ICEBERG 2: Study to Assess the Efficacy and Safety of a PARP Inhibitor for the Treatment of BRCA-positive Advanced Ovarian Cancer

• Sponsor: AstraZeneca (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00494442
• Collaborator: KuDOS Pharmaceuticals Limited (Industry)
• Enrollment: 58
• Locations: 11
• Arms: 2
• Actual Duration (Months): 121.3
• Patients Per Site: 5.3
• 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 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.

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 58 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 Given Orally Twice Daily in Patients With Advanced BRCA1 or BRCA2 Associated Ovarian Cancer
• Actual Study Start Date: Jun 11, 2007
• Actual Primary Completion Date: Mar 17, 2009
• Actual Study Completion Date: Jul 20, 2017

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); oral

Outcome Measures

Primary Outcome Measures

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

   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. Clinical Benefit (CB) [End of study]

   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)

2. Duration of Response [End of study]

   Duration of response to olaparib

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

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

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

   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.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Advanced ovarian 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	Los Angeles	California	United States	90048
2	Research Site	San Francisco	California	United States	94115
3	Research Site	Boston	Massachusetts	United States	02115
4	Research Site	New York	New York	United States	10065
5	Research Site	Houston	Texas	United States	77030
6	Research Site	Melbourne, Parkville		Australia	VIC 3050
7	Research Site	Melbourne		Australia	3000
8	Research Site	Randwick		Australia	2031
9	Research Site	Köln		Germany	50931
10	Research Site	Hospitalet deLlobregat		Spain	08907
11	Research Site	Lund		Sweden	S-221 85

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_D0810C00009(KU36-58).pdf

Publications

None provided.

• Responsible Party: AstraZeneca
• ClinicalTrials.gov Identifier: NCT00494442
• Other Study ID Numbers: KU36-58; D0810C00009
• First Posted: Jun 29, 2007
• Last Update Posted: Aug 1, 2018
• Last Verified: Jun 1, 2018

• Keywords provided by AstraZeneca: Advanced ovarian cancer; Poly(ADP ribose) polymerases; KU-0059436; AZD2281; BRCA1 protein; BRCA2 protein
• Additional relevant MeSH terms: Ovarian Neoplasms; Carcinoma, Ovarian Epithelial; Olaparib; Poly(ADP-ribose) Polymerase Inhibitors

Study Results

Participant Flow

Recruitment Details	The first patient was enrolled on June 11, 2007 and efficacy and safety data were collected up to the data cut-off of March 17, 2009. Patients were enrolled at 12 centres in 5 countries: Australia, Germany, Spain, Sweden and the USA.
Pre-assignment Detail	Two cohorts of women with Breast Cancer gene 1 (BRCA1)- or BRCA2-associated ovarian cancer who had failed at least one prior chemotherapy in the advanced/metastatic setting, were planned to receive olaparib 100 mg bd (n= up to 24) or 400 mg bd (n= up to 40). Enrolment to 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	olaparib (KU-0059436; AZD2281) 100 mg oral capsules, twice daily	olaparib (KU-0059436; AZD2281) 400 mg oral capsules, twice daily
Period Title: Overall Study
STARTED	24	33
COMPLETED	7	17
NOT COMPLETED	17	16

Baseline Characteristics

Arm/Group Title	Olaparib 100 mg bd	Olaparib 400 mg bd	Total
Arm/Group Description	olaparib (KU-0059436; AZD2281) 100 mg oral capsules, twice daily	olaparib (KU-0059436; AZD2281) 400 mg oral capsules, twice daily	Total of all reporting groups
Overall Participants	24	33	57
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	55.6 (8.02)	56.8 (10.49)	56 (9)
Sex: Female, Male (Count of Participants)
Female	24 100%	33 100%	57 100%
Male	0 0%	0 0%	0 0%
BRCA mutation (Count of Participants)
BRCA1	19 79.2%	21 63.6%	40 70.2%
BRCA2	5 20.8%	12 36.4%	17 29.8%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

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)

Arm/Group Title	Olaparib 100 mg bd	Olaparib 400 mg bd
Arm/Group Description	olaparib (KU-0059436; AZD2281) 100 mg oral capsules, twice daily	olaparib (KU-0059436; AZD2281) 400 mg oral capsules, twice daily
Measure Participants	24	33
PP Analysis Set	3 12.5%	11 33.3%
ITT Analysis Set	3 12.5%	11 33.3%

2. Secondary Outcome

Title	Clinical Benefit (CB)
Description	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)
Time Frame	End of study

Outcome Measure Data

Analysis Population Description

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)

Arm/Group Title	Olaparib 100 mg bd	Olaparib 400 mg bd
Arm/Group Description	olaparib (KU-0059436; AZD2281) 100 mg oral capsules, twice daily	olaparib (KU-0059436; AZD2281) 400 mg oral capsules, twice daily
Measure Participants	24	33
Number (95% Confidence Interval) [Percentage of participants]	45.5 189.6%	71.0 215.2%

