Adult Solid TumorPhase 1NCT01791595
A Phase I Trial of AZD3965 in Patients With Advanced Cancer
A Phase 1 study testing AZD3965 in people with Adult Solid Tumor and Diffuse Large B Cell Lymphoma, run by Cancer Research UK at 7 sites in United Kingdom.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Adult Solid Tumor, Diffuse Large B Cell Lymphoma, Burkitt Lymphoma
- What is being tested?
- AZD3965
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 53 participants
- Where
- 7 sitesUnited Kingdom
- Study dates
- 23 Apr 2013to 17 Nov 2020
- Phase
- Phase 1
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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 DLBCL or BL, which is relapsed or refractory to conventional treatment or for which no conventional therapy exists or has been refused by the patient.
- Confirmed available tumour samples which can be obtained and used for the study to confirm MCT1 and MCT4 expression as demonstrated by immunohistochemistry.
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- Measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 or International Working Group (IWG) criteria for Lymphoma.
- Life expectancy of at least 12 weeks.
- World Health Organization (WHO) performance status of 0 or 1.
- Haematological and biochemical indices within the ranges shown below.
- 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 (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) <7.8 mmol/L;
- Lactate between 0.5 and 2.5 mmol/L inclusive and bicarbonate between 22 mmol/L and 1.5 x ULN inclusive.
- Left ventricular ejection fraction (LVEF) >50%.
- 18 years or over.
- Written (signed and dated) informed consent and be capable of co-operating with treatment and follow-up.
Who cannot join
- 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.
- Ongoing toxic manifestations of previous treatments greater than National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Grade 1. Exceptions to this are alopecia or certain Grade 1 toxicities, which in the opinion of the Investigator and the Cancer Research UK Centre for Drug Development should not exclude the patient.
- Symptomatic brain or leptomeningeal metastases.
- Patients with known retinal disease or macular degeneration affecting visual acuity as assessed by ophthalmologic tests.
- 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.
- 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.
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- 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.
- Patients who are unable to swallow oral medication.
- Alterations to corticosteroid dose within 2 weeks prior to first dose of AZD3965.
- Gastrointestinal disorders likely to interfere with absorption of the study drug (e.g. partial bowel obstruction or malabsorption).
- At high medical risk because of non-malignant systemic disease including active uncontrolled infection.
- Known to be serologically positive for hepatitis B, hepatitis C or human immunodeficiency virus (HIV). (N.B. Mandatory testing not required).
- History of serious allergy or auto-immune disease.
- Diabetes mellitus (patients with diet controlled diabetes may be included with fasting glucose <7.8 mmol/l and normal haemoglobin A1c [HbA1c]).
- Cardiac conditions as follows:
- Clinically significant cardiovascular event within 6 months prior to study entry to include:
- acute coronary syndrome (myocardial infarction or unstable angina),
- 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).
- Second degree Mobitz type 1 (Wenckebach) heart block with symptoms, or second degree Mobitz type 2 or third degree heart block with or without symptoms unless functioning pacing system.
- QTc >450 msec in adult male and >460 msec in adult females (QTc to be verified manually [Fridericia's Correction]).
- History of congenital long QT syndrome.
- History of Torsade de Pointes (or any concurrent medication with a known risk of inducing QT prolongation).
- Uncontrolled hypertension (blood pressure ≥160/100 mmHg despite medical therapy).
- Extensive radiotherapy to greater than 25% of bone marrow within 8 weeks. Prior autologous bone transplant will not exclude a patient.
- 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.
- Any other condition which in the Investigator's opinion would not make the patient a good candidate for the clinical trial.
- For Part 2 only: Current malignancies of other types, with the exception of adequately treated cone-biopsied in situ carcinoma of the cervix uteri; basal or squamous cell carcinoma of the skin; and patients with low risk prostate cancer on surveillance (with a Gleason score of ≤6 and a Prostate Specific Antigen of ≤10).
Trial locations and contacts
7 sites in 1 country.
