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Olaparib

Poly(ADP-ribose) Polymerase Inhibitors

Enzyme Inhibitors

Olaparib is given orally at the dose of 300 mg bid continually as maintenance therapy after a platinum based chemotherapy

Olaparib tablets

Sandro Pignata, MD, PhD

Clorinda Schettino, MD

Francesco Perrone, MD, PhD

The aim of the study is to explore a prognostic clinical and molecular biomarker profile in a population of BRCA wild-type recurrent high-grade ovarian cancer patients treated with olaparib as maintenance after response to a platinum based therapy as platinum sensitive recurrence treatment.

This is a single arm, open-label Phase 2 study designed to evaluate the effect of maintenance olaparib treatment after response to platinum-based chemotherapy in patients with BRCA wild type platinum sensitive recurrent ovarian cancer. The goal is to identify a clinical and molecular profile able to select a group of patients, treated with olaparib as maintenance, with a favorable prognosis.

This is a single arm, multicentre, open-label Phase 2 study

Female patients with histologically diagnosed relapsed high grade ovarian cancer (including primary peritoneal and /or fallopian tube cancer)

Olaparib in Patients With Recurrent Ovarian Cancer Wild Type for Germline and Somatic BRCA 1 and 2 Genes: The MITO 31 Translational Study

A Phase II Trial of Olaparib in Patients With Recurrent Ovarian Cancer Wild Type for Germline and Somatic BRCA 1 and 2 Genes: The MITO 31 Translational Study

as determined by investigator, after the subsequent line of treatment

graded according to Common Terminology Criteria for Adverse Event (CTCAE) version 5.0

according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1

National Cancer Institute, Naples

Anti-Arrhythmia Agents

Vasodilator Agents

Analgesics

Camptothecin

Adenosine

Patients with advanced platinum resistant ovarian cancer who have received no more than 1 prior line of therapy which must be platinum-based chemotherapy

Patients with advanced ovarian cancer who have received at least 1 prior line of therapy which must include at least 1 line of platinum-based chemotherapy followed by a PARP inhibitor as maintenance treatment as their last treatment regimen

EP0057 is an investigational nanoparticle-drug conjugate with a Camptothecin payload, that is administered intravenously

EP0057

Olaparib is a PARP inhibitor (poly \[adenosine diphosphate-ribose\] polymerase inhibitor)

EP0057-201 is a Phase 2A/B adaptive design study. Phase 2A will test EP0057 in combination with Olaparib and Phase 2B, the randomised part of the study, will test EP0057 in combination with Olaparib against SOC chemotherapy. When EP0057 is combined with Olaparib, it is envisaged that the combination should improve therapeutic responses in the recurrent ovarian cancer disease setting.

EP0057 is an investigational nanoparticle-drug conjugate administered intravenously. The rationale for developing EP0057 is to enable selective entry of EP0057 into tumour tissue and as a result create preferential accumulation of EP0057, and therefore of the payload Camptothecin, to translate into maximum tumour cell killing.

EP0057-201 is an adaptive Phase 2A/B study in patients with advanced ovarian cancer.

Phase 2A

Phase 2A will be comprised of 2 single-arm treatment cohorts:

Cohort 1 will explore EP0057 in combination with Olaparib in patients with advanced platinum resistant ovarian cancer (see inclusion criteria for definition of platinum resistant) who have received no more than 1 prior line of therapy which must be platinum-based chemotherapy (n\~=30)

Cohort 2 will explore EP0057 in combination with Olaparib in patients with advanced ovarian cancer who have received at least 1 prior line of therapy which must include at least 1 line of platinum-based chemotherapy followed by a PARP inhibitor as maintenance treatment as their last treatment regimen (n\~=30)

It is anticipated that up to approximately 60 patients (approximately 30 patients per cohort) will be enrolled into Phase 2A. Both treatment cohorts will open in parallel and patients will be enrolled into each cohort concurrently.

At the end of Phase 2A, the Safety Review Committee will guide the decision to initiate 1 or both cohorts in Phase 2B, or terminate further recruitment into the study.

Phase 2B

Phase 2B will be comprised of 2 treatment cohorts, each randomised versus SOC. One or both cohorts may be opened concurrently to recruitment:

Cohort 1 will explore EP0057 in combination with Olaparib compared with SOC chemotherapy (TBC) in patients with advanced platinum resistant ovarian cancer who have received no more than 1 prior line of therapy which must be platinum-based chemotherapy (n=\~132)

Cohort 2 will explore EP0057 in combination with Olaparib compared with SOC chemotherapy (TBC) in patients with advanced ovarian cancer who have received at least 1 prior line of therapy which must include at least 1 line of platinum-based chemotherapy followed by a PARP inhibitor as maintenance treatment as their last therapy (n=\~192)

It is anticipated that \~324 patients will be enrolled into Phase 2B. Both treatment cohorts may open in parallel and patients may be enrolled into each cohort concurrently.

