Efficacy Study of Olaparib With Paclitaxel Versus Paclitaxel in Gastric Cancer Patients

A Randomised, Double Blinded, Multicentre Phase II Study to Assess the Efficacy of Olaparib (AZD2281, KU-0059436) in Combination With Paclitaxel Versus Paclitaxel in Patients With Recurrent or Metastatic Gastric Cancer Who Progress Following First-line Therapy

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01063517

Enrollment

124

Registered

2010-02-05

Start date

2010-02-02

Completion date

2023-06-29

Last updated

2023-07-20

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Gastric Cancer

Keywords

Poly(ADP ribose), polymerase (PARP), Gastric cancer, olaparib, PARP inhibitor, ATM AZD2281, Ku0059436, Homologous Recombination deficiency (HRD), Recurrent gastric cancer, metastatic gastric cancer

Brief summary

To assess the efficacy of olaparib when given in combination with paclitaxel compared with paclitaxel alone as defined by progression-free survival (PFS), in all patients with recurrent and metastatic gastric cancer who progress following first-line therapy.

Interventions

DRUGolaparib

100mg BID oral tablet continuous

DRUGpaclitaxel

iv infusion 80mg/m2 on Day 1, 8 and 15 of a 28 day cycle

DRUGPlacebo

100mg BID oral tablet to match olaparib tablet

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

18 Years to 130 Years

Healthy volunteers

Inclusion criteria

* Recurrent or metastatic gastric cancer that has progressed following first line-therapy * Confirmed ATM protein status by IHC archival tumour sample * At least one lesion (measurable and/or non-measurable) that can be accurately assessed by imaging (CT/MRI) at baseline and follow up visits

Exclusion criteria

* More than one prior chemotherapy regimen for the treatment of gastric cancer in the metastatic or recurrent setting * Any previous treatment with a PARP inhibitor, including olaparib * Patients with second primary cancer, except; adequately treated non melanoma skin cancer, curatively treated in situ cancer of the cervix, or other solid tumours curatively treated with no evidence of disease for \>5 years

Design outcomes

Primary

Measure	Time frame	Description
Progression Free Survival (PFS) in the Overall Study Population	Tumour assessments were carried out at baseline and then follow up assessments taken every 8 weeks up to Week 40 and then every 16 weeks until objective disease progression as defined by RECIST 1.1, assessed maximum up to 27 months	PFS is defined as the time from randomisation till objective progression or death. In absence of progression or death, the time is calculated from randomisation till last evaluable scanning visit.
Progression Free Survival (PFS) in Patients With Tumours Defined as Homologous Recombination Deficient by Loss of Ataxia-Telangiectasia Mutation (ATM) Protein [ATM Negative Patients]	Tumour assessments are carried out at baseline and then follow up assessments taken every 8 weeks up to Week 40 and then every 16 weeks until objective disease progression as defined by RECIST 1.1, assessed maximum up to 27 months	PFS is defined as the time from randomisation till objective progression or death. In absence of progression or death, the time is calculated from randomisation till last evaluable scanning visit.

