A Phase I Trial of AZD3965 in Patients With Advanced Cancer
Condition: Adult Solid Tumor; Diffuse Large B Cell Lymphoma; Burkitt Lymphoma
MeSH terms: Burkitt Lymphoma; Lymphoma; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse
Intervention: AZD3965; AZD3965; AZD3965; AZD3965; AZD3965; AZD3965; AZD3965
Intervention description: 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.; 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.
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 53.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Phase I; Cancer; Solid Tumours; Diffuse Large B Cell Lymphoma; Monocarboxylate Transporter 1 Inhibitor; lactate; Burkitt Lymphoma

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.
    

Eligibility criteria:

        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).