NCT00494234: ICEBERG 1

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

Completed Phase 2 Results posted Last updated 19 January 2024

What this trial tests

Phase 2 trial testing Olaparib in Breast Neoplasms in 54 participants. Completed in 21 December 2022.

Timeline

15 June 2007

Primary endpoint
27 February 2009

21 December 2022

Quick facts

Lead sponsor	AstraZeneca
Phase	Phase 2
Status	Completed
Study type	INTERVENTIONAL
Allocation	non randomized
Design	parallel
Masking	none
Primary purpose	treatment
Enrollment	54
Start date	15 June 2007
Primary completion	27 February 2009
Estimated completion	21 December 2022
Sites	17 locations across Sweden, United Kingdom, Israel, Germany, Canada, Australia, United States, Spain

Drugs / interventions tested

• Olaparib (olaparib) — full drug profile →

Conditions studied

• Breast Neoplasms — all drugs for Breast Neoplasms →

Sponsor

AstraZeneca — full company profile →

Who can join

Adults 18 to 130, female only, with Breast Neoplasms. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Confirmed Objective Response Rate (ORR) According to Response Evaluation Criteria in Solid Tumors (RECIST) Criteria Primary · Baseline (Days -28 to 0), Day 1 of Cycle 3, thereafter every alternate cycles until study termination or withdrawal (approximately up to 2 years)

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.

Group	Value	95% CI
Olaparib 100 mg	25.0
Olaparib 400 mg	42.3

Duration of Response (DoR) to Olaparib Secondary · Baseline (Days -28 to 0), Day 1 of Cycle 3, thereafter every alternate cycles until study termination or withdrawal (approximately up to 2 years)

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.

Group	Value	95% CI
Olaparib 100 mg	140.5	55 – 175
Olaparib 400 mg	144.0	92 – 393

Clinical Benefit Rate (CBR) Secondary · From Day 1 of Cycle 3 through study withdrawal (approximately up to 2 years)

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.

Group	Value	95% CI
Olaparib 100 mg	70.8	50.8 – 85.1
Olaparib 400 mg	84.6	66.5 – 93.9

Best Percentage Change in Tumor Size Secondary · Baseline (Days -28 to 0) through study withdrawal (approximately up to 2 years)

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).

Group	Value	95% CI
Olaparib 100 mg	-10.14	-68.9 – 286.7
Olaparib 400 mg	-29.43	-100.0 – 26.7

Progression-free Survival (PFS) Secondary · Baseline (Days -28 to 0), Day 1 of Cycle 3, thereafter every alternate cycles until study termination or withdrawal (approximately up to 2 years)

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.

Group	Value	95% CI
Olaparib 100 mg	122	67 – 167
Olaparib 400 mg	193.5	140 – 226

Number of Participants With Improvement in Eastern Co-operative Oncology Group (ECOG) Performance Status Total Score From Baseline Secondary · Screening (Days -7 to 0), Day 1 Cycle 7 (ie, after completing 6 cycles of treatment) and study withdrawal (approximately up to 2 years).

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

Cycle 7 Day 1

Group	Value	95% CI
Olaparib 100 mg	1
Olaparib 400 mg	6

Withdrawal visit

Group	Value	95% CI
Olaparib 100 mg	0
Olaparib 400 mg	2

Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) Secondary · Day 1 through Day 480 (maximum observed duration)

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

Any TEAE

Group	Value	95% CI
Olaparib 100 mg	27
Olaparib 400 mg	27

Any TESAE

Group	Value	95% CI
Olaparib 100 mg	5
Olaparib 400 mg	9

Number of Participants With Clinically Significant Changes in Vital Signs From Baseline Secondary · Day 1 through Day 480 (maximum observed duration)

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

Tachycardia

Group	Value	95% CI
Olaparib 100 mg	1
Olaparib 400 mg	0

Supraventricular arrhythmia

Group	Value	95% CI
Olaparib 100 mg	1
Olaparib 400 mg	0

Number of Participants With at Least 2-Grade Change From Baseline to Worst Toxicity Grade in Clinical Laboratory Parameters Secondary · Day 1 through Day 480 (maximum observed duration)

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.

Hemoglobin

Group	Value	95% CI
Olaparib 100 mg	2
Olaparib 400 mg	3

White blood cells

Group	Value	95% CI
Olaparib 100 mg	5
Olaparib 400 mg	11

Absolute neutrophil count

Group	Value	95% CI
Olaparib 100 mg	3
Olaparib 400 mg	6

Lymphocytes

Group	Value	95% CI
Olaparib 100 mg	3
Olaparib 400 mg	2

Platelets

Group	Value	95% CI
Olaparib 100 mg	0
Olaparib 400 mg	2

Activated partial thromboplastin time

Group	Value	95% CI
Olaparib 100 mg	1
Olaparib 400 mg	2

Alanine aminotransferase

Group	Value	95% CI
Olaparib 100 mg	2
Olaparib 400 mg	3

Aspartate aminotransferase

Group	Value	95% CI
Olaparib 100 mg	3
Olaparib 400 mg	1

Adverse events — posted to ClinicalTrials.gov

Time frame: Day 1 to 480 (maximum observed duration). Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Olaparib 100 mg

Serious: 5/27 (19%)

Deaths: 3/27

Olaparib 400 mg

Serious: 9/27 (33%)

Deaths: 6/27

Serious adverse events (15 terms)

