A Phase I Trial of AZD3965 in Patients With Advanced Cancer

Study Overview
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Brief Summary
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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
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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).

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

Conditions
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Adult Solid Tumor, Diffuse Large B Cell Lymphoma, Burkitt Lymphoma

Intervention / Treatment
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* Drug: AZD3965
* Drug: AZD3965
* Drug: AZD3965
* Drug: AZD3965
* Drug: AZD3965
* Drug: AZD3965
* Drug: AZD3965


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. 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. Exclusion Criteria: 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. 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).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AZD3965 Cohort 1 (5 mg OD)<br> | Drug: AZD3965<br>* 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.<br>|
| Experimental: AZD3965 Cohort 2 (10 mg OD)<br> | Drug: AZD3965<br>* 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.<br>|
| Experimental: AZD3965 Cohort 3 (20 mg OD)<br> | Drug: AZD3965<br>* 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.<br>|
| Experimental: AZD3965 Cohort 4 (30 mg OD)<br> | Drug: AZD3965<br>* 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.<br>|
| Experimental: AZD3965 Cohort 5 (15 mg BD)<br> | Drug: AZD3965<br>* 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.<br>|
| Experimental: AZD3965 Cohort 6 (10 mg BD)<br> | Drug: AZD3965<br>* 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.<br>|
| Experimental: AZD3965 Expansion Cohort (10 mg BD)<br> | Drug: AZD3965<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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) | 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) | 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 | 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 | 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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 | 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) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Phase I, Cancer, Solid Tumours, Diffuse Large B Cell Lymphoma, Monocarboxylate Transporter 1 Inhibitor, lactate, Burkitt Lymphoma