ICEBERG 1: Study to Assess the Efficacy and Safety of a PARP Inhibitor for the Treatment of BRCA-positive Advanced Breast Cancer

• Sponsor: AstraZeneca (Industry)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT00494234
• Collaborator: KuDOS Pharmaceuticals Limited (Industry)
• Enrollment: 54
• Locations: 25
• Arms: 2
• Anticipated Duration (Months): 186.5
• Patients Per Site: 2.2
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

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

Condition or Disease	Intervention/Treatment	Phase
Breast Neoplasms	Drug: KU-0059436 (AZD2281) (PARP inhibitor); Drug: KU-0059436 (AZD2281) (PARP inhibitor)	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 54 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Open-label, Non-comparative, International, Multicentre Study to Assess the Efficacy and Safety of KU 0059436 (Olaparib) Given Orally Twice Daily in Patients With Advanced BRCA1 or BRCA2 Associated Breast Cancer
• Actual Study Start Date: Jun 15, 2007
• Actual Primary Completion Date: Feb 27, 2009
• Anticipated Study Completion Date: Dec 30, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: KU-0059436 (AZD2281) 100 mg BID	Drug: KU-0059436 (AZD2281) (PARP inhibitor); oral; Other Names: Olaparib
Experimental: KU-0059436 (AZD2281) 400 mg BID	Drug: KU-0059436 (AZD2281) (PARP inhibitor)

Outcome Measures

Primary Outcome Measures

1. Confirmed Objective Tumour Response (According to RECIST Criteria) [Baseline, every 8 also at study termination or initiation of confounding anti-cancer therapy. Up to 2 years.]

   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.

Secondary Outcome Measures

1. Duration of Response to Olaparib [Time from response (CR or PR) to progression per RECIST criteria]

2. The Clinical Benefit Rate (CBR) [End of study]

   The Clinical Benefit Rate (CBR) is defined as the percentage of patients with a RECIST tumour response of confirmed CR, PR or stable disease (SD) for ≥8 weeks +/- 1 week visit window.

3. Best Percent Change in Tumour Size [End of study]

   The tumour size is defined as the sum of the longest diameters as measured among all target lesions.

4. Progression-Free Survival (PFS) [End of study]

   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 patients who were withdrawn from the study without disease progression were regarded as censored at their last evaluable RECIST assessment. Where patients had not progressed at the termination of the study, they were also regarded as censored at their last evaluable RECIST assessment.

5. Change From Baseline in ECOG Performance Status: Improvement Rate [At cycle 7 day 1 (ie, after completing 6 cycles of treatment)]

   The change in ECOG performance status was defined as improved (meaning the ECOG score is less than the baseline value), no change (ECOG is same as at baseline), worsened (ECOG score is greater than the baseline value) or missing (the ECOG 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 130 Years
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Advanced breast cancer with positive BRCA1 or BRCA2 status

• Failed at least one prior chemotherapy

• In investigators opinion, no curative standard therapy exists

• Measurable disease

Exclusion Criteria:

• Brain metastases

• Less than 28 days since last treatment used to treat the disease

• Considered a poor medical risk due to a serious uncontrolled disorder

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Duarte	California	United States	91010
2	Research Site	San Francisco	California	United States	94115
3	Research Site	West Hollywood	California	United States	90048
4	Research Site	Boston	Massachusetts	United States	02115
5	Research Site	New York	New York	United States	10065
6	Research Site	Philadelphia	Pennsylvania	United States	19104-4322
7	Research Site	Dallas	Texas	United States	75390
8	Research Site	Melbourne, Parkville		Australia	VIC 3050
9	Research Site	Melbourne		Australia	3000
10	Research Site	Randwick		Australia	2031
11	Research Site	Duarte	CA	Canada	91010
12	Research Site	Heidelberg		Germany	69115
13	Research Site	Kiel		Germany	24105
14	Research Site	Köln		Germany	50937
15	Research Site	München		Germany	81675
16	Research Site	Haifa		Israel	31096
17	Research Site	Tel-Aviv		Israel	6423906
18	Research Site	Hospitalet deLlobregat		Spain	08907
19	Research Site	Madrid		Spain	08035
20	Research Site	Lund		Sweden	221 85
21	Research Site	Cambridge		United Kingdom	CB2 0QQ
22	Research Site	Edinburgh		United Kingdom	EH4 2XR
23	Research Site	Fulham		United Kingdom	SW3 6JJ
24	Research Site	London		United Kingdom	SE1 9RT
25	Research Site	Manchester		United Kingdom	M20 4BX

Sponsors and Collaborators

• AstraZeneca
• KuDOS Pharmaceuticals Limited

Investigators

• Study Director: James Carmichael, BSc, MBChB, MD, FRCP, KuDOS Pharmaceuticals Limited
• Principal Investigator: Andrew Tutt, PhD MRCP FRCR, Guy's and St Thomas's NHS Foundation Trust, London, UK

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• CSR_Synopsis_D0810C00008(KU36-44).pdf

Publications

None provided.

• Responsible Party: AstraZeneca
• ClinicalTrials.gov Identifier: NCT00494234
• Other Study ID Numbers: KU36-44; D0810C00008
• First Posted: Jun 29, 2007
• Last Update Posted: Jun 30, 2022
• Last Verified: Jun 1, 2022

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by AstraZeneca: Advanced breast cancer; Poly(ADP ribose) polymerases; AZD2281,KU-0059436 (olaparib); BRCA1 protein; BRCA2 protein
• Additional relevant MeSH terms: Breast Neoplasms; Olaparib; Poly(ADP-ribose) Polymerase Inhibitors

Study Results

Participant Flow

Recruitment Details	The first patient was enrolled on June 15, 2007 and efficacy and safety data were collected up to the data cut-off of February 27, 2009. Patients were enrolled at 16 centres in 6 countries: Australia, Germany, Spain, Sweden, UK and the USA.
Pre-assignment Detail	Two cohorts of up to 27 women with BRCA1- or BRCA2-associated breast cancer who had failed at least one prior chemotherapy and/or endocrine therapy in the advanced/metastatic setting, were assigned to receive olaparib 100 mg bd or 400 mg bd. Enrolment into the 2 cohorts was sequential with the 400 mg bd cohort being recruited first.

Arm/Group Title	Olaparib 100 mg bd	Olaparib 400 mg bd
Arm/Group Description	Full Analysis Set	Full Analysis Set
Period Title: Overall Study
STARTED	27	27
COMPLETED	12	17
NOT COMPLETED	15	10

Baseline Characteristics

Arm/Group Title	AZD2281 100 mg	AZD2281 400 mg	Total
Arm/Group Description	Total of all reporting groups
Overall Participants	27	27	54
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	44.7 (11.99)	44.7 (9.55)	44.7 (10.74)
Age, Customized (Number) [Number]
<35 years	7 25.9%	3 11.1%	10 18.5%
>=35 - <50 years	11 40.7%	18 66.7%	29 53.7%
>=50 - <65 years	6 22.2%	5 18.5%	11 20.4%
>=65 years	3 11.1%	1 3.7%	4 7.4%
Sex: Female, Male (Count of Participants)
Female	27 100%	27 100%	54 100%
Male	0 0%	0 0%	0 0%
Race/Ethnicity, Customized (Number) [Number]
Asian	1 3.7%	1 3.7%	2 3.7%
Black or african american	1 3.7%	0 0%	1 1.9%
White	25 92.6%	26 96.3%	51 94.4%

Outcome Measures

1. Primary Outcome

Title	Confirmed Objective Tumour Response (According to RECIST Criteria)
Description	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.
Time Frame	Baseline, every 8 also at study termination or initiation of confounding anti-cancer therapy. Up to 2 years.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Olaparib 100 mg bd	Olaparib 400 mg bd
Arm/Group Description	Per Protocol Set	Per Protocol Set
Measure Participants	24	26
Number [Participants]	6 22.2%	11 40.7%

2. Secondary Outcome

Title	Duration of Response to Olaparib
Time Frame	Time from response (CR or PR) to progression per RECIST criteria

Outcome Measure Data

Analysis Population Description

Per protocol

Arm/Group Title	Olaparib 100 mg bd	Olaparib 400 mg bd
Arm/Group Description	Number of responders	Number of responders
Measure Participants	6	11
Median (Full Range) [Days]	140.5	144.0

3. Secondary Outcome

Title	The Clinical Benefit Rate (CBR)
Description	The Clinical Benefit Rate (CBR) is defined as the percentage of patients with a RECIST tumour response of confirmed CR, PR or stable disease (SD) for ≥8 weeks +/- 1 week visit window.
Time Frame	End of study

Outcome Measure Data

Analysis Population Description

Per protocol

Arm/Group Title	Olaparib 100 mg bd	Olaparib 400 mg bd
Arm/Group Description	Per Protocol Set	Per Protocol Set
Measure Participants	24	26
Number (95% Confidence Interval) [Percentage of Participants]	62.5 231.5%	84.6 313.3%

