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A Cancer Research United Kingdom Phase I Trial of AZD3965, a Monocarboxylate Transporter 1 Inhibitor (MCT1) in Patients With Advanced Cancer

Phase 1
18 Years
Open (Enrolling)
Adult Solid Tumor, Prostate Cancer, Gastric Cancer, Diffuse Large B Cell Lymphoma

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Trial Information

A Cancer Research United Kingdom Phase I Trial of AZD3965, a Monocarboxylate Transporter 1 Inhibitor (MCT1) in Patients With Advanced Cancer

Part 1 will follow a standard 3 + 3 dose escalation schedule of AZD3965 until a tolerated
dose at which MCT1 is inhibited (as measured by at least a four-fold change relative to
baseline in peak lactate levels in PBMCs) and/or the maximum tolerated dose (MTD) is

Approximately 18 patients with advanced solid tumours or lymphoma will be entered into Part
1. The final number will depend on the number of dose escalations required to reach MTD or
the tolerated dose at which MCT1 is inhibited. A recommended Phase II dose (RP2D) will be
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 (prostate) or in which AZD3965 showed some effect
pre-clinically (gastric and diffuse large B cell lymphoma).

Inclusion Criteria:

1. Part 1:

- Histologically or cytologically proven advanced solid tumour or lymphoma,
refractory to conventional treatment or for which no conventional therapy

- Available archived tumour samples.

Part 2:

- Histologically proven castration resistant prostate cancer, diffuse large B-cell
lymphoma or gastric cancer, which is refractory to conventional treatment or for
which no conventional therapy exists or has been refused by the patient.

- Available archived tumour samples.

- Measurable disease according to RECIST criteria version 1.1 or documented rising
prostate-specific antigen (PSA) for prostate cancer.

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 or ≥10.0 g/dL if transfusion within last 4

Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L

Platelet count ≥ 100 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) ≤ 5.0 x ULN in presence of bone metastases

Glomerular filtration rate (GFR)


Calculated creatinine clearance


Isotope clearance measurement (uncorrected) ≥ 50 mL/min

Prothrombin time <1.5 x ULN

Glucose (fasting) < 7.8 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. Part 2 gastric
patients only: received more than two lines of chemotherapy for advanced disease

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 DDO
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. Ability to become pregnant (or already pregnant or lactating). However, those female
patients who have a negative serum or urine pregnancy test before enrollment and
agree to use two highly effective forms of contraception (oral, injected or implanted
hormonal contraception and condom, have a intrauterine device and condom, diaphragm
with spermicidal gel and condom) during 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 one form of highly effective contraception
[condom plus spermicide] during the trial and for six months afterwards). Men with
pregnant or lactating partners should be advised to use barrier method contraception
(for example, condom plus spermicidal gel) to prevent exposure to the foetus or

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

- 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

- History of congenital long QT syndrome

- History of Torsade de Pointes (or any concurrent medication with a known risk of
inducing Torsades de Pointes) - See Appendix 5

- 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 trial 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.

Type of Study:


Study Design:

Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

A recommended safe and biologically active dose of AZD3965 for evaluation in Phase II trials.

Outcome Time Frame:

48 Months

Safety Issue:



United Kingdom: Medicines and Healthcare Products Regulatory Agency

Study ID:




Start Date:

February 2013

Completion Date:

Related Keywords:

  • Adult Solid Tumor
  • Prostate Cancer
  • Gastric Cancer
  • Diffuse Large B Cell Lymphoma
  • Phase I
  • Cancer
  • Solid Tumours
  • Prostate Cancer
  • Gastric Cancer
  • Diffuse Large B Cell Lymphoma
  • Monocarboxylate Transporter 1 Inhibitor
  • lactate
  • Lymphoma
  • Stomach Neoplasms
  • Prostatic Neoplasms
  • Lymphoma, B-Cell
  • Lymphoma, Large B-Cell, Diffuse