NCT00628251: ICEBERG 3

Dose-finding Study Comparing Efficacy and Safety of a PARP Inhibitor Against Doxil in BRCA+ve Advanced Ovarian Cancer

Completed Phase 2 Results posted Last updated 5 December 2019

What this trial tests

Phase 2 trial testing AZD2281 in Ovarian Neoplasms in 97 participants. Completed in 19 September 2018.

Timeline

30 July 2008

Primary endpoint
15 September 2009

19 September 2018

Quick facts

Lead sponsor	AstraZeneca
Phase	Phase 2
Status	Completed
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	none
Primary purpose	treatment
Enrollment	97
Start date	30 July 2008
Primary completion	15 September 2009
Estimated completion	19 September 2018
Sites	24 locations across Belgium, Sweden, United Kingdom, Israel, Germany, Poland, Australia, United States

Drugs / interventions tested

• AZD2281 — full drug profile →
• Liposomal Doxorubicin (liposomal-doxorubicin) — full drug profile →
• AZD2281 — full drug profile →

Conditions studied

• Ovarian Neoplasms — all drugs for Ovarian Neoplasms →

Sponsor

AstraZeneca — full company profile →

Who can join

Adults 18 to 130, female only, with Ovarian 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.

Progression Free Survival (PFS) Primary · Tumour assessment was to be assessed at screening, every 8 weeks during the study and at the withdrawal visit, up to 56 weeks. (Data cut-off for primary analysis of PFS: 15 September 2009)

PFS was defined as the time to progression from the date of randomisation until the date of radiological assessment of progression per RECIST criteria or death (by any cause in the absence of progression)

Group	Value	95% CI
Olaparib 200 mg bd	19
Olaparib 400 mg bd	20
Liposomal Doxorubicin	20

Objective Response Rate (ORR) Secondary · At the time that 57 PFS events had occurred (Data cut-off for primary analysis of PFS: 15 September 2009)

ORR was defined according to RECIST. Complete response (CR) or partial response - (PR)- 30% decrease Patients with a best RECIST response of CR or PR had to have a confirmed response at least 28 days later.

Complete response

Group	Value	95% CI
Olaparib 200 mg bd	0
Olaparib 400 mg bd	0
Liposomal Doxorubicin	0

Number of Partial responders

Group	Value	95% CI
Olaparib 200 mg bd	8
Olaparib 400 mg bd	10
Liposomal Doxorubicin	6

Disease Control Rate Secondary · At the time that 57 PFS events had occurred (Data cut-off for primary analysis of PFS: 15 September 2009)

The number of patients with confirmed CR (disappearance of all target lesions) or PR (30% decrease in the sum of the longest diameter of target lesions ) or SD ( small changes ) \>4 months, divided by the number of randomised patients

Group	Value	95% CI
Olaparib 200 mg bd	21
Olaparib 400 mg bd	21
Liposomal Doxorubicin	19

Overall Duration of Response Secondary · At the time that 57 PFS events had occurred (Data cut-off for primary analysis of PFS: 15 September 2009)

The duration of response was defined as time (months) from initial assessment of PR/CR until earliest date of objective progression or death. (Values may be underestimated as some patients had not progressed at final analysis so true duration is likely to be greater than that in database.)

Group	Value	95% CI
Olaparib 200 mg bd	5.95	3.71 – NA
Olaparib 400 mg bd	6.80	5.52 – 7.39
Olaparib 200 mg bd + Olaparib 400 mg bd,	6.24	5.52 – 7.39
Liposomal Doxorubicin	5.49	4.67 – 9.13

Best Percentage Change in Tumour Size Secondary · At the time that 57 PFS events had occurred (Data cut-off for primary analysis of PFS: 15 September 2009)

The percentage change (reduction) from baseline in the sum of the lengths of the longest diameter (LD) of the RECIST target lesions were objectively documented, regardless of whether the patient was still taking study medication

Group	Value	95% CI
Olaparib 200 mg bd	-15.90	-75.30 – 31.48
Olaparib 400 mg bd	-24.60	-100.00 – 51.10
Liposomal Doxorubicin	-14.3	-87.5 – 32.4

