Preconditioning of Tumor, Tumor Microenvironment and the Immune System to Immunotherapy (PROMIT)

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

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.

Study Overview

• Status: Recruiting
• Conditions: Immunotherapy
• Intervention / Treatment: Drug: Dacarbazine (DTIC)

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.

• Study Type: Interventional
• Enrollment (Anticipated): 38
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Lucie Heinzerling, Prof. Dr. MPH; Phone Number: +49 (0) 9131- 85 45 804; Email: lucie.heinzerling@uk-erlangen.de

Study Locations

• Germany
  • Bavaria
    • Erlangen, Bavaria, Germany, 91054
      • Recruiting
      • University Hospital
      • Contact: Lucie Heinzerling, Prof. Dr.; Email: Lucie.Heinzerling@uk-erlangen.de

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dacarbazine; Dacarbazine (day1 and day21) 850 mg/m² i.v. followed by re-exposure to the previous immunotherapy	Drug: Dacarbazine (DTIC); Dacarbazine powder for IV solution; Other Names: DTIC

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of participents with CR, PR, SD or PD	A patient is defined as responder if a complete response (CR) or partial response (PR) can be seen. A patient with stable disease (SD) or progressive disease (PD) will be defined as non-responder.	week 14

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival (OS)	Overall survival (OS), defined as the time between study inclusion and date of death (any cause). For subjects without documentation of death, OS will be censored on the last date the subject was known to be alive. OS will be followed continuously while subjects are on the study drug and every 12 weeks via phone contact after subjects discontinue the treatment phase.	up to 5 years

Collaborators and Investigators

• Sponsor: University of Erlangen-Nürnberg Medical School
• Collaborators: Wuerzburg University Hospital; University Hospital Regensburg

Study record dates

Study Major Dates

• Study Start (Actual): January 13, 2020
• Primary Completion (Anticipated): June 1, 2023
• Study Completion (Anticipated): July 1, 2023

Study Registration Dates

• First Submitted: January 3, 2020
• First Submitted That Met QC Criteria: January 8, 2020
• First Posted (Actual): January 13, 2020

Study Record Updates

• Last Update Posted (Actual): May 27, 2022
• Last Update Submitted That Met QC Criteria: May 25, 2022
• Last Verified: May 1, 2022

More Information

Terms related to this study

• Keywords: dacarbazine; resistance; immune checkpoint blockade
• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Dacarbazine
• Other Study ID Numbers: PROMIT

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No