7 sites in 1 country
United Kingdom7 sites
The Beatson West of Scotland, Glasgow
Glasgow
Leicester Royal Infirmary
Leicester
University College London Hospitals
London
The Christie
Manchester
Freeman Hospital
Newcastle upon Tyne
Derriford Hospital
Plymouth
Royal Marsden Hospital
Sutton, London
About this study
Official title: A Cancer Research UK Phase I Trial of AZD3965, a Monocarboxylate Transporter 1 Inhibitor (MCT1) in Patients With Advanced Cancer
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.
Read more
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 are treated at increasing doses to find the highest safe dose and best dose to give to patients in Part 2 of the study. It is planned that 40 patients will be entered into Part 1 of the trial.
In Part 2, the dose found to be safe in Part 1 is given to patients with diffuse large B-cell lymphoma (DLBCL) and Burkitt's lymphoma (BL). It is planned that 20 patients will be entered into Part 2 of the trial.
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 is planned to be given for up to 6 months, but patients benefiting from treatment will be able to keep having it for as long as they continue to benefit. 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.
Read the detailed description
Part 1 follows a rolling six dose escalation schedule of AZD3965 given once daily (OD) or twice daily (BD) until the maximum tolerated dose (MTD) is defined.
The recommended Phase II dose (RP2D) is based on the safety and pharmacokinetic (PK) results from Part 1.
All patients in Part 2 are 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 (DLBCL and BL).
- Being tested
- AZD3965
- Keywords
- Phase I, Cancer, Solid Tumours, Diffuse Large B Cell Lymphoma, Monocarboxylate Transporter 1 Inhibitor, lactate, Burkitt Lymphoma
- Medical subject headings
- Lymphoma, Large B-Cell, Diffuse, Burkitt Lymphoma, Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
AZD3965Drug
Day -7: single dose of 5 mg AZD3965 orally prior to start of continuous treatment.
Cycle 1, Day 1: commenced dosing of 5 mg AZD3965 OD orally for up to 6 28-day cycles.
Trial participants benefitting from treatment could continue beyond 6 cycles for as long as they continued to benefit on agreement between the Investigator and the Sponsor.
AZD3965Drug
Day -7: single dose of 10 mg AZD3965 orally prior to start of continuous treatment.
Cycle 1, Day 1: commenced dosing of 10 mg AZD3965 OD orally for up to 6 28-day cycles.
Trial participants benefitting from treatment could continue beyond 6 cycles for as long as they continued to benefit on agreement between the Investigator and the Sponsor.
AZD3965Drug
Day -7: single dose of 20 mg AZD3965 orally prior to start of continuous treatment.
Cycle 1, Day 1: commenced dosing of 20 mg AZD3965 OD orally for up to 6 28-day cycles.
Trial participants benefitting from treatment could continue beyond 6 cycles for as long as they continued to benefit on agreement between the Investigator and the Sponsor.
AZD3965Drug
Day -7: single dose of 30 mg AZD3965 orally prior to start of continuous treatment.
Cycle 1, Day 1: commenced dosing of 30 mg AZD3965 OD orally for up to 6 28-day cycles.
Trial participants benefitting from treatment could continue beyond 6 cycles for as long as they continued to benefit on agreement between the Investigator and the Sponsor.
AZD3965Drug
Day -7: single dose of 30 mg AZD3965 orally prior to start of continuous treatment.
Cycle 1, Day 1: commenced dosing of 15 mg AZD3965 BD orally for up to 6 28-day cycles.
Trial participants benefitting from treatment could continue beyond 6 cycles for as long as they continued to benefit on agreement between the Investigator and the Sponsor.
AZD3965Drug
Day -7: single dose of 20 mg AZD3965 orally prior to start of continuous treatment.
Cycle 1, Day 1: commenced dosing of 10 mg AZD3965 BD orally for up to 6 28-day cycles.
Trial participants benefitting from treatment could continue beyond 6 cycles for as long as they continued to benefit on agreement between the Investigator and the Sponsor.
AZD3965Drug
Day -7: single dose of 20 mg AZD3965 orally prior to start of continuous treatment (first 3 trial participants in the Expansion Cohort only; subsequent patients started treatment at Cycle 1, Day 1).
Cycle 1, Day 1: commenced dosing of 10 mg AZD3965 BD orally for up to 6 28-day cycles.
