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 -DONIMI.
- Conditions
- melanomaskin cancer10040900
- Registration Number
- NL-OMON54971
- Lead Sponsor
- Antoni van Leeuwenhoek Ziekenhuis
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Recruiting
- Sex
- Not specified
- Target Recruitment
- 30
- 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.
- IFN-gamma signature low or high according to the NanoString test (IFN-gamma
signature intermediate not allowed).
- 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.
- 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.
- 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 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
- Study Type
- Interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method <p>- Safety and feasibility of patients as measured by the adherence to the<br /><br>timelines in the study protocol. A treatment arm will be declared as not<br /><br>feasible if 2/5 or 4/10 patients cannot adhere to the planned time of surgery<br /><br>(week 6 +/- 1 week) due to treatment related adverse events.<br /><br>- Pathologic response rates (pPR, near-pCR, and pCR).</p><br>
- Secondary Outcome Measures
Name Time Method <p>- Frequency of treatment-related toxicities as measured according to CTCAE 5.0.<br /><br>- RFS, as determined according to RECIST 1.1 criteria.<br /><br>- Identification of RNA signatures associated with pathologic response and RFS<br /><br>for each arm (by RNAseq and NanoString gene expression analysis).<br /><br>- Characterization of changes in immune infiltrates/markers at week 3 and/or 6<br /><br>compared to baseline by NanoString DSP technology.<br /><br>- Inter-arm comparison of the expansion of tumor-resident T cell clones, as<br /><br>measured by TCR sequencing of the baseline tumor-biopsy and PBMC samples from<br /><br>baseline week 3 and week 6.<br /><br>- Feces microbiome diversity analyses and its correlation with pathologic<br /><br>response and toxicities.<br /><br>- Quality of life as measured by EORTC QLQ C30, the melanoma and the surgery<br /><br>subscale of FACT-M, the Cancer Worry Scale, HADS questionnaire and assessment<br /><br>of work performance. </p><br>