Adult Solid Tumor, Burkitt Lymphoma, Diffuse Large B Cell Lymphoma
Conditions
Keywords
Phase I, Cancer, Solid Tumours, Diffuse Large B Cell Lymphoma, Monocarboxylate Transporter 1 Inhibitor, lactate, Burkitt Lymphoma
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 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).
Interventions
DRUGAZD3965
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.
Sponsors
AstraZeneca
Cancer Research UK
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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 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. * Measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 or International Working Group (IWG) criteria for Lymphoma. 2. Life expectancy of at least 12 weeks. 3. World Health Organization (WHO) performance status of 0 or 1. 4. 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. 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 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. 3. Symptomatic 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 haemoglobin A1c \[HbA1c\]). 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). * 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). 16. 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; 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).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| MTD of AZD3965 | 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 | 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 | 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 | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Maximum Observed Concentration of AZD3965 | 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]) | 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. |
| Elimination Half Life for AZD3965 | 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 samples were analysed to determine the concentrations of AZD3965 using a previously developed LC-MS/MS method. |
| Area Under the Concentration-Time Curve (AUC) From 0 to 24 Hours Post AZD3965 Dosing | 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) | 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 Level of Cell Death Marker M65 (Total Plus Caspase-Cleaved CK18; Part 1 Only) | Baseline (Day -14 to -8), Day -7 (pre-dose) Day 1 (24 hours post-dose), Day 8 (pre-dose), Day 29 (pre-dose) | 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. |
| 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) | 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) | 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 |
| Plasma Level of Cell Death Marker M30 (Caspase-Cleaved CK18; Part 1 Only) | Baseline (Day -14 to -8), Day -7 (pre-dose) Day 1 (24 hours post-dose), Day 8 (pre-dose), Day 29 (pre-dose) | 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. |
| AUC From 0 to 12 Hours Post AZD3965 Dosing | Part 1 (Cohorts 5-6): Day 1 (pre-dose; 0.25, 0.5, 1, 2, 4, 6, 12 hours post-dose) | 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 Level of Nucleosomal DNA (nDNA) as a Measure of Apoptosis (Part 1 Only) | Baseline (Day -14 to -8), Day -7 (pre-dose) Day 1 (24 hours post-dose), Day 8 (pre-dose), Day 29 (pre-dose) | 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. |
| Maximum Observed Plasma Concentration of AZD3965 | 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) | 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. |
Countries
United Kingdom
Participant flow
Recruitment details
Trial participants were enrolled at seven trial sites between 23 April 2013 and 24 July 2019. Two additional patients were recruited to the trial but were withdrawn prior to receiving AZD3965.
Participants by arm
| Arm | Count |
|---|---|
| AZD3965 Cohort 1 (5 mg OD) 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. | 3 |
| AZD3965 Cohort 2 (10 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. | 5 |
| AZD3965 Cohort 3 (20 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. | 8 |
| 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 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. | 5 |
| AZD3965 Cohort 5 (15 mg BD) 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. | 11 |
| AZD3965 Cohort 6 (10 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. | 8 |
| 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. | 11 |
| Total | 51 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 |
|---|---|---|---|---|---|---|---|---|
| Part 1 AZD3965 Cohort 1 (5 mg OD) | Death | 1 | 0 | 0 | 0 | 0 | 0 | 0 |
| Part 1 AZD3965 Cohort 1 (5 mg OD) | Evidence of disease progression | 2 | 0 | 0 | 0 | 0 | 0 | 0 |
| Part 1 AZD3965 Cohort 2 (10 mg OD) | Evidence of disease progression | 0 | 5 | 0 | 0 | 0 | 0 | 0 |
| Part 1 AZD3965 Cohort 3 (20 mg OD) | Adverse Event | 0 | 0 | 1 | 0 | 0 | 0 | 0 |
| Part 1 AZD3965 Cohort 3 (20 mg OD) | Evidence of disease progression | 0 | 0 | 6 | 0 | 0 | 0 | 0 |
| Part 1 AZD3965 Cohort 3 (20 mg OD) | Physician Decision | 0 | 0 | 1 | 0 | 0 | 0 | 0 |
| Part 1 AZD3965 Cohort 4 (30 mg OD) | Adverse Event | 0 | 0 | 0 | 2 | 0 | 0 | 0 |
| Part 1 AZD3965 Cohort 4 (30 mg OD) | Evidence of disease progression | 0 | 0 | 0 | 2 | 0 | 0 | 0 |
| Part 1 AZD3965 Cohort 5 (15 mg BD) | Adverse Event | 0 | 0 | 0 | 0 | 4 | 0 | 0 |
| Part 1 AZD3965 Cohort 5 (15 mg BD) | Evidence of disease progression | 0 | 0 | 0 | 0 | 5 | 0 | 0 |
