Neoplasms

Skin and Connective Tissue Diseases

All Conditions

Rare Diseases

Melanoma

Neuroendocrine Tumors

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Nerve Tissue

Nevus, Pigmented

Nevus

Nevi and Melanomas

Skin Neoplasms

Skin Diseases

Neuroendocrine Tumor

Neuroepithelioma

Antineoplastic Agents

All Drugs and Chemicals

Nivolumab

Ipilimumab

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

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

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)

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)

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).

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).

Domatinostat

Christian Blank, Prof.

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 45 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).

NanoString IFN-gamma signature high patients will be randomized to be treated pre-surgically for 6 weeks with nivolumab (arm A; 10 patients) or domatinostat + nivolumab (arm B; 10 patients).

IFN-gamma signature low patients will be randomized to be treated pre-surgically for 6 weeks with domatinostat + nivolumab (arm C; 10 patients) or domatinostat + nivolumab + ipilimumab (arm D; 15 patients). Patients will be stratified according to center.

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.

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

A treatment arm will be declared as not safe if 8/10 patients develop gr 3-4 adverse events or if 2/10 patients develop longlasting (\>6 months) gr 3-4 adverse events.

A treatment arm will be declared as not feasible if 2/5 or 4/10 patients cannot adhere to the planned time of surgery (week 6 +/- 1 week) due to treatment related adverse events.

Spots Global Cancer Trial Database for domatinostat

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