Trial participants benefitting from treatment could continue beyond 6 cycles for as long as they continued to benefit on agreement between the Investigator and the Sponsor.
| Study group | Role | What they receive |
|---|---|---|
| AZD3965 Cohort 1 (5 mg OD) | Experimental | Not described Receives: Drug: AZD3965 |
| AZD3965 Cohort 2 (10 mg OD) | Experimental | Not described Receives: Drug: AZD3965 |
| AZD3965 Cohort 3 (20 mg OD) | Experimental | Not described Receives: Drug: AZD3965 |
| AZD3965 Cohort 4 (30 mg OD) | Experimental | Not described Receives: Drug: AZD3965 |
| AZD3965 Cohort 5 (15 mg BD) | Experimental | Not described Receives: Drug: AZD3965 |
| AZD3965 Cohort 6 (10 mg BD) | Experimental | Not described Receives: Drug: AZD3965 |
| AZD3965 Expansion Cohort (10 mg BD) | Experimental | Not described Receives: Drug: AZD3965 |
What is being measured
The primary outcome is the main question the study is designed to answer.
MTD of AZD3965
MTD was determined by testing increasing AZD3965 doses in Part 1 dose escalation cohorts (Cohorts 1-6) and defined as the total daily dose level below that at which ≥2 out of ≤6 evaluable patients had a dose-limiting toxicity (DLT) during Cycle 1 (including Day -7). DLTs were defined as highly probably/probably AZD3965 related haematological, cardiac, ophthalmic, other Grade 3/4 toxicity, death or drug-related toxicity causing AZD3965 interruption >2 weeks (see protocol for specific criteria)
Measured: Day -7 to Day 28
Number of Patients Who Experienced DLTs
Number of patients who experienced protocol-defined DLTs (defined according to NCI CTCAE version 4.02). DLTs were defined as highly probably/probably AZD3965 related haematological, cardiac, ophthalmic, other Grade 3/4 toxicity, death or drug-related toxicity causing AZD3965 interruption >2 weeks (see protocol for specific criteria)
Measured: Day -7 to Day 28
Number of Patients Who Experienced Serious AEs
A serious adverse event (SAE) is any AE, regardless of dose, causality or expectedness, that results in death, is life-threatening, requires in-patient hospitalisation or prolongs existing in-patient hospitalisation, results in persistent or significant incapacity or disability, is a congenital anomaly or birth defect or is any other medically important event. Any ophthalmic and/or cardiac DLT is considered a medically important event and therefore an SAE in this trial. Specific AE terms are provided in the Adverse Events section
Measured: From the date of written informed consent and until 28 days after the last dose of AZD3965; an average (median) of 80 days (range: 36 to 517 days)
Number of Patients Who Experienced Non-Serious AEs
A non-serious AE is any untoward medical occurrence that does not meet the serious criteria described for outcome measure 3 above. Specific AE terms are provided in the Adverse Events section
Measured: From the date of written informed consent and until 28 days after the last dose of AZD3965; an average (median) of 80 days (range: 36 to 517 days)
Secondary outcomes (9)
Area Under the Concentration-Time Curve (AUC) From 0 to 24 Hours Post AZD3965 Dosing
Plasma samples were analysed to determine the concentrations of AZD3965 using a previously developed liquid chromatography tandem mass spectrometry (LC-MS/MS) method. For twice daily dosing, Day -7 data reflect the full daily dose but subsequent timepoints reflect half the daily dose as PK sampling was conducted up to 12 hours following the first of the two daily doses; therefore, AUC is from 0 to 12 hours at those timepoints and is reported as a separate outcome measure.
Measured: Part 1 (Cohorts 1-4): Day -7 (pre-dose; 0.25, 0.5, 1, 2, 4, 6, 24, 48 hours post-dose) and Day 1 (pre-dose; 0.25, 0.5, 1, 2, 4, 6, 24 hours post-dose)
AUC From 0 to 12 Hours Post AZD3965 Dosing
Plasma samples were analysed to determine the concentrations of AZD3965 using a previously developed LC-MS/MS method. AUC from 0 to 12 hours was applicable to twice daily dosing on Day 1 only. See AUC From 0 to 24 Hours Post AZD3965 Dosing for AUC for other cohorts and timepoints.
