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

Conditions

• Malignant Melanoma Stage III

Eligibility Criteria

Sex

ALL

Age

18 Years - N/A

Healthy Volunteers

Not accepted

Interventions

• Domatinostat — DRUG
  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).
• Nivolumab — DRUG
  2 courses nivolumab 240 mg q3weeks
• Ipilimumab — DRUG
  2 courses ipilimumab 80 mg q3weeks

Study Details

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.

Key Dates

Start date

Jan 7, 2020

Status verified

Mar 2025

Primary completion

Jan 11, 2022

Completion

Nov 26, 2024

Study Design

Enrollment

44 participants (actual)

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Arms

• 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).

Primary Outcome Measure

Safety of patients as measured by the adherence to the timelines in the study protocol [ Time Frame: 6 months ]