Reaction	System	Olaparib 100 mg	Olaparib 400 mg
Nausea	Gastrointestinal disorders	—	—
Vomiting	Gastrointestinal disorders	—	—
Dyspnoea	Respiratory, thoracic and mediastinal disorders	—	—
Anaemia	Blood and lymphatic system disorders	—	—
Angina pectoris	Cardiac disorders	—	—
Allergic transfusion reaction	Injury, poisoning and procedural complications	—	—
Haemoglobin decreased	Investigations	—	—
Musculoskeletal chest pain	Musculoskeletal and connective tissue disorders	—	—
Cerebral haemorrhage	Nervous system disorders	—	—
Convulsion	Nervous system disorders	—	—
Renal failure acute	Renal and urinary disorders	—	—
Pleural effusion	Respiratory, thoracic and mediastinal disorders	—	—
Pneumothorax	Respiratory, thoracic and mediastinal disorders	—	—
Respiratory disorder	Respiratory, thoracic and mediastinal disorders	—	—
Purpura	Skin and subcutaneous tissue disorders	—	—

Other adverse events (53 terms — click to expand)

Reaction	System	Olaparib 100 mg	Olaparib 400 mg
Fatigue	General disorders	—	—
Nausea	Gastrointestinal disorders	—	—
Vomiting	Gastrointestinal disorders	—	—
Headache	Nervous system disorders	—	—
Dyspnoea	Respiratory, thoracic and mediastinal disorders	—	—
Constipation	Gastrointestinal disorders	—	—
Diarrhoea	Gastrointestinal disorders	—	—
Cough	Respiratory, thoracic and mediastinal disorders	—	—
Pain in extremity	Musculoskeletal and connective tissue disorders	—	—
Insomnia	Psychiatric disorders	—	—
Oedema peripheral	General disorders	—	—
Arthralgia	Musculoskeletal and connective tissue disorders	—	—
Back pain	Musculoskeletal and connective tissue disorders	—	—
Anaemia	Blood and lymphatic system disorders	—	—
Abdominal pain	Gastrointestinal disorders	—	—
Dyspepsia	Gastrointestinal disorders	—	—
Anorexia	Metabolism and nutrition disorders	—	—
Upper respiratory tract infection	Infections and infestations	—	—
Cancer pain	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—
Stomatitis	Gastrointestinal disorders	—	—
Pyrexia	General disorders	—	—
Urinary tract infection	Infections and infestations	—	—
Aspartate aminotransferase increased	Investigations	—	—
Weight increased	Investigations	—	—
Migraine	Nervous system disorders	—	—
Peripheral sensory neuropathy	Nervous system disorders	—	—
Depression	Psychiatric disorders	—	—
Neutropenia	Blood and lymphatic system disorders	—	—
Gastrooesophageal reflux disease	Gastrointestinal disorders	—	—
Toothache	Gastrointestinal disorders	—	—
Abdominal pain lower	Gastrointestinal disorders	—	—
Abdominal pain upper	Gastrointestinal disorders	—	—
Flatulence	Gastrointestinal disorders	—	—
Chest pain	General disorders	—	—
Asthenia	General disorders	—	—
Influenza like illness	General disorders	—	—
Oral candidiasis	Infections and infestations	—	—
Bronchitis	Infections and infestations	—	—
Nasopharyngitis	Infections and infestations	—	—
Sinusitis	Infections and infestations	—	—

Most-reported serious reactions: Nausea, Vomiting, Dyspnoea, Anaemia, Angina pectoris, Allergic transfusion reaction, Haemoglobin decreased, Musculoskeletal chest pain.

Data from ClinicalTrials.gov NCT00494234 adverse events section.

Sponsor's own description

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.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial.
   Tutt A, Robson M, Garber JE, Domchek SM, et al · · 2010 · cited 1296× · PMID 20609467 · DOI 10.1016/s0140-6736(10)60892-6
2. Triple-negative breast cancer: treatment challenges and solutions.
   Collignon J, Lousberg L, Schroeder H, Jerusalem G. · · 2016 · cited 246× · PMID 27284266 · DOI 10.2147/bctt.s69488
3. Targeting DNA damage response in cancer therapy.
   Hosoya N, Miyagawa K. · · 2014 · cited 232× · PMID 24484288 · DOI 10.1111/cas.12366
4. Recent advances in targeted strategies for triple-negative breast cancer.
   Zhu S, Wu Y, Song B, Yi M, et al · · 2023 · cited 200× · PMID 37641116 · DOI 10.1186/s13045-023-01497-3
5. Harnessing synthetic lethal interactions in anticancer drug discovery.
   Chan DA, Giaccia AJ. · · 2011 · cited 195× · PMID 21532565 · DOI 10.1038/nrd3374
6. PARP inhibitors in the management of breast cancer: current data and future prospects.
   Livraghi L, Garber JE. · · 2015 · cited 188× · PMID 26268938 · DOI 10.1186/s12916-015-0425-1
7. Targeting DNA repair pathways for cancer treatment: what's new?
   Kelley MR, Logsdon D, Fishel ML. · · 2014 · cited 143× · PMID 24947262 · DOI 10.2217/fon.14.60
8. BRCA1/2 testing: therapeutic implications for breast cancer management.
   Tung NM, Garber JE. · · 2018 · cited 133× · PMID 29867226 · DOI 10.1038/s41416-018-0127-5