3. Secondary Outcome

Title	Duration of Response
Description	Duration of response to olaparib
Time Frame	End of study

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Olaparib 100 mg bd	Olaparib 400 mg bd
Arm/Group Description	olaparib (KU-0059436; AZD2281) 100 mg oral capsules, twice daily	olaparib (KU-0059436; AZD2281) 400 mg oral capsules, twice daily
Measure Participants	24	33
Median (Full Range) [Days]	242	301

4. Secondary Outcome

Title	Best Percentage Change in Tumour Size
Description	The best % change (reduction) from baseline in tumour size (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

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

Arm/Group Title	Olaparib 100 mg bd	Olaparib 400 mg bd
Arm/Group Description	olaparib (KU-0059436; AZD2281) 100 mg oral capsules, twice daily	olaparib (KU-0059436; AZD2281) 400 mg oral capsules, twice daily
Measure Participants	24	33
Median (Full Range) [Percent change]	-5.1	-25.8

5. Secondary Outcome

Title	Progression-Free Survival (PFS)
Description	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.
Time Frame	End of study

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Olaparib 100 mg bd	Olaparib 400 mg bd
Arm/Group Description	olaparib (KU-0059436; AZD2281) 100 mg oral capsules, twice daily	olaparib (KU-0059436; AZD2281) 400 mg oral capsules, twice daily
Measure Participants	24	33
Median (95% Confidence Interval) [Days]	62.5	226