Secondary

Measure	Time frame	Description
Objective Response Rate (ORR) in the Overall Study Population	Tumour assessments carried out at baseline, 28 days before randomisation then every 8 weeks until week 40, after week 40 assessments will be carried out every 16 weeks until objective disease progression, assessed maximum up to 27 months	Objective response rate is the proportion of patients with at least one measurable lesion at baseline, who experienced complete or partial response at least once during the assessment period, according to the definitions of Response Evaluation Criteria In Solid Tumours (RECIST version 1.1).
Objective Response Rate (ORR) in the ATM Negative Patients	Tumour assessments carried out at baseline, 28 days before randomisation then every 8 weeks until week 40, after week 40 assessments will be carried out every 16 weeks until objective disease progression, assessed maximum up to 27 months	Objective response rate is the proportion of ATM negative patients with at least one measurable lesion at baseline, who experienced complete or partial response at least once during the assessment period, according to the definitions of Response Evaluation Criteria In Solid Tumours (RECIST version 1.1).
Percentage Change in Tumour Size at Week 8 in the Overall Study Population	Tumour scans done at Baseline and week 8	Percentage change in tumour size from baseline to Week 8 calculated as 100 X (week 8 tumour size - baseline tumour size) / (baseline tumour size)
Percentage Change in Tumour Size at Week 8 in the ATM Negative Patients	Tumour scans done at Baseline and week 8	Percentage change in tumour size from baseline to Week 8 calculated as 100 X (week 8 tumour size - baseline tumour size) / (baseline tumour size)
Time to Deterioration in Global Quality of Life (QoL) Score in the Overall Study Population	Questionnaire data collected at Baseline ie on or before date of randomisation, every 4 weeks post baseline, assessed maximum up to 27 months	Time calculated from randomisation till worsening of Global QoL score based on European Organisation for Research and Treatment of Cancer (EORTC) questionnaire data
Time to Deterioration in QoL Fatigue Score in the Overall Study Population	Questionnaire data collected at Baseline ie on or before date of randomisation, every 4 weeks post baseline, assessed maximum up to 27 months	Time calculated from randomisation till worsening of fatigue score based on European Organisation for Research and Treatment of Cancer (EORTC) questionnaire data
Overall Survival (OS) in the Overall Study Population	Survival follow up from randomisation till death of the patient or till end of study in absence of death, assessed maximum up to 27 months	Overall survival is defined as the duration from randomisation till death. In absence of death, the time is calculated from randomisation till the date subject last known to be alive.
Time to Deterioration in QoL Pain Domain Score in the Overall Study Population	Questionnaire data collected at Baseline ie on or before date of randomisation, every 4 weeks post baseline, assessed maximum up to 27 months	Time calculated from randomisation till worsening of pain domain score based on European Organisation for Research and Treatment of Cancer (EORTC) questionnaire data
Time to Deterioration in QoL Dysphagia Domain Score in the Overall Study Population	Questionnaire data collected at Baseline ie on or before date of randomisation, every 4 weeks post baseline, assessed maximum up to 27 months	Time calculated from randomisation till worsening of dysphagia domain score based on European Organisation for Research and Treatment of Cancer (EORTC) questionnaire data
Time to Deterioration in QoL Eating Restriction Domain Score in the Overall Study Population	Questionnaire data collected at Baseline ie on or before date of randomisation, every 4 weeks post baseline, assessed maximum up to 27 months	Time calculated from randomisation till worsening of eating restriction domain score based on European Organisation for Research and Treatment of Cancer (EORTC) questionnaire data
Time to Deterioration in QoL Stomach Pain Domain Score in the Overall Study Population	Questionnaire data collected at Baseline ie on or before date of randomisation, every 4 weeks post baseline, assessed maximum up to 27 months	Time calculated from randomisation till worsening of stomach pain domain score based on European Organisation for Research and Treatment of Cancer (EORTC) questionnaire data
Time to Deterioration in QoL Reflux Domain Score in the Overall Study Population	Questionnaire data collected at Baseline ie on or before date of randomisation, every 4 weeks post baseline, assessed maximum up to 27 months	Time calculated from randomisation till worsening of reflux domain score based on European Organisation for Research and Treatment of Cancer (EORTC) questionnaire data
Time to Deterioration in QoL Anxiety Domain Score in the Overall Study Population	Questionnaire data collected at Baseline ie on or before date of randomisation, every 4 weeks post baseline, assessed maximum up to 27 months	Time calculated from randomisation till worsening of anxiety domain score based on European Organisation for Research and Treatment of Cancer (EORTC) questionnaire data
Time to Deterioration in QoL Nausea & Vomiting Domain Score in the Overall Study Population	Questionnaire data collected at Baseline ie on or before date of randomisation, every 4 weeks post baseline, assessed maximum up to 27 months	Time calculated from randomisation till worsening of nausea & vomiting domain score based on European Organisation for Research and Treatment of Cancer (EORTC) questionnaire data
Overall Survival (OS) in ATM Negative Patients	Survival follow up from randomisation till death of the patient or till end of study in absence of death, assessed maximum up to 27 months	Overall survival is defined as the duration from randomisation till death. In absence of death, the time is calculated from randomisation till the date subject last known to be alive.

Countries

South Korea

Participant flow

Recruitment details

This study was conducted at 13 sites in South Korea. Enrolment started in February 2010 and was completed in May 2012. In total 124 patients were randomised in the study (62 in the olaparib+paclitaxel arm and 62 in the placebo+paclitaxel arm).

Pre-assignment details

Patients of either sex, age more than 17 years with recurrent or metastatic gastric cancer that had progressed following first line therapy, a confirmed Ataxia Telangiectasia Mutation (ATM) status, Eastern Co operative Oncology Group (ECOG) performance status ≤2, normal organ and bone marrow function, and life expectancy ≥16 weeks.