Measured: Part 1 (Cohorts 5-6): Day 1 (pre-dose; 0.25, 0.5, 1, 2, 4, 6, 12 hours post-dose)
Maximum Observed Plasma Concentration of AZD3965
Plasma samples were analysed to determine the concentrations of AZD3965 using a previously developed LC-MS/MS method. For twice daily dosing, Day -7 data reflect the full daily dose and other timepoints reflect half the daily dose.
Measured: Part 1 (Cohorts 1-6): Day -7 (pre-dose; 0.25, 0.5, 1, 2, 4, 6, 24, 48 hours post-dose), Day 1 & 29 (each pre-dose; 0.25, 0.5, 1, 2, 4, 6, 24 hours post-dose [12 hours post-dose if BD]); Part 2 (Expansion): Day 1 (pre-dose; 4, 6, 12 hours post-dose)
Time to Maximum Observed Concentration of AZD3965
Plasma samples were analysed to determine the concentrations of AZD3965 using a previously developed LC-MS/MS method. For twice daily dosing, Day -7 data reflect the full daily dose and other timepoints reflect half the daily dose.
Measured: Part 1 (Cohorts 1-6): Day -7 (pre-dose; 0.25, 0.5, 1, 2, 4, 6, 24, 48 hours post-dose) and Day 1 (pre-dose, 0.25, 0.5, 1, 2, 4, 6, 24 hours post-dose [12 hours post-dose if BD])
Elimination Half Life for AZD3965
Plasma samples were analysed to determine the concentrations of AZD3965 using a previously developed LC-MS/MS method.
Measured: Part 1 (Cohorts 1-6): Day -7 (pre-dose; 0.25, 0.5, 1, 2, 4, 6, 24, 48 hours post-dose and Day 1 pre-dose (168 hours post Day -7 dose)
Plasma Level of Cell Death Marker M30 (Caspase-Cleaved CK18; Part 1 Only)
Plasma samples were analysed to determine the level of M30 using a validated cell death ELISA in Part 1 (Cohorts 1-6). Assays not conducted for Part 2 of the trial as considered uninformative.
Measured: Baseline (Day -14 to -8), Day -7 (pre-dose) Day 1 (24 hours post-dose), Day 8 (pre-dose), Day 29 (pre-dose)
Plasma Level of Cell Death Marker M65 (Total Plus Caspase-Cleaved CK18; Part 1 Only)
Plasma samples were analysed to determine the level of M65 using a validated cell death enzyme-linked immunosorbent assay (ELISA) in Part 1 (Cohorts 1-6). Assays not conducted for Part 2 of the trial as considered uninformative.
Measured: Baseline (Day -14 to -8), Day -7 (pre-dose) Day 1 (24 hours post-dose), Day 8 (pre-dose), Day 29 (pre-dose)
Plasma Level of Nucleosomal DNA (nDNA) as a Measure of Apoptosis (Part 1 Only)
Plasma samples were analysed to determine the level of nDNA using validated methodology in Part 1 (Cohorts 1-6). Assays not conducted for Part 2 of the trial as considered uninformative.
Measured: Baseline (Day -14 to -8), Day -7 (pre-dose) Day 1 (24 hours post-dose), Day 8 (pre-dose), Day 29 (pre-dose)
Number of Patients Who Experienced a Complete Response, Partial Response or Stable Disease According to RECIST 1.1 or a Complete Remission, Partial Remission or Stable Disease According to the IWG Criteria for Lymphoma (Part 2 Only)
Antitumour activity measured according to RECIST version 1.1 (solid tumours)(see Eishenhauer et al; Eur J Cancer 2009, 45:228-247) or IWG criteria for Lymphoma (lymphoma)(see Cheson, Fisher et al; JCO 2014, 32:3059-3067). Complete or partial response/remission was confirmed by repeat measurements ≥4 weeks after response criteria were met; patients with stable disease met criteria at least once ≥6 weeks after first dose of AZD3965
Measured: Radiological disease assessment at screening/baseline and every 6 weeks to end of treatment; an average (median) of 44 days (range: 36 to 432 days)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted15 Feb 2013 (estimated)
- Study start23 Apr 2013
- Primary completion17 Nov 2020
- Study completion17 Nov 2020
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (5)Papers the sponsor has linked to this study.
