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Dose Escalation Study of Lithium With Oxaliplatin and Capecitabine in Advanced Oesophago-Gastric or Colorectal Cancer (Lithium)

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ClinicalTrials.gov Identifier: NCT03153280
Recruitment Status : Not yet recruiting
First Posted : May 15, 2017
Last Update Posted : August 1, 2019
Sponsor:
Collaborator:
University College Cork
Information provided by (Responsible Party):
Cancer Trials Ireland

Brief Summary:

This study is a phase Ib, open label, multi-centre trial designed to estimate the Maximum Tolerated Dose (MTD) of lithium when combined with a standard chemotherapy regimen of oxaliplatin and capecitabine in patients with advanced, unresectable, oesophago-gastric or colorectal cancer who have received no previous treatment for advanced disease (previous adjuvant or neo-adjuvant treatment is acceptable if completed at least 6 months prior to registration).

The study follows a modified Fibonacci, 3+3, dose escalation design. Patients are enrolled in cohorts of 3. All three patients in each cohort must complete at least two cycles of treatment to be evaluable for toxicity. If a patient cannot complete 2 cycles, another patient will be enrolled.


Condition or disease Intervention/treatment Phase
Colorectal Neoplasms Stomach Neoplasm Esophageal Neoplasms Drug: Lithium Drug: Oxaliplatin Drug: Capecitabine Phase 1

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 24 participants
Intervention Model: Single Group Assignment
Intervention Model Description:

Lithium: starting dose: 2x 400mg p.o. per day. Initial target blood concentration (Level 1 = 0.6mmol/L).

Oxaliplatin: 130 mg/m2 in 500 ml normal saline (NS) over 120 minutes on Day 1 of each 3 week cycle.

Capecitabine: 1000 mg/m2 b.i.d po on Days 1 to 14 of each 3 week cycle.

Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase Ib, Dose Escalation Study of Lithium When Added to Standard Chemotherapy of Oxaliplatin and Capecitabine in Patients With Advanced Oesophago-Gastric or Colorectal Cancer
Estimated Study Start Date : September 2019
Estimated Primary Completion Date : August 2020
Estimated Study Completion Date : August 2021


Arm Intervention/treatment
Experimental: Lithium, Oxaliplatin & Capecitabine
Target serum concentrations of escalating doses of lithium (0.6, 0.9, 1.26 or 1.4 mmol/L) in combination standard chemotherapy - oxaliplatin and capecitabine.
Drug: Lithium
Dose escalation of Lithium to determine the maximum tolerated dose (MTD)

Drug: Oxaliplatin
Dose as used in standard of care - 130 mg/m2.

Drug: Capecitabine
Dose as used in standard of care - 800 - 1000 mg/m2




Primary Outcome Measures :
  1. Incidence of dose limiting toxicity (DLT) within the two first cycles at each dose level. [ Time Frame: 26 months ]
    The MTD will be based on the incidence of DLT within the two first cycles of lithium in combination with standard chemotherapy of oxaliplatin and capecitabine at each dose level.


Secondary Outcome Measures :
  1. Progression Free Survival (PFS) as defined by RECIST Criteria Version 1.1. [ Time Frame: 3 years ]
    PFS will be defined as the time from the start of treatment until disease progression or death as a result of any cause.

  2. Objective Response Rate (ORR) as defined by RECIST Criteria Version 1.1. [ Time Frame: 3 years ]
    ORR is defined as the proportion of patients who receive a Complete Response or a Partial Response (CR + PR).

  3. Incidence of adverse events reported as per the NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. (Safety and Tolerability). [ Time Frame: 3 years ]
    Safety will be assessed by standard clinical and laboratory tests.



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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:

  1. Written informed consent must be given according to ICH/GCP and national/local regulations, and be obtained prior to any study-related procedures.
  2. Histologically or cytologically confirmed adenocarcinoma of the colon, rectum, stomach, gastro-oesophageal junction or lower third of the oesophagus.
  3. Metastatic disease not amenable to surgical resection with curative intent.
  4. Eastern Co-operative Oncology Group (ECOG) performance status 2 (Appendix B).
  5. Age ≥ to 18.
  6. Estimated life expectancy ≥ 3 months.
  7. Measurable disease, defined as at least 1 uni-dimensionally measurable lesion on a CT scan as defined by RECIST criteria, Version 1.1 (Appendix F).
  8. Adequate haematological, hepatic, and renal function defined as:

    a. Renal: i. Calculated creatinine clearance (CrCl) 50ml/min (see Appendix G) b. Liver function tests: i. Total Bilirubin ≤ ULN ii. ALT and AST ≤ 2.5 x ULN (≤ 5 x ULN with liver involvement of their cancer) iii. Alkaline Phosphatase ≤ 2.5 x ULN (≤ 5 x ULN with liver involvement of their cancer) c. Haematology: i. Haemoglobin 9.0 g/dL for females and 10.0 g/dL for males ii. Absolute neutrophil count 1.5 x 109/L iii. Platelet count 100 x109/L