| Part 1 AZD3965 Cohort 5 (15 mg BD) | Physician Decision | 0 | 0 | 0 | 0 | 1 | 0 | 0 |
| Part 1 AZD3965 Cohort 5 (15 mg BD) | Withdrawal by Subject | 0 | 0 | 0 | 0 | 1 | 0 | 0 |
| Part 1 AZD3965 Cohort 6 (10 mg BD) | Adverse Event | 0 | 0 | 0 | 0 | 0 | 5 | 0 |
| Part 1 AZD3965 Cohort 6 (10 mg BD) | Evidence of disease progression | 0 | 0 | 0 | 0 | 0 | 3 | 0 |
| Part 2 AZD3965 Expansion (10 mg BD) | Adverse Event | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
| Part 2 AZD3965 Expansion (10 mg BD) | Evidence of disease progression | 0 | 0 | 0 | 0 | 0 | 0 | 6 |
| Part 2 AZD3965 Expansion (10 mg BD) | Physician Decision | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
| Part 2 AZD3965 Expansion (10 mg BD) | Withdrawal by Subject | 0 | 0 | 0 | 0 | 0 | 0 | 2 |
Baseline characteristics
| Characteristic | AZD3965 Cohort 1 (5 mg OD) | AZD3965 Cohort 2 (10 mg OD) | AZD3965 Cohort 3 (20 mg OD) | AZD3965 Cohort 4 (30 mg OD) | AZD3965 Cohort 5 (15 mg BD) | AZD3965 Cohort 6 (10 mg BD) | AZD3965 Expansion Cohort (10 mg BD) | Total |
|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 62 years | 66 years | 64.5 years | 72 years | 63 years | 63.5 years | 70 years | 65 years |
| Race and Ethnicity Not Collected | — | — | — | — | — | — | — | 0 Participants |
| Region of Enrollment United Kingdom | 3 participants | 5 participants | 8 participants | 5 participants | 11 participants | 8 participants | 11 participants | 51 participants |
| Sex: Female, Male Female | 1 Participants | 3 Participants | 3 Participants | 2 Participants | 5 Participants | 1 Participants | 4 Participants | 19 Participants |
| Sex: Female, Male Male | 2 Participants | 2 Participants | 5 Participants | 3 Participants | 6 Participants | 7 Participants | 7 Participants | 32 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 3 | 1 / 5 | 0 / 8 | 0 / 5 | 0 / 11 | 0 / 8 | 0 / 11 |
| other Total, other adverse events | 3 / 3 | 5 / 5 | 7 / 8 | 5 / 5 | 11 / 11 | 7 / 8 | 11 / 11 |
| serious Total, serious adverse events | 1 / 3 | 1 / 5 | 3 / 8 | 2 / 5 | 8 / 11 | 4 / 8 | 8 / 11 |
Outcome results
Primary
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)
Time frame: Day -7 to Day 28
Population: All patients recruited to dose escalation cohorts 1 to 6 who received at least one dose of AZD3965 (n=40)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1 Dose Escalation (Cohorts 1-6) | MTD of AZD3965 | 10 mg (twice daily) |
Primary
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)
Time frame: Day -7 to Day 28
Population: All recruited patients who received at least one dose of AZD3965 (N=51)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1 Dose Escalation (Cohorts 1-6) | Number of Patients Who Experienced DLTs | 0 Participants |
| AZD3965 Cohort 2 (10 mg OD) | Number of Patients Who Experienced DLTs | 0 Participants |
| AZD3965 Cohort 3 (20 mg OD) | Number of Patients Who Experienced DLTs | 1 Participants |
| AZD3965 Cohort 4 (30 mg OD) | Number of Patients Who Experienced DLTs | 1 Participants |
| AZD3965 Cohort 5 (15 mg BD) | Number of Patients Who Experienced DLTs | 3 Participants |
| AZD3965 Cohort 6 (10 mg BD) | Number of Patients Who Experienced DLTs | 2 Participants |
| AZD3965 Expansion Cohort (10 mg BD) | Number of Patients Who Experienced DLTs | 1 Participants |
Primary
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
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)
Population: All recruited patients who received at least one dose of AZD3965 (N=51)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1 Dose Escalation (Cohorts 1-6) | Number of Patients Who Experienced Non-Serious AEs | 3 Participants |
| AZD3965 Cohort 2 (10 mg OD) | Number of Patients Who Experienced Non-Serious AEs | 5 Participants |
| AZD3965 Cohort 3 (20 mg OD) | Number of Patients Who Experienced Non-Serious AEs | 7 Participants |
| AZD3965 Cohort 4 (30 mg OD) | Number of Patients Who Experienced Non-Serious AEs | 5 Participants |
| AZD3965 Cohort 5 (15 mg BD) | Number of Patients Who Experienced Non-Serious AEs | 11 Participants |
| AZD3965 Cohort 6 (10 mg BD) | Number of Patients Who Experienced Non-Serious AEs | 7 Participants |
| AZD3965 Expansion Cohort (10 mg BD) | Number of Patients Who Experienced Non-Serious AEs | 11 Participants |
Primary
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
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)
Population: All recruited patients who received at least one dose of AZD3965 (N=51)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1 Dose Escalation (Cohorts 1-6) | Number of Patients Who Experienced Serious AEs | 1 Participants |
| AZD3965 Cohort 2 (10 mg OD) | Number of Patients Who Experienced Serious AEs | 1 Participants |
| AZD3965 Cohort 3 (20 mg OD) | Number of Patients Who Experienced Serious AEs | 3 Participants |
| AZD3965 Cohort 4 (30 mg OD) | Number of Patients Who Experienced Serious AEs | 2 Participants |
| AZD3965 Cohort 5 (15 mg BD) | Number of Patients Who Experienced Serious AEs | 8 Participants |
| AZD3965 Cohort 6 (10 mg BD) | Number of Patients Who Experienced Serious AEs | 4 Participants |
| AZD3965 Expansion Cohort (10 mg BD) | Number of Patients Who Experienced Serious AEs | 8 Participants |
Secondary
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.
