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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Pancreas Cancer

Intervention / Treatment
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* Drug: Plerixafor


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: All Subjects<br>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<br>* 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<br>|

What is the study measuring?
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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 |