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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

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ClinicalTrials.gov Identifier: NCT03277209
Recruitment Status : Terminated (terminated due to slow accrual)
First Posted : September 8, 2017
Last Update Posted : March 2, 2020
Sponsor:
Collaborator:
Cambridge University Hospitals NHS Foundation Trust
Information provided by (Responsible Party):
Weill Medical College of Cornell University

Brief 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.

Condition or disease Intervention/treatment Phase
Pancreas Cancer Drug: Plerixafor Phase 1

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 2 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : July 25, 2017
Actual Primary Completion Date : December 30, 2019
Actual Study Completion Date : December 30, 2019

Resource links provided by the National Library of Medicine

Drug Information available for: Plerixafor

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




Primary Outcome Measures :
  1. Causality of adverse events (AEs) and serious adverse events (SAEs) and grading according to NCI CTCAE v.4.03. [ Time Frame: From baseline through Day 56 ]
    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)


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


Other Outcome Measures:
  1. Change in T cell distribution within tumour regions within primary or metastatic lesions (e.g. CD3+ T cell accumulation in cancer cell "nests") [ Time Frame: From baseline through Day 56 ]
    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.

  2. Changes in circulating tumour ctDNA levels within plasma, during and after treatment. [ Time Frame: From baseline through Day 56 ]
  3. Changes in proliferation and apoptosis markers (e.g. Ki67/Mib1), changes in tumour cell populations in samples. [ Time Frame: From baseline through Day 56 ]
    To assess modulation of the immune tumour microenvironment following CXCR4 inhibition by plerixafor administration.

  4. Changes in immune cytokine serum levels. [ Time Frame: From baseline through Day 56 ]
  5. T cell receptor (TCR) sequencing in tumour tissue. [ Time Frame: From baseline through Day 56 ]
  6. DNA and RNA sequencing in tumour tissue. [ Time Frame: From baseline through Day 56 ]
  7. Evidence of systemic pharmacodynamic response to CXCR4i, such as increase in CD34+ cell numbers in blood. [ Time Frame: From baseline through Day 56 ]
  8. Correlation between changes in T cell distribution and diurnal cortisol variation. [ Time Frame: From baseline through Day 56 ]


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03277209


Locations
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United States, New York
Weill Cornell Medical College
New York, New York, United States, 10065
United Kingdom
Cambridge University Hospitals NHS Foundation Trust
Cambridge, United Kingdom, CB2 0QQ
Sponsors and Collaborators
Weill Medical College of Cornell University
Cambridge University Hospitals NHS Foundation Trust
Investigators
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Principal Investigator: Elizabeta Popa, MD Weill Medical College of Cornell University
Study Chair: Duncan Jodrell, MD Cambridge University Hospitals NHS Foundation Trust
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Responsible Party: Weill Medical College of Cornell University
ClinicalTrials.gov Identifier: NCT03277209    
Other Study ID Numbers: 1508016466
First Posted: September 8, 2017    Key Record Dates
Last Update Posted: March 2, 2020
Last Verified: February 2020

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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
Additional relevant MeSH terms:
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Adenocarcinoma
Pancreatic Neoplasms
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Endocrine Gland Neoplasms
Digestive System Diseases
Pancreatic Diseases
Endocrine System Diseases
Plerixafor octahydrochloride
Anti-HIV Agents
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents