient in the PK sampling group | 
| To estimate baseline presence and incidence of ONCOS-102 anti-drug antibodies (ADA) and neutralising antibodies (NAb) during study | ADA (screening, confirmatory results: positive or negative; titres), NAb (titres) | Up to 24 months after last patient in the pharmacokinetic sampling group | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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refractory, metastatic, ONCOS-102, balstilimab, checkpoint inhibitor, oncolytic virus, PD-1, PD-L1