Adverse Events

Time Frame	From baseline, every visit until 30 days after last dose.
Arm/Group Title	Olaparib 100 mg bd		Olaparib 400 mg bd
Arm/Group Description	olaparib (KU-0059436; AZD2281) 100 mg oral capsules, twice daily		olaparib (KU-0059436; AZD2281) 400 mg oral capsules, twice daily
All Cause Mortality
	Olaparib 100 mg bd		Olaparib 400 mg bd
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	10/24 (41.7%)		11/33 (33.3%)
Serious Adverse Events
	Olaparib 100 mg bd		Olaparib 400 mg bd
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/24 (29.2%)		12/33 (36.4%)
Blood and lymphatic system disorders
Neutropenia	1/24 (4.2%)		1/33 (3%)
Anaemia	0/24 (0%)		1/33 (3%)
Cardiac disorders
Cardiac Failure Congestive	1/24 (4.2%)		0/33 (0%)
Gastrointestinal disorders
Intestinal Obstruction	0/24 (0%)		2/33 (6.1%)
Nausea	1/24 (4.2%)		2/33 (6.1%)
Vomiting	1/24 (4.2%)		2/33 (6.1%)
Abdominal Pain	1/24 (4.2%)		0/33 (0%)
Large Intestinal Obstruction	1/24 (4.2%)		1/33 (3%)
Gastrointestinal Obstruction	0/24 (0%)		1/33 (3%)
Ileus	0/24 (0%)		1/33 (3%)
Intestinal Perforation	0/24 (0%)		1/33 (3%)
Small Intestinal Obstruction	0/24 (0%)		1/33 (3%)
General disorders
Oedema Peripheral	0/24 (0%)		1/33 (3%)
Hepatobiliary disorders
Bile Duct Stone	0/24 (0%)		1/33 (3%)
Infections and infestations
Pneumonia	0/24 (0%)		1/33 (3%)
Injury, poisoning and procedural complications
Humerus Fracture	0/24 (0%)		1/33 (3%)
Blood Pressure Increased	1/24 (4.2%)		0/33 (0%)
Metabolism and nutrition disorders
Hyponatraemia	1/24 (4.2%)		0/33 (0%)
Dehydration	0/24 (0%)		1/33 (3%)
Hypokalaemia	0/24 (0%)		1/33 (3%)
Nervous system disorders
Encephalopathy	1/24 (4.2%)		0/33 (0%)
Convulsion	0/24 (0%)		1/33 (3%)
Psychiatric disorders
Mental Status Changes	1/24 (4.2%)		0/33 (0%)
Renal and urinary disorders
Renal Failure	1/24 (4.2%)		0/33 (0%)
Renal Failure Acute	0/24 (0%)		1/33 (3%)
Respiratory, thoracic and mediastinal disorders
Pulmonary Embolism	1/24 (4.2%)		0/33 (0%)
Respiratory Failure	1/24 (4.2%)		0/33 (0%)
Vascular disorders
Deep Vein Thrombosis	0/24 (0%)		1/33 (3%)
Other (Not Including Serious) Adverse Events
	Olaparib 100 mg bd		Olaparib 400 mg bd
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	23/24 (95.8%)		33/33 (100%)
Blood and lymphatic system disorders
Anaemia	3/24 (12.5%)		7/33 (21.2%)
Lymphopenia	2/24 (8.3%)		0/33 (0%)
Thrombocytopenia	3/24 (12.5%)		1/33 (3%)
Neutropenia	2/24 (8.3%)		3/33 (9.1%)
Gastrointestinal disorders
Nausea	15/24 (62.5%)		21/33 (63.6%)
Diarrhoea	7/24 (29.2%)		12/33 (36.4%)
Abdominal Pain	4/24 (16.7%)		9/33 (27.3%)
Vomiting	6/24 (25%)		11/33 (33.3%)
Constipation	6/24 (25%)		4/33 (12.1%)
Abdominal Distension	4/24 (16.7%)		6/33 (18.2%)
Dyspepsia	4/24 (16.7%)		4/33 (12.1%)
Abdominal Pain Upper	3/24 (12.5%)		3/33 (9.1%)
Abdominal Discomfort	1/24 (4.2%)		3/33 (9.1%)
Abdominal Pain Lower	0/24 (0%)		3/33 (9.1%)
Gastrooesophageal Reflux Disease	1/24 (4.2%)		3/33 (9.1%)
Gastrointestinal Pain	2/24 (8.3%)		0/33 (0%)
Ascites	0/24 (0%)		2/33 (6.1%)
Gastritis	0/24 (0%)		2/33 (6.1%)
Rectal Haemorrhage	0/24 (0%)		2/33 (6.1%)
Salivary Hypersecretion	0/24 (0%)		2/33 (6.1%)
Stomatitis	1/24 (4.2%)		2/33 (6.1%)
Intestinal obstruction	0/24 (0%)		2/33 (6.1%)
General disorders
Fatigue	13/24 (54.2%)		17/33 (51.5%)
Oedema Peripheral	1/24 (4.2%)		6/33 (18.2%)
Pyrexia	2/24 (8.3%)		2/33 (6.1%)
Asthenia	0/24 (0%)		2/33 (6.1%)
Infections and infestations
Urinary Tract Infection	5/24 (20.8%)		2/33 (6.1%)
Upper Respiratory Tract Infection	2/24 (8.3%)		3/33 (9.1%)
Oral Herpes	2/24 (8.3%)		0/33 (0%)
Cellulitis	0/24 (0%)		2/33 (6.1%)
Herpes Zoster	0/24 (0%)		2/33 (6.1%)
Nasopharyngitis	0/24 (0%)		2/33 (6.1%)
Sinusitis	0/24 (0%)		2/33 (6.1%)
Injury, poisoning and procedural complications
Contusion	1/24 (4.2%)		4/33 (12.1%)
Investigations
Waist Circumference Increased	4/24 (16.7%)		0/33 (0%)
Haemoglobin Urine	3/24 (12.5%)		0/33 (0%)
Blood Urine Present	2/24 (8.3%)		0/33 (0%)
Gamma-Glutamyltransferase Increased	0/24 (0%)		2/33 (6.1%)
Metabolism and nutrition disorders
Hypokalaemia	2/24 (8.3%)		4/33 (12.1%)
Hypomagnesaemia	1/24 (4.2%)		4/33 (12.1%)
Anorexia	1/24 (4.2%)		3/33 (9.1%)
Hyperkalaemia	2/24 (8.3%)		0/33 (0%)
Decreased Appetite	1/24 (4.2%)		2/33 (6.1%)
Musculoskeletal and connective tissue disorders
Arthralgia	4/24 (16.7%)		2/33 (6.1%)
Back Pain	4/24 (16.7%)		2/33 (6.1%)
Muscle Spasms	0/24 (0%)		4/33 (12.1%)
Pain In Extremity	0/24 (0%)		3/33 (9.1%)
Flank Pain	0/24 (0%)		2/33 (6.1%)
Joint Swelling	0/24 (0%)		2/33 (6.1%)
Myalgia	1/24 (4.2%)		2/33 (6.1%)
Nervous system disorders
Headache	4/24 (16.7%)		7/33 (21.2%)
Neuropathy Peripheral	4/24 (16.7%)		1/33 (3%)
Dizziness	2/24 (8.3%)		3/33 (9.1%)
Dysgeusia	2/24 (8.3%)		1/33 (3%)
Sinus Headache	1/24 (4.2%)		2/33 (6.1%)
Psychiatric disorders
Insomnia	1/24 (4.2%)		4/33 (12.1%)
Depression	2/24 (8.3%)		3/33 (9.1%)
Anxiety	1/24 (4.2%)		2/33 (6.1%)
Renal and urinary disorders
Pollakiuria	2/24 (8.3%)		0/33 (0%)
Reproductive system and breast disorders
Pelvic Pain	2/24 (8.3%)		2/33 (6.1%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	4/24 (16.7%)		0/33 (0%)
Cough	3/24 (12.5%)		1/33 (3%)
Dyspnoea Exertional	0/24 (0%)		2/33 (6.1%)
Oropharyngeal Pain	1/24 (4.2%)		2/33 (6.1%)
Skin and subcutaneous tissue disorders
Rash	5/24 (20.8%)		5/33 (15.2%)
Dry Skin	2/24 (8.3%)		1/33 (3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The sponsor can review and comment prior to publication. In order to ensure that the Sponsor will be able to make comments and suggestions where pertinent, material for public dissemination will be submittted to the Sponsor for review at least sixty (60) days prior to submission for publication, public dissemination, or review by a publication committee