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)
Population: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1 Dose Escalation (Cohorts 1-6) | Area Under the Concentration-Time Curve (AUC) From 0 to 24 Hours Post AZD3965 Dosing | Day -7 | 211.7 h*ng/mL | Standard Deviation 84.9 |
| Part 1 Dose Escalation (Cohorts 1-6) | Area Under the Concentration-Time Curve (AUC) From 0 to 24 Hours Post AZD3965 Dosing | Day 1 | 274 h*ng/mL | Standard Deviation 1 |
| AZD3965 Cohort 2 (10 mg OD) | Area Under the Concentration-Time Curve (AUC) From 0 to 24 Hours Post AZD3965 Dosing | Day -7 | 730.8 h*ng/mL | Standard Deviation 311.4 |
| AZD3965 Cohort 2 (10 mg OD) | Area Under the Concentration-Time Curve (AUC) From 0 to 24 Hours Post AZD3965 Dosing | Day 1 | 999 h*ng/mL | Standard Deviation 126.3 |
| AZD3965 Cohort 3 (20 mg OD) | Area Under the Concentration-Time Curve (AUC) From 0 to 24 Hours Post AZD3965 Dosing | Day -7 | 1509.3 h*ng/mL | Standard Deviation 384.8 |
| AZD3965 Cohort 3 (20 mg OD) | Area Under the Concentration-Time Curve (AUC) From 0 to 24 Hours Post AZD3965 Dosing | Day 1 | 2123.5 h*ng/mL | Standard Deviation 589.6 |
| AZD3965 Cohort 4 (30 mg OD) | Area Under the Concentration-Time Curve (AUC) From 0 to 24 Hours Post AZD3965 Dosing | Day -7 | 2843 h*ng/mL | Standard Deviation 1337.4 |
| AZD3965 Cohort 4 (30 mg OD) | Area Under the Concentration-Time Curve (AUC) From 0 to 24 Hours Post AZD3965 Dosing | Day 1 | 3031 h*ng/mL | Standard Deviation 1360.5 |
| AZD3965 Cohort 5 (15 mg BD) | Area Under the Concentration-Time Curve (AUC) From 0 to 24 Hours Post AZD3965 Dosing | Day -7 | 3984.7 h*ng/mL | Standard Deviation 2339.9 |
| AZD3965 Cohort 5 (15 mg BD) | Area Under the Concentration-Time Curve (AUC) From 0 to 24 Hours Post AZD3965 Dosing | Day 1 | NA h*ng/mL | — |
| AZD3965 Cohort 6 (10 mg BD) | Area Under the Concentration-Time Curve (AUC) From 0 to 24 Hours Post AZD3965 Dosing | Day -7 | 1540 h*ng/mL | Standard Deviation 693.6 |
| AZD3965 Cohort 6 (10 mg BD) | Area Under the Concentration-Time Curve (AUC) From 0 to 24 Hours Post AZD3965 Dosing | Day 1 | NA h*ng/mL | — |
Secondary
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.
Time frame: Part 1 (Cohorts 5-6): Day 1 (pre-dose; 0.25, 0.5, 1, 2, 4, 6, 12 hours post-dose)
Population: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1 Dose Escalation (Cohorts 1-6) | AUC From 0 to 12 Hours Post AZD3965 Dosing | 1251.5 h*ng/mL | Standard Deviation 654.2 |
| AZD3965 Cohort 2 (10 mg OD) | AUC From 0 to 12 Hours Post AZD3965 Dosing | 620 h*ng/mL | Standard Deviation 272.2 |
Secondary
Elimination Half Life for AZD3965
Plasma samples were analysed to determine the concentrations of AZD3965 using a previously developed LC-MS/MS method.
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)
Population: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1 Dose Escalation (Cohorts 1-6) | Elimination Half Life for AZD3965 | 51.9 Hour | Standard Deviation 4.9 |
| AZD3965 Cohort 2 (10 mg OD) | Elimination Half Life for AZD3965 | 45.4 Hour | Standard Deviation 6.4 |
| AZD3965 Cohort 3 (20 mg OD) | Elimination Half Life for AZD3965 | 38.3 Hour | Standard Deviation 5.9 |
| AZD3965 Cohort 4 (30 mg OD) | Elimination Half Life for AZD3965 | 38.7 Hour | Standard Deviation 13.3 |
| AZD3965 Cohort 5 (15 mg BD) | Elimination Half Life for AZD3965 | 37.5 Hour | Standard Deviation 8.5 |
| AZD3965 Cohort 6 (10 mg BD) | Elimination Half Life for AZD3965 | 33.6 Hour | Standard Deviation 4.3 |
Secondary
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.