- Other trials for Adult Solid TumorStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 53 participants (actual)
Sponsor and investigators
- Lead sponsor
- Cancer Research UK
- Sponsor type
- University, hospital or other
- Collaborators
- AstraZeneca
- Responsible party
- Sponsor
- Investigators
- Ruth Plummer, Prof, Principal investigator, Freeman Hospital, Newcastle
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01791595
- Sponsor's protocol ID
- CRUKD/12/004
- Other IDs
- 2010-024463-41
- Status last verified
- Feb 2022
- First submitted
- 11 Feb 2013
- Last updated
- 11 Apr 2022
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Noble RA, Bell N, Blair H, Sikka A, Thomas H, Phillips N, Nakjang S, Miwa S, Crossland R, Rand V, Televantou D, Long A, Keun HC, Bacon CM, Bomken S, Critchlow SE, Wedge SR. Inhibition of monocarboxyate transporter 1 by AZD3965 as a novel therapeutic approach for diffuse large B-cell lymphoma and Burkitt lymphoma. Haematologica. 2017 Jul;102(7):1247-1257. doi: 10.3324/haematol.2016.163030. Epub 2017 Apr 6.
PubMed 28385782Chen Z, Li K, Wei Y, Zhu Q. Decoding lactylation landscapes: Metabolic-epigenetic crosstalk through histone/non-histone modifications as drivers of disease progression and treatment resistance. Biochem Biophys Res Commun. 2025 Nov 28;791:152957. doi: 10.1016/j.bbrc.2025.152957. Epub 2025 Nov 10.
PubMed 41223704McNeillis R, Greystoke A, Walton J, Bacon C, Keun H, Siskos A, Petrides G, Leech N, Jenkinson F, Bowron A, Halford S, Plummer R. A case of malignant hyperlactaemic acidosis appearing upon treatment with the mono-carboxylase transporter 1 inhibitor AZD3965. Br J Cancer. 2020 Apr;122(8):1141-1145. doi: 10.1038/s41416-020-0727-8. Epub 2020 Feb 20.
PubMed 32076124Kershaw S, Cummings J, Morris K, Tugwood J, Dive C. Optimisation of immunofluorescence methods to determine MCT1 and MCT4 expression in circulating tumour cells. BMC Cancer. 2015 May 10;15:387. doi: 10.1186/s12885-015-1382-y.
PubMed 25957999Lamb R, Harrison H, Hulit J, Smith DL, Lisanti MP, Sotgia F. Mitochondria as new therapeutic targets for eradicating cancer stem cells: Quantitative proteomics and functional validation via MCT1/2 inhibition. Oncotarget. 2014 Nov 30;5(22):11029-37. doi: 10.18632/oncotarget.2789.
PubMed 25415228
Study at a glance
From the registry record, last updated by the sponsor on 11 Apr 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Cancer Research UK Phase I Trial of AZD3965, a Monocarboxylate Transporter 1 Inhibitor (MCT1) in Patients With Advanced Cancer
- ClinicalTrials.gov ID
- NCT01791595
- Acronym / sponsor ID
- CRUKD/12/004
- Keywords
- Phase I, Cancer, Solid Tumours, Diffuse Large B Cell Lymphoma, Monocarboxylate Transporter 1 Inhibitor, lactate, Burkitt Lymphoma
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 53 participants (actual)
- Lead sponsor
- Cancer Research UKUniversity, hospital or other
- Collaborators
- AstraZeneca
- Study start
- 23 Apr 2013 (actual)
- Primary completion
- 17 Nov 2020 (actual)
- Study completion
- 17 Nov 2020 (actual)
- First posted
- 15 Feb 2013 (estimated)
- Results
- Posted 11 Apr 2022
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 are treated at increasing doses to find the highest safe dose and best dose to give to patients in Part 2 of the study. It is planned that 40 patients will be entered into Part 1 of the trial.
In Part 2, the dose found to be safe in Part 1 is given to patients with diffuse large B-cell lymphoma (DLBCL) and Burkitt's lymphoma (BL). It is planned that 20 patients will be entered into Part 2 of the trial.
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 is planned to be given for up to 6 months, but patients benefiting from treatment will be able to keep having it for as long as they continue to benefit. 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.
