Bone Density Conservation Agents

Antineoplastic Agents

All Drugs and Chemicals

Tamoxifen

Letrozole

Olaparib

Anastrozole

Aromatase Inhibitors

Enzyme Inhibitors

Estrogens

Estrogen Antagonists

Estrogen Receptor Antagonists

Hormones

Hormone Antagonists

Antineoplastic Agents, Hormonal

Selective Estrogen Receptor Modulators

Estrogen Receptor Modulators

Poly(ADP-ribose) Polymerase Inhibitors

Olaparib-alone Steady state PK, Tamoxifen-alone steady state PK, Combined olaparib and Tamoxifen steady state PK.

Olaparib-alone Steady state PK, Anastrozole-alone steady state PK, Combined olaparib and Anastrozole steady state PK.

Olaparib-alone Steady state PK, Letrozole-alone steady state PK, Combined olaparib and Letrozole steady state PK.

2 x 150mg tablets, twice daily Day 1-5, and Day 27 onwards (Cohort 1), Day 20 onwards (Cohort 2) or Day 39 onwards (Cohort 3)

60mg Tamoxifen once daily, Day 10 - Day 13; 20mg Tamoxifen once daily, Day 14 - Day 31

1mg Anastrozole once daily Day 10 - Day 24

2.5mg Letrozole once daily Day 10 - Day 43

Blood sampling over 12-24 hour period for pharmacokinetic analysis

Pharmacokinetic sampling

Tsveta Milenkova

Ruth Plummer

This is an open-label 2-part Phase I study in patients with advanced solid tumours. Part A of the study (mandatory) will assess the effect of olaparib on the pharmacokinetics (PK) of anastrozole, letrozole and tamoxifen and vice versa; Part B will allow patients (if eligible) continued access to olaparib after the PK phase and will provide additional safety data.

To Assess Safety and Effect of Olaparib on the Pharmacokinetics of Anastrozole, Letrozole & Tamoxifen, and Their Effect on Olaparib, in Patients With Advanced Solid Cancer

An Open-Label, Non-randomised, Parallel Group, Multicentre, Phase I Study to Assess the Safety and Effect of Olaparib at Steady State on the Pharmacokinetics of the Anti-hormonal Agents Anastrozole, Letrozole and Tamoxifen at Steady State, and the Effect of the Anti-hormonal Agents on Olaparib, Following Administration in Patients With Advanced Solid Cancer

Tamoxifen, N-desmethyl tamoxifen (N-DMT) and endoxifen Cmax ss in the presence and absence of co-administered olaparib, and associated Cmax ss treatment ratios

Olaparib Cmax ss in the presence and absence of co-administered tamoxifen, and associated Cmax ss treatment ratios

Anastrozole maximum plasma concentration at steady state (Cmax ss) in the presence and absence of co-administered olaparib, and associated Cmax ss treatment ratios

Olaparib Cmax ss in the presence and absence of co-administered anastrozole, and associated Cmax ss treatment ratios

Letrozole Cmax ss in the presence and absence of co-administered olaparib, and associated Cmax ss treatment ratios

Olaparib Cmax ss in the presence and absence of co-administered letrozole, and associated Cmax ss treatment ratios

Tamoxifen, N-DMT and endoxifen AUC0-τ, in the presence and absence of co-administered olaparib, and associated AUC0-τ treatment ratios

Olaparib AUC0-τ, in the presence and absence of co-administered tamoxifen, and associated AUC0-τ treatment ratios

Anastrozole Area under plasma concentration-time curve over the dosing interval at steady state (AUC0-τ), in the presence and absence of co-administered olaparib, and associated AUC0-τ treatment ratios

Olaparib AUC0-τ, in the presence and absence of co-administered anastrozole, and associated AUC0-τ treatment ratios

Letrozole AUC0-τ, in the presence and absence of co-administered olaparib, and associated AUC0-τ treatment ratios

Olaparib AUC0-τ, in the presence and absence of co-administered letrozole, and associated AUC0-τ treatment ratios

AstraZeneca

AE data is reported as treatment-emergent AEs. Each Part A cohort received treatment over 3 Treatment Periods. There was a washout period of 4 days between Treatment Periods 1 and 2, and no washout period between Treatment Periods 2 and 3. MedDRA v18.1 was used for Part B.

In Part A, patients in Cohort 1 received olaparib 300 mg twice daily (bd) for 5 days in Treatment Period 1; tamoxifen 60 mg once daily (od) (loading dose) for 4 days then 20 mg od for 13 days (maintenance dose) in Treatment Period 2; and tamoxifen 20 mg od concomitantly with olaparib 300 mg bd for 5 days in Treatment Period 3.

Cohort 1 - Tamoxifen

In Part A, patients in Cohort 2 received olaparib 300 mg bd for 5 days in Treatment Period 1; anastrozole 1 mg od for 10 days in Treatment Period 2; and anastrozole 1 mg od concomitantly with olaparib 300 mg bd for 5 days in Treatment Period 3.

Cohort 2 - Anastrozole

In Part A, patients in Cohort 3 received olaparib 300 mg bd for 5 days in Treatment Period 1; letrozole 2.5 mg od for 29 days in Treatment Period 2; and letrozole 2.5 mg od concomitantly with olaparib 300 mg bd for 5 days in Treatment Period 3.

Cohort 3 - Letrozole

In Part B, patients continued to receive olaparib 300 mg bd either as monotherapy or in combination with routine clinical regimes of letrozole, anastrazole or tamoxifen if deemed necessary by the investigator.

Olaparib (Part B)

Total

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

All patients enrolled in Part A of the study and who received at least 1 dose of olaparib were included in the baseline analysis.

At the end of Part B, the continued access phase (CAP) allowed patients to continue to receive olaparib if deriving clinical benefit. No clinical data was databased during the CAP, thus AE data is presented to the end of Part B only.

Dr Carsten Goessl, Indication Lead

PK analysis of tamoxifen

PK analysis of N-DMT

PK analysis of endoxifen

Patients in Cohort 1 received tamoxifen 60 mg od from Day 10 to Day 13 (loading dose). From Day 14 to Day 26 patients received tamoxifen 20 mg od (maintenance dose). Blood sampling for PK analysis was taken on Day 26.

Cohort 1 - Tamoxifen Alone (Treatment Period 2)

Patients in Cohort 1 received tamoxifen 20 mg od concomitantly with olaparib 300 mg bd for 5 days from Day 27 to Day 31. Blood sampling for PK analysis was taken on Day 31.

Cohort 1 - Olaparib + Tamoxifen (Treatment Period 3)

The PK Analysis set included all patients who received a study drug dose and provided evaluable PK profiles for at least 1 treatment period in Part A.

Effect of Olaparib on Exposure to Tamoxifen - Cmax ss

Patients received olaparib 300 mg bd from Day 1 to Day 4, and on Day 5 received olaparib 300 mg once (morning dose only). Blood sampling for PK analysis was taken on Day 5.

Cohort 1 - Olaparib (Treatment Period 1)

Effect of Tamoxifen on Exposure to Olaparib - Cmax ss

Patients in Cohort 2 received anastrozole 1 mg od from Day 10 to Day 19. Blood sampling for PK analysis was taken on Day 19.

Cohort 2 - Anastrozole Alone (Treatment Period 2)

Patients in Cohort 2 received anastrozole 1 mg od concomitantly with olaparib 300 mg bd for 5 days from Day 20 to Day 24. Blood sampling for PK analysis was taken on Day 24.

Cohort 2 - Olaparib + Anastrozole (Treatment Period 3)

PK Analysis set included all patients who received a study drug dose and provided evaluable PK profiles for at least 1 treatment period in Part A.

Effect of Olaparib on Exposure to Anastrozole - Cmax ss

Cohort 2 - Olaparib (Treatment Period 1)

Effect of Anastrozole on Exposure to Olaparib - Cmax ss

Patients in Cohort 3 received letrozole 2.5 mg od from Day 10 to Day 38. Blood sampling for PK analysis was taken on Day 38.

Cohort 3 - Letrozole Alone (Treatment Period 2)

Patients in Cohort 3 received letrozole 2.5 mg od concomitantly with olaparib 300 mg bd for 5 days from Day 39 to Day 43. Blood sampling for PK analysis was taken on Day 43.

Spots Global Cancer Trial Database for oncology, cancer, tumour, neoplasm, anticancer drug, pharmacokinetics, olaparib, anastrozole, tamoxifen, letrozole,