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)
Population: 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)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1 Dose Escalation (Cohorts 1-6) | Maximum Observed Plasma Concentration of AZD3965 | Day 1 | 38.4 ng/mL | Standard Deviation 9.5 |
| Part 1 Dose Escalation (Cohorts 1-6) | Maximum Observed Plasma Concentration of AZD3965 | Day -7 | 43.4 ng/mL | Standard Deviation 22 |
| Part 1 Dose Escalation (Cohorts 1-6) | Maximum Observed Plasma Concentration of AZD3965 | Day 29 | 48.6 ng/mL | — |
| AZD3965 Cohort 2 (10 mg OD) | Maximum Observed Plasma Concentration of AZD3965 | Day 1 | 135.0 ng/mL | Standard Deviation 53.2 |
| AZD3965 Cohort 2 (10 mg OD) | Maximum Observed Plasma Concentration of AZD3965 | Day -7 | 122 ng/mL | Standard Deviation 62.7 |
| AZD3965 Cohort 2 (10 mg OD) | Maximum Observed Plasma Concentration of AZD3965 | Day 29 | 271.6 ng/mL | Standard Deviation 123.3 |
| AZD3965 Cohort 3 (20 mg OD) | Maximum Observed Plasma Concentration of AZD3965 | Day 1 | 219.9 ng/mL | Standard Deviation 62.1 |
| AZD3965 Cohort 3 (20 mg OD) | Maximum Observed Plasma Concentration of AZD3965 | Day -7 | 222.7 ng/mL | Standard Deviation 95.1 |
| AZD3965 Cohort 3 (20 mg OD) | Maximum Observed Plasma Concentration of AZD3965 | Day 29 | 310.1 ng/mL | Standard Deviation 180.6 |
| AZD3965 Cohort 4 (30 mg OD) | Maximum Observed Plasma Concentration of AZD3965 | Day 1 | 458.4 ng/mL | Standard Deviation 237 |
| AZD3965 Cohort 4 (30 mg OD) | Maximum Observed Plasma Concentration of AZD3965 | Day -7 | 377.6 ng/mL | Standard Deviation 80.2 |
| AZD3965 Cohort 4 (30 mg OD) | Maximum Observed Plasma Concentration of AZD3965 | Day 29 | 239.2 ng/mL | — |
| AZD3965 Cohort 5 (15 mg BD) | Maximum Observed Plasma Concentration of AZD3965 | Day 1 | 213.6 ng/mL | Standard Deviation 122.1 |
| AZD3965 Cohort 5 (15 mg BD) | Maximum Observed Plasma Concentration of AZD3965 | Day -7 | 483.9 ng/mL | Standard Deviation 205.7 |
| AZD3965 Cohort 6 (10 mg BD) | Maximum Observed Plasma Concentration of AZD3965 | Day -7 | 226 ng/mL | Standard Deviation 85.7 |
| AZD3965 Cohort 6 (10 mg BD) | Maximum Observed Plasma Concentration of AZD3965 | Day 29 | 132.3 ng/mL | Standard Deviation 38.6 |
| AZD3965 Cohort 6 (10 mg BD) | Maximum Observed Plasma Concentration of AZD3965 | Day 1 | 106.2 ng/mL | Standard Deviation 57.1 |
| AZD3965 Expansion Cohort (10 mg BD) | Maximum Observed Plasma Concentration of AZD3965 | Day 1 | 78.5 ng/mL | Standard Deviation 42.3 |
Secondary
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
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)
Population: 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)
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part 1 Dose Escalation (Cohorts 1-6) | 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) | Stable disease | 1 Participants |
| Part 1 Dose Escalation (Cohorts 1-6) | 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) | Complete remission | 1 Participants |
Secondary
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.
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)
Population: 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
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1 Dose Escalation (Cohorts 1-6) | Plasma Level of Cell Death Marker M30 (Caspase-Cleaved CK18; Part 1 Only) | Day 8 | 226 U/L | Standard Deviation 86.2 |
| Part 1 Dose Escalation (Cohorts 1-6) | Plasma Level of Cell Death Marker M30 (Caspase-Cleaved CK18; Part 1 Only) | Day -7 | 201 U/L | Standard Deviation 17 |
| Part 1 Dose Escalation (Cohorts 1-6) | Plasma Level of Cell Death Marker M30 (Caspase-Cleaved CK18; Part 1 Only) | Baseline | 383 U/L | — |
| Part 1 Dose Escalation (Cohorts 1-6) | Plasma Level of Cell Death Marker M30 (Caspase-Cleaved CK18; Part 1 Only) | Day 29 | 176 U/L | Standard Deviation 46.7 |
| Part 1 Dose Escalation (Cohorts 1-6) | Plasma Level of Cell Death Marker M30 (Caspase-Cleaved CK18; Part 1 Only) | Day 1 | 174.5 U/L | Standard Deviation 60.1 |
