Tinostamustine and Nivolumab in Advanced Melanoma (ENIgMA)

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

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.

Study Overview

• Status: Recruiting
• Conditions: Malignant Melanoma
• Intervention / Treatment: Drug: Tinostamustine

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.

• Study Type: Interventional
• Enrollment (Anticipated): 21
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Elke Hiendlmeyer, Dr.; Phone Number: +41 714941111; Email: elke.hiendlmeyer@kssg.ch
• Study Contact Backup: Name: Christina Jodlauk; Phone Number: +41 714941111; Email: christina.jodlauk@kssg.ch

Study Locations

• Switzerland
  • Chur, Switzerland, 7000
    • Recruiting
    • Kantonsspital Graubünden
    • Contact: Roger von Moos, Prof.; Phone Number: +41 81 256 66 46; Email: rogervonmoos@ksgr.ch
    • Principal Investigator: Roger von Moos, Prof.
  • St.Gallen, Switzerland, 9007
    • Recruiting
    • Cantonal Hospital St.Gallen
    • Contact: Elke Hiendlmeyer, Dr.; Phone Number: +41 714941111; Email: elke.hiendlmeyer@kssg.ch
    • Contact: Christina Jodlauk; Phone Number: +41 714941111; Email: christina.jodlauk@kssg.ch
    • Principal Investigator: Markus Joerger, Prof.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Tinostamustine and Nivolumab; Experimental drug combination arm	Drug: Tinostamustine; First-in-human administration of the combination of Tinostamustine and Nivolumab.; Other Names: Nivolumab

What is the study measuring?

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)

Collaborators and Investigators

• Sponsor: Markus Joerger
• Investigators: Study Chair: Markus Joerger, Prof., Cantonal Hospital St. Gallen, Switzerland

Publications and helpful links

Helpful Links

• Clinical Trials Unit St. Gallen, Switzerland

Study record dates

Study Major Dates

• Study Start (Actual): March 7, 2019
• Primary Completion (Anticipated): December 15, 2021
• Study Completion (Anticipated): March 15, 2024

Study Registration Dates

• First Submitted: March 13, 2019
• First Submitted That Met QC Criteria: April 3, 2019
• First Posted (Actual): April 4, 2019

Study Record Updates

• Last Update Posted (Actual): April 8, 2019
• Last Update Submitted That Met QC Criteria: April 4, 2019
• Last Verified: April 1, 2019

More Information

Terms related to this study

• Keywords: immunotherapy; systemic anticancer treatment; epigenetic treatment
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Nevi and Melanomas; Melanoma; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Nivolumab
• Other Study ID Numbers: CTU 17.022

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No