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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT04133948




Registration number
NCT04133948
Ethics application status
Date submitted
14/10/2019
Date registered
21/10/2019

Titles & IDs
Public title
Multicenter Phase 1b Trial Testing the Neoadjuvant Combination of Domatinostat, Nivolumab and Ipilimumab in IFN-gamma Signature-low and IFN-gamma Signature-high RECIST 1.1-measurable Stage III Cutaneous or Unknown Primary Melanoma
Scientific title
Multicenter Phase 1b Trial Testing the Neoadjuvant Combination of Domatinostat, Nivolumab and Ipilimumab in IFN-gamma Signature-low and IFN-gamma Signature-high RECIST 1.1-measurable Stage III Cutaneous or Unknown Primary Melanoma
Secondary ID [1] 0 0
M19DON
Universal Trial Number (UTN)
Trial acronym
DONIMI
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Malignant Melanoma Stage III 0 0
Condition category
Condition code
Cancer 0 0 0 0
Malignant melanoma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Domatinostat
Treatment: Drugs - Nivolumab
Treatment: Drugs - Ipilimumab

Experimental: A - For IFN-gamma high patients: patients will receive pre-surgically 2 courses nivolumab 240 mg (q3weeks)

Experimental: B - For IFN-gamma high patients: patients will receive pre-surgically 2 courses nivolumab 240 mg (q3weeks) + domatinostat 200 mg BID, on days 1-14 (q3weeks)

Experimental: C - For IFN-gamma low patients: patients will receive pre-surgically 2 courses nivolumab 240 mg (q3weeks) + domatinostat 200 mg BID, on days 1-14 (q3weeks)

Experimental: D - For IFN-gamma low patients: patients will receive pre-surgically 2 courses nivolumab 240 mg (q3weeks) + ipilimumab 80 mg (q3weeks) + domatinostat. Patients in arm D will start with once daily (OD) dosing scheme of domatinostat 200 mg, on days 1-14 (q3weeks). Based on safety data of the first 5 patients in this arm, the next patients will be treated with either a higher dosing scheme (200 mg BID, days 1-14, q3weeks), a lower dosing scheme (100 mg OD, days 1-14, q3weeks), or the same dosing scheme (200 mg OD, days 1-14, q3weeks).


Treatment: Drugs: Domatinostat
Patients in arm B and C will receive domatinostat 200 mg BID, days 1-14 q3weeks.

Patients in arm D will start with once daily (OD) dosing scheme of domatinostat 200mg, d1-14 q3wks. Based on safety data of the first 5 patients in this arm, the next patients will be treated with either a higher dosing scheme (200mg BID, d1-14, q3wks), a lower dosing scheme (100mg OD, d1-14, q3wks) or the same dosing scheme (200mg OD, d1-14, q3wks).

Treatment: Drugs: Nivolumab
2 courses nivolumab 240 mg q3weeks

Treatment: Drugs: Ipilimumab
2 courses ipilimumab 80 mg q3weeks
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Safety of patients as measured by the adherence to the timelines in the study protocol
Timepoint [1] 0 0
6 months
Primary outcome [2] 0 0
Feasability of patients as measured by the adherence to the timelines in the study protocol
Timepoint [2] 0 0
6 weeks
Secondary outcome [1] 0 0
Pathologic response rates (pPR, near-pCR, and pCR).
Timepoint [1] 0 0
At 6 weeks
Secondary outcome [2] 0 0
Frequency of treatment-related toxicities as measured according to CTCAE 5.0.
Timepoint [2] 0 0
At 6 weeks
Secondary outcome [3] 0 0
Radiologic response rate according to RECIST 1.1 criteria
Timepoint [3] 0 0
At 6 weeks
Secondary outcome [4] 0 0
Relapse Free Survival (RFS)
Timepoint [4] 0 0
Up to 3 years after treatment
Secondary outcome [5] 0 0
RNA signatures associated with pathologic response and RFS for each arm (by RNAseq and NanoString gene expression analysis).
Timepoint [5] 0 0
Up to 3 years after treatment
Secondary outcome [6] 0 0
Changes in immune infiltrates/markers at week 3 and/or 6 compared to baseline by NanoString DSP technology or alternative immunohistochemistry analysis.
Timepoint [6] 0 0
At week 3 and/or 6
Secondary outcome [7] 0 0
Inter-arm comparison of the expansion of tumor-resident T cell clones, as measured by TCR sequencing of the baseline tumor-biopsy and PBMC samples from baseline week 3 and week 6.
Timepoint [7] 0 0
At week 3 and/or 6
Secondary outcome [8] 0 0
Feces microbiome diversity analyses and its correlation with pathologic response and toxicities.
Timepoint [8] 0 0
Up to 3 years after treatment
Secondary outcome [9] 0 0
Quality of life as measured by EORTC QLQ C30
Timepoint [9] 0 0
Up to 3 years after treatment
Secondary outcome [10] 0 0
Quality of life as measured by the the Melanoma Subscale and Melanoma Surgery Subscale of FACT-M
Timepoint [10] 0 0
Up to 3 years after treatment
Secondary outcome [11] 0 0
Quality of life as measured by the Cancer Worry Scale
Timepoint [11] 0 0
Up to 3 years after treatment
Secondary outcome [12] 0 0
Quality of life as measured by HADS questionnaire
Timepoint [12] 0 0
Up to 3 years after treatment
Secondary outcome [13] 0 0
Quality of life as measured by EQ-5D-5L
Timepoint [13] 0 0
Up to 3 years after treatment
Secondary outcome [14] 0 0
Quality of life as measured by the immunotherapy-specific questionnaire
Timepoint [14] 0 0
Up to 3 years after treatment
Secondary outcome [15] 0 0
Quality of life as measured by an assessment of work performance.
Timepoint [15] 0 0
Up to 3 years after treatment