| AZD3965 Cohort 2 (10 mg OD) | Plasma Level of Cell Death Marker M30 (Caspase-Cleaved CK18; Part 1 Only) | Day -7 | 865.6 U/L | Standard Deviation 250.3 |
| AZD3965 Cohort 2 (10 mg OD) | Plasma Level of Cell Death Marker M30 (Caspase-Cleaved CK18; Part 1 Only) | Day 8 | 959.4 U/L | Standard Deviation 90.8 |
| AZD3965 Cohort 2 (10 mg OD) | Plasma Level of Cell Death Marker M30 (Caspase-Cleaved CK18; Part 1 Only) | Baseline | 944.8 U/L | Standard Deviation 72.6 |
| AZD3965 Cohort 2 (10 mg OD) | Plasma Level of Cell Death Marker M30 (Caspase-Cleaved CK18; Part 1 Only) | Day 29 | 836.7 U/L | Standard Deviation 282.9 |
| AZD3965 Cohort 2 (10 mg OD) | Plasma Level of Cell Death Marker M30 (Caspase-Cleaved CK18; Part 1 Only) | Day 1 | 860.6 U/L | Standard Deviation 191.5 |
| AZD3965 Cohort 3 (20 mg OD) | Plasma Level of Cell Death Marker M30 (Caspase-Cleaved CK18; Part 1 Only) | Day -7 | 410.1 U/L | Standard Deviation 296.5 |
| AZD3965 Cohort 3 (20 mg OD) | Plasma Level of Cell Death Marker M30 (Caspase-Cleaved CK18; Part 1 Only) | Day 8 | 457.1 U/L | Standard Deviation 339.5 |
| AZD3965 Cohort 3 (20 mg OD) | Plasma Level of Cell Death Marker M30 (Caspase-Cleaved CK18; Part 1 Only) | Day 29 | 428 U/L | Standard Deviation 366.6 |
| AZD3965 Cohort 3 (20 mg OD) | Plasma Level of Cell Death Marker M30 (Caspase-Cleaved CK18; Part 1 Only) | Day 1 | 428.4 U/L | Standard Deviation 302.9 |
| AZD3965 Cohort 3 (20 mg OD) | Plasma Level of Cell Death Marker M30 (Caspase-Cleaved CK18; Part 1 Only) | Baseline | 392.3 U/L | Standard Deviation 300.3 |
| AZD3965 Cohort 4 (30 mg OD) | Plasma Level of Cell Death Marker M30 (Caspase-Cleaved CK18; Part 1 Only) | Day 1 | 220.6 U/L | Standard Deviation 112.7 |
| AZD3965 Cohort 4 (30 mg OD) | Plasma Level of Cell Death Marker M30 (Caspase-Cleaved CK18; Part 1 Only) | Baseline | 196.0 U/L | Standard Deviation 96.3 |
| AZD3965 Cohort 4 (30 mg OD) | Plasma Level of Cell Death Marker M30 (Caspase-Cleaved CK18; Part 1 Only) | Day -7 | 225.6 U/L | Standard Deviation 114.5 |
| AZD3965 Cohort 4 (30 mg OD) | Plasma Level of Cell Death Marker M30 (Caspase-Cleaved CK18; Part 1 Only) | Day 8 | 206.8 U/L | Standard Deviation 90.2 |
| AZD3965 Cohort 4 (30 mg OD) | Plasma Level of Cell Death Marker M30 (Caspase-Cleaved CK18; Part 1 Only) | Day 29 | 267.8 U/L | Standard Deviation 157.8 |
| AZD3965 Cohort 5 (15 mg BD) | Plasma Level of Cell Death Marker M30 (Caspase-Cleaved CK18; Part 1 Only) | Day 8 | 418.6 U/L | Standard Deviation 327.8 |
| AZD3965 Cohort 5 (15 mg BD) | Plasma Level of Cell Death Marker M30 (Caspase-Cleaved CK18; Part 1 Only) | Baseline | 464.9 U/L | Standard Deviation 304.9 |
| AZD3965 Cohort 5 (15 mg BD) | Plasma Level of Cell Death Marker M30 (Caspase-Cleaved CK18; Part 1 Only) | Day 29 | 660.3 U/L | Standard Deviation 489.7 |
| AZD3965 Cohort 5 (15 mg BD) | Plasma Level of Cell Death Marker M30 (Caspase-Cleaved CK18; Part 1 Only) | Day -7 | 464.8 U/L | Standard Deviation 312.3 |
| AZD3965 Cohort 5 (15 mg BD) | Plasma Level of Cell Death Marker M30 (Caspase-Cleaved CK18; Part 1 Only) | Day 1 | 487.9 U/L | Standard Deviation 326.9 |
| AZD3965 Cohort 6 (10 mg BD) | Plasma Level of Cell Death Marker M30 (Caspase-Cleaved CK18; Part 1 Only) | Baseline | 359.6 U/L | Standard Deviation 364 |
| AZD3965 Cohort 6 (10 mg BD) | Plasma Level of Cell Death Marker M30 (Caspase-Cleaved CK18; Part 1 Only) | Day 8 | 343.4 U/L | Standard Deviation 370.8 |
| AZD3965 Cohort 6 (10 mg BD) | Plasma Level of Cell Death Marker M30 (Caspase-Cleaved CK18; Part 1 Only) | Day -7 | 342 U/L | Standard Deviation 371.9 |
| AZD3965 Cohort 6 (10 mg BD) | Plasma Level of Cell Death Marker M30 (Caspase-Cleaved CK18; Part 1 Only) | Day 29 | 344.6 U/L | Standard Deviation 369.5 |
| AZD3965 Cohort 6 (10 mg BD) | Plasma Level of Cell Death Marker M30 (Caspase-Cleaved CK18; Part 1 Only) | Day 1 | 336.6 U/L | Standard Deviation 375.9 |
Secondary
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.