Detailed description
Part 1 follows a rolling six dose escalation schedule of AZD3965 given once daily (OD) or twice daily (BD) until the maximum tolerated dose (MTD) is defined.
The recommended Phase II dose (RP2D) is based on the safety and pharmacokinetic (PK) results from Part 1.
All patients in Part 2 are 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 (DLBCL and BL).
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 7
| Arm | Type | Receives |
|---|---|---|
| AZD3965 Cohort 1 (5 mg OD) | Experimental | Drug: AZD3965 |
| AZD3965 Cohort 2 (10 mg OD) | Experimental | Drug: AZD3965 |
| AZD3965 Cohort 3 (20 mg OD) | Experimental | Drug: AZD3965 |
| AZD3965 Cohort 4 (30 mg OD) | Experimental | Drug: AZD3965 |
| AZD3965 Cohort 5 (15 mg BD) | Experimental | Drug: AZD3965 |
| AZD3965 Cohort 6 (10 mg BD) | Experimental | Drug: AZD3965 |
| AZD3965 Expansion Cohort (10 mg BD) | Experimental | Drug: AZD3965 |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (23 listed)
- Part 1:
- Life expectancy of at least 12 weeks.
- World Health Organization (WHO) performance status of 0 or 1.
- Haematological and biochemical indices within the ranges shown below.
- Left ventricular ejection fraction (LVEF) >50%.
Key exclusion criteria (29 listed)
- 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.
- Ongoing toxic manifestations of previous treatments greater than National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Grade 1. Exceptions to this are alopecia or certain Grade 1 toxicities, which in the opinion of the Investigator and the Cancer Research UK Centre for Drug Development should not exclude the patient.
- Symptomatic brain or leptomeningeal metastases.
- Patients with known retinal disease or macular degeneration affecting visual acuity as assessed by ophthalmologic tests.
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| AZD3965Day -7: single dose of 5 mg AZD3965 orally prior to start of continuous treatment. Cycle 1, Day 1: commenced dosing of 5 mg AZD3965 OD orally for up to 6 28-day cycles. Trial participants benefitting from treatment could continue beyond 6 cycles for as long as they continued to benefit on agreement between the Investigator and the Sponsor. | Drug | AZD3965 Cohort 1 (5 mg OD) |
| AZD3965Day -7: single dose of 10 mg AZD3965 orally prior to start of continuous treatment. Cycle 1, Day 1: commenced dosing of 10 mg AZD3965 OD orally for up to 6 28-day cycles. Trial participants benefitting from treatment could continue beyond 6 cycles for as long as they continued to benefit on agreement between the Investigator and the Sponsor. | Drug | AZD3965 Cohort 2 (10 mg OD) |
| AZD3965Day -7: single dose of 20 mg AZD3965 orally prior to start of continuous treatment. Cycle 1, Day 1: commenced dosing of 20 mg AZD3965 OD orally for up to 6 28-day cycles. Trial participants benefitting from treatment could continue beyond 6 cycles for as long as they continued to benefit on agreement between the Investigator and the Sponsor. | Drug | AZD3965 Cohort 3 (20 mg OD) |
| AZD3965Day -7: single dose of 30 mg AZD3965 orally prior to start of continuous treatment. Cycle 1, Day 1: commenced dosing of 30 mg AZD3965 OD orally for up to 6 28-day cycles. Trial participants benefitting from treatment could continue beyond 6 cycles for as long as they continued to benefit on agreement between the Investigator and the Sponsor. | Drug | AZD3965 Cohort 4 (30 mg OD) |
| AZD3965Day -7: single dose of 30 mg AZD3965 orally prior to start of continuous treatment. Cycle 1, Day 1: commenced dosing of 15 mg AZD3965 BD orally for up to 6 28-day cycles. Trial participants benefitting from treatment could continue beyond 6 cycles for as long as they continued to benefit on agreement between the Investigator and the Sponsor. | Drug | AZD3965 Cohort 5 (15 mg BD) |
