Clinical Trial: Combination Study of Guadecitabine and Pembrolizumab.

Study Status: Not yet recruiting
Recruit Status: Not yet recruiting
Study Type: Interventional

Official Title: HyPeR: A Phase 1 Dose Escalation Study of Guadecitabine (SGI-110) a Second Generation Hypo-Methylating Agent in Combination With Pembrolizumab (MK3475) in Patients With Refractory Solid Tumours

Brief Summary: HyPeR is a multi-centre Phase 1 Dose Escalation Study of Guadecitabine (SGI-110) a Second Generation Hypo-Methylating Agent in Combination with Pembrolizumab (MK3475) in Patients with Refractory Solid Tumours. The investigators will be investigating the safety and toxicity of the combination.

Detailed Summary:

This is a phase I trial of the combination of the hypo-methylating agent guadecitabine and an anti-PD1 antibody (anti- programmed cell death protein 1) pembrolizumab. Patients will receive subcutaneous guadecitabine daily on Days 1-4 of each 21-day cycle. Patients will receive pembrolizumab intravenously once per 21-day cycle: on Day 8 of Cycle 2 and on Day 1 of each cycle from Cycle 3 onwards.

The rational for this design is that this pre-loading with Guadecitabine will sensitise the tumour to Pembrolizumab through the re-expression of genes that enhance tumour recognition, the increase in density of tumour infiltrating T-cells and stimulation of the adaptive immune response.

In Part A (Dose Escalation) the investigators will investigate escalating doses of Guadecitabine in combination with Pembrolizumab. Patients with advanced solid tumours will be recruited in cohorts of 3 to 6 patients to investigate the combination of 200 mg of pembrolizumab, administered as an intravenous injection, with escalating doses of guadecitabine, administered via a subcutaneous injection, once a day for 4 days (Days 1-4). Guadecitabine dosing will start at 45mg/m2 but can be decreased to 30mg/m2 in the event of toxicities or increased to 60mg/m2 in the absence of toxicities. Once the maximum tolerated dose is reached (or under the advice from the Safety Review Committee) patients will be enrolled to the dose expansion phase (Part B).

Part B (Dose Expansion): 20 patients will be recruited to Part B to further explore the safety and activity of the combination of guadecitabine and pembrolizumab. This cohort will include, but not be limited to patients with: castration resistant prostate cancer (CRPC), non-small cell lung cancer (NSCLC) and possibly other solid tumours based on emerging anti-tum
Sponsor: Royal Marsden NHS Foundation Trust

Current Primary Outcome:

  • Establish maximum tolerated dose (MTD) [ Time Frame: 12 months ]

    To establish a maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of the combination of guadecitabine and pembrolizumab in patients with advanced solid tumours.

    To determine the maximum dose at which no more than 1 of 6 patients at the same dose level experience a drug related toxicity (DLT), as defined in section 3.1.4 of the protocol.

  • Measure Adverse Events according to CTCAE v4.0 [ Time Frame: 24 months ]

    To assess the safety and toxicity profile of the combination of guadecitabine and pembrolizumab.

    To determine causality and grading severity of each adverse event by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0



Original Primary Outcome: Same as current

Current Secondary Outcome:

  • Pharmacodynamic profile of guadecitabine in combination with pembrolizumab. [ Time Frame: 24 months ]
    Transcriptome analysis in whole bloods using the PAXgene assay.
  • Pharmacodynamic profile of guadecitabine in combination with pembrolizumab. [ Time Frame: 24 months ]
    Targeted sequencing in plasma circulating free DNA.
  • Pharmacodynamic profile of guadecitabine in combination with pembrolizumab. [ Time Frame: 24 months ]
    White blood cell analysis by flow cytometry.
  • Pharmacodynamic profile of guadecitabine in combination with pembrolizumab. [ Time Frame: 24 months ]
    DNA methylation analysis in blood peripheral blood mononuclear cells (PBMC).
  • Pharmacodynamic studies in guadecitabine in combination with pembrolizumab. [ Time Frame: 24 months ]
    Immunohistochemistry of immune cell in serial biopsies.
  • Pharmacodynamic studies in guadecitabine in combination with pembrolizumab. [ Time Frame: 24 months ]
    DNA methylation analysis in serial biopsies.
  • Pharmacodynamic studies in guadecitabine in combination with pembrolizumab. [ Time Frame: 24 months ]
    Transcriptome analysis in serial biopsies.


Original Secondary Outcome:

  • Pharmacodynamic profile of guadecitabine in combination with pembrolizumab. [ Time Frame: 24 months ]
    Transcriptome analysis in whole bloods using PAXgene.
  • Pharmacodynamic profile of guadecitabine in combination with pembrolizumab. [ Time Frame: 24 months ]
    Targeted sequencing in plasma circulating free DNA.
  • Pharmacodynamic profile of guadecitabine in combination with pembrolizumab. [ Time Frame: 24 months ]
    White blood cell analysis by flow cytometry.
  • Pharmacodynamic profile of guadecitabine in combination with pembrolizumab. [ Time Frame: 24 months ]
    DNA methylation analysis in blood PBMC.
  • Pharmacodynamic studies in guadecitabine in combination with pembrolizumab. [ Time Frame: 24 months ]
    Immunohistochemistry of immune cell in serial biopsies.
  • Pharmacodynamic studies in guadecitabine in combination with pembrolizumab. [ Time Frame: 24 months ]
    DNA methylation analysis in serial biopsies.
  • Pharmacodynamic studies in guadecitabine in combination with pembrolizumab. [ Time Frame: 24 months ]
    Transcriptome analysis in serial biopsies.


Information By: Royal Marsden NHS Foundation Trust

Dates:
Date Received: November 2, 2016
Date Started: December 2016
Date Completion:
Last Updated: December 20, 2016
Last Verified: December 2016