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)
Population: 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
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1 Dose Escalation (Cohorts 1-6) | Plasma Level of Cell Death Marker M65 (Total Plus Caspase-Cleaved CK18; Part 1 Only) | Day 8 | 841.3 U/L | Standard Deviation 651.4 |
| Part 1 Dose Escalation (Cohorts 1-6) | Plasma Level of Cell Death Marker M65 (Total Plus Caspase-Cleaved CK18; Part 1 Only) | Day -7 | 623.5 U/L | Standard Deviation 446.2 |
| Part 1 Dose Escalation (Cohorts 1-6) | Plasma Level of Cell Death Marker M65 (Total Plus Caspase-Cleaved CK18; Part 1 Only) | Baseline | 533.0 U/L | — |
| Part 1 Dose Escalation (Cohorts 1-6) | Plasma Level of Cell Death Marker M65 (Total Plus Caspase-Cleaved CK18; Part 1 Only) | Day 29 | 801.5 U/L | Standard Deviation 314.7 |
| Part 1 Dose Escalation (Cohorts 1-6) | Plasma Level of Cell Death Marker M65 (Total Plus Caspase-Cleaved CK18; Part 1 Only) | Day 1 | 469.0 U/L | Standard Deviation 12.7 |
| AZD3965 Cohort 2 (10 mg OD) | Plasma Level of Cell Death Marker M65 (Total Plus Caspase-Cleaved CK18; Part 1 Only) | Day -7 | 3846.4 U/L | Standard Deviation 1772.5 |
| AZD3965 Cohort 2 (10 mg OD) | Plasma Level of Cell Death Marker M65 (Total Plus Caspase-Cleaved CK18; Part 1 Only) | Day 8 | 4478.4 U/L | Standard Deviation 730.2 |
| AZD3965 Cohort 2 (10 mg OD) | Plasma Level of Cell Death Marker M65 (Total Plus Caspase-Cleaved CK18; Part 1 Only) | Baseline | 4496.0 U/L | Standard Deviation 1008 |
| AZD3965 Cohort 2 (10 mg OD) | Plasma Level of Cell Death Marker M65 (Total Plus Caspase-Cleaved CK18; Part 1 Only) | Day 29 | 5000.0 U/L | Standard Deviation 0 |
| AZD3965 Cohort 2 (10 mg OD) | Plasma Level of Cell Death Marker M65 (Total Plus Caspase-Cleaved CK18; Part 1 Only) | Day 1 | 3935.6 U/L | Standard Deviation 1522 |
| AZD3965 Cohort 3 (20 mg OD) | Plasma Level of Cell Death Marker M65 (Total Plus Caspase-Cleaved CK18; Part 1 Only) | Day -7 | 1796.4 U/L | Standard Deviation 1697.6 |
| AZD3965 Cohort 3 (20 mg OD) | Plasma Level of Cell Death Marker M65 (Total Plus Caspase-Cleaved CK18; Part 1 Only) | Day 8 | 1807.0 U/L | Standard Deviation 2072.6 |
| AZD3965 Cohort 3 (20 mg OD) | Plasma Level of Cell Death Marker M65 (Total Plus Caspase-Cleaved CK18; Part 1 Only) | Day 29 | 1226.8 U/L | Standard Deviation 2123.2 |
| AZD3965 Cohort 3 (20 mg OD) | Plasma Level of Cell Death Marker M65 (Total Plus Caspase-Cleaved CK18; Part 1 Only) | Day 1 | 1742.0 U/L | Standard Deviation 1840.9 |
| AZD3965 Cohort 3 (20 mg OD) | Plasma Level of Cell Death Marker M65 (Total Plus Caspase-Cleaved CK18; Part 1 Only) | Baseline | 1602.1 U/L | Standard Deviation 1627.4 |
| AZD3965 Cohort 4 (30 mg OD) | Plasma Level of Cell Death Marker M65 (Total Plus Caspase-Cleaved CK18; Part 1 Only) | Day 1 | 981.0 U/L | Standard Deviation 1054.8 |
| AZD3965 Cohort 4 (30 mg OD) | Plasma Level of Cell Death Marker M65 (Total Plus Caspase-Cleaved CK18; Part 1 Only) | Baseline | 1046.6 U/L | Standard Deviation 1338.7 |
| AZD3965 Cohort 4 (30 mg OD) | Plasma Level of Cell Death Marker M65 (Total Plus Caspase-Cleaved CK18; Part 1 Only) | Day -7 | 935.6 U/L | Standard Deviation 1000.7 |
| AZD3965 Cohort 4 (30 mg OD) | Plasma Level of Cell Death Marker M65 (Total Plus Caspase-Cleaved CK18; Part 1 Only) | Day 8 | 474.2 U/L | Standard Deviation 568.5 |
| AZD3965 Cohort 4 (30 mg OD) | Plasma Level of Cell Death Marker M65 (Total Plus Caspase-Cleaved CK18; Part 1 Only) | Day 29 | 443.0 U/L | Standard Deviation 566.5 |
| AZD3965 Cohort 5 (15 mg BD) | Plasma Level of Cell Death Marker M65 (Total Plus Caspase-Cleaved CK18; Part 1 Only) | Day 8 | 1418.4 U/L | Standard Deviation 1472.6 |
| AZD3965 Cohort 5 (15 mg BD) | Plasma Level of Cell Death Marker M65 (Total Plus Caspase-Cleaved CK18; Part 1 Only) | Baseline | 1344.3 U/L | Standard Deviation 1202.5 |
| AZD3965 Cohort 5 (15 mg BD) | Plasma Level of Cell Death Marker M65 (Total Plus Caspase-Cleaved CK18; Part 1 Only) | Day 29 | 2609.3 U/L | Standard Deviation 2452.2 |
| AZD3965 Cohort 5 (15 mg BD) | Plasma Level of Cell Death Marker M65 (Total Plus Caspase-Cleaved CK18; Part 1 Only) | Day -7 | 1488.7 U/L | Standard Deviation 1409.6 |
| AZD3965 Cohort 5 (15 mg BD) | Plasma Level of Cell Death Marker M65 (Total Plus Caspase-Cleaved CK18; Part 1 Only) | Day 1 | 1673.0 U/L | Standard Deviation 1450.2 |
| AZD3965 Cohort 6 (10 mg BD) | Plasma Level of Cell Death Marker M65 (Total Plus Caspase-Cleaved CK18; Part 1 Only) | Baseline | 287.6 U/L | Standard Deviation 192.2 |
| AZD3965 Cohort 6 (10 mg BD) | Plasma Level of Cell Death Marker M65 (Total Plus Caspase-Cleaved CK18; Part 1 Only) | Day 8 | 252.0 U/L | Standard Deviation 155.1 |
| AZD3965 Cohort 6 (10 mg BD) | Plasma Level of Cell Death Marker M65 (Total Plus Caspase-Cleaved CK18; Part 1 Only) | Day -7 | 233.2 U/L | Standard Deviation 126.9 |
| AZD3965 Cohort 6 (10 mg BD) | Plasma Level of Cell Death Marker M65 (Total Plus Caspase-Cleaved CK18; Part 1 Only) | Day 29 | 285.0 U/L | Standard Deviation 172.3 |
| AZD3965 Cohort 6 (10 mg BD) | Plasma Level of Cell Death Marker M65 (Total Plus Caspase-Cleaved CK18; Part 1 Only) | Day 1 | 255.4 U/L | Standard Deviation 157.3 |
Secondary
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.
