Neoplasms

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All Conditions

Neoplasm Metastasis

Neoplastic Processes

Antineoplastic Agents

All Drugs and Chemicals

Bevacizumab

Olaparib

Poly(ADP-ribose) Polymerase Inhibitors

Antineoplastic Agents, Immunological

Angiogenesis Inhibitors

Growth Inhibitors

Enzyme Inhibitors

Dose Escalation Study 50, 100, 200, 400 mg

Oral Capsule, Dose Escalation 50, 100, 200, 400 mgContinuous twice daily dosing

AZD2281

James Carmichael, BSc MBChB MD FRCP

Malcolm Ranson

Phase I, open label, dual centre, dose finding study to evaluate the safety and tolerability of continuous twice daily oral dosing with AZD2281 when administered in combination with Bevacizumab 10mg/kg given every 2 weeks to patients with advanced solid tumours.

Study to Assess Safety & Tolerability of AZD2281 in Combination With Bevacizumab in Patients With Advanced Solid Tumours

A Phase I, Open Label, Dual Centre Study To Assess The Safety And Tolerability Of AZD2281 In Combination With Bevacizumab (Avastin®) In Patients With Advanced Solid Tumours

AstraZeneca

James Carmichael, BSc, MBChB, MD, FRCP

Johann deBono, MD, FRCP, MSc PhD

Open, non-randomized, radiolabelled, single centre study designed to characterize the metabolism, excretion and pharmacokinetics of a single oral dose of 100 mg \[14C\]-radiolabelled AZD2281 (KU-0059436) in patients with advanced or metastatic solid tumours.

Study Assessing Metabolism, Excretion and Pharmacokinetics of a Poly (ADP-Ribose) Polymerase (PARP) Inhibitor in Patients With Solid Metastatic Tumours

Open, Non-Randomized, Single Centre Phase I Study to Assess the Metabolism, Excretion and Pharmacokinetics of a Single Oral 100 mg Dose of [14C]-AZD2281 (KU-0059436) in Patients With Advanced or Metastatic Solid Tumours Refractory to Standard Treatments

KuDOS Pharmaceuticals Limited

Jim Carmichael - CMO

Skin and Connective Tissue Diseases

Breast Neoplasms

Breast Diseases

Skin Diseases

Participants will receive two 50 mg capsules in the morning and two 50 mg capsules in the evening in 28-days cycle until confirmed disease progression, continuous treatment interruption, unacceptable toxicity or any other discontinuation criterion is met.

Participants will receive eight 50 mg capsules in the morning and eight 50 mg capsules in the evening in 28-days cycle until confirmed disease progression, continuous treatment interruption, unacceptable toxicity or any other discontinuation criterion is met.

Participants will receive capsules of olaparib orally as stated in arm description.

Andrew Tutt, PhD MRCP FRCR

The purpose of the study is to see if the drug KU-0059436 (olaparib) is effective and well tolerated in treating participants with measurable breast cancer gene (BRCA)1- or BRCA2-positive advanced breast cancer and for whom no curative therapeutic option exists.

This is a Phase II, open-label, non-comparative, international, multicenter study to assess the efficacy and safety of olaparib when given orally twice daily (bd) in participants with advanced BRCA1- or BRCA2- associated breast cancer. Two sequential participant cohorts will receive continuous oral olaparib in 28-day cycles. The first cohort will receive 400 mg bd and the second cohort will receive 100 mg bd.

Study to Assess The Efficacy and Safety of a PARP Inhibitor For The Treatment of BRCA-positive Advanced Breast Cancer

A Phase II, Open-label, Non-comparative, International, Multicentre Study to Assess the Efficacy and Safety of KU-0059436 Given Orally Twice Daily in Patients With Advanced BRCA1- or BRCA2-associated Breast Cancer.

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

The ORR is the percentage of participants whose best tumor response is either complete response (CR) or partial response (PR), according to the RECIST v1.0 criteria. The CR is defined as disappearance of all target lesions (TLs). The PR is defined as at least a 30% decrease in the sum of longest diameters (LD) taking as reference the baseline sum of LD. Percentage of participants with ORR is reported.

Duration of response is defined as the date of progression per RECIST criteria - the date when CR or PR \[whichever is earliest\] is confirmed + 1. The CR is defined as disappearance of all TLs. The PR is defined as at least a 30% decrease in the sum of LD taking as reference the baseline sum of LD. Duration of response was analyzed for those participants who had OR.

The CBR is defined as the percentage of participants with a RECIST tumor response of confirmed CR, PR or stable disease (SD) for ≥ 8 weeks +/- 1 week visit window. The CR is defined as disappearance of all TLs. The PR is defined as at least a 30% decrease in the sum of LD taking as reference the baseline sum of LD. Stable disease is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as references the smallest sum of LD since the treatment started.