Best Percentage Change From Baseline in CA-125 Levels Secondary · At the time that 57 PFS events had occurred (Data cut-off for primary analysis of PFS: 15 September 2009)

Best percentage change in cancer antigen 125 (CA-125) levels

Group	Value	95% CI
Olaparib 200 mg bd	-37.42	-98.77 – 327.76
Olaparib 400 mg bd	-71.19	-96.88 – 70.56
Liposomal Doxorubicin	-55.8	-99.5 – 192.1

Confirmed RECIST Response and/or CA-125 Response Secondary · At the time that 57 PFS events had occurred (Data cut-off for primary analysis of PFS: 15 September 2009)

The percentage of patients reporting a RECIST confirmed response and/or a CA-125 response (in the absence of progression). A CA-125 response was defined as a confirmed greater or equal to 50% reduction in CA-125.

Group	Value	95% CI
Olaparib 200 mg bd	37.5
Olaparib 400 mg bd	59.4
Liposomal Doxorubicin	39.4

Overall Survival (OS) Secondary · At the time of the cut-off for the final analysis of overall survival (30 April 2010)

OS was defined as time from randomisation to date of death from any cause. Patients who had not died at time of analysis were censored at last date they were known to be alive. Median OS was not calculable for olaparib groups due to an insufficient number of deaths so the percentage of participants who died are shown along with 95% confidence intervals

Group	Value	95% CI
Olaparib 200 mg bd	9
Olaparib 400 mg bd	11
Liposomal Doxorubicin	13

Best Quality of Life (QoL) Response for Trial Outcome Index (TOI) Secondary · At the time that 57 PFS events had occurred (Data cut-off for primary analysis of PFS: 15 September 2009)

Best HRQoL response using the TOI endpoint. Improvement was defined as a change from baseline of greater than or equal to +7. The TOI score ranges from 0-100.

Improved

Group	Value	95% CI
Olaparib 200 mg bd	7
Olaparib 400 mg bd	5
Liposomal Doxorubicin	3

No change

Group	Value	95% CI
Olaparib 200 mg bd	10
Olaparib 400 mg bd	10
Liposomal Doxorubicin	11

Worsened

Group	Value	95% CI
Olaparib 200 mg bd	3
Olaparib 400 mg bd	7
Liposomal Doxorubicin	6

Non-evaluable

Group	Value	95% CI
Olaparib 200 mg bd	5
Olaparib 400 mg bd	7
Liposomal Doxorubicin	7

Best QoL Response for Total Functional Analysis of Cancer Therapy - Ovarian (FACT-O) Secondary · At the time that 57 PFS events had occurred (Data cut-off for primary analysis of PFS: 15 September 2009)

Best HRQoL response using the total FACT-O endpoint. Improvement was defined as a change from baseline of greater than or equal to +9.

Improved

Group	Value	95% CI
Olaparib 200 mg bd	3
Olaparib 400 mg bd	6
Liposomal Doxorubicin	1

No Change

Group	Value	95% CI
Olaparib 200 mg bd	14
Olaparib 400 mg bd	11
Liposomal Doxorubicin	11

Worsened

Group	Value	95% CI
Olaparib 200 mg bd	3
Olaparib 400 mg bd	5
Liposomal Doxorubicin	7

Non-evaluable

Group	Value	95% CI
Olaparib 200 mg bd	5
Olaparib 400 mg bd	7
Liposomal Doxorubicin	8

Best QoL Response for FACT-O Symptom Index (FOSI) Secondary · At the time that 57 PFS events had occurred (Data cut-off for primary analysis of PFS: 15 September 2009)

Best HRQoL response using the FOSI endpoint. Improvement was defined as a change from baseline of greater than or equal to +3.

Improved

Group	Value	95% CI
Olaparib 200 mg bd	5
Olaparib 400 mg bd	4
Liposomal Doxorubicin	3

No change

Group	Value	95% CI
Olaparib 200 mg bd	14
Olaparib 400 mg bd	9
Liposomal Doxorubicin	10

Worsened

Group	Value	95% CI
Olaparib 200 mg bd	1
Olaparib 400 mg bd	9
Liposomal Doxorubicin	7

Non-evaluable

Group	Value	95% CI
Olaparib 200 mg bd	5
Olaparib 400 mg bd	7
Liposomal Doxorubicin	7

Progression Free Survival (PFS) Primary · Tumour assessment was to be assessed at screening, every 8 weeks during the study and at the withdrawal visit, up to 56 weeks. (Data cut-off for primary analysis of PFS: 15 September 2009)

PFS was defined as the time to progression from the date of randomisation until the date of radiological assessment of progression per RECIST criteria or death (by any cause in the absence of progression)

Group	Value	95% CI
Olaparib 200 mg bd	6.5	5.5 – 10.1
Olaparib 400 mg bd	8.8	5.4 – 9.2
Liposomal Doxorubicin	7.1	3.7 – 10.7

Adverse events — posted to ClinicalTrials.gov

Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Olaparib 200 mg bd

Serious: 5/32 (16%)

Deaths: —

Olaparib 400 mg bd

Serious: 6/32 (19%)

Deaths: —

Liposomal Doxorubicin

Serious: 5/32 (16%)

Deaths: —

Serious adverse events (23 terms)

Reaction	System	Olaparib 200 mg bd	Olaparib 400 mg bd	Liposomal Doxorubicin
Cerebrovascular Accident	Nervous system disorders	—	—	—
Vomiting	Gastrointestinal disorders	—	—	—
Abdominal Pain Lower	Gastrointestinal disorders	—	—	—
Constipation	Gastrointestinal disorders	—	—	—
Intestinal Obstruction	Gastrointestinal disorders	—	—	—
Nausea	Gastrointestinal disorders	—	—	—
Small Intestinal Obstruction	Gastrointestinal disorders	—	—	—
Subileus	Gastrointestinal disorders	—	—	—
Fatigue	General disorders	—	—	—
Pyrexia	General disorders	—	—	—
Cholelithiasis	Hepatobiliary disorders	—	—	—
Bacteraemia	Infections and infestations	—	—	—
Haemoglobin Decreased	Injury, poisoning and procedural complications	—	—	—
Intervertebral Disc Degeneration	Musculoskeletal and connective tissue disorders	—	—	—
Musculoskeletal Chest Pain	Musculoskeletal and connective tissue disorders	—	—	—
Myelodysplastic Syndrome	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—	—
Syncope	Nervous system disorders	—	—	—
Dyspnoea	Respiratory, thoracic and mediastinal disorders	—	—	—
Deep Vein Thrombosis	Vascular disorders	—	—	—
Overdose	Injury, poisoning and procedural complications	—	—	—
Hypokalaemia	Metabolism and nutrition disorders	—	—	—
Hyponatraemia	Metabolism and nutrition disorders	—	—	—
Back Pain	Musculoskeletal and connective tissue disorders	—	—	—

Other adverse events (84 terms — click to expand)

