A Phase I, Open-Label, Multicentre Study to Assess the Safety, Tolerability, Pharmacokinetics and Preliminary Anti-tumour Activity of Ascending Doses of AZD5363 under Adaptable Dosing Schedules in Patients with Advanced Solid Malignancies
- Conditions
- advanced solid malignanciesadvanced solid tumours10027655
- Registration Number
- NL-OMON43802
- Lead Sponsor
- Astra Zeneca
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Completed
- Sex
- Not specified
- Target Recruitment
- 40
-provision of written informed consent
-aged at least 18 years
-histological or cytological confirmation of a solid malignant tumour, excluding lymphoma, that is refractory to standard therapies or for which no standard therapies exist
-parts A & B - at least one lesion (measurable and/or non-measurable) that can be assessed at baseline by CT/MRI or plain X-ray and is suitable for accurate repeated measurements
-parts C & D & E & F - at least one lesion, not previously irradiated that can be accurately measured at baseline as >=10 mm in the longest diameter (except lymph nodes which must have short axis >=15 mm) with CT or MRI and which is suitable for accurate repeated measurements
-WHO performance status 0-1
-minimum life expectancy of 12 weeks
-post-menopausal or negative pregnancy test
-male patients should use condoms
-parts C & D & E & F - Provision of a tumour and blood sample for central mutation testing.;Part C:
- gynaecological cancer or breast cancer or other solid malignant tumour, that is resistance to standard therapies or for which no standard therapies exist and confirmation of PIK3CA mutation;Part D:
- gynaecological cancer or breast cancer or other solid malignant tumour, that is resistance to standard therapies or for which no standard therapies exist and confirmation of AKT1 mutation or other molecular aberration of the PI3K/AKT pathway;Part E:
- ER positive advanced or metastatic breast cancer and confirmation of the presence of an AKT1 mutation;Part F:
- ER positive advanced or metastatic breast cancer and confirmation of the presence of one of the mutations in PTEN listed in the study lab manual
-Clinically significant abnormalities of glucose metabolism
-Treatment with any of the following:
*nitrosurea or mitomycin C within 6 weeks of the first dose of study treatment
*any investigational agents or study drugs from a previous clincal study within 30 days of the first dose of study treatment
*any other chemotherapy, immunotherapy or anticancer agents within 3 weeks of the first dose of study treatment, except hormonal therapy with LHRH analogues for medical castration in patients with prostate cancer, which are permitted
*potent inhibitors or inducers or substrates of CYP3A4 or substrates of CYP2D6 within 2 weeks before the first dose of study treatment (3 weeks for St John's Wort)
*AZD5363 in the present study
*major surgery within 4 weeks of the first dose of study treatment
*radiotherapy with a wide field of radiation within 4 weeks or radiotherapy with a limited field of radiation for palliation within 2 weeks of the first dose of study treatment
-With the exception of alopecia, any unresolved toxicities from prior therapy greater than CTCAE grade 1 at the time of starting study treatment
-Spinal Cord compression or brain metastases unless asymptomatic, treated and stable and not requiring steroids for at least 4 weeks prior to start of study treatment
-Any evidence of severe or uncontrolled systemic diseases, including active bleeding diatheses, or active infection including hepatitis B, hepatitis C and HIV.
-Evidence of clinically significant cardiac abnormalities.
-Inadequate bone marrow reserve or organ function as demonstrated by any of the following laboratory values:
*Absolute neutrophil count <1.5 x10^9/L
*Platelet count < 100 x 10^9/L
*Haemoglobin <90 g/L
*ALT > 2.5 x ULN if no demonstrable liver metastases, or > 5 x ULN in presence of liver metastases
*AST >2.5 x ULN if no demonstrable liver metastases, or > 5 x ULN in presence of liver metastases
*Total bilirubin >1.5 x ULN (Patients with confirmed Glibert's syndrome may be included in the study)
*Creatinine > 1.5 x ULN concurrent with creatinine clearance < 50 ml/min
*Proteinuria 3+ on dipstick analysis or >500mg/24 hours
*Sodium or potassium outside normal reference range for site -Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product or previous significant bowel resection that would preclude adequate absorption fo AZD5363
-History of hypersensitivity to active or inactive excipients of AZD5363 or drugs with a similar chemical structure or calss to AZD5363.
-Judgment by the investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements
- Part C: triple negative breastcancer
- Part C and D: where known, other solid tumours (ie, not breast or gynaecological) should be negative for mutations of KRAS, NRAS, HRAS and BRAF
- Part C: any prior treatment with PI3K/mTOR inhibitors or AKT inhibitors
- Part D, E and F: Any prior treatment with AKT inhibitors
Study & Design
- Study Type
- Interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method <p>Safety and tolerability </p><br>
- Secondary Outcome Measures
Name Time Method <p>AZD5363 pharmacokinetics<br /><br>AZD5363 pharmacodynamics<br /><br>Assesment of tumour response with RECIST </p><br>