To Assess the Safety of Continuous IV Administration of Plerixafor and Assess Impact on the Immune Microenvironment in Patients With Pancreatic, Ovarian and Colorectal Adenocarcinomas

To Assess the Safety of Continuous IV Administration of the CXCR4 Antagonist, Plerixafor at Potentially Active Plasma Concentrations and Assess Its Impact on the Immune Microenvironment in Patients With Advanced Pancreatic, High Grade Serous Ovarian and Colorectal Adenocarcinomas

A dose escalation trial to assess the safety of plerixafor in patients with advanced pancreatic, high grade serous ovarian and colorectal cancer. To identify the proof of mechanism, by demonstrating alterations in T-cell tumour distribution, ideally associated with loss of tumour cells, measured by immunostaining, and changes in FDG uptake.

Study Overview

• Status: Terminated
• Conditions: Pancreas Cancer
• Intervention / Treatment: Drug: Plerixafor

Detailed Description

This is a prospective, non-randomised, open label, Phase I, dose escalation trial of plerixafor in patients with histological documentation of advanced pancreatic, high grade serous ovarian or colorectal adenocarcinoma. We will investigate the feasibility of administering plerixafor in terms of safety, and will try to identify the proof of mechanism in patients. This trial will follow the standard 3+3, Phase I trial design, leading to a treatment expansion phase to confirm the RP2D.

• Study Type: Interventional
• Enrollment (Actual): 2
• Phase: Phase 1

Contacts and Locations

Study Locations

• United Kingdom
  • Cambridge, United Kingdom, CB2 0QQ
    • Cambridge University Hospitals NHS Foundation Trust
• United States
  • New York
    • New York, New York, United States, 10065
      • Weill Cornell Medical College

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:

• Aged 16 years or over (In the US, aged 18 years or over only).
• Dose escalation phase only: Patients with inoperable, histologically proven locally advanced or metastatic pancreatic, high grade serous ovarian or colorectal adenocarcinoma, refractory to conventional chemotherapy or a patient who has declined conventional chemotherapy OR;
• Treatment expansion phase only: Patients with inoperable, histologically proven locally advanced or metastatic pancreatic, refractory to conventional chemotherapy or a patient who has declined conventional chemotherapy.
• Tumour lesions considered to be accessible for core biopsy and immunostaining assessment.
• ECOG performance status 0-1.
• Life expectancy of at least 12 weeks.
• All women of child-bearing potential and all sexually active male patients must agree to use effective contraception methods throughout the trial and for 3 months after the final dose of trial drug.

Exclusion Criteria:

• Inadequate haematological function defined by:

  • Absolute neutrophil count (ANC) <1.5 x 109/L
  • Absolute lymphocyte count <1.0 x 109/L (counts shall be rounded to the nearest tenth. (e.g. 0.96 will be rounded to 1.0 x 109/L))
  • Haemoglobin <9.0 g/dL (90 g/L) (may be increased to this level with transfusion as long as there is no evidence of active bleeding)
  • Platelets <100 x 109/L
  • Clotting; INR >1.3
• Inadequate renal function defined by calculated creatinine clearance by Cockcroft-Gault of <50 ml/min.

• Inadequate hepatic function defined by:

  • Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) >2.5 x upper limit of normal (ULN) or >5 x in the presence of liver metastases
  • Total bilirubin >1.5 x ULN
• Current treatment (within 28 days of entry) with chemotherapy, steroids or other immunosuppressive drugs.
• Significant acute or chronic medical or psychiatric condition, disease or laboratory abnormality which in the judgment of the Investigator would place the patient at undue risk or interfere with the trial.

• Cardiac co-morbidity:

  • Past history of significant rhythm disturbance (e.g. SVT, AF or ventricular irregularities)
  • Requirement for pacemaker
  • Myocardial infarction in the previous 6 months
  • Known medical history of proven postural hypotension.
• Active infection.
• Patients with known allergy to plerixafor or its excipients.
• Patients known to have hepatitis B, hepatitis C or HIV infection.
• Participation in any other interventional clinical trial
• Women, who are pregnant, plan to become pregnant or are lactating (during the trial or for up to 3 months after the last dose)

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: All Subjects; Plerixafor will be administered via IV as a continuous 7 day intravenous infusion starting at a dose of 20 ug/kg/hr and subsequent dose levels of 40, 80 and 120 ug/kg/hr	Drug: Plerixafor; Plerixafor will be administered via IV as a continuous 7 day intravenous infusion starting at a dose of 20 ug/kg/hr and subsequent dose levels of 40, 80 and 120 ug/kg/hr

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Causality of adverse events (AEs) and serious adverse events (SAEs) and grading according to NCI CTCAE v.4.03.	Assess safety of continuous IV administration of plerixafor in doses needed to achieve and maintain circulating levels similar to those active in a murine model of PDAC (2 μg/ml)	From baseline through Day 56

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Assessment of metabolic changes in tumour using non-invasive imaging (18FDG-PET)	To explore objective anticancer clinical impact of this strategy.	From baseline through Day 56

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in T cell distribution within tumour regions within primary or metastatic lesions (e.g. CD3+ T cell accumulation in cancer cell "nests")	To explore relationships between intratumoural T-cell distribution, CXCR4 and CXCL12 immunostaining and other potential biomarkers of immune activation in tissue and blood, such as circulating CD34+ cell counts and diurnal cortisol variation.	From baseline through Day 56
Changes in circulating tumour ctDNA levels within plasma, during and after treatment.		From baseline through Day 56
Changes in proliferation and apoptosis markers (e.g. Ki67/Mib1), changes in tumour cell populations in samples.	To assess modulation of the immune tumour microenvironment following CXCR4 inhibition by plerixafor administration.	From baseline through Day 56
Changes in immune cytokine serum levels.		From baseline through Day 56
T cell receptor (TCR) sequencing in tumour tissue.		From baseline through Day 56
DNA and RNA sequencing in tumour tissue.		From baseline through Day 56
Evidence of systemic pharmacodynamic response to CXCR4i, such as increase in CD34+ cell numbers in blood.		From baseline through Day 56
Correlation between changes in T cell distribution and diurnal cortisol variation.		From baseline through Day 56

Collaborators and Investigators

• Sponsor: Weill Medical College of Cornell University
• Collaborators: Cambridge University Hospitals NHS Foundation Trust
• Investigators: Principal Investigator: Elizabeta Popa, MD, Weill Medical College of Cornell University; Study Chair: Duncan Jodrell, MD, Cambridge University Hospitals NHS Foundation Trust

Study record dates

Study Major Dates

• Study Start (Actual): July 25, 2017
• Primary Completion (Actual): December 30, 2019
• Study Completion (Actual): December 30, 2019

Study Registration Dates

• First Submitted: September 6, 2017
• First Submitted That Met QC Criteria: September 6, 2017
• First Posted (Actual): September 8, 2017

Study Record Updates

• Last Update Posted (Actual): March 2, 2020
• Last Update Submitted That Met QC Criteria: February 27, 2020
• Last Verified: February 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Carcinoma; Neoplasms, Glandular and Epithelial; Endocrine System Diseases; Digestive System Neoplasms; Endocrine Gland Neoplasms; Pancreatic Diseases; Adenocarcinoma; Pancreatic Neoplasms; Anti-Infective Agents; Antiviral Agents; Anti-HIV Agents; Anti-Retroviral Agents; Plerixafor
• Other Study ID Numbers: 1508016466

Drug and device information, study documents

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