Evaluation of Safety and Activity of an Anti-PDL1 Antibody (DURVALUMAB) Combined With CSF-1R TKI (PEXIDARTINIB) in Patients With Metastatic/Advanced Pancreatic or Colorectal Cancers

Sponsor
Centre Leon Berard
Study ID
NCT02777710
Phase
PHASE1
Status
Completed

Conditions

Eligibility Criteria

Sex
ALL
Age
18 Years - N/A
Healthy Volunteers
Not accepted

Interventions

  • Pexidartinib — DRUG
    Treatment will be administered as long as patient experience clinical benefit in the opinion of the investigator or until unacceptable toxicity or symptomatic deterioration attributed to disease progression as determined by the investigator after an integrated assessment of radiographic data and clinical status or withdrawal of consent. If a DLT or a toxicity meeting the DLT definition but occurring outside of the DLT period, resolves to Grade ≤2 or the patient's baseline level within 14 days after toxicity onset, dosing may be resumed if agreed by the Sponsor at the same DL.
  • Durvalumab — DRUG
    Treatment will be administered as long as patient experience clinical benefit in the opinion of the investigator or until unacceptable toxicity or symptomatic deterioration attributed to disease progression as determined by the investigator after an integrated assessment of radiographic data and clinical status or withdrawal of consent. If a DLT or a toxicity meeting the DLT definition but occurring outside of the DLT period, resolves to Grade ≤2 or the patient's baseline level within 14 days after toxicity onset, dosing may be resumed if agreed by the Sponsor at the same DL.

Study Details

Colorectal cancer (CRC) and pancreatic ductal adenocarcinoma (PDAC) are the most common gastrointestinal cancers in Western countries and are both associated with significant morbidity and mortality. An intriguing similarity between CRC and PDAC is the fact that the newly developed immune checkpoint inhibitors, especially PD1/PDL1 inhibitors, seem to have limited efficacy as single agents in both of these tumor types. Recent preclinical studies point towards alternatively activated (M2-type) macrophages as possible culprits in inducing local immune protection from cytotoxic T cells and resistance to PD1/PD-L1 targeted agents. We hypothesize that CSF1R blockade will deplete the tumor microenvironment of M2 macrophages, thus favoring the induction of a cytotoxic anti-tumor T-cell response following PD-L1 blockade with an anti-PD-L1 monoclonal antibody. So we propose to conduct a Phase I dose escalation study in order to evaluate the safety and clinical activity of a combined treatment associating an anti-CSF1R (PEXIDARTINIB) with an anti-PD-L1 (DURVALUMAB) in patients with advanced/metastatic colorectal or pancreatic cancers. Dose escalation part will determine the Maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of Pexidartinib given in combination with Durvalumab. Extension part will evaluate the clinical activity of the combination at the RP2D.

Key Dates

Start date
Jun 30, 2016
Status verified
Sep 2021
Primary completion
Nov 30, 2019
Completion
Dec 31, 2019

Study Design

Enrollment
48 participants (actual)
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT

Arms

  • Experimental: Combination Pexidartinib-Durvalumab
    * DURVALUMAB (MEDI4736): therapeutic Class anti-PD-L1 mAb, given IV every 4 weeks at a fixed dose of 1500mg, AstraZeneca * PEXIDARTINIB (PLX3397): therapeutic Class Kinase inhibitor targeting CSF1-R, Flt3 and Kit. Administered daily as split dose regimen, orally. Five dose-levels possible in dose escalation part: 400mg 5 days on 2 days off (intermittent schedule), 400 mg, 600 mg, 800 mg or 1000 mg. In this combination trial, Pexidartinib should be taken first and the Durvalumab IV infusion should be scheduled 1 hour after the Pexidartinib morning dose.

Primary Outcome Measure

part 1 (dose escalation part) : Dose-Limiting Toxicities (DLT) [ Time Frame: during the DLT assessment window (i.e. 1 cycle = 28 days) ]

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