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)
Population: 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
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1 Dose Escalation (Cohorts 1-6) | Plasma Level of Nucleosomal DNA (nDNA) as a Measure of Apoptosis (Part 1 Only) | Day 8 | 0.441 Optical density | Standard Deviation 0.28 |
| Part 1 Dose Escalation (Cohorts 1-6) | Plasma Level of Nucleosomal DNA (nDNA) as a Measure of Apoptosis (Part 1 Only) | Day -7 | 0.450 Optical density | Standard Deviation 0.18 |
| Part 1 Dose Escalation (Cohorts 1-6) | Plasma Level of Nucleosomal DNA (nDNA) as a Measure of Apoptosis (Part 1 Only) | Baseline | 0.123 Optical density | — |
| Part 1 Dose Escalation (Cohorts 1-6) | Plasma Level of Nucleosomal DNA (nDNA) as a Measure of Apoptosis (Part 1 Only) | Day 29 | 0.298 Optical density | Standard Deviation 0.27 |
| Part 1 Dose Escalation (Cohorts 1-6) | Plasma Level of Nucleosomal DNA (nDNA) as a Measure of Apoptosis (Part 1 Only) | Day 1 | 0.397 Optical density | Standard Deviation 0.372 |
| AZD3965 Cohort 2 (10 mg OD) | Plasma Level of Nucleosomal DNA (nDNA) as a Measure of Apoptosis (Part 1 Only) | Day -7 | 0.731 Optical density | Standard Deviation 0.86 |
| AZD3965 Cohort 2 (10 mg OD) | Plasma Level of Nucleosomal DNA (nDNA) as a Measure of Apoptosis (Part 1 Only) | Day 8 | 1.111 Optical density | Standard Deviation 1.059 |
| AZD3965 Cohort 2 (10 mg OD) | Plasma Level of Nucleosomal DNA (nDNA) as a Measure of Apoptosis (Part 1 Only) | Baseline | 0.778 Optical density | Standard Deviation 1.144 |
| AZD3965 Cohort 2 (10 mg OD) | Plasma Level of Nucleosomal DNA (nDNA) as a Measure of Apoptosis (Part 1 Only) | Day 29 | 1.060 Optical density | Standard Deviation 0.538 |
| AZD3965 Cohort 2 (10 mg OD) | Plasma Level of Nucleosomal DNA (nDNA) as a Measure of Apoptosis (Part 1 Only) | Day 1 | 0.924 Optical density | Standard Deviation 1.114 |
| AZD3965 Cohort 3 (20 mg OD) | Plasma Level of Nucleosomal DNA (nDNA) as a Measure of Apoptosis (Part 1 Only) | Day -7 | 0.580 Optical density | Standard Deviation 0.889 |
| AZD3965 Cohort 3 (20 mg OD) | Plasma Level of Nucleosomal DNA (nDNA) as a Measure of Apoptosis (Part 1 Only) | Day 8 | 0.697 Optical density | Standard Deviation 1.033 |
| AZD3965 Cohort 3 (20 mg OD) | Plasma Level of Nucleosomal DNA (nDNA) as a Measure of Apoptosis (Part 1 Only) | Day 29 | 0.841 Optical density | Standard Deviation 1.208 |
| AZD3965 Cohort 3 (20 mg OD) | Plasma Level of Nucleosomal DNA (nDNA) as a Measure of Apoptosis (Part 1 Only) | Day 1 | 0.593 Optical density | Standard Deviation 0.796 |
| AZD3965 Cohort 3 (20 mg OD) | Plasma Level of Nucleosomal DNA (nDNA) as a Measure of Apoptosis (Part 1 Only) | Baseline | 0.614 Optical density | Standard Deviation 0.865 |
| AZD3965 Cohort 4 (30 mg OD) | Plasma Level of Nucleosomal DNA (nDNA) as a Measure of Apoptosis (Part 1 Only) | Day 1 | 0.200 Optical density | Standard Deviation 0.186 |
| AZD3965 Cohort 4 (30 mg OD) | Plasma Level of Nucleosomal DNA (nDNA) as a Measure of Apoptosis (Part 1 Only) | Baseline | 0.170 Optical density | Standard Deviation 0.138 |
| AZD3965 Cohort 4 (30 mg OD) | Plasma Level of Nucleosomal DNA (nDNA) as a Measure of Apoptosis (Part 1 Only) | Day -7 | 0.204 Optical density | Standard Deviation 0.187 |
| AZD3965 Cohort 4 (30 mg OD) | Plasma Level of Nucleosomal DNA (nDNA) as a Measure of Apoptosis (Part 1 Only) | Day 8 | 0.206 Optical density | Standard Deviation 0.135 |
