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Tinostamustine and Nivolumab in Advanced Melanoma (ENIgMA)

Primary Purpose

Malignant Melanoma

Status

Recruiting

Phase

Phase 1

Locations

Switzerland

Study Type

Interventional

Intervention

Tinostamustine

About this trial

This is an interventional treatment trial for Malignant Melanoma focused on measuring systemic anticancer treatment, immunotherapy, epigenetic treatment

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept 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:

Known risk of TdP. https://www.crediblemeds.org).

Pregnant and breast feeding patients

Sites / Locations

Kantonsspital GraubündenRecruiting
Cantonal Hospital St.GallenRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Tinostamustine and Nivolumab

Arm Description

Experimental drug combination arm

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

Overall safety profile of the tinostamustine/nivolumab drug combination

All adverse events (AE) including laboratory safety parameters according to CTCAE v.4.03

Radiological response

Objective tumor response according to RECIST 1.1 and iRECIST

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

Overall survival

Overall survival (OS) from registration of study participation

Full Information

NCT ID

NCT03903458

First Posted

March 13, 2019

Last Updated

April 4, 2019

Sponsor

Markus Joerger

1. Study Identification

Unique Protocol Identification Number

NCT03903458

Brief Title

Tinostamustine and Nivolumab in Advanced Melanoma

Acronym

ENIgMA

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

2. Study Status

Record Verification Date

April 2019

Overall Recruitment Status

Recruiting

Study Start Date

March 7, 2019 (Actual)

Primary Completion Date

December 15, 2021 (Anticipated)

Study Completion Date

March 15, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor-Investigator

Name of the Sponsor

Markus Joerger

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Data Monitoring Committee

5. 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.

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Malignant Melanoma

Keywords

systemic anticancer treatment, immunotherapy, epigenetic treatment

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Single Group Assignment

Model Description

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

Masking

None (Open Label)

Masking Description

open-label

Allocation

N/A

Enrollment

21 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Tinostamustine and Nivolumab

Arm Type

Experimental

Arm Description

Experimental drug combination arm

Intervention Type

Drug

Intervention Name(s)

Tinostamustine

Other Intervention Name(s)

Nivolumab

Intervention Description

First-in-human administration of the combination of Tinostamustine and Nivolumab.

Primary Outcome Measure Information:

Title

Safety and dose-limiting toxicity

Description

Time Frame

at 6 weeks

Secondary Outcome Measure Information:

Title

Overall safety profile of the tinostamustine/nivolumab drug combination

Description

All adverse events (AE) including laboratory safety parameters according to CTCAE v.4.03

Time Frame

during a maximum 2 years of study treatment plus 100 days thereafter (3 years)

Title

Radiological response

Description

Objective tumor response according to RECIST 1.1 and iRECIST

Time Frame

every 8 weeks until progressive disease or end of study (5 years)

Title

Progression-free survival

Description

Time Frame

through study completion (5 years)

Title

Overall survival

Description

Overall survival (OS) from registration of study participation

Time Frame

through study completion (5 years)

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

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

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Elke Hiendlmeyer, Dr.

Phone

714941111

Ext

+41

elke.hiendlmeyer@kssg.ch

First Name & Middle Initial & Last Name or Official Title & Degree

Christina Jodlauk

Phone

714941111

Ext

+41

christina.jodlauk@kssg.ch

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Markus Joerger, Prof.

Organizational Affiliation

Cantonal Hospital St. Gallen, Switzerland

Official's Role

Study Chair

Facility Information:

Facility Name

Kantonsspital Graubünden

City

Chur

ZIP/Postal Code

7000

Country

Switzerland

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Roger von Moos, Prof.

Phone

+41 81 256 66 46

rogervonmoos@ksgr.ch

First Name & Middle Initial & Last Name & Degree

Roger von Moos, Prof.

Facility Name

Cantonal Hospital St.Gallen

City

St.Gallen

ZIP/Postal Code

9007

Country

Switzerland

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Elke Hiendlmeyer, Dr.

Phone

714941111

Ext

+41

elke.hiendlmeyer@kssg.ch

First Name & Middle Initial & Last Name & Degree

Christina Jodlauk

Phone

714941111

Ext

+41

christina.jodlauk@kssg.ch

First Name & Middle Initial & Last Name & Degree

Markus Joerger, Prof.

12. IPD Sharing Statement

Plan to Share IPD

Links:

URL

https://www.kssg.ch/mfz/clinical-trials-unit-ctu

Description

Clinical Trials Unit St. Gallen, Switzerland

Learn more about this trial

Tinostamustine and Nivolumab in Advanced Melanoma

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