EP0057 in Combination With Olaparib in Advanced Ovarian Cancer

Phase 2 Study to Evaluate the Safety & Efficacy of EP0057 in Combination With Olaparib in Advanced Ovarian Cancer Patients Who Have: Cohort 1 - Platinum Resistant Disease; Cohort 2 - Had at Least 1 Prior Line of Therapy Which Must Include at Least 1 Line of Platinum-based Chemotherapy Followed by PARP Inhibitor Maintenance

Overall Response Rate as measured using RECIST1.1

Ellipses Pharma

Respiratory Tract (Lung and Bronchial) Diseases

Digestive System Diseases

Lung Neoplasms

Stomach Neoplasms

Small Cell Lung Carcinoma

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Stomach Diseases

Carcinoma, Bronchogenic

Bronchial Neoplasms

Stomach Cancer

Small Cell Lung Cancer

patients with ataxia-telangiectasia mutated protein (ATM)-negative relapsed, advanced GC.

patients with relapsed extensive stage SCLC.

Olaparib is a PARP inhibitor (poly \[adenosine diphosphate-ribose\] polymerase inhibitor) Other names: Lynparza

The aim of EP0057 - 202 is to assess the safety and efficacy of EP0057 in combination with Olaparib (a PARP inhibitor) in two cancers where there is a high unmet need: extensive stage small cell lung cancer (SCLC) and ATM-negative gastric cancer (GC).

EP0057-202 is a non-comparative, multi-arm, multi-centre, open label, Phase 2 study to determine the efficacy, safety, and tolerability of EP0057 in combination with olaparib (an approved PARP inhibitor) in defined patient populations with relapsed\* GC and SCLC.

\*(see Eligibility Criteria for definition of "relapse" for each tumour type/population) The treatment cohorts will open sequentially at the Sponsor's discretion and patients may be enrolled into each cohort concurrently.

EP0057 is an investigational nanoparticle-drug conjugate administered intravenously. The rationale for developing EP0057 is to enable selective entry of EP0057 into tumour tissue and as a result create preferential accumulation of EP0057, and therefore of the payload Camptothecin, to translate into maximum tumour cell killing.

EP0057 - 202 is a Phase 2 multi arm, open label study in defined populations of patients with SCLC and GC.

The Primary objectives of Arm 1 will be to investigate the efficacy, as defined by best Objective Response Rate (ORR) of EP0057 in combination with Olaparib in patients with ataxia-telangiectasia mutated protein (ATM)-negative relapsed, advanced GC.

The Primary objectives of Arm 2 will be to investigate the efficacy, as defined by the best ORR of EP0057 in combination with Olaparib in patients with relapsed extensive stage SCLC.

The secondary objectives of both arms will be to further investigate the efficacy of EP0057 in combination with olaparib in the target patient population of each arm by assessment of the following:

* Progression-free survival (PFS)
* Overall survival (OS)
* Duration of overall response (DoR)
* Disease control rate (DCR)

Secondary objectives of arms 1 and 2 also include exploring the safety and tolerability of EP0057 when combined with olaparib in patients with GC and SCLC.

Exploratory objectives may or may not be performed during the course of the study, but if so, where available at the time of publication, results from these analyses will be reported in the clinical study report (CSR). Exploratory objectives are to:

* Examine the PK characteristics of EP0057 in combination with olaparib
* Investigate the impact of HRD (homologous recombination deficiency) status on primary and secondary endpoints, as analysed by sub-groups of HRD status.

It is estimated that approximately 115 patients will be enrolled into the study. The study will aim to recruit 34 patients across both arms of the study in stage 1. The study will then aim to recruit an additional 81 patients across both arms in the second stage.

EP0057 in Combination With Olaparib in Relapsed Advanced Gastric Cancer and Small Cell Lung Cancer

A Phase 2 Multi-arm, Open Label Study to Assess the Safety and Efficacy of EP0057 in Combination With Olaparib in Defined Populations of Patients With Relapsed Advanced Gastric Cancer and Small Cell Lung Cancer

Derived PK parameters will include: AUC0-48 for C1D1 dosing

Olaparib tablets after high-fat breakfast

Olaparib dosing (2X 150mg tablets) following allocated meal

Blood samples taken pre and post dosing with 2x 150 mg olaparib tablet

Pharmacokinetic sampling

2x 150 mg olaparib tablet formulation taken in fasted state. 5-14 days washout period

Dietary Fasted

2x 150 mg olaparib tablet formulation taken 30 minutes after allocated meal. 5-14 days washout period.

Dietary High Fat

Anitra Fielding

Ruth Plummer, Prof

This is a 3 part study for patients with solid tumours. The purpose of Part A is to measure the amount of olaparib or its breakdown products in the bloodstream for up to 72 hours after eating and the effect of olaparib on QT interval following a single oral dose of olaparib tablets. Part B will determine the effect of olaparib on the QT interval following multiple oral dosing. Part C will allow patients continued access to olaparib tablets and will provide additional safety data collection.

To Determine the Effect of Food on the Pharmacokinetics of Olaparib and the Effect of Olaparib on QT Interval Following Oral Dosing of a Tablet Formulation in Patients With Advanced Solid Tumours

A Randomised, Open-label, Three-part, Phase I Study to Determine the Effect of Food on the Pharmacokinetics of Olaparib and to Provide Data on the Effect of Olaparib on QT Interval Following Oral Dosing of a Tablet Formulation in Patients With Advanced Solid Tumours

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.