| AZD3965 Cohort 4 (30 mg OD) | Plasma Level of Nucleosomal DNA (nDNA) as a Measure of Apoptosis (Part 1 Only) | Day 29 | 0.144 Optical density | Standard Deviation 0.116 |
| AZD3965 Cohort 5 (15 mg BD) | Plasma Level of Nucleosomal DNA (nDNA) as a Measure of Apoptosis (Part 1 Only) | Day 8 | 0.287 Optical density | Standard Deviation 0.305 |
| AZD3965 Cohort 5 (15 mg BD) | Plasma Level of Nucleosomal DNA (nDNA) as a Measure of Apoptosis (Part 1 Only) | Baseline | 0.485 Optical density | Standard Deviation 0.879 |
| AZD3965 Cohort 5 (15 mg BD) | Plasma Level of Nucleosomal DNA (nDNA) as a Measure of Apoptosis (Part 1 Only) | Day 29 | 0.195 Optical density | Standard Deviation 0.179 |
| AZD3965 Cohort 5 (15 mg BD) | Plasma Level of Nucleosomal DNA (nDNA) as a Measure of Apoptosis (Part 1 Only) | Day -7 | 0.259 Optical density | Standard Deviation 0.257 |
| AZD3965 Cohort 5 (15 mg BD) | Plasma Level of Nucleosomal DNA (nDNA) as a Measure of Apoptosis (Part 1 Only) | Day 1 | 0.241 Optical density | Standard Deviation 0.191 |
| AZD3965 Cohort 6 (10 mg BD) | Plasma Level of Nucleosomal DNA (nDNA) as a Measure of Apoptosis (Part 1 Only) | Baseline | 0.139 Optical density | Standard Deviation 0.134 |
| AZD3965 Cohort 6 (10 mg BD) | Plasma Level of Nucleosomal DNA (nDNA) as a Measure of Apoptosis (Part 1 Only) | Day 8 | 0.149 Optical density | Standard Deviation 0.136 |
| AZD3965 Cohort 6 (10 mg BD) | Plasma Level of Nucleosomal DNA (nDNA) as a Measure of Apoptosis (Part 1 Only) | Day -7 | 0.140 Optical density | Standard Deviation 0.158 |
| AZD3965 Cohort 6 (10 mg BD) | Plasma Level of Nucleosomal DNA (nDNA) as a Measure of Apoptosis (Part 1 Only) | Day 29 | 0.156 Optical density | Standard Deviation 0.144 |
| AZD3965 Cohort 6 (10 mg BD) | Plasma Level of Nucleosomal DNA (nDNA) as a Measure of Apoptosis (Part 1 Only) | Day 1 | 0.140 Optical density | Standard Deviation 0.146 |
Secondary
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.
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])
Population: 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).
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Part 1 Dose Escalation (Cohorts 1-6) | Time to Maximum Observed Concentration of AZD3965 | Day -7 | 1.1 Hour |
| Part 1 Dose Escalation (Cohorts 1-6) | Time to Maximum Observed Concentration of AZD3965 | Day 1 | 2 Hour |
| AZD3965 Cohort 2 (10 mg OD) | Time to Maximum Observed Concentration of AZD3965 | Day -7 | 1.1 Hour |
| AZD3965 Cohort 2 (10 mg OD) | Time to Maximum Observed Concentration of AZD3965 | Day 1 | 2 Hour |
| AZD3965 Cohort 3 (20 mg OD) | Time to Maximum Observed Concentration of AZD3965 | Day -7 | 1 Hour |
| AZD3965 Cohort 3 (20 mg OD) | Time to Maximum Observed Concentration of AZD3965 | Day 1 | 2.05 Hour |
| AZD3965 Cohort 4 (30 mg OD) | Time to Maximum Observed Concentration of AZD3965 | Day -7 | 1.1 Hour |
| AZD3965 Cohort 4 (30 mg OD) | Time to Maximum Observed Concentration of AZD3965 | Day 1 | 1.1 Hour |
| AZD3965 Cohort 5 (15 mg BD) | Time to Maximum Observed Concentration of AZD3965 | Day -7 | 1.5 Hour |
| AZD3965 Cohort 5 (15 mg BD) | Time to Maximum Observed Concentration of AZD3965 | Day 1 | 2 Hour |
| AZD3965 Cohort 6 (10 mg BD) | Time to Maximum Observed Concentration of AZD3965 | Day -7 | 1.92 Hour |
| AZD3965 Cohort 6 (10 mg BD) | Time to Maximum Observed Concentration of AZD3965 | Day 1 | 1.075 Hour |