Participants by arm

Arm	Count
Olaparib+Paclitaxel Olaparib 100 mg twice daily in tablet formulation in combination with paclitaxel 80 mg/m2 intravenous on Days 1, 8, and 15 of a 4 week schedule. It was expected that patients would receive between 6 to 10 cycles of paclitaxel after which olaparib dose was increased to 200 mg bd as monotherapy.	62
Placebo+Paclitaxel Matching placebo 100 mg twice daily in tablet formulation in combination with paclitaxel 80 mg/m2 intravenous on Days 1, 8, and 15 of a 4 week schedule. It was expected that patients would receive between 6 to 10 cycles of paclitaxel after which placebo dose was increased to 200 mg bd as monotherapy.	62
Total	124

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Consent withdrawal	1	0
Overall Study	Death	33	48
Overall Study	Lost to Follow-up	4	3
Overall Study	Study reached data cut-off	19	7
Overall Study	Withdrawal by Subject	1	2

Baseline characteristics

Characteristic	Olaparib+Paclitaxel	Placebo+Paclitaxel	Total
Age, Continuous	59.0 years STANDARD_DEVIATION 11.61	59.4 years STANDARD_DEVIATION 11.98	59.2 years STANDARD_DEVIATION 11.75
Age, Customized >=50 to <65 years	22 Participants	30 Participants	52 Participants
Age, Customized < 50 years	13 Participants	10 Participants	23 Participants
Age, Customized >= 65 years	27 Participants	22 Participants	49 Participants
ATM status Negative	31 Participants	32 Participants	63 Participants
ATM status Positive	31 Participants	30 Participants	61 Participants
Race/Ethnicity, Customized Asian	62 Participants	62 Participants	124 Participants
Race/Ethnicity, Customized Other	0 Participants	0 Participants	0 Participants
Sex: Female, Male Female	13 Participants	18 Participants	31 Participants
Sex: Female, Male Male	49 Participants	44 Participants	93 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	— / —	— / —
other Total, other adverse events	61 / 61	62 / 62
serious Total, serious adverse events	17 / 61	23 / 62

Outcome results

Primary

Progression Free Survival (PFS) in Patients With Tumours Defined as Homologous Recombination Deficient by Loss of Ataxia-Telangiectasia Mutation (ATM) Protein [ATM Negative Patients]

PFS is defined as the time from randomisation till objective progression or death. In absence of progression or death, the time is calculated from randomisation till last evaluable scanning visit.

Time frame: Tumour assessments are carried out at baseline and then follow up assessments taken every 8 weeks up to Week 40 and then every 16 weeks until objective disease progression as defined by RECIST 1.1, assessed maximum up to 27 months

Population: Full analysis set including randomised ATM negative patients

Arm	Measure	Value (MEDIAN)
Olaparib+Paclitaxel	Progression Free Survival (PFS) in Patients With Tumours Defined as Homologous Recombination Deficient by Loss of Ataxia-Telangiectasia Mutation (ATM) Protein [ATM Negative Patients]	5.29 months
Placebo+Paclitaxel	Progression Free Survival (PFS) in Patients With Tumours Defined as Homologous Recombination Deficient by Loss of Ataxia-Telangiectasia Mutation (ATM) Protein [ATM Negative Patients]	3.68 months

Comparison: The analysis was performed using a Cox proportional hazards model with factors for treatment group and gastrectomy (full, partial, none).80% CI: [0.51, 1.08]

Primary

Progression Free Survival (PFS) in the Overall Study Population

PFS is defined as the time from randomisation till objective progression or death. In absence of progression or death, the time is calculated from randomisation till last evaluable scanning visit.

Time frame: Tumour assessments were carried out at baseline and then follow up assessments taken every 8 weeks up to Week 40 and then every 16 weeks until objective disease progression as defined by RECIST 1.1, assessed maximum up to 27 months

Population: Full analysis set including all randomised patients

Arm	Measure	Value (MEDIAN)
Olaparib+Paclitaxel	Progression Free Survival (PFS) in the Overall Study Population	3.91 months
Placebo+Paclitaxel	Progression Free Survival (PFS) in the Overall Study Population	3.55 months

Comparison: The analysis was performed using a Cox proportional hazards model with factors for treatment group, ATM status and gastrectomy (full, partial, none).80% CI: [0.62, 1.03]

Secondary

Objective Response Rate (ORR) in the ATM Negative Patients

Objective response rate is the proportion of ATM negative patients with at least one measurable lesion at baseline, who experienced complete or partial response at least once during the assessment period, according to the definitions of Response Evaluation Criteria In Solid Tumours (RECIST version 1.1).

Time frame: Tumour assessments carried out at baseline, 28 days before randomisation then every 8 weeks until week 40, after week 40 assessments will be carried out every 16 weeks until objective disease progression, assessed maximum up to 27 months

Population: Evaluable for response population ATM negative patients - randomised ATM negative patients having measurable disease at baseline.

Arm	Measure	Value (NUMBER)
Olaparib+Paclitaxel	Objective Response Rate (ORR) in the ATM Negative Patients	9 Participants
Placebo+Paclitaxel	Objective Response Rate (ORR) in the ATM Negative Patients	6 Participants

Secondary

Objective Response Rate (ORR) in the Overall Study Population

Objective response rate is the proportion of patients with at least one measurable lesion at baseline, who experienced complete or partial response at least once during the assessment period, according to the definitions of Response Evaluation Criteria In Solid Tumours (RECIST version 1.1).

Population: Evaluable for response population - randomised patients having measurable disease at baseline.

Arm	Measure	Value (NUMBER)
Olaparib+Paclitaxel	Objective Response Rate (ORR) in the Overall Study Population	14 Participants
Placebo+Paclitaxel	Objective Response Rate (ORR) in the Overall Study Population	9 Participants

Secondary

Overall Survival (OS) in ATM Negative Patients

Overall survival is defined as the duration from randomisation till death. In absence of death, the time is calculated from randomisation till the date subject last known to be alive.

Time frame: Survival follow up from randomisation till death of the patient or till end of study in absence of death, assessed maximum up to 27 months

Population: Full analysis set including randomised ATM negative patients

Arm	Measure	Value (MEDIAN)
Olaparib+Paclitaxel	Overall Survival (OS) in ATM Negative Patients	NA months
Placebo+Paclitaxel	Overall Survival (OS) in ATM Negative Patients	8.20 months

Comparison: The analysis was performed using a Cox proportional hazards model with factors for treatment group and gastrectomy (full, partial, none).80% CI: [0.22, 0.56]

Secondary

Overall Survival (OS) in the Overall Study Population

Overall survival is defined as the duration from randomisation till death. In absence of death, the time is calculated from randomisation till the date subject last known to be alive.

Time frame: Survival follow up from randomisation till death of the patient or till end of study in absence of death, assessed maximum up to 27 months

Population: Full analysis set including all randomised patients

Arm	Measure	Value (MEDIAN)
Olaparib+Paclitaxel	Overall Survival (OS) in the Overall Study Population	13.1 months
Placebo+Paclitaxel	Overall Survival (OS) in the Overall Study Population	8.3 months

Comparison: The analysis was performed using a Cox proportional hazards model with factors for treatment group, ATM status and gastrectomy (full, partial, none).80% CI: [0.41, 0.75]

Secondary

Percentage Change in Tumour Size at Week 8 in the ATM Negative Patients

Percentage change in tumour size from baseline to Week 8 calculated as 100 X (week 8 tumour size - baseline tumour size) / (baseline tumour size)

Time frame: Tumour scans done at Baseline and week 8

Population: Evaluable for response population ATM negative patients - randomised ATM negative patients having measurable disease at baseline.

Arm	Measure	Value (MEAN)	Dispersion
Olaparib+Paclitaxel	Percentage Change in Tumour Size at Week 8 in the ATM Negative Patients	-6.9 Percent change	Standard Deviation 29.31
Placebo+Paclitaxel	Percentage Change in Tumour Size at Week 8 in the ATM Negative Patients	-5.9 Percent change	Standard Deviation 26.36

Secondary

Percentage Change in Tumour Size at Week 8 in the Overall Study Population

Percentage change in tumour size from baseline to Week 8 calculated as 100 X (week 8 tumour size - baseline tumour size) / (baseline tumour size)

Time frame: Tumour scans done at Baseline and week 8

Population: Evaluable for response population - randomised patients having measurable disease at baseline.

Arm	Measure	Value (MEAN)	Dispersion
Olaparib+Paclitaxel	Percentage Change in Tumour Size at Week 8 in the Overall Study Population	-5.8 Percent change	Standard Deviation 29.09
Placebo+Paclitaxel	Percentage Change in Tumour Size at Week 8 in the Overall Study Population	2.2 Percent change	Standard Deviation 35.6

Secondary

Time to Deterioration in Global Quality of Life (QoL) Score in the Overall Study Population

Time calculated from randomisation till worsening of Global QoL score based on European Organisation for Research and Treatment of Cancer (EORTC) questionnaire data