Rate and extent of absorption of olaparib following single (Part A) and multiple (Part B) oral doses of olaparib tablet formulation by assessment of area under the plasma concentration time curve from zero to infinity (AUC)

Rate and extent of absorption of olaparib following single (Part A) and multiple (Part B) oral doses of olaparib tablet formulation by assessment of maximum plasma olaparib concentration (Cmax)

Rate and extent of absorption of olaparib following single (Part A) and multiple (Part B) oral doses of olaparib tablet formulation by assessment of area under the plasma concentration time curve from zero to the last measurable time point (AUC0-t), if AUC is not adequately estimable.

Rate and extent of absorption of olaparib following single (Part A) and multiple (Part B) oral doses of olaparib tablet formulation by assessment of time to reach maximum plasma concentration for olaparib (tmax)

Rate and extent of absorption of olaparib following single (Part A) and multiple (Part B) oral doses of olaparib tablet formulation by assessment of olaparib apparent clearance (CL/F)

Rate and extent of absorption of olaparib following single (Part A) and multiple (Part B) oral doses of olaparib tablet formulation by assessment of olaparib apparent volume of distribution (Vz/F)

Rate and extent of absorption of olaparib following single (Part A) and multiple (Part B) oral doses of olaparib tablet formulation by assessment of terminal rate constant (λz)

Rate and extent of absorption of olaparib following single (Part A) and multiple (Part B) oral doses of olaparib tablet formulation by assessment of olaparib terminal half-life (t1/2).

The QT interval uncorrected and corrected for heart rate (QTc) following single (Part A) and multiple (Part B) oral doses of olaparib tablet formulation.

Adverse events (AEs) will be collected from the time of signed informed consent throughout the treatment period in Part A and Part B up to and including the 30-day follow-up period. In Part C, AEs will be collected until 12 months after the last patient entered Part C, and including the 30 day follow-up period for any patients who discontinue.

Assessment of AEs, graded by CTCAE (v4.03),

Assessment of AEs, graded by CTCAE (v4.0), physical examination, vital signs (including BP and pulse), standard 12-lead ECG and evaluation of laboratory parameters (clinical chemistry, haematology, and urinalysis). Assessment of physical examination, vital signs, ECG and evaluation of laboratory parameters will occur at screening, on the day before dosing in each treatment period and 30 days after last dose in Parts A and B. In Part C, all except ECG will be assessed weekly for a 28-day period followed by every 4 weeks up to 12 months after the last patient enters Part C and at treatment discontinuation. All will be assessed 30 days after last dose.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Olaparib in Patients With Recurrent Ovarian Cancer Wild Type for Germline and Somatic BRCA 1 and 2 Genes: The MITO 31 Translational Study	NCT04091204	BRCA Wild Type ...	Olaparib tablet...	18 Years -	National Cancer Institute, Naples
EP0057 in Combination With Olaparib in Advanced Ovarian Cancer	NCT04669002	Ovarian Cancer	EP0057 Olaparib tablet...	18 Years -	Ellipses Pharma
EP0057 in Combination With Olaparib in Relapsed Advanced Gastric Cancer and Small Cell Lung Cancer	NCT05411679	Gastric Cancer Small-cell Lung...	EP0057 Olaparib tablet...	18 Years -	Ellipses Pharma
To Determine the Effect of Food on the Pharmacokinetics of Olaparib and the Effect of Olaparib on QT Interval Following Oral Dosing of a Tablet Formulation in Patients With Advanced Solid Tumours	NCT01921140	Solid Tumours	Olaparib tablet... Pharmacokinetic... Dietary Fasted Dietary High Fa...	18 Years - 130 Years	AstraZeneca
To Determine the Effect of Food on the Pharmacokinetics of Olaparib and the Effect of Olaparib on QT Interval Following Oral Dosing of a Tablet Formulation in Patients With Advanced Solid Tumours	NCT01921140	Solid Tumours	Olaparib tablet... Pharmacokinetic... Dietary Fasted Dietary High Fa...	18 Years - 130 Years	AstraZeneca
Olaparib in Patients With Recurrent Ovarian Cancer Wild Type for Germline and Somatic BRCA 1 and 2 Genes: The MITO 31 Translational Study	NCT04091204	BRCA Wild Type ...	Olaparib tablet...	18 Years -	National Cancer Institute, Naples
To Determine the Effect of Food on the Pharmacokinetics of Olaparib and the Effect of Olaparib on QT Interval Following Oral Dosing of a Tablet Formulation in Patients With Advanced Solid Tumours	NCT01921140	Solid Tumours	Olaparib tablet... Pharmacokinetic... Dietary Fasted Dietary High Fa...	18 Years - 130 Years	AstraZeneca
Olaparib in Patients With Recurrent Ovarian Cancer Wild Type for Germline and Somatic BRCA 1 and 2 Genes: The MITO 31 Translational Study	NCT04091204	BRCA Wild Type ...	Olaparib tablet...	18 Years -	National Cancer Institute, Naples

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