Tinostamustine and Nivolumab in Advanced Melanoma

Study Overview
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Brief Summary
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This trial is a first-in-human drug combination with the first-in-class alkylating histone deacetylase inhibition (HDACi) fusion molecule Tinostamustine (EDO-S101) and the anti-PD-1 monoclonal antibody Nivolumab in patients with refractory, locally advanced or metastatic melanoma.

Detailed Description
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Despite improvement of systemic treatment in patients with advanced melanoma, there is still unmet medical need in this group of patients. Tinostamustine is a medication without marketing authorization, while Nivolumab is approved for several tumor entities. The primary objective of this trial is to assesses the safety, tolerability and recommended dose of Tinostamustine in combination with Nivolumab in patients with advanced melanoma.Secondary objectives of this trial in patients with advanced solid tumors are to assess the preliminary efficacy of Tinostamustine when given in combination with Nivolumab and to characterize potential predictive biomarkers of the combination treatment of Tinostamustine and Nivolumab. The trial includeds patients with either histologically or cytologically confirmed inoperable stage III or metastatic stage IV melanoma with an indication for the regular systemic treatment with Nivolumab and a maximum of 1 prior systemic palliative line of treatment.

Official Title
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Open Label, Non-randomized, Phase IB Study to Characterize Safety, Tolerability and Recommended Dose of Tinostamustine and Nivolumab in Patients With Refractory, Locally Advanced or Metastatic MelAnoma

Conditions
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Malignant Melanoma

Intervention / Treatment
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* Drug: Tinostamustine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent Patients with either histologically or cytologically confirmed inoperable stage III or metastatic stage IV melanoma Indication for the regular systemic treatment with the anti-PD-1 monoclonal antibody Nivolumab monotherapy Patient received a maximum of 1 prior systemic palliative line of treatment ECOG ≤2 Patients with brain metastases must have undergone definitive treatment (surgery or radiotherapy) at least 2 weeks prior to starting study drug and be documented as having stable disease by imaging Adequate bone marrow, renal and hepatic function Adequate contraception Exclusion Criteria: Prior treatment with a PD-(L)1 targeted monoclonal antibody Patients who have received systemic treatments or radiotherapy within 2 weeks prior to starting study drug Concomittant treatment with systemic steroids at a daily dose equivalent to ≥10mg of prednisone, or concomittant treatment with immunosuppressive drugs such as methotrexate Patients with a prior malignancy are excluded (except non-melanoma skin cancers, and in situ cancers such as the following: bladder, colon,cervical/dysplasia, melanoma, or breast). Patients with other second malignancies diagnosed more than 2 years ago who have received therapy with curative intent with no evidence of disease during the interval who are considered by the Investigator to present a low risk for recurrence will be eligible. NYHA stage III/IV congestive heart failure and/or arrhythmia not adequately controlled QTc interval (Fridericia's formula) > 450msec Patients who are on treatment with drugs known to prolong the QT/QTc interval (Credible Meds list: Known risk of TdP. https://www.crediblemeds.org). Pregnant and breast feeding patients

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
Intervention Model: Single Group Assignment
Interventional Model Description: this is an open label, non-randomized, Phase IB clinical trial studying a new anticancer drug combination
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tinostamustine and Nivolumab<br>Experimental drug combination arm | Drug: Tinostamustine<br>* First-in-human administration of the combination of Tinostamustine and Nivolumab.<br>* Other names: Nivolumab;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and dose-limiting toxicity | Dose limiting toxicity defined as any of the following AEs (according to CTCAE v 4.03) occurring during the first 42 days of study treatment for each study patient of the safety part of the trial, and regarded to be related (possibly, probably or definitely) to Tinostamustine: CTC °4 neutropenia during ≥ 5 days Febrile neutropenia CTC °4 thrombocytopenia or CTC° 3 thrombocytopenia with bleeding Any other ≥ CTC °4 hematological AE ≥ CTC °3 AST or ALT elevations for >7 days, or CTC °4 AST/ALT elevations for any duration ≥ CTC °3 nausea, vomiting or diarrhea despite appropriate pre-medication Any other ≥ CTC °3 non-hematological study-treatment-related AE, excluding alopecia ≥ CTC °3 uveitis, pneumonitis, bronchospasm, neurological toxicity, hypersensi-tivity reactions or infusion reactions that result in discontinuation of study treat-ment Any study treatment-related AE that results in a delay of the administration of Tinostamustine of at least 4 weeks | at 6 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall safety profile of the tinostamustine/nivolumab drug combination | All adverse events (AE) including laboratory safety parameters according to CTCAE v.4.03 | during a maximum 2 years of study treatment plus 100 days thereafter (3 years) | 
| Radiological response | Objective tumor response according to RECIST 1.1 and iRECIST | every 8 weeks until progressive disease or end of study (5 years) | 
| Progression-free survival | Progression-free survival (PFS, iPFS), defined as the time between registration to the study and the time of disease progression according to RECIST v.1.1 and iRECIST or death of the patient, whatever occurs first | through study completion (5 years) | 
| Overall survival | Overall survival (OS) from registration of study participation | through study completion (5 years) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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systemic anticancer treatment, immunotherapy, epigenetic treatment