Clinical trial NCT04225390: Preconditioning of Tumor, Tumor Microenvironment and the Immune System to Immunotherapy
Official title: A Phase 2, Single Arm Study on Dacarbazine (DTIC) Followed by Immunotherapy Re-challenge in Unresectable or Metastatic Melanoma With Primary Resistance to PD-1/PD-L1 or PD-1 + CTLA-4 Blockade
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Immunotherapy
Keywords: immune checkpoint blockade
resistance
dacarbazine
Lead sponsor: University of Erlangen-Nürnberg Medical School
Sponsor class: OTHER
Collaborators: name: University Hospital Regensburg
name: Wuerzburg University Hospital
First posted: 2020-01-13
Enrollment: 38
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: PROMIT is a single arm phase 2 trial evaluating the clinical activity of immune checkpoint blockade (ICB) after administration of dacarbazine (DTIC) in patients with unresectable or metastatic, BRAF wildtype melanoma with primary resistance to anti-programmed-cell-death-1 (PD-1/PD-L1) or PD-1 plus anti-cytotoxic-T-lymphocyte antigen 4 (CTLA-4) blockade therapy. If the activity is clinically meaningful, DTIC could become a new therapeutic option to break primary resistance to immunotherapy.

Detailed description: PROMIT is a phase 2, single arm, open label study of DTIC followed by combined immune checkpoint blockade (ICB) therapy or PD-1/PD-L1-blockade monotherapy in adult (≥ 18 years) subjects with previously treated, unresectable or metastatic melanoma (Stage III or Stage IV melanoma as per the AJCC staging system). Subjects must be BRAF wildtype and must have shown primary resistance to ICB. Fresh tumor tissue from an unresectable or metastatic site of disease must be available.

Subjects will be treated with DTIC 850 mg/m² day 1 and 21 i.v. (DTIC phase). Afterwards, patients will receive combined ipilimumab (3 mg/kg) and nivolumab (1 mg/kg) 4 times every 3 weeks i.v. OR nivolumab 240 mg every 2 weeks OR pembrolizumab 200 mg every 3 weeks (ICB re-exposure phase; EMA-approved dosing scheme). By the end of the ICB phase, response will be documented (primary endpoint). A safety follow-up for treatment-related adverse events will be performed until 30 days after the last dose of combined ICB. Patients will be followed for survival every 12 weeks after the end of the combined ICB phase (second primary endpoint). Tumor and blood samples will be assessed over the course of the study to evaluate changes in tumor, tumor microenvironment and immune system.

Eligibility criteria: Inclusion Criteria:

1. Histologically confirmed metastatic melanoma
2. Progression after checkpoint inhibitor therapy (PD-1/PD-L1 or PD-1 + CTLA-4 blockade)
3. Accessible tumor metastases
4. ECOG 0 or 1
5. Adequate organ function

Exclusion Criteria:

1. Uvea melanoma, mucosal melanoma
2. Previous chemotherapy in metastatic disease
3. Previous response to checkpoint inhibitor therapy (PD-1/PD-L1 or PD-1 + CTLA-4 blockade) in metastatic disease
4. BRAF V600 mutation
5. Active brain metastases
6. Autoimmune disease requiring more than 10 mg prednisolone daily or other immunosuppressive drugs

Primary outcomes:
measure: Rate of participents with CR, PR, SD or PD
timeFrame: week 14
Secondary outcomes:
measure: Overall survival (OS)
timeFrame: up to 5 years
Other outcomes:
Locations:
city: Erlangen
country: Germany
facility: University Hospital
state: Bavaria
Study officials:
References: