Neoplasm
Conditions
Keywords
advanced solid tumours, hADME, bioavailability, AZD6738, ceralasertib
Brief summary
This is an open-label, two-part study in participants with solid tumours and will be conducted at multiple study sites. Participants will be assessed for study eligibility prior to admission to the study site. Participants may be enrolled in either Part A or Part B of the study or in both. Part A will assess the absolute bioavailability, determine the excretory routes of \[14C\]-Ceralasertib, and evaluate the PK parameters of a Ceralasertib oral dose and a radiolabelled IV microdose of \[14C\]-Ceralasertib. Participants will be admitted to the study site pre-dose Part A and will remain at the study site for excreta (urine and faeces) collections, PK sampling and safety assessments. A washout period days will be observed between dosing in Part A and Part B if participants are taking part in both parts of the study. Part B will assess the ADME of \[14C\]-Ceralasertib. Participants will be readmitted to the study site for Part B and will remain at the study site for excreta (urine, faeces, and any vomitus) collections, PK sampling, and safety assessments. Participants will return to the study site for a Follow-up Visit after the last dose of Ceralasertib which will include routine safety assessments. After the completion of Parts A and/or B, and following the Follow-up Visit, participants may be allowed further access to Ceralasertib if in the opinion of the investigator they may derive clinical benefit.
Interventions
DRUG[14C] AZD6738
radiolabeled AZD6738 / ceralasertib
DRUGAZD6738 / ceralasertib
Ceralasertib (AZD6738) is a potent, selective inhibitor of the serine/threonine-specific protein kinase ATR
Sponsors
AstraZeneca
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Participants are eligible to be included in the study only if all of the following criteria apply: Age 1. Male or female ≥ 18 years of age (or the legal age of consent in the jurisdiction in which the study is taking place), at the time of signing the ICF. Type of Participant and Disease Characteristics 2. Sufficient ECOG performance status, life expectancy, and ability to swallow and retain oral medication 3. Adequate organ and marrow function 4. Willingness and ability to comply with study and follow-up procedures. 5. Able and willing to stay in hospital for specified residential periods following administration of Ceralasertib/\[14C\]-Ceralasertib 6. Regular bowel movements 7. Locally advanced or metastatic solid tumour, for which standard therapy does not exist or has proven to be ineffective or intolerable. 8. Sex and Contraceptive/Barrier Requirements: Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies 9. Informed Consent: patient must be capable of giving signed informed consent as described in Appendix A which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.
Exclusion criteria
* Participants are excluded from the study if any of the following criteria apply: 1. History of Diagnosis of protocol-specified medical conditions 2. Spinal cord compression or brain metastasis prior to start of study intervention unless asymptomatic and stable 3. Persistent toxicities (CTCAE Grade ≥ 2), with the exception of alopecia and vitiligo, caused by previous anticancer therapy. 4. Any medical or surgical condition that would preclude adequate absorption of Ceralasertib 5. Inadequate cardiac function / status or other cardiovascular diseases 6. Participants with active infection requiring systemic antibiotics, antifungal or antiviral drugs 7. Any evidence of severe or uncontrolled systemic disease, as judged by the investigator that would make it undesirable for the participant to participate in the study or would jeopardise compliance with the protocol 8. Protocol-specified prior/concomitant therapy exclusions 9. Protocol-specified prior/concurrent clinical study experience 10. Other Exclusions including but not limited to tobacco/nicotine and/or alcohol use, or drug/alcohol abuse history 11. Not currently pregnant, breast-feeding, or planning to become pregnant
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| To characterise the PK of Ceralasertib and total radioactivity following oral dose of [14C]-Ceralasertib including the extent of distribution into blood cells (Part B) - Urine Fe | Through end of the part B, approximately 10 weeks (Including screening period) | Urine - Fe |
| To characterise the PK of Ceralasertib and total radioactivity following oral dose of [14C]-Ceralasertib including the extent of distribution into blood cells (Part B) - Urine CumFe | Through end of the part B, approximately 10 weeks (Including screening period) | Urine - CumFe |
| To characterise the PK of Ceralasertib and total radioactivity following oral dose of [14C]-Ceralasertib including the extent of distribution into blood cells (Part B) - Faeces Ae | Through end of the part B, approximately 10 weeks (Including screening period) | Faeces - Ae |
| To characterise the PK of Ceralasertib and total radioactivity following oral dose of [14C]-Ceralasertib including the extent of distribution into blood cells (Part B) - Faeces CumAe | Through end of the part B, approximately 10 weeks (Including screening period) | Faeces - CumAe |
| To characterise the PK of Ceralasertib and total radioactivity following oral dose of [14C]-Ceralasertib including the extent of distribution into blood cells (Part B) - Faeces Fe | Through end of the part B, approximately 10 weeks (Including screening period) | Faeces - Fe |
| To characterise the PK of Ceralasertib and total radioactivity following oral dose of [14C]-Ceralasertib including the extent of distribution into blood cells (Part B) - Faeces CumFe | Through end of the part B, approximately 10 weeks (Including screening period) | Faeces - CumFe |
| To characterise the PK of Ceralasertib and total radioactivity following oral dose of [14C]-Ceralasertib including the extent of distribution into blood cells (Part B) - Total (Urine+Faeces) Ae | Through end of the part B, approximately 10 weeks (Including screening period) | Total (Urine + Faeces) Ae |
| To characterise the PK of Ceralasertib and total radioactivity following oral dose of [14C]-Ceralasertib including the extent of distribution into blood cells (Part B) - Total (Urine+Faeces) CumAe | Through end of the part B, approximately 10 weeks (Including screening period) | Total (Urine + Faeces) CumAe |
| To characterise the PK of Ceralasertib and total radioactivity following oral dose of [14C]-Ceralasertib including the extent of distribution into blood cells (Part B) - Total (Urine+Faeces) Fe | Through end of the part B, approximately 10 weeks (Including screening period) | Total (Urine + Faeces) Fe |
| To characterise the PK of Ceralasertib and total radioactivity following oral dose of [14C]-Ceralasertib including the extent of distribution into blood cells (Part B) - Total (Urine+Faeces) CumFe | Through end of the part B, approximately 10 weeks (Including screening period) | Total (Urine + Faeces) CumFe |
| To characterise the PK of Ceralasertib and total radioactivity following oral dose of [14C]-Ceralasertib including the extent of distribution into blood cells (Part B) - Urine Ae | Through end of the part B, approximately 10 weeks (Including screening period) | Urine - Ae |
| To characterise the PK of Ceralasertib and total radioactivity following oral dose of [14C]-Ceralasertib including the extent of distribution into blood cells (Part B) - Urine CumAe | Through end of the part B, approximately 10 weeks (Including screening period) | Urine - CumAe |
| To evaluate absolute bioavailability Ceralasertib and PK of Ceralasertib and [14C]-Ceralasertib after administration of oral dose of Ceralasertib and IV [14C]-Ceralasertib (Part A) | Through end of Part A, approximately 5 weeks including screening period | Absolute bioavailability (F) of Ceralasertib and PK parameters and recovery in urine and faeces |
| To determine the rates and major excretory routes of Ceralasertib and its metabolites after IV dose of [14C]-Ceralasertib (Part A) and a oral dose of [14C]-Ceralasertib (Part B) | Through end of Part B, approximately 10 weeks including screening period | \[14C\]-Ceralasertib (Part A) or total radioactivity (Part B) recovery in urine and faeces |
| To characterise the PK of Ceralasertib and total radioactivity following oral dose of [14C]-Ceralasertib including the extent of distribution into blood cells (Part B) | Through end of the part B, approximately 10 weeks (Including screening period) | AUCinf |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| To provide biologic samples for metabolic profiling and identification after oral dose of [14C]-Ceralasertib (Part B) | Through end of the part B, approximately 10 weeks (Including screening period) | Quantification and identification of major metabolites of Ceralasertib in plasma and excreta (will be reported separately) |
| To assess the safety of Ceralasertib in participants with advanced solid tumours (Parts A and B) | Through study completion, approximately 9 - 11 weeks, with screening included | Incidence and severity of AEs Incidence of laboratory abnormalities, based on haematology, clinical chemistry, and urinalysis test results 12-lead ECG parameters Vital signs measurements Physical examinations |
Countries
United Kingdom
Outcome results
None listed