Breast CancerPhase 1NCT02561832
A Phase I, Open-Label, 2 Part Multicentre Study to Assess the Safety and Efficacy of Olaparib in Combination With Carboplatin in Patients With Advanced HER-2 Negative Breast Cancer
A Phase 1 study testing Olaparib, Carboplatin and Anthracycline in people with Breast Cancer, run by AstraZeneca at 7 sites in 2 countries.
Trial summary
This is an open-label study to assess the safety, tolerability and efficacy of olaparib in combination with carboplatin. There are two parts in this study: Part A, a dose escalation in patients with advanced Human Epidermal Growth Factor 2 (HER-2) negative breast cancer and Part B, a dose expansion in the neoadjuvant… Read more about this study
- Who is it for?
- Ages 18 to 130 years
- Conditions the study is for
- Breast Cancer
- What is being tested?
- Olaparib, Carboplatin and Anthracycline
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 15 participants
- Where
- 7 sitesin 2 countries
- Study dates
- 6 Nov 2015to 1 Feb 2017
- Phase
- Phase 1
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 130 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Male or female aged ≥18 years
- Normal organ and bone marrow function, measured within 28 days prior to administration of study treatment
- Eastern Cooperative Oncology Group performance status of 0-1
- Postmenopausal or evidence of non-childbearing status for women of childbearing potential.
- Additional for patients participating in Part A only
- Advanced or metastatic breast cancer that is HER-2 negative (HR positive or HR negative)
Show all 31Show fewer
- Between 0 and 2 lines of prior cytotoxic chemotherapy. Additional for patients participating in Part B only
- Patients with operable breast adenocarcinoma and no evidence of metastatic disease are allowed.
- Patient must meet at least one of the following criteria: Clinical primary tumour size defined as T2 or above, clinical or patho-histological evidence of regional lymph nodes involvement (N+), grade 2-3 disease
- Availability of formalin fixed, paraffin embedded tumour sample from diagnostic biopsies (Not Applicable for patients at sites in Israel)
- Histological confirmation of HER-2 negative breast cancer
- Documented germline mutation in BRCA1 or BRCA2 that is predicted to be deleterious or suspected deleterious
- Eligible for neo-adjuvant chemotherapy, but have not yet received neoadjuvant chemotherapy for breast cancer (chemo-naive) Exclusion criteria
- Exposure to an investigational product within 30 days or 5 half-lives (whichever is the longer) prior to enrolment
- Prior use of Poly ADP Ribose Polymerase (PARP) inhibitors
- Patients with a known hypersensitivity to olaparib or carboplatin
- Concurrent treatment with an ovarian hormonal replacement therapy or with hormonal agents such as raloxifene, tamoxifen or other selective estrogen receptor modulator. Patient must have discontinued use of such agents 3 weeks prior to beginning study treatment. Luteinising hormone-Releasing hormone (LHRH) analogues are allowed for all patients in Part A.
- Concomitant use of known potent Cytochrome P450 3A4 (CYP3A4) inhibitors and inducers
- Persistent toxicities (Common Terminology Criteria for Adverse Event (CTCAE) grade ≥2 and neuropathy CTCAE > grade 1) caused by previous cancer therapy, excluding alopecia - Patient with myelodysplastic syndrome (MDS)/acute myeloid leukaemia (AML) or with features suggestive of MDS/AML
- Patient must have recovered from any effects of any major surgery
- Patient considered at poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled seizures or active uncontrolled infection
- Patient with known active Hepatitis B or C, or Human immunodeficiency virus (HIV)
- Other malignancy within the last 5 years (few exceptions apply). Additional for patients participating in Part A only
- Prior chemotherapy within 3 weeks of study entry
- Other anti-cancer therapy (eg, targeted biotherapy of hormonal agents) within 3 weeks of study entry
- Radiation therapy within 4 weeks or radionuclide treatment within 6 weeks of treatment start
- Prior use of platinum compound in the advanced or metastatic setting. Previous exposure to platinum compounds is allowed only if they were used in early adjuvant or neoadjuvant setting with relapse occurring >6 months after the last platinum administration and if there is no residual toxicity
- Patient with a history of treated Central Nervous System (CNS) metastases are eligible, provided they meet certain protocol-specified criteria.
- Additional for patients participating in Part B only
- Prior treatment (local or systemic) of their breast tumour. Sentinel lymph node biopsy is considered as diagnostic procedure and therefore is authorized before neoadjuvant treatment in part B
- Patients with inflammatory breast cancer or patients with inoperable locally advanced breast cancer (including T4 lesions) at the time of enrolment.
Who cannot join
None listed.
Trial locations and contacts
7 sites in 2 countries.
7 sites in 2 countries
Spain5 sites
Research Site
Barcelona, 08035
Research Site
Madrid, 28034
Research Site
Madrid, 28050
Research Site
Valencia, 46010
Research Site
Zaragoza, 50009
United States2 sites
Research Site
New York, New York, 10065
Research Site
Stony Brook, New York, 11794
About this study
Official title: A Phase I, Open-Label, 2 Part Multicentre Study to Assess the Safety, Tolerability and Efficacy of Olaparib in Combination With Carboplatin: Part A: Dose Escalation of Olaparib in Combination With Carboplatin in Patients With Advanced HER-2 Negative Breast Cancer; Followed by Part B: an Expansion Phase of Olaparib in Combination With Carboplatin in the Neoadjuvant Treatment of HER-2 Negative Breast