A Phase I Trial of AZD3965 in Patients With Advanced Cancer

NCT01791595 | Completed Phase 1 Results

• 2 other identifiers: CRUKD/12/0042010-024463-41
• Study Type: interventional
• Target: 53
• Locations: 1 country
• Sites: 7

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.

Conditions

Adult Solid Tumor; Diffuse Large B Cell Lymphoma; Burkitt Lymphoma

Keywords

Phase I; Cancer; Solid Tumours; Diffuse Large B Cell Lymphoma; Monocarboxylate Transporter 1 Inhibitor; lactate; Burkitt Lymphoma

Outcome Measures

Primary Outcomes (4)

• 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 Outcomes (9)

• 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)

• 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)

• 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)

• 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])

• 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)

Study Arms (7)

AZD3965 Cohort 1 (5 mg OD)

EXPERIMENTAL

Drug: AZD3965

AZD3965 Cohort 2 (10 mg OD)

EXPERIMENTAL

Drug: AZD3965

AZD3965 Cohort 3 (20 mg OD)

EXPERIMENTAL

Drug: AZD3965

AZD3965 Cohort 4 (30 mg OD)

EXPERIMENTAL

Drug: AZD3965

AZD3965 Cohort 5 (15 mg BD)

EXPERIMENTAL

Drug: AZD3965

AZD3965 Cohort 6 (10 mg BD)

EXPERIMENTAL

Drug: AZD3965

AZD3965 Expansion Cohort (10 mg BD)

EXPERIMENTAL

Drug: AZD3965

Interventions

AZD3965 DRUG

Day -7: single dose of 5 mg AZD3965 orally prior to start of continuous treatment. Cycle 1, Day 1: commenced dosing of 5 mg AZD3965 OD orally for up to 6 28-day cycles. Trial participants benefitting from treatment could continue beyond 6 cycles for as long as they continued to benefit on agreement between the Investigator and the Sponsor.

AZD3965 Cohort 1 (5 mg OD)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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).

You may not qualify if:

• 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:

Sponsors & Collaborators

• Cancer Research UK: lead
• AstraZeneca: collaborator

Study Sites (7)

Royal Marsden Hospital

Sutton, London, United Kingdom

Location

The Beatson West of Scotland, Glasgow

Glasgow, United Kingdom

Location

Leicester Royal Infirmary

Leicester, United Kingdom

Location

University College London Hospitals

London, United Kingdom

Location

The Christie

Manchester, United Kingdom

Location

Freeman Hospital

Newcastle upon Tyne, United Kingdom

Location

Derriford Hospital

Plymouth, United Kingdom

Location

Related Publications (4)

• Noble RA, Bell N, Blair H, Sikka A, Thomas H, Phillips N, Nakjang S, Miwa S, Crossland R, Rand V, Televantou D, Long A, Keun HC, Bacon CM, Bomken S, Critchlow SE, Wedge SR. Inhibition of monocarboxyate transporter 1 by AZD3965 as a novel therapeutic approach for diffuse large B-cell lymphoma and Burkitt lymphoma. Haematologica. 2017 Jul;102(7):1247-1257. doi: 10.3324/haematol.2016.163030. Epub 2017 Apr 6.

  PMID: 28385782 BACKGROUND

• McNeillis R, Greystoke A, Walton J, Bacon C, Keun H, Siskos A, Petrides G, Leech N, Jenkinson F, Bowron A, Halford S, Plummer R. A case of malignant hyperlactaemic acidosis appearing upon treatment with the mono-carboxylase transporter 1 inhibitor AZD3965. Br J Cancer. 2020 Apr;122(8):1141-1145. doi: 10.1038/s41416-020-0727-8. Epub 2020 Feb 20.

  PMID: 32076124 DERIVED

• Kershaw S, Cummings J, Morris K, Tugwood J, Dive C. Optimisation of immunofluorescence methods to determine MCT1 and MCT4 expression in circulating tumour cells. BMC Cancer. 2015 May 10;15:387. doi: 10.1186/s12885-015-1382-y.

  PMID: 25957999 DERIVED

• Lamb R, Harrison H, Hulit J, Smith DL, Lisanti MP, Sotgia F. Mitochondria as new therapeutic targets for eradicating cancer stem cells: Quantitative proteomics and functional validation via MCT1/2 inhibition. Oncotarget. 2014 Nov 30;5(22):11029-37. doi: 10.18632/oncotarget.2789.

  PMID: 25415228 DERIVED

Related Links

• Simple summary of trial on Cancer Research UK Trial Database

MeSH Terms

Conditions

Lymphoma, Large B-Cell, Diffuse; Burkitt Lymphoma; Neoplasms

Interventions

AZD3965

Condition Hierarchy (Ancestors)

Lymphoma, B-Cell; Lymphoma, Non-Hodgkin; Lymphoma; Neoplasms by Histologic Type; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Epstein-Barr Virus Infections; Herpesviridae Infections; DNA Virus Infections; Virus Diseases; Infections; Tumor Virus Infections

Limitations and Caveats

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

Results Point of Contact

• Title: Regulatory Affairs Manager
• Organization: Cancer Research UK Centre for Drug Development

regulatory@cancer.org.uk

+44 203 4696878

Study Officials

• Ruth Plummer, Prof

  Freeman Hospital, Newcastle

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 11, 2013
• First Posted: February 15, 2013
• Study Start: April 23, 2013
• Primary Completion: November 17, 2020
• Study Completion: November 17, 2020
• Last Updated: April 11, 2022
• Results First Posted: April 11, 2022

Record last verified: 2022-02

Data Sharing

• IPD Sharing: Will not share

Locations

GB (7)