Reaction	System	Olaparib 200 mg bd	Olaparib 400 mg bd	Liposomal Doxorubicin
Nausea	Gastrointestinal disorders	—	—	—
Fatigue	General disorders	—	—	—
Palmar-Plantar Erythrodysaesthesia Syndrome	Skin and subcutaneous tissue disorders	—	—	—
Stomatitis	Gastrointestinal disorders	—	—	—
Vomiting	Gastrointestinal disorders	—	—	—
Rash	Skin and subcutaneous tissue disorders	—	—	—
Abdominal Pain	Gastrointestinal disorders	—	—	—
Constipation	Gastrointestinal disorders	—	—	—
Diarrhoea	Gastrointestinal disorders	—	—	—
Anaemia	Blood and lymphatic system disorders	—	—	—
Asthenia	General disorders	—	—	—
Urinary Tract Infection	Infections and infestations	—	—	—
Headache	Nervous system disorders	—	—	—
Decreased Appetite	Metabolism and nutrition disorders	—	—	—
Dyspepsia	Gastrointestinal disorders	—	—	—
Mucosal Inflammation	General disorders	—	—	—
Dizziness	Nervous system disorders	—	—	—
Alopecia	Skin and subcutaneous tissue disorders	—	—	—
Hypertension	Vascular disorders	—	—	—
Neutropenia	Blood and lymphatic system disorders	—	—	—
Back Pain	Musculoskeletal and connective tissue disorders	—	—	—
Cough	Respiratory, thoracic and mediastinal disorders	—	—	—
Erythema	Skin and subcutaneous tissue disorders	—	—	—
Leukopenia	Blood and lymphatic system disorders	—	—	—
Abdominal Distension	Gastrointestinal disorders	—	—	—
Upper Respiratory Tract Infection	Infections and infestations	—	—	—
Dysgeusia	Nervous system disorders	—	—	—
Pruritus	Skin and subcutaneous tissue disorders	—	—	—
Dry Mouth	Gastrointestinal disorders	—	—	—
Flatulence	Gastrointestinal disorders	—	—	—
Pyrexia	General disorders	—	—	—
Insomnia	Psychiatric disorders	—	—	—
Dyspnoea	Respiratory, thoracic and mediastinal disorders	—	—	—
Oropharyngeal Pain	Respiratory, thoracic and mediastinal disorders	—	—	—
Blister	Skin and subcutaneous tissue disorders	—	—	—
Dry Skin	Skin and subcutaneous tissue disorders	—	—	—
Hot Flush	Vascular disorders	—	—	—
Gastrooesophageal Reflux Disease	Gastrointestinal disorders	—	—	—
Haemorrhoids	Gastrointestinal disorders	—	—	—
Chills	General disorders	—	—	—

Most-reported serious reactions: Cerebrovascular Accident, Vomiting, Abdominal Pain Lower, Constipation, Intestinal Obstruction, Nausea, Small Intestinal Obstruction, Subileus.

Data from ClinicalTrials.gov NCT00628251 adverse events section.

Sponsor's own description

The purpose of the study is to compare the efficacy and safety of 2 doses of drug AZD2281 against liposomal doxorubicin to see which is effective and well tolerated in treating patients with measurable BRCA1- or BRCA2-positive advanced ovarian cancer and who have failed previous platinum therapy.

Publications & conference data

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

1. Targeting DNA damage response in cancer therapy.
   Hosoya N, Miyagawa K. · · 2014 · cited 232× · PMID 24484288 · DOI 10.1111/cas.12366
2. PARP Inhibitors in the Management of Ovarian Cancer: ASCO Guideline.
   Tew WP, Lacchetti C, Ellis A, Maxian K, et al · · 2020 · cited 217× · PMID 32790492 · DOI 10.1200/jco.20.01924
3. Olaparib Versus Nonplatinum Chemotherapy in Patients With Platinum-Sensitive Relapsed Ovarian Cancer and a Germline BRCA1/2 Mutation (SOLO3): A Randomized Phase III Trial.
   Penson RT, Valencia RV, Cibula D, Colombo N, et al · · 2020 · cited 203× · PMID 32073956 · DOI 10.1200/jco.19.02745
4. Harnessing synthetic lethal interactions in anticancer drug discovery.
   Chan DA, Giaccia AJ. · · 2011 · cited 195× · PMID 21532565 · DOI 10.1038/nrd3374
5. PARP inhibitors for BRCA1/2-mutated and sporadic ovarian cancer: current practice and future directions.
   Konecny GE, Kristeleit RS. · · 2016 · cited 155× · PMID 27736844 · DOI 10.1038/bjc.2016.311
6. Alternate therapeutic pathways for PARP inhibitors and potential mechanisms of resistance.
   Kim DS, Camacho CV, Kraus WL. · · 2021 · cited 136× · PMID 33487630 · DOI 10.1038/s12276-021-00557-3
7. PARP Inhibitors in Ovarian Cancer: A Review.
   O'Malley DM, Krivak TC, Kabil N, Munley J, et al · · 2023 · cited 128× · PMID 37268756 · DOI 10.1007/s11523-023-00970-w
8. Olaparib monotherapy in patients with advanced relapsed ovarian cancer and a germline BRCA1/2 mutation: a multistudy analysis of response rates and safety.
   Matulonis UA, Penson RT, Domchek SM, Kaufman B, et al · · 2016 · cited 127× · PMID 26961146 · DOI 10.1093/annonc/mdw133