ENIgMA: Tinostamustine and Nivolumab in Advanced Melanoma

Sponsor

Markus Joerger (Other)

Overall Status

Recruiting

CT.gov ID

NCT03903458

Collaborator

(none)

Enrollment

Locations

Arm

60.3

Anticipated Duration (Months)

10.5

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Malignant Melanoma	Drug: Tinostamustine	Phase 1

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 Design

Study Type:

Interventional

Anticipated Enrollment :

21 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Intervention Model Description:

this is an open label, non-randomized, Phase IB clinical trial studying a new anticancer drug combinationthis is an open label, non-randomized, Phase IB clinical trial studying a new anticancer drug combination

Masking:

None (Open Label)

Masking Description:

open-label

Primary Purpose:

Treatment

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

Actual Study Start Date :

Mar 7, 2019

Anticipated Primary Completion Date :

Dec 15, 2021

Anticipated Study Completion Date :

Mar 15, 2024

Arms and Interventions

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

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

Outcome Measures

Primary Outcome Measures

Safety and dose-limiting toxicity [at 6 weeks]
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

Secondary Outcome Measures

Overall safety profile of the tinostamustine/nivolumab drug combination [during a maximum 2 years of study treatment plus 100 days thereafter (3 years)]
All adverse events (AE) including laboratory safety parameters according to CTCAE v.4.03
Radiological response [every 8 weeks until progressive disease or end of study (5 years)]
Objective tumor response according to RECIST 1.1 and iRECIST
Progression-free survival [through study completion (5 years)]
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
Overall survival [through study completion (5 years)]
Overall survival (OS) from registration of study participation

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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: