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A Phase I Trial of AZD3965 in Patients With Advanced Cancer

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ClinicalTrials.gov Identifier: NCT01791595
Recruitment Status : Recruiting
First Posted : February 15, 2013
Last Update Posted : October 12, 2018
Sponsor:
Information provided by (Responsible Party):
Cancer Research UK

Brief Summary:

The main aims of this clinical study are to find out the maximum dose that can be given safely to patients, the potential side effects of the drug and how they can be managed and what happens to AZD3965 inside the body.

AZD3965 is a type of drug called a monocarboxylate transporter 1 inhibitor which is being used to stop the growth of cancer cells and kill cancer cells by blocking the action of one of the proteins involved in moving chemical compounds in and out of the cells of the body. This will be the first time that this type of drug has been given to patients.

The drug is a capsule and is taken daily. The study is in two parts. In Part 1 of the study, small groups of patients were treated at increasing doses to find the highest safe dose and best dose to give to patients in Part 2 of the study. 43 patients with advanced solid tumours were treated in Part 1.

In Part 2, the dose found to be safe in Part 1 is given to patients with diffuse large B cell lymphoma and Burkitt's Lymphoma. 15 - 20 patients will be treated in Part 2.

Patients will need to visit the hospital weekly for two months and then every fortnight. Patients will have regular blood and urine tests, scans, heart traces and eye tests amongst other clinical tests. Research blood samples will also be taken to look at what happens to the drug inside the body. Treatment will continue until a patient's cancer starts growing but can continue for up to a maximum of 12 months if the cancer is responding to the drug. It is important to explain that this is the first study of this drug and patients will have advanced cancer so it is unlikely that patients will benefit directly from taking part but the study may help improve future treatment of cancer.


Condition or disease Intervention/treatment Phase
Adult Solid Tumor Diffuse Large B Cell Lymphoma Burkitt Lymphoma Drug: AZD3965 Phase 1

Detailed Description:

Part 1 followed a rolling six dose escalation schedule of AZD3965 until the maximum tolerated dose (MTD) was defined.

43 patients with advanced solid tumours were treated in Part 1 of the study. A recommended Phase II dose (RP2D) has been proposed from the safety, pharmacokinetic, and proof of mechanism of lactate transport inhibition in peripheral blood mononuclear cells (PBMCs) results from Part 1.

All patients in Part 2 will be treated at this RP2D to further explore the tolerability of this dose and schedule and to explore proof of principle of MCT1 inhibition in tumour types that were shown to express MCT1 and in which AZD3965 showed some effect pre-clinically (diffuse large B cell lymphoma and Burkitt's Lymphoma).


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 63 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Cancer Research United Kingdom Phase I Trial of AZD3965, a Monocarboxylate Transporter 1 Inhibitor (MCT1) in Patients With Advanced Cancer
Study Start Date : February 2013
Estimated Primary Completion Date : August 2019



Intervention Details:
  • Drug: AZD3965
    AZD3965 is available as 5, 10, 20 and 30mg capsules and patients took their dose orally once or twice every day of each 28 day cycle including a single dosing day at day-7 prior to Cycle 1 in Part 1 of the study. The RP2D for Part 2 of the study is 10mg BID. Patients can have up to 12 cycles of treatment if patient is benefitting.


Primary Outcome Measures :
  1. A recommended safe and biologically active dose of AZD3965 for evaluation in Phase II trials. [ Time Frame: 48 Months ]

Secondary Outcome Measures :
  1. Pharmacokinetic profile of AZD3965 in plasma including area under the plasma concentration-time curve (AUC) maximum concentration (Cmax), time to maximum concentration (Tmax) and elimination half-life (T1/2) [ Time Frame: Pre-dose, Day -7, Day1, Day 8 & Day 29 ]
  2. Changes in the cell death markers M65,M30 and nuclear DNA (nDNA) [ Time Frame: Pre-dose, Day -7, Day1, Day 8 & Day 29 ]
  3. Objective tumour responses to AZD3965 according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 measured after every 2 cycles [ Time Frame: 48 Months ]


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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. Part 1:

    • Histologically or cytologically proven advanced solid tumour or lymphoma, refractory to conventional treatment or for which no conventional therapy exists.
    • Available archived tumour samples.

    Part 2:

    • Histologically proven diffuse large B-cell Lymphoma (DLBCL) or Burkitt Lymphoma (BL), which is relapsed or refractory to conventional treatment or for which no conventional therapy exists or has been refused by the patient.
    • Available tumour samples which express high MCT1 and low MCT4 as demonstrated by IHC.
    • Measurable disease according to RECIST criteria version 1.1 or International Working Group criteria for Lymphoma
  2. Life expectancy of at least 12 weeks
  3. World Health Organization (WHO) performance status of 0 or 1 (Appendix 1)
  4. Haematological and biochemical indices within the ranges shown below. These measurements must be performed within one week (Day -14 to Day -7) before the patient receives their first dose of AZD3965.

    Laboratory Test Value required

    Haemoglobin (Hb) ≥ 9.0 g/dL (90 g/L) or ≥10.0 g/dL (100 g/L) if transfusion within last 4 weeks

    Absolute neutrophil count (ANC) Part 1: ≥ 1.5 x 10^9/L Part 2: ≥ 1.0 x 10^9/L

    Platelet count Part 1: ≥ 100 x 10^9/L Part 2: ≥ 50 x 10^9/L

    Serum bilirubin ≤ 1.5 x upper limit of normal (ULN)

    Alanine aminotransferase (ALT), aspartate aminotransferase(AST) and alkaline phosphatase (ALP) ≤ 2.5 x ULN or ≤ 5 x ULN in presence of liver metastases

    Alkaline phosphatase (ALP) ALP ≤ 5 x ULN in presence of bone metastases

    Glomerular filtration rate (GFR)

    Either:

    Calculated creatinine clearance

    Or:

    Isotope clearance measurement (uncorrected) ≥ 50 mL/min

    Prothrombin time <1.5 x ULN

    Glucose (fasting) Part 1: < 7.8 mmol/L Part 2: < 6.1 mmol/L

  5. Left ventricular ejection fraction (LVEF)>50%
  6. 18 years or over
  7. Written (signed and dated) informed consent and be capable of co- operating with treatment and follow-up

Exclusion Criteria:

  1. Radiotherapy (except for palliative reasons), endocrine therapy, immunotherapy or chemotherapy during the previous four weeks (six weeks for nitrosoureas, Mitomycin-C and 4 weeks for investigational medicinal products) before treatment.
  2. Ongoing toxic manifestations of previous treatments. Exceptions to this are alopecia or certain Grade 1 toxicities, which in the opinion of the Investigator and the CDD should not exclude the patient.
  3. Known brain or leptomeningeal metastases.
  4. Patients with known retinal disease or macular degeneration affecting visual acuity as assessed by ophthalmologic tests.
  5. Female patients who are able to become pregnant (or are already pregnant or lactating). However, those patients who have a negative serum or urine pregnancy test before enrolment and agree to use two forms of contraception (one highly effective form plus a barrier method) [oral, injected or implanted hormonal contraception and condom; intra-uterine device and condom; diaphragm with spermicidal gel and condom] or agree to sexual abstinence, effective from the first administration of AZD3965, throughout the trial and for six months afterwards are considered eligible.
  6. Male patients with partners of child-bearing potential (unless they agree to take measures not to father children by using a barrier method of contraception [condom plus spermicide] or to sexual abstinence effective from the first administration of AZD3965, throughout the trial and for six months afterwards. Men with partners of child-bearing potential must also be willing to ensure that their partner uses an effective method of contraception for the same duration for example, hormonal contraception, intrauterine device, diaphragm with spermicidal gel or sexual abstinence). Men with pregnant or lactating partners must be advised to use barrier method contraception (for example, condom plus spermicidal gel) to prevent exposure of the foetus or neonate.
  7. Any major surgery in the preceding eight weeks prior to the start of treatment or major thoracic or abdominal surgery from which the patient has not yet recovered.
  8. Patients who are unable to swallow oral medication.
  9. Alterations to corticosteroid dose within 2 weeks prior to first dose of AZD3965.
  10. Gastrointestinal disorders likely to interfere with absorption of the study drug (e.g. partial bowel obstruction or malabsorption).
  11. At high medical risk because of non-malignant systemic disease including active uncontrolled infection.
  12. Known to be serologically positive for hepatitis B, hepatitis C or human immunodeficiency virus (HIV). (N.B. Mandatory testing not required).
  13. History of serious allergy or auto-immune disease.
  14. Diabetes mellitus (patients with diet controlled diabetes may be included with fasting glucose < 7.8 mmol/l and normal HbA1c)
  15. Cardiac conditions as follows:

    • Clinically significant cardiovascular event within 6 months prior to study entry to include:

      1. Acute coronary syndrome (myocardial infarction or unstable angina)
      2. congestive heart failure requiring therapy;
    • Severe valvular heart disease (as defined by British Society of Echocardiography)
    • Presence of an atrial or ventricular arrhythmia, other than atrial fibrillation with well controlled ventricular rate, for which treatment is indicated (anti-arrhythmic drugs or implantable cardioverter defibrillator)
    • First, second or third degree heart block with or without symptoms unless functioning pacemaker
    • QTc > 450 msec in adult male and > 460 msec in adult females (QTc to be verified manually)
    • History of congenital long QT syndrome
    • History of Torsade de Pointes (or any concurrent medication with a known risk of inducing Torsades de Pointes)
    • Uncontrolled hypertension (BP ≥ 160/100mmHg despite medical therapy)
  16. Prior allogeneic bone marrow transplant or have had extensive radiotherapy to greater than 25% of bone marrow within 8 weeks. Prior autologous bone transplant will not exclude a patient,
  17. Is a participant, or plans to participate in another interventional clinical trial, whilst taking part in this Phase I study of AZD3965. Participation in an observational or interventional clinical trial that does not involve administration of an IMP would be acceptable.
  18. Any other condition which in the Investigator's opinion would not make the patient a good candidate for the clinical trial.
  19. For Part 2 only: Current malignancies of other types, with the exception of adequately treated cone-biopsied in situ carcinoma of the cervix uteri and basal or squamous cell carcinoma of the skin.

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): NCT01791595


Contacts
Contact: Ruth Plummer, Prof 08088004040 Ruth.Plummer@newcastle.ac.uk

Locations
United Kingdom
Royal Marsden Hospital Active, not recruiting
Sutton, London, United Kingdom, SM2 5PT
The Beatson West of Scotland, Glasgow Recruiting
Glasgow, United Kingdom
Principal Investigator: Pam McKay, Dr         
Leicester Royal Infirmary Recruiting
Leicester, United Kingdom
Principal Investigator: Martin Dyer, Prof.         
The Christie Recruiting
Manchester, United Kingdom
Principal Investigator: Kim Linton, Dr         
Freeman Hospital Active, not recruiting
Newcastle upon Tyne, United Kingdom, NE7 7DN
Derriford Hospital Recruiting
Plymouth, United Kingdom
Principal Investigator: Simon Rule, Prof.         
Sponsors and Collaborators
Cancer Research UK

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Cancer Research UK
ClinicalTrials.gov Identifier: NCT01791595     History of Changes
Other Study ID Numbers: CRUKD/12/004
First Posted: February 15, 2013    Key Record Dates
Last Update Posted: October 12, 2018
Last Verified: July 2018

Keywords provided by Cancer Research UK:
Phase I
Cancer
Solid Tumours
Diffuse Large B Cell Lymphoma
Monocarboxylate Transporter 1 Inhibitor
lactate
Burkitt Lymphoma

Additional relevant MeSH terms:
Lymphoma
Lymphoma, B-Cell
Burkitt Lymphoma
Lymphoma, Large B-Cell, Diffuse
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Lymphoma, Non-Hodgkin
Epstein-Barr Virus Infections
Herpesviridae Infections
DNA Virus Infections
Virus Diseases
Tumor Virus Infections