4. Secondary Outcome

Title	Best Percent Change in Tumour Size
Description	The tumour size is defined as the sum of the longest diameters as measured among all target lesions.
Time Frame	End of study

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Olaparib 100 mg bd	Olaparib 400 mg bd
Arm/Group Description	Per Protocol Set	Per Protocol Set
Measure Participants	24	26
Mean (95% Confidence Interval) [Percent change in tumour size]	1.15	-36.06

5. Secondary Outcome

Title	Progression-Free Survival (PFS)
Description	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 patients who were withdrawn from the study without disease progression were regarded as censored at their last evaluable RECIST assessment. Where patients had not progressed at the termination of the study, they were also regarded as censored at their last evaluable RECIST assessment.
Time Frame	End of study

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Olaparib 100 mg bd	Olaparib 400 mg bd
Arm/Group Description	Per Protocol Set	Per Protocol Set
Measure Participants	24	26
Median (95% Confidence Interval) [Days]	122	193

6. Secondary Outcome

Title	Change From Baseline in ECOG Performance Status: Improvement Rate
Description	The change in ECOG performance status was defined as improved (meaning the ECOG score is less than the baseline value), no change (ECOG is same as at baseline), worsened (ECOG score is greater than the baseline value) or missing (the ECOG 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.
Time Frame	At cycle 7 day 1 (ie, after completing 6 cycles of treatment)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Olaparib 100 mg bd	Olaparib 400 mg bd
Arm/Group Description	Patients who compled 6 cycles of treatment	Patients who compled 6 cycles of treatment
Measure Participants	11	15
Number [Participants with an improvement in ECOG]	1 3.7%	6 22.2%

