Clinical trial NCT03903458: Tinostamustine and Nivolumab in Advanced Melanoma
Official title: 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
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE1
Conditions: Malignant Melanoma
Keywords: systemic anticancer treatment
immunotherapy
epigenetic treatment
Lead sponsor: Cantonal Hospital of St. Gallen
Sponsor class: OTHER
First posted: 2019-04-04
Enrollment: 21
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: this is an open label, non-randomized, Phase IB clinical trial studying a new anticancer drug combination
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Safety and dose-limiting toxicity
timeFrame: at 6 weeks
Secondary outcomes:
measure: Overall safety profile of the tinostamustine/nivolumab drug combination
timeFrame: during a maximum 2 years of study treatment plus 100 days thereafter (3 years)
measure: Radiological response
timeFrame: every 8 weeks until progressive disease or end of study (5 years)
measure: Progression-free survival
timeFrame: through study completion (5 years)
measure: Overall survival
timeFrame: through study completion (5 years)
Other outcomes:
Locations:
city: Chur
country: Switzerland
facility: Kantonsspital Graubünden
city: St.Gallen
country: Switzerland
facility: Cantonal Hospital St.Gallen
Study officials:
affiliation: Cantonal Hospital St. Gallen, Switzerland
name: Markus Joerger, Prof.
role: STUDY_CHAIR
References: