Phase I Comparative Bioavailability Study

Study Overview
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Brief Summary
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The purpose of this phase I randomised cross over study is to determine and compare the bioavailability of two different oral formulations of AZD2281 in advanced solid tumour cancer patients

Official Title
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A Phase I, Randomised, 2 Period Cross Over Study to Determine the Comparative Bioavailability of Two Different Oral Formulations of AZD2281 in Cancer Patients With Advanced Solid Tumours

Conditions
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Solid Tumors

Intervention / Treatment
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* Drug: AZD2281


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed malignant advanced solid tumour, which is refractory to standard therapies (except Group 8 patients who must not be platinum refractory) or for which no suitable effective standard therapy exists Patients must have adequate organ and bone marrow function measured within 7 days prior to administration of study treatment Female patients must have evidence of non-child bearing status: negative urine or serum pregnancy test within 7 days of study treatment for women of child bearing, or postmenopausal status Exclusion Criteria: Patients receiving chemotherapy, radiotherapy (except for palliative reasons) or any other anti-cancer therapy within 4 weeks of the last dose prior to study entry. Patients may continue the use of biphosphonates for bone metastases and corticosteroids Patients with symptomatic uncontrolled brain metastases Major surgery within 2 weeks of starting study and patients must have recovered from any effects of any major surgery Patients who are platinum refractory (Group 8 only) Patients with myelodysplastic syndrome/acute myeloid leukaemia (Group 8 only).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 130 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment A<br>300mg bid (twice daily) tablet dose | Drug: AZD2281<br>* Oral single dose formulation<br>* Other names: Olaparib;|
| Experimental: Treatment B<br>400 mg twice daily (bid) capsule dose | Drug: AZD2281<br>* Oral single dose formulation<br>* Other names: Olaparib;|
| Experimental: Treatment C<br>400mg bid (twice daily) tablet dose | Drug: AZD2281<br>* Oral single dose formulation<br>* Other names: Olaparib;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PK Phase Primary Outcome: To determine the comparative bioavailability of a new tablet formulation of AZD2281 compared to the existing capsule formulation |  | Blood samples (12) will be taken at pre-defined intervals following dosing of a single capsule and a single tablet dose | 
| Continued Supply Phase: To enable patients to continue to receive treatment with AZD2281. Safety and tolerability data will be collected to further determine the safety and tolerability of the capsule formulation of AZD2281 in these patients |  | every 28 days | 
| Continued Supply Expansion Phase: To compare the safety and tolerability of the tablet and capsule formulation of AZD2281 in all patients: Safety, AEs, Physical Exam, vital signs |  | at every visit | 
| Dose Escalation Phase of continued supply expansion: To determine safety & tolerability of higher than 200mg bid (to 400mg) of tablet & compare safety & tolerability profile of tablet with 400mg capsule |  | at every visit | 
| Randomised tablet formulation continued supply expansion phase (Group 8): To determine the safety and tolerability profile of selected tablet dose schedules of the melt-extrusion (tablet) formulation. |  | at every visit | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PK Phase Secondary Outcome: To generate single dose PK data for the new tablet formulation in man, and to generate information on dose linearity for the new tablet formulation |  | Blood samples (12) will be taken at pre-defined intervals prior to and following dosing of a single capsule and a single tablet dose | 
| To compare the extent of PARP inhibition achieved in peripheral blood mononuclear cells (PBMCs) following dosing of both the new tablet formulation and existing capsule formulation |  | Blood samples (4) will be taken at pre-defined intervals prior to and following dosing of a single capsule and a single tablet dose | 
| To determine the safety and tolerability of AZD2281 for both the new tablet formulation and existing capsule formulations |  | every 28 days | 
| Continued Supply Expansion Phase: To compare the steady state exposure achieved with 200mg bid tablet formulation and 400mg bid capsule formulation |  | at visit 3 and visit 4 | 
| Continued Supply Expansion Phase: To describe the efficacy data observed in patients treated with the capsule and the tablet |  | RECIST, Progression Free Survival, Best overall response and CA-125 response | 
| Dose Escalation Phase of the continued supply expansion: To determine the single dose and steady state exposures achieved with higher doses of AZD2281 tablet formulation |  | at every visit | 
| Dose Escalation Phase of the continued supply expansion: To compare between patients the single dose and steady state exposures of AZD2281 achieved with selected tablet doses and the 400mg bid capsule dose |  | at every visit | 
| Dose Escalation Phase of the continued supply expansion: To describe the efficacy data observed in patients treated with the capsule formulation and the tablet formulation |  | at every visit | 
| Randomised tablet formulation continued supply expansion phase (Group 8): To determine the single dose and steady state exposures achieved with the selected table dose schedules of AZD2281 melt-extrusion (tablet) formulation |  | at every visit | 
| Randomised tablet formulation continued supply expansion phase (Group 8): To obtain a preliminary assessment of the effect of food on the exposure to AZD2281 following dosing of the melt-extrusion (tablet) formulation. |  | at every visit | 
| Randomised tablet formulation continued supply expansion phase (Group 8): To describe the efficacy data observed in patients treated with the melt-extrusion (tablet) formulation |  | at every visit | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Poly (ADP ribose) polymerases, Homologous Recombination Deficiency (HRD), Advanced solid tumours