| AZD3965Day -7: single dose of 20 mg AZD3965 orally prior to start of continuous treatment. Cycle 1, Day 1: commenced dosing of 10 mg AZD3965 BD orally for up to 6 28-day cycles. Trial participants benefitting from treatment could continue beyond 6 cycles for as long as they continued to benefit on agreement between the Investigator and the Sponsor. | Drug | AZD3965 Cohort 6 (10 mg BD) |
| AZD3965Day -7: single dose of 20 mg AZD3965 orally prior to start of continuous treatment (first 3 trial participants in the Expansion Cohort only; subsequent patients started treatment at Cycle 1, Day 1). Cycle 1, Day 1: commenced dosing of 10 mg AZD3965 BD orally for up to 6 28-day cycles. Trial participants benefitting from treatment could continue beyond 6 cycles for as long as they continued to benefit on agreement between the Investigator and the Sponsor. | Drug | AZD3965 Expansion Cohort (10 mg BD) |
Primary outcome
MTD of AZD3965
Time frame: Day -7 to Day 28
MTD was determined by testing increasing AZD3965 doses in Part 1 dose escalation cohorts (Cohorts 1-6) and defined as the total daily dose level below that at which ≥2 out of ≤6 evaluable patients had a dose-limiting toxicity (DLT) during Cycle 1 (including Day -7). DLTs were defined as highly probably/probably AZD3965 related haematological, cardiac, ophthalmic, other Grade 3/4 toxicity, death or drug-related toxicity causing AZD3965 interruption >2 weeks (see protocol for specific criteria)
Number of Patients Who Experienced DLTs
Time frame: Day -7 to Day 28
Number of patients who experienced protocol-defined DLTs (defined according to NCI CTCAE version 4.02). DLTs were defined as highly probably/probably AZD3965 related haematological, cardiac, ophthalmic, other Grade 3/4 toxicity, death or drug-related toxicity causing AZD3965 interruption >2 weeks (see protocol for specific criteria)
Number of Patients Who Experienced Serious AEs
Time frame: From the date of written informed consent and until 28 days after the last dose of AZD3965; an average (median) of 80 days (range: 36 to 517 days)
A serious adverse event (SAE) is any AE, regardless of dose, causality or expectedness, that results in death, is life-threatening, requires in-patient hospitalisation or prolongs existing in-patient hospitalisation, results in persistent or significant incapacity or disability, is a congenital anomaly or birth defect or is any other medically important event. Any ophthalmic and/or cardiac DLT is considered a medically important event and therefore an SAE in this trial. Specific AE terms are provided in the Adverse Events section
Number of Patients Who Experienced Non-Serious AEs
Time frame: From the date of written informed consent and until 28 days after the last dose of AZD3965; an average (median) of 80 days (range: 36 to 517 days)
A non-serious AE is any untoward medical occurrence that does not meet the serious criteria described for outcome measure 3 above. Specific AE terms are provided in the Adverse Events section
9 secondary outcomes
Area Under the Concentration-Time Curve (AUC) From 0 to 24 Hours Post AZD3965 Dosing
Time frame: Part 1 (Cohorts 1-4): Day -7 (pre-dose; 0.25, 0.5, 1, 2, 4, 6, 24, 48 hours post-dose) and Day 1 (pre-dose; 0.25, 0.5, 1, 2, 4, 6, 24 hours post-dose)
AUC From 0 to 12 Hours Post AZD3965 Dosing
Time frame: Part 1 (Cohorts 5-6): Day 1 (pre-dose; 0.25, 0.5, 1, 2, 4, 6, 12 hours post-dose)
Maximum Observed Plasma Concentration of AZD3965
Time frame: Part 1 (Cohorts 1-6): Day -7 (pre-dose; 0.25, 0.5, 1, 2, 4, 6, 24, 48 hours post-dose), Day 1 & 29 (each pre-dose; 0.25, 0.5, 1, 2, 4, 6, 24 hours post-dose [12 hours post-dose if BD]); Part 2 (Expansion): Day 1 (pre-dose; 4, 6, 12 hours post-dose)
Time to Maximum Observed Concentration of AZD3965
Time frame: Part 1 (Cohorts 1-6): Day -7 (pre-dose; 0.25, 0.5, 1, 2, 4, 6, 24, 48 hours post-dose) and Day 1 (pre-dose, 0.25, 0.5, 1, 2, 4, 6, 24 hours post-dose [12 hours post-dose if BD])
Elimination Half Life for AZD3965