Adverse Events

Arm/Group Title	AZD2281 100 mg		AZD2281 400 mg
Arm/Group Description
All Cause Mortality
	AZD2281 100 mg		AZD2281 400 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	AZD2281 100 mg		AZD2281 400 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/27 (18.5%)		9/27 (33.3%)
Blood and lymphatic system disorders
ANAEMIA	1/27 (3.7%)	1	1/27 (3.7%)	1
Cardiac disorders
ANGINA PECTORIS	0/27 (0%)	0	1/27 (3.7%)	1
Gastrointestinal disorders
NAUSEA	0/27 (0%)	0	3/27 (11.1%)	3
VOMITING	0/27 (0%)	0	2/27 (7.4%)	2
Injury, poisoning and procedural complications
ALLERGIC TRANSFUSION REACTION	0/27 (0%)	0	1/27 (3.7%)	1
Investigations
HAEMOGLOBIN DECREASED	0/27 (0%)	0	1/27 (3.7%)	1
Musculoskeletal and connective tissue disorders
MUSCULOSKELETAL CHEST PAIN	1/27 (3.7%)	1	0/27 (0%)	0
Nervous system disorders
CEREBRAL HAEMORRHAGE	1/27 (3.7%)	1	0/27 (0%)	0
CONVULSION	1/27 (3.7%)	1	0/27 (0%)	0
Renal and urinary disorders
RENAL FAILURE ACUTE	1/27 (3.7%)	1	0/27 (0%)	0
Respiratory, thoracic and mediastinal disorders
DYSPNOEA	2/27 (7.4%)	2	0/27 (0%)	0
PLEURAL EFFUSION	1/27 (3.7%)	1	0/27 (0%)	0
PNEUMOTHORAX	0/27 (0%)	0	1/27 (3.7%)	1
RESPIRATORY DISORDER	1/27 (3.7%)	1	0/27 (0%)	0
Skin and subcutaneous tissue disorders
PURPURA	0/27 (0%)	0	1/27 (3.7%)	1
Other (Not Including Serious) Adverse Events
	AZD2281 100 mg		AZD2281 400 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	27/27 (100%)		26/27 (96.3%)
Blood and lymphatic system disorders
ANAEMIA	3/27 (11.1%)	3	5/27 (18.5%)	5
NEUTROPENIA	0/27 (0%)	0	2/27 (7.4%)	2
Gastrointestinal disorders
ABDOMINAL PAIN	2/27 (7.4%)	2	5/27 (18.5%)	5
ABDOMINAL PAIN LOWER	2/27 (7.4%)	2	0/27 (0%)	0
ABDOMINAL PAIN UPPER	0/27 (0%)	0	2/27 (7.4%)	3
CONSTIPATION	8/27 (29.6%)	8	6/27 (22.2%)	6
DIARRHOEA	4/27 (14.8%)	5	8/27 (29.6%)	10
DYSPEPSIA	2/27 (7.4%)	2	5/27 (18.5%)	5
FLATULENCE	0/27 (0%)	0	2/27 (7.4%)	3
GASTROOESOPHAGEAL REFLUX DISEASE	1/27 (3.7%)	1	2/27 (7.4%)	2
NAUSEA	15/27 (55.6%)	19	14/27 (51.9%)	17
STOMATITIS	3/27 (11.1%)	3	1/27 (3.7%)	1
TOOTHACHE	2/27 (7.4%)	2	1/27 (3.7%)	1
VOMITING	6/27 (22.2%)	8	10/27 (37%)	16
General disorders
ASTHENIA	0/27 (0%)	0	2/27 (7.4%)	2
CHEST PAIN	1/27 (3.7%)	1	2/27 (7.4%)	2
FATIGUE	17/27 (63%)	19	19/27 (70.4%)	25
INFLUENZA LIKE ILLNESS	0/27 (0%)	0	2/27 (7.4%)	2
OEDEMA PERIPHERAL	4/27 (14.8%)	4	6/27 (22.2%)	6
PYREXIA	2/27 (7.4%)	2	3/27 (11.1%)	3
Infections and infestations
BRONCHITIS	0/27 (0%)	0	2/27 (7.4%)	2
NASOPHARYNGITIS	0/27 (0%)	0	2/27 (7.4%)	4
ORAL CANDIDIASIS	2/27 (7.4%)	2	1/27 (3.7%)	1
SINUSITIS	2/27 (7.4%)	2	0/27 (0%)	0
UPPER RESPIRATORY TRACT INFECTION	4/27 (14.8%)	5	2/27 (7.4%)	3
URINARY TRACT INFECTION	2/27 (7.4%)	2	3/27 (11.1%)	3
Investigations
ALANINE AMINOTRANSFERASE INCREASED	2/27 (7.4%)	2	0/27 (0%)	0
ASPARTATE AMINOTRANSFERASE INCREASED	3/27 (11.1%)	3	0/27 (0%)	0
WEIGHT INCREASED	0/27 (0%)	0	3/27 (11.1%)	3
Metabolism and nutrition disorders
ANOREXIA	5/27 (18.5%)	5	3/27 (11.1%)	3
HYPOKALAEMIA	0/27 (0%)	0	2/27 (7.4%)	2
Musculoskeletal and connective tissue disorders
ARTHRALGIA	6/27 (22.2%)	7	4/27 (14.8%)	4
BACK PAIN	6/27 (22.2%)	6	1/27 (3.7%)	1
BONE PAIN	1/27 (3.7%)	2	2/27 (7.4%)	2
MUSCULAR WEAKNESS	2/27 (7.4%)	2	0/27 (0%)	0
MUSCULOSKELETAL CHEST PAIN	2/27 (7.4%)	2	2/27 (7.4%)	3
PAIN IN EXTREMITY	7/27 (25.9%)	7	2/27 (7.4%)	2
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
CANCER PAIN	4/27 (14.8%)	4	1/27 (3.7%)	1
Nervous system disorders
HEADACHE	6/27 (22.2%)	9	10/27 (37%)	23
HYPOAESTHESIA	0/27 (0%)	0	2/27 (7.4%)	2
LETHARGY	0/27 (0%)	0	2/27 (7.4%)	2
MIGRAINE	1/27 (3.7%)	1	3/27 (11.1%)	5
PERIPHERAL SENSORY NEUROPATHY	3/27 (11.1%)	3	0/27 (0%)	0
Psychiatric disorders
DEPRESSION	3/27 (11.1%)	3	1/27 (3.7%)	1
INSOMNIA	7/27 (25.9%)	7	2/27 (7.4%)	2
Renal and urinary disorders
URINARY TRACT PAIN	2/27 (7.4%)	2	1/27 (3.7%)	1
Reproductive system and breast disorders
PELVIC PAIN	2/27 (7.4%)	2	0/27 (0%)	0
Respiratory, thoracic and mediastinal disorders
COUGH	8/27 (29.6%)	8	4/27 (14.8%)	5
DYSPNOEA	9/27 (33.3%)	9	1/27 (3.7%)	1
DYSPNOEA EXERTIONAL	0/27 (0%)	0	2/27 (7.4%)	2
PLEURAL EFFUSION	2/27 (7.4%)	2	0/27 (0%)	0
Skin and subcutaneous tissue disorders
RASH	1/27 (3.7%)	1	2/27 (7.4%)	2
SKIN LESION	0/27 (0%)	0	2/27 (7.4%)	2

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.