The tumor size is defined as the sum of the longest diameters as measured among all target lesions. At each assessment, the percentage change in tumor size is defined as 100 × 1 - (sum of all target lesion diameters at visit/sum of all target lesion diameters at baseline).

PFS is defined as the time from first dose to the earlier date of radiologic progression (as per RECIST criteria) or death by any cause in the absence of objective progression. Those participants who were withdrawn from the study without disease progression were regarded as censored at their last evaluable RECIST assessment. Where participants had not progressed at the termination of the study, they were also regarded as censored at their last evaluable RECIST assessment. PFS was analyzed using Kaplan-Meier estimate.

ECOG performance status is used by researchers to assess how a participant's disease is progressing. The scores are: 0=Fully Active, able to carry out work without restrictions; 1=Restricted activity and able to carry out light work or sedentary nature; 2=capable of self-care but unable to carry out work activities; 3=Capable of only limited self-care, confined to bed or chair more than 50% of waking hours; 4=Completely Disabled, and totally confined to bed or chair; 5=Dead. Change in ECOG performance status was defined as improved (less than the baseline value), no change (same as at baseline), worsened (greater than the baseline value) or missing (score is missing or was not recorded at baseline). If no measurement was recorded at Cycle 1 Day 1, the change was calculated in relation to the last recorded ECOG value prior to Day 1.

An adverse event (AE) is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event (SAE) is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. The TEAEs are defined as events present at baseline that worsened in intensity after administration of study drug or events absent at baseline that emerged after administration of study drug.

Number of participants with clinically significant changes in vital signs are reported. Vital sign parameters included body temperature, blood pressure, and pulse rate.

Number of participants with at least 2-grade change from baseline to worst toxicity grade in clinical laboratory parameters are reported. Laboratory parameters included hematology, clinical chemistry, and urinalysis.

Safety population included all participants who received at least one dose of study drug.

Participants received two 50 mg capsules in the morning and two 50 mg capsules in the evening in 28-days cycle until confirmed disease progression, continuous treatment interruption, unacceptable toxicity or any other discontinuation criterion was met.

Olaparib 100 mg

Participants received eight 50 mg capsules in the morning and eight 50 mg capsules in the evening in 28-days cycle until confirmed disease progression, continuous treatment interruption, unacceptable toxicity or any other discontinuation criterion was met.

Olaparib 400 mg

Total

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

The full analysis set comprised of all enrolled participants with positive BRCA status, who took at least one dose of investigational medicinal product irrespective of whether they completed the trial schedule and IMP regime or not.

The plasma concentration data was analysed using a population approach and polyadenosine 5' diphosphoribose polymerase (PARP) inhibition data had already been obtained from Study D0810C00002. Hence no pharmacokinetic and PARP inhibition data are included.

Global Clinical Lead

The per-protocol (PP) population included all enrolled participants who completed the trial schedule and medication regime without any major deviations to the protocol.

Confirmed Objective Response Rate (ORR) According to Response Evaluation Criteria in Solid Tumors (RECIST) Criteria

The PP population included all enrolled participants who completed the trial schedule and medication regime without any major deviations to the protocol.

Duration of Response (DoR) to Olaparib

Clinical Benefit Rate (CBR)

Best Percentage Change in Tumor Size

Progression-free Survival (PFS)

Cycle 7 Day 1

Withdrawal visit

Number of Participants With Improvement in Eastern Co-operative Oncology Group (ECOG) Performance Status Total Score From Baseline

Any TEAE

Any TESAE

Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)

Tachycardia

Supraventricular arrhythmia

Number of Participants With Clinically Significant Changes in Vital Signs From Baseline

Hemoglobin

White blood cells

Absolute neutrophil count

Lymphocytes

Platelets

Activated partial thromboplastin time

Alanine aminotransferase

Aspartate aminotransferase

Alkaline phosphatase

Gamma glutamyl transferase

Albumin

Total bilirubin

Sodium (decrease)

Potassium (increase)

Creatinine

Glucose (increase)

Glucose (decrease)

Calcium (decrease)

Amylase

Lipase

Number of Participants With at Least 2-Grade Change From Baseline to Worst Toxicity Grade in Clinical Laboratory Parameters

Overall Study

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Gland and Hormone Related Diseases

Rare Diseases

Ovarian Neoplasms

Carcinoma, Ovarian Epithelial

Carcinoma

Endocrine Gland Neoplasms

Ovarian Diseases

Adnexal Diseases

Genital Diseases, Female

Genital Diseases

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Genital Neoplasms, Female

Urogenital Neoplasms

Endocrine System Diseases

Gonadal Disorders

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Ovarian Cancer

Ovarian Epithelial Cancer

KU-0059436 (AZD2281)(PARP inhibitor)

The purpose of the study is to see if the drug KU 0059436 is effective and well tolerated in treating patients with measurable BRCA1- or BRCA2-positive advanced ovarian cancer and for whom no curative therapeutic option exists.

Study to Assess the Efficacy and Safety of a PARP Inhibitor for the Treatment of BRCA-positive Advanced Ovarian Cancer

A Phase II Open-label, Non-comparative, International, Multicentre Study to Assess the Efficacy and Safety of KU 0059436 Given Orally Twice Daily in Patients With Advanced BRCA1 or BRCA2 Associated Ovarian Cancer

Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by CT/MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease from baseline in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.

Clinical Benefit (CB) is defined as the percentage of patients with a RECIST tumour response of confirmed complete response, partial response or stable disease for ≥8 weeks)

The best % change (reduction) from baseline in tumour size (defined as the sum of the longest diameters as measured among all target lesions).

Progression-Free Survival (PFS) is defined as the time from first dose to the earlier date of radiologic progression (as per RECIST criteria) or death by any cause in the absence of objective progression.

olaparib (KU-0059436; AZD2281) 100 mg oral capsules, twice daily

Olaparib 100 mg bd

olaparib (KU-0059436; AZD2281) 400 mg oral capsules, twice daily

Olaparib 400 mg bd

BRCA1 or BRCA2 mutations known to cause loss of gene function (clinical deleterious or suspected deleterious mutations).

BRCA mutation

Gerard Lynch

PP Analysis Set

ITT Analysis Set

PP Analysis Set (includes all enrolled patients who complete the trial schedule and medication regime without any major deviations to the protocol - this is the main analysis population, with ITT used to confirm)

Confirmed Objective Tumour Response (According to Response Evaluation Criteria In Solid Tumors (RECIST)

Clinical Benefit (CB)

PP Analysis Set (includes all enrolled patients who complete the trial schedule and medication regime without any major deviations to the protocol - this is the main analysis population, with ITT used to confirm

Duration of Response

Best Percentage Change in Tumour Size

Progression-Free Survival (PFS)

Anti-Infective Agents

Doxorubicin

Liposomal doxorubicin

Anti-Bacterial Agents

Antibiotics, Antitubercular

Liposomal Doxorubicin

Jane Robertson, BSc, MBCHB, MD

Stan Kaye, BSc, MB, FRCP, FRCR, SMedSCi

The purpose of the study is to compare the efficacy and safety of 2 doses of drug AZD2281 against liposomal doxorubicin to see which is effective and well tolerated in treating patients with measurable BRCA1- or BRCA2-positive advanced ovarian cancer and who have failed previous platinum therapy.

Dose-finding Study Comparing Efficacy and Safety of a PARP Inhibitor Against Doxil in BRCA+ve Advanced Ovarian Cancer

A Phase II, Open-Label, Randomised, Comparative, International Multicentre Study to Assess the Safety and Efficacy of Different Doses of AZD2281 Given Orally Twice Daily Versus Intravenous Liposomal Doxorubicin Given Monthly in Patients With Advanced BRCA1- or BRCA2-Associated Ovarian Cancer Who Have Failed Previous Platinum-based Chemotherapy

PFS was defined as the time to progression from the date of randomisation until the date of radiological assessment of progression per RECIST criteria or death (by any cause in the absence of progression)

ORR was defined according to RECIST. Complete response (CR) or partial response - (PR)- 30% decrease Patients with a best RECIST response of CR or PR had to have a confirmed response at least 28 days later.

The number of patients with confirmed CR (disappearance of all target lesions) or PR (30% decrease in the sum of the longest diameter of target lesions ) or SD ( small changes ) \>4 months, divided by the number of randomised patients

The duration of response was defined as time (months) from initial assessment of PR/CR until earliest date of objective progression or death. (Values may be underestimated as some patients had not progressed at final analysis so true duration is likely to be greater than that in database.)

The percentage change (reduction) from baseline in the sum of the lengths of the longest diameter (LD) of the RECIST target lesions were objectively documented, regardless of whether the patient was still taking study medication

Best percentage change in cancer antigen 125 (CA-125) levels

The percentage of patients reporting a RECIST confirmed response and/or a CA-125 response (in the absence of progression). A CA-125 response was defined as a confirmed greater or equal to 50% reduction in CA-125.

OS was defined as time from randomisation to date of death from any cause. Patients who had not died at time of analysis were censored at last date they were known to be alive. Median OS was not calculable for olaparib groups due to an insufficient number of deaths so the percentage of participants who died are shown along with 95% confidence intervals

Best HRQoL response using the TOI endpoint. Improvement was defined as a change from baseline of greater than or equal to +7. The TOI score ranges from 0-100.

Best HRQoL response using the total FACT-O endpoint. Improvement was defined as a change from baseline of greater than or equal to +9.

Best HRQoL response using the FOSI endpoint. Improvement was defined as a change from baseline of greater than or equal to +3.

AEs reported = all events up to OS data cut-off. After PFS data cut-off, AEs only collected for olaparib and cross-over groups. The safety profile of these 2 groups at OS was consistent with that at time of PFS. One patient was recorded as crossing over to olaparib but not receiving cross-over treatment.

Olaparib (AZD2281) 200 mg oral capsules twice daily

Olaparib 200 mg bd

Olaparib (AZD2281) 400 mg oral capsules twice daily

Liposomal doxorubicin 50 mg/m2 intravenously every 4 weeks

African-Caribbean

Ashkenazi Jewish

Sephardic Jewish

Not applicable

Other

Race/Ethnicity, Customized

Deleterious BRCA1 mutation

Deleterious BRCA2 mutation

BRCA status

The AEs reported include all events up to the OS data cut-off. After the PFS data cut-off, AEs were only collected for the olaparib and cross-over groups. The safety profile of these 2 groups at OS was consistent with that at the time of PFS.

Paula del Rosario

Analysis of olaparib 200 or 400 mg bd (n=64) versus liposomal doxorubicin (n=33). A hazard ratio \< 1 favours olaparib.

Analysis of olaparib 200 (n=32) versus liposomal doxorubicin (n=33). A hazard ratio \< 1 favours olaparib.

Analysis of olaparib 400 (n=32) versus liposomal doxorubicin (n=33). A hazard ratio \< 1 favours olaparib.

Progression Free Survival (PFS)

Analysis of olaparib 200 or 400 (n=64) versus liposomal doxorubicin (n=33).

Analysis of olaparib 200 (n=32) versus liposomal doxorubicin (n=33).

Analysis of olaparib 400 (n=32) versus liposomal doxorubicin (n=33).

Complete response

Number of Partial responders

Objective Response Rate (ORR)

Disease Control Rate

Olaparib (AZD2281) 200 or 400 mg oral capsules twice daily

Olaparib 200 mg bd + Olaparib 400 mg bd,

Duration of response is analysed for patients experiencing a response.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Study to Assess Safety & Tolerability of AZD2281 in Combination With Bevacizumab in Patients With Advanced Solid Tumours	NCT00710268	Neoplasm Metast...	AZD2281 Bevacizumab	18 Years -	AstraZeneca
Study Assessing Metabolism, Excretion and Pharmacokinetics of a Poly (ADP-Ribose) Polymerase (PARP) Inhibitor in Patients With Solid Metastatic Tumours	NCT00633269	Neoplasm Metast...	AZD2281	18 Years -	AstraZeneca
Study to Assess The Efficacy and Safety of a PARP Inhibitor For The Treatment of BRCA-positive Advanced Breast Cancer	NCT00494234	Breast Neoplasm...	Olaparib	18 Years - 130 Years	AstraZeneca
Study to Assess the Efficacy and Safety of a PARP Inhibitor for the Treatment of BRCA-positive Advanced Ovarian Cancer	NCT00494442	Ovarian Neoplas...	KU-0059436 (AZD... KU-0059436 (AZD...	18 Years - 130 Years	AstraZeneca
Dose-finding Study Comparing Efficacy and Safety of a PARP Inhibitor Against Doxil in BRCA+ve Advanced Ovarian Cancer	NCT00628251	Ovarian Neoplas...	AZD2281 Liposomal Doxor... AZD2281	18 Years - 130 Years	AstraZeneca
Dose-finding Study Comparing Efficacy and Safety of a PARP Inhibitor Against Doxil in BRCA+ve Advanced Ovarian Cancer	NCT00628251	Ovarian Neoplas...	AZD2281 Liposomal Doxor... AZD2281	18 Years - 130 Years	AstraZeneca
Study to Assess Safety & Tolerability of AZD2281 in Combination With Bevacizumab in Patients With Advanced Solid Tumours	NCT00710268	Neoplasm Metast...	AZD2281 Bevacizumab	18 Years -	AstraZeneca
Study to Assess the Efficacy and Safety of a PARP Inhibitor for the Treatment of BRCA-positive Advanced Ovarian Cancer	NCT00494442	Ovarian Neoplas...	KU-0059436 (AZD... KU-0059436 (AZD...	18 Years - 130 Years	AstraZeneca

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