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

Pancreas Cancer Clinical Trial

Official title:

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT03277209
• Other study ID #: 1508016466
• Status: Terminated
• Phase: Phase 1
• Start date: July 25, 2017
• Est. completion date: December 30, 2019

Study information

• Verified date: February 2020
• Source: Weill Medical College of Cornell University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 2
• Est. completion date: December 30, 2019
• Est. primary completion date: December 30, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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)

Related Conditions & MeSH terms

• Adenocarcinoma
• Pancreas Cancer
• Pancreatic Neoplasms

Intervention

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

Locations

Country	Name	City	State
United Kingdom	Cambridge University Hospitals NHS Foundation Trust	Cambridge
United States	Weill Cornell Medical College	New York	New York

Sponsors (2)

Lead Sponsor	Collaborator
Weill Medical College of Cornell University	Cambridge University Hospitals NHS Foundation Trust

Countries where clinical trial is conducted

United States,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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
Other	Changes in circulating tumour ctDNA levels within plasma, during and after treatment.		From baseline through Day 56
Other	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
Other	Changes in immune cytokine serum levels.		From baseline through Day 56
Other	T cell receptor (TCR) sequencing in tumour tissue.		From baseline through Day 56
Other	DNA and RNA sequencing in tumour tissue.		From baseline through Day 56
Other	Evidence of systemic pharmacodynamic response to CXCR4i, such as increase in CD34+ cell numbers in blood.		From baseline through Day 56
Other	Correlation between changes in T cell distribution and diurnal cortisol variation.		From baseline through Day 56
Primary	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	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