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

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

Publication date: Oct 21, 2019

DONIMI is a phase 1b trial testing the combination of domatinostat + nivolumab or nivolumab monotherapy in IFN-gamma signature high patients and of domatinostat + nivolumab or domatinostat + nivolumab + ipilimumab in IFN-gamma signature low patients with de-novo or recurrent macroscopic stage III cutaneous or unknown primary melanoma. The trial will include 40 stage III cutaneous or unknown primary melanoma patients with RECIST 1.1 measurable de-novo or recurrent disease (short axis lymph node metastasis ≥1.5cm). IFN-gamma signature low patients will be randomized to be treated pre-surgically for 6 weeks with domatinostat + nivolumab or domatinostat + nivolumab + ipilimumab (each 10 patients). NanoString IFN-gamma signature high patients will be randomized to be treated pre-surgically for 6 weeks with nivolumab or domatinostat + nivolumab (each 10 patients). Post-surgery (starting at week 12), the patients will start with adjuvant nivolumab or pembrolizumab for 52 weeks according to institute’s standard. BRAF V600E/K mutation positive patients with no pathologic response after neoadjuvant therapy may also receive adjuvant BRAF + MEK inhibition if commercially available and according to the patient’s and the treating physician’s decision. Follow-up after the adjuvant therapy will be for 2 years, according to the institutes’ standard. Toxicity and pathologic response rates will be descriptive. In case of 2/5 or 4/10 patients not undergoing their lymph node dissection at week 6 +/- 1 week due to treatment related toxicity, this arm will be declared unfeasible.

Concepts Keywords
Adjuvant Lymph node metastases
Adjuvant Therapy Tumor
AIDS Valvular heart disease
Allergies History severe hypersensitivity
Allergy Unstable angina
ALT Cancer
Angina Pectoris Acute chronic infection
Antibody Active gastrointestinal disorder
Antigen AIDS
AST Uncontrolled hypertension
Asthma Transit metastases
Atopy III cutaneous melanoma
Autoimmune Quadruple tumor
Autoimmune Disease Disease diabetic gastroparesis
Bilirubin Childhood asthma
Biopsied HCV
Biopsies Long QT Syndrome
Blood Neoadjuvant therapy
BRAF Radiotherapy
Cancer Surgery
Cardiac Disease Immunotherapy
Cardiovascular Clinical medicine
Congestive Heart Failure Cancer treatments
Creatinine Bristol-Myers Squibb
Cytologically Antineoplastic drugs
De Novo Breakthrough therapy
Diabetic Gastroparesis Ipilimumab
Gastrointestinal Disorder Melanoma
HBV Nivolumab
HCV Pembrolizumab
Hemoglobin Adjuvant therapy
Hepatitis
Histologically
HIV
Hypersensitivity Reaction
Hypertension
IFN Gamma
Immunodeficiency
Immunosuppressive Medications
Immunotherapy
Implantation
Infection
Ipilimumab
Ischemic
IU
Lactating
LDH
Lesion
Life Expectancy
Long QT Syndrome
Lymph Node
Lymph Node Dissection
Macroscopic
Malabsorption
Malignancies
MEK
Melanoma
Metastases
Metastasis
Metastasized
Monoclonal Antibody
Monotherapy
Msec
Mutation
Myocardial Infarction
NCI
Neoadjuvant Therapy
Netherlands
Neutrophils
Pace Maker
Physician
Platelets
Pregnancy Test
Protocol
QTc Interval
Radiotherapy
Relapse
Ribonucleic Acid
Serum
Steroids
Syndrome
Toxicity
Transit
Tumor
Ulcerative Colitis
Unstable Angina
Urine
Valvular Heart Disease
Virus
Vitiligo
WBC
X10

Semantics

Type Source Name
drug DRUGBANK Nivolumab
drug DRUGBANK Ipilimumab
gene UNIPROT IFNG
disease MESH Melanoma
disease DOID Melanoma
pathway BSID Melanoma
disease MESH metastasis
gene UNIPROT DESI1
gene UNIPROT SLC35G1
drug DRUGBANK Pembrolizumab
gene UNIPROT BRAF
disease DOID cutaneous melanoma
disease MESH malignancies
disease DOID cancer
disease MESH relapse
drug DRUGBANK Creatinine
gene UNIPROT SLC17A5
drug DRUGBANK Chorionic Gonadotropin (Human)
disease DOID mucosal melanoma
disease MESH autoimmune disease
disease DOID autoimmune disease
disease MESH syndrome
disease DOID syndrome
disease MESH vitiligo
disease DOID vitiligo
disease MESH asthma
disease DOID asthma
pathway BSID Asthma
disease DOID gastrointestinal disorder
disease MESH ulcerative colitis
disease DOID ulcerative colitis
disease MESH gastroparesis
disease DOID gastroparesis
gene UNIPROT CTLA4
gene UNIPROT RPL17
gene UNIPROT CD274
disease MESH hepatitis B
disease DOID hepatitis B
pathway BSID Hepatitis B
gene UNIPROT RNF7
gene UNIPROT SAG
gene UNIPROT DMBT1
disease MESH hepatitis C
disease DOID hepatitis C
pathway BSID Hepatitis C
disease MESH infection
disease MESH acquired immunodeficiency syndrome
disease DOID acquired immunodeficiency syndrome
disease MESH Allergies
disease MESH Adverse Drug Reaction
disease DOID allergy
disease MESH Torsades de Pointes
disease MESH cardiovascular disease
disease MESH Unstable angina pectoris
disease MESH hypertension
disease DOID hypertension
disease MESH Congestive heart failure
disease DOID Congestive heart failure
disease MESH cardiac disease
gene UNIPROT FURIN
disease MESH valvular heart disease
disease DOID valvular heart disease
disease MESH myocardial infarction
disease DOID myocardial infarction
gene UNIPROT NR4A2
gene UNIPROT ALG3

Original Article

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