A Cancer Research UK Phase I Trial of AZD3965, a Monocarboxylate Transporter 1 Inhibitor (MCT1) in Patients With Advanced Cancer
Overview
- Phase
- Phase 1
- Intervention
- AZD3965
- Conditions
- Adult Solid Tumor
- Sponsor
- Cancer Research UK
- Enrollment
- 53
- Locations
- 7
- Primary Endpoint
- MTD of AZD3965
- Status
- Completed
- Last Updated
- 4 years ago
Overview
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).
Investigators
Eligibility Criteria
Inclusion Criteria
- •Histologically or cytologically proven advanced solid tumour or lymphoma, refractory to conventional treatment or for which no conventional therapy exists.
- •Available archived tumour samples.
- •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
- •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.
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
- •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 AZD
Arms & Interventions
AZD3965 Expansion Cohort (10 mg BD)
Intervention: AZD3965
AZD3965 Cohort 1 (5 mg OD)
Intervention: AZD3965
AZD3965 Cohort 2 (10 mg OD)
Intervention: AZD3965
AZD3965 Cohort 3 (20 mg OD)
Intervention: AZD3965
AZD3965 Cohort 4 (30 mg OD)
Intervention: AZD3965
AZD3965 Cohort 5 (15 mg BD)
Intervention: AZD3965
AZD3965 Cohort 6 (10 mg BD)
Intervention: AZD3965
Outcomes
Primary Outcomes
MTD of AZD3965
Time Frame: Day -7 to Day 28
MTD was determined by testing increasing AZD3965 doses in Part 1 dose escalation cohorts (Cohorts 1-6) and defined as the total daily dose level below that at which ≥2 out of ≤6 evaluable patients had a dose-limiting toxicity (DLT) during Cycle 1 (including Day -7). DLTs were defined as highly probably/probably AZD3965 related haematological, cardiac, ophthalmic, other Grade 3/4 toxicity, death or drug-related toxicity causing AZD3965 interruption \>2 weeks (see protocol for specific criteria)
Number of Patients Who Experienced DLTs
Time Frame: Day -7 to Day 28
Number of patients who experienced protocol-defined DLTs (defined according to NCI CTCAE version 4.02). DLTs were defined as highly probably/probably AZD3965 related haematological, cardiac, ophthalmic, other Grade 3/4 toxicity, death or drug-related toxicity causing AZD3965 interruption \>2 weeks (see protocol for specific criteria)
Number of Patients Who Experienced Serious AEs
Time Frame: From the date of written informed consent and until 28 days after the last dose of AZD3965; an average (median) of 80 days (range: 36 to 517 days)
A serious adverse event (SAE) is any AE, regardless of dose, causality or expectedness, that results in death, is life-threatening, requires in-patient hospitalisation or prolongs existing in-patient hospitalisation, results in persistent or significant incapacity or disability, is a congenital anomaly or birth defect or is any other medically important event. Any ophthalmic and/or cardiac DLT is considered a medically important event and therefore an SAE in this trial. Specific AE terms are provided in the Adverse Events section
Number of Patients Who Experienced Non-Serious AEs
Time Frame: From the date of written informed consent and until 28 days after the last dose of AZD3965; an average (median) of 80 days (range: 36 to 517 days)
A non-serious AE is any untoward medical occurrence that does not meet the serious criteria described for outcome measure 3 above. Specific AE terms are provided in the Adverse Events section
Secondary Outcomes
- 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))
- 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))
- 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))
- 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))
- 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))
- 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))
- 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 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 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))