Time frame: Part 1 (Cohorts 1-6): Day -7 (pre-dose; 0.25, 0.5, 1, 2, 4, 6, 24, 48 hours post-dose and Day 1 pre-dose (168 hours post Day -7 dose)
Plasma Level of Cell Death Marker M30 (Caspase-Cleaved CK18; Part 1 Only)
Time frame: Baseline (Day -14 to -8), Day -7 (pre-dose) Day 1 (24 hours post-dose), Day 8 (pre-dose), Day 29 (pre-dose)
Plasma Level of Cell Death Marker M65 (Total Plus Caspase-Cleaved CK18; Part 1 Only)
Time frame: Baseline (Day -14 to -8), Day -7 (pre-dose) Day 1 (24 hours post-dose), Day 8 (pre-dose), Day 29 (pre-dose)
Plasma Level of Nucleosomal DNA (nDNA) as a Measure of Apoptosis (Part 1 Only)
Time frame: Baseline (Day -14 to -8), Day -7 (pre-dose) Day 1 (24 hours post-dose), Day 8 (pre-dose), Day 29 (pre-dose)
Number of Patients Who Experienced a Complete Response, Partial Response or Stable Disease According to RECIST 1.1 or a Complete Remission, Partial Remission or Stable Disease According to the IWG Criteria for Lymphoma (Part 2 Only)
Time frame: Radiological disease assessment at screening/baseline and every 6 weeks to end of treatment; an average (median) of 44 days (range: 36 to 432 days)
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 11 Apr 2022.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 28385782Noble RA, Bell N, Blair H, Sikka A, Thomas H, Phillips N, Nakjang S, Miwa S, Crossland R, Rand V, Televantou D, Long A, Keun HC, Bacon CM, Bomken S, Critchlow SE, Wedge SR. Inhibition of monocarboxyate transporter 1 by AZD3965 as a novel therapeutic approach for diffuse large B-cell lymphoma and Burkitt lymphoma. Haematologica. 2017 Jul;102(7):1247-1257. doi: 10.3324/haematol.2016.163030. Epub 2017 Apr 6.
- Derived from this study: PubMed 41223704Chen Z, Li K, Wei Y, Zhu Q. Decoding lactylation landscapes: Metabolic-epigenetic crosstalk through histone/non-histone modifications as drivers of disease progression and treatment resistance. Biochem Biophys Res Commun. 2025 Nov 28;791:152957. doi: 10.1016/j.bbrc.2025.152957. Epub 2025 Nov 10.
- Derived from this study: PubMed 32076124McNeillis R, Greystoke A, Walton J, Bacon C, Keun H, Siskos A, Petrides G, Leech N, Jenkinson F, Bowron A, Halford S, Plummer R. A case of malignant hyperlactaemic acidosis appearing upon treatment with the mono-carboxylase transporter 1 inhibitor AZD3965. Br J Cancer. 2020 Apr;122(8):1141-1145. doi: 10.1038/s41416-020-0727-8. Epub 2020 Feb 20.
- Derived from this study: PubMed 25957999Kershaw S, Cummings J, Morris K, Tugwood J, Dive C. Optimisation of immunofluorescence methods to determine MCT1 and MCT4 expression in circulating tumour cells. BMC Cancer. 2015 May 10;15:387. doi: 10.1186/s12885-015-1382-y.
- Derived from this study: PubMed 25415228Lamb R, Harrison H, Hulit J, Smith DL, Lisanti MP, Sotgia F. Mitochondria as new therapeutic targets for eradicating cancer stem cells: Quantitative proteomics and functional validation via MCT1/2 inhibition. Oncotarget. 2014 Nov 30;5(22):11029-37. doi: 10.18632/oncotarget.2789.
- Simple summary of trial on Cancer Research UK Trial DatabaseLink provided by the sponsor.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Ruth Plummer, Prof principal investigator
Freeman Hospital, Newcastle
7 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing AZD3965 in people with Adult Solid Tumor and Diffuse Large B Cell Lymphoma, run by Cancer Research UK at 7 sites in United Kingdom.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 23 inclusion and 29 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 11 Apr 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 7 sites in United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 11 Apr 2022). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
MTD of AZD3965 (time frame: Day -7 to Day 28). The study lists 4 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01791595, which also lists 5 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 11 Apr 2022.