  9. Normal thyroid function (TSH 0.4-3.5mUL).
  10. Able to swallow and retain oral medication.
  11. Women of child-bearing potential and male patients must agree to use adequate contraception for the duration of study participation and for up to 3 months following discontinuation of therapy. Adequate contraception is defined as any medically recommended (or combination of methods) as per standard of care.
  12. Women of child bearing potential must have pregnancy excluded by urine or serum beta-HCG testing within 7 days prior to registration.

Exclusion Criteria:

  1. Received prior chemotherapy for metastatic disease. (Patients who received prior adjuvant or neo-adjuvant chemotherapy or definitive radio-chemotherapy for localised disease are eligible if the chemotherapy has stopped at least 6 months before registration).
  2. Previous or concurrent malignancy within the past 5 years, with the exception of basal cell carcinoma of the skin or in-situ neoplasia of the uterine cervix or bladder.
  3. Brain or other Central Nervous System (CNS) metastases.
  4. Known di-hydropyrimidine dehydrogenase (DPD) deficiency.
  5. Screening electrocardiogram (ECG) with evidence of:

    1. QT prolongation (QTc > 450 ms in males and > 470 ms in females)
    2. 2nd or 3rd degree heart block
    3. Other severe cardiac dysfunction (ECG must be assessed for all patients within 14 days prior to registration)
  6. Clinically significant cardiovascular disease including:

    1. Cerebrovascular accident within 6 months prior to registration
    2. Myocardial infarction within 6 months prior to registration
    3. Uncontrolled angina
    4. Uncontrolled hypertension
    5. Clinically significant valvular disease
    6. Congestive Heart Failure (NYHA Class 2) (See Appendix E).
  7. Severe chronic obstructive pulmonary disease (COPD) > Grade 2 according to NCI CTCAE v4.0.
  8. Known history or family history of Brugada Syndrome.
  9. Symptoms or signs of peripheral neuropathy.
  10. Ongoing infection > Grade 2 according to NCI CTCAE v4.0.
  11. Seizure disorder requiring medication.
  12. Dehydration Grade 1 according to NCI CTCAE v4.0; patients on Low sodium diet; Addison's disease.
  13. Known hypersensitivity to lithium, oxaliplatin or fluoropyrimidines.
  14. Pregnant or nursing women.
  15. Concurrent treatment with any other investigational agents within 30 days prior to registration.
  16. Any psychological, physical, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; (those conditions should be discussed with the patient before registration in the trial).
  17. Unable or unwilling to discontinue (and substitute if necessary) use of prohibited medications for at least 30 days prior to and for the duration of study treatment (see section 7.5 for a description of prohibited medications).
  18. Patients weighing less than 50kg.

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): NCT03153280


Contacts
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Contact: Cancer Trials Ireland, Innovation House, Glasnevin, Dublin 11 Dublin 11, Ireland +353 1 6677211 info@cancertrials.ie

Locations
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Ireland
Cancer Trials Ireland Investigative Site Not yet recruiting
Cork, Ireland
Cancer Trials Ireland Investigative Site Not yet recruiting
Dublin 8, Ireland
Cancer Trials Ireland Investigative Site Not yet recruiting
Dublin 9, Ireland
Sponsors and Collaborators
Cancer Trials Ireland
University College Cork
Investigators
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Study Director: Cancer Trials Ireland Dublin 11, Ireland Cancer Trials Ireland

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Responsible Party: Cancer Trials Ireland
ClinicalTrials.gov Identifier: NCT03153280     History of Changes
Other Study ID Numbers: CTRIAL-IE (ICORG) 11-32
2014-000186-47 ( EudraCT Number )
First Posted: May 15, 2017    Key Record Dates
Last Update Posted: August 1, 2019
Last Verified: October 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Colorectal Neoplasms
Stomach Neoplasms
Esophageal Neoplasms
Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Colonic Diseases
Head and Neck Neoplasms
Capecitabine
Digestive System Diseases
Gastrointestinal Diseases
Intestinal Diseases
Rectal Diseases
Stomach Diseases
Esophageal Diseases
Oxaliplatin
Lithium Carbonate
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antidepressive Agents
Psychotropic Drugs
Enzyme Inhibitors
Antimanic Agents
Tranquilizing Agents
Central Nervous System Depressants
Physiological Effects of Drugs