Eligibility
Key inclusion criteria
* Adults at least 18 years of age.
* World Health Organization (WHO) Performance Status 0 or 1.
* Cytologically or histologically confirmed resectable stage III cutaneous melanoma (unknown primary also allowed) with one or more macroscopic lymph node metastases (measurable according to RECIST 1.1), that can be biopsied, and no history of in-transit metastases within the last 6 months.
* No other malignancies, except adequately treated and a cancer-related life-expectancy of more than 5 years.
* Patient willing to undergo quadruple tumor biopsies and extra blood withdrawal during screening, week 3 and in case of relapse.
* The biopsies at screening should contain at least 30% tumor cells in order to get a reliable IFN-gamma signature
* No immunosuppressive medications within 6 months prior trial registration.
* Screening laboratory values must meet the following criteria: WBC = 2.0x109/L, Neutrophils =1.5x109/L, Platelets =100 x109/L, Hemoglobin =5.5 mmol/L, Creatinine =1.5x ULN, AST = 1.5 x ULN, ALT = 1.5 x ULN, Bilirubin =1.5 X ULN.
* Normal LDH.
* Women of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of ipilimumab + nivolumab.
* Patient is capable of understanding and complying with the protocol requirements and has signed the Informed Consent document.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Distantly metastasized melanoma

* Uveal or mucosal melanoma.
* History of in-transit metastases within the last 6 months.
* No measurable lymph node lesion according to RECIST 1.1.
* Subjects with any active autoimmune disease or a documented history of autoimmune disease, or history of syndrome that required systemic steroids or immunosuppressive medications, except for subjects with vitiligo or resolved childhood asthma/atopy.
* Patients with any active gastrointestinal disorder that could interfere with the absorption of domatinostat (as per judgement of the investigator), such as ulcerative colitis, Crohn's disease, diabetic gastroparesis, or other syndromes characterized by malabsorption.
* Prior CTLA-4 or PD-1/PD-L1 targeting immunotherapy.
* Prior targeted therapy targeting BRAF and/or MEK.
* Prior radiotherapy.
* Patients will be excluded if they test positive for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody), indicating acute or chronic infection; if treated and being at least one year free from HCV patients are allowed to participate.
* Patients will be excluded if they have known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).
* Allergies and Adverse Drug Reaction:

* History of allergy to study drug components;
* History of severe hypersensitivity reaction to any monoclonal antibody.
* Underlying medical conditions that, in the Investigator's opinion, will make the administration of study drug hazardous or obscure the interpretation of toxicity or adverse events.
* Patients with a marked baseline prolongation of QT/QTc interval, e.g., repeated demonstration of a QTc interval >450 msec (Grade 1 NCI-CTCAE); Long-QT-Syndrome) and patients receiving agents known to prolong the QT interval and known risk of Torsades de Pointes.
* Patients with significant current cardiovascular disease including:

* Unstable angina pectoris within 6 months prior to screening
* Uncontrolled hypertension
* Congestive heart failure (New York Heart Association (NYHA) Class III or IV) related to primary cardiac disease
* Conditions requiring anti-arrhythmic therapy (patients with status post pace maker implantation can be included)
* Symptomatic ischemic or severe valvular heart disease, or a myocardial infarction within 6 months prior to the trial entry
* Women who are pregnant or lactating
* Use of other investigational drugs before study drug administration 30 days and 5 half-times before trial registration.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 1
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
7/01/2020
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
26/11/2024
Sample size
Target
Accrual to date
Final
44
Recruitment in Australia
Recruitment state(s)
Wollstonecraft NS
Recruitment hospital [1] 0 0
Melanoma Institute Australia - Sydney
Recruitment postcode(s) [1] 0 0
2065 - Sydney
Recruitment outside Australia
Country [1] 0 0
Netherlands
State/province [1] 0 0
Amsterdam

Funding & Sponsors
Primary sponsor type
Other
Name
The Netherlands Cancer Institute
Address
Country
Other collaborator category [1] 0 0
Other
Name [1] 0 0
4SC
Address [1] 0 0
Country [1] 0 0

Ethics approval
Ethics application status

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Christian Blank, Prof.
Address 0 0
Medical oncologist/researcher
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

Data sharing statement


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

No documents have been uploaded by study researchers.


Results not provided in https://clinicaltrials.gov/study/NCT04133948