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Communicable Diseases

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Virus Diseases

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Diffuse Large B-Cell Lymphoma

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.

AZD3965

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.

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.

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.

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.

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.

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.

Ruth Plummer, Prof

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.

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).

A Phase I Trial of AZD3965 in Patients With Advanced Cancer

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

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 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)

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

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

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.

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.

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.

Plasma samples were analysed to determine the concentrations of AZD3965 using a previously developed LC-MS/MS method.

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.

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.

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.

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

AstraZeneca

Cancer Research UK

AE terms from vocabulary, NCI CTCAE V4.02 for Part 1 (AZD3965 Cohorts 1-6) and MedDRA V23.0 for Part 2 (Expansion Cohort)

AZD3965: 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.

AZD3965 Cohort 1 (5 mg OD)

AZD3965: 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.

AZD3965 Cohort 2 (10 mg OD)

AZD3965: 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.

AZD3965 Cohort 3 (20 mg OD)

AZD3965: 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.

AZD3965 Cohort 4 (30 mg OD)

AZD3965: 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.

AZD3965 Cohort 5 (15 mg BD)

AZD3965: 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.

AZD3965 Cohort 6 (10 mg BD)

AZD3965: 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.

Patients benefitting from treatment could continue beyond 6 cycles for as long as they continued to benefit on agreement between the Investigator and the Sponsor.

AZD3965 Expansion Cohort (10 mg BD)

AZD3965: 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.

Total

Age, Continuous

Sex: Female, Male

Race and Ethnicity were not collected from any participant.

Race and Ethnicity Not Collected

United Kingdom

Region of Enrollment

Lactate accumulation in peripheral blood mononuclear cells was originally a measure for assessment of the primary objective but the assay was confounded by methodological problems and high inter-patient variability. This measure was removed for Part 2 and not used for assessment of the primary objective. M30, M65 and nDNA assays are only quasi quantitative; data \>upper limit substituted with upper limit and data \<lower limit substituted with lower limit/2.

Regulatory Affairs Manager

All eligible participants recruited to dose escalation cohorts 1 to 6 who received at least one dose of AZD3965.

Part 1 Dose Escalation (Cohorts 1-6)

All patients recruited to dose escalation cohorts 1 to 6 who received at least one dose of AZD3965 (n=40)

MTD of AZD3965

All recruited patients who received at least one dose of AZD3965 (N=51)

Number of Patients Who Experienced DLTs

Number of Patients Who Experienced Serious AEs

Number of Patients Who Experienced Non-Serious AEs

Day -7

Day 1

Part 1: Eligible patients who received AZD3965 on Day -7 and had a baseline and post-dose sample analysed (N=32; could only be calculated for N=5 in Cohort 6 \[N=6 for some PK parameters\]); Part 2: Eligible patients who received AZD3965 on Day 1 and had a baseline and post-dose sample analysed (N=11). Only calculated for Day -7 and Day 1 in Part 1 and not calculated for other timepoints due to low number of samples or for Part 2 due to limited number of sampling timepoints.

Area Under the Concentration-Time Curve (AUC) From 0 to 24 Hours Post AZD3965 Dosing

AUC From 0 to 12 Hours Post AZD3965 Dosing

Day 29

Part 1: Eligible patients who received AZD3965 on Day -7 and had a baseline and post-dose sample analysed (N=33) (Only limited samples were available at Day 29); Part 2: Eligible patients who received AZD3965 on Day 1 and had a baseline and post-dose sample analysed (in Part 2 of the trial, PK data were only collected for Day 1)

Maximum Observed Plasma Concentration of AZD3965

Part 1: Eligible patients who received AZD3965 on Day -7 and had a baseline and post-dose sample analysed (N=33); Part 2: Eligible patients who received AZD3965 on Day 1 and had a baseline and post-dose sample analysed (N=11). Only calculated for Day -7 and Day 1 in Part 1; not calculated for other timepoints due to low number of samples or for Part 2 due to number of sampling time points. One patient in Cohort 6 did not have Day -7 data (N=5).

Time to Maximum Observed Concentration of AZD3965

Part 1: Eligible patients who received AZD3965 on Day -7 and had a baseline and post-dose sample analysed (N=32; one patient had a reduced dose in Cohort 6 at Day -7 so these data are not included in half life calculation). Not calculated for Part 2 due to limited number of sampling timepoints.

Elimination Half Life for AZD3965

Baseline

Day 8

All patients in Part 1 who received AZD3965 and provided pre and post-treatment blood samples (N=37). Some patients did not have data at all timepoints

Plasma Level of Cell Death Marker M30 (Caspase-Cleaved CK18; Part 1 Only)

Plasma Level of Cell Death Marker M65 (Total Plus Caspase-Cleaved CK18; Part 1 Only)

Plasma Level of Nucleosomal DNA (nDNA) as a Measure of Apoptosis (Part 1 Only)

Stable disease

Complete remission

Part 2: All patients who met the eligibility criteria, received at least 75% of their first continuous treatment cycle (28 days) and had a baseline assessment of disease (N=5)

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)

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
A Phase I Trial of AZD3965 in Patients With Advanced Cancer	NCT01791595	Adult Solid Tum... Diffuse Large B... Burkitt Lymphom...	AZD3965 AZD3965 AZD3965 AZD3965 AZD3965 AZD3965 AZD3965	18 Years -	Cancer Research UK
A Phase I Trial of AZD3965 in Patients With Advanced Cancer	NCT01791595	Adult Solid Tum... Diffuse Large B... Burkitt Lymphom...	AZD3965 AZD3965 AZD3965 AZD3965 AZD3965 AZD3965 AZD3965	18 Years -	Cancer Research UK

Spots Global Cancer Trial Database for azd3965

Every month we try and update this database with for azd3965 cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Spots Global Cancer Trial Database for azd3965

Every month we try and update this database with for azd3965 cancer trials from around the world to help patients and their families find trials that might be right for them. We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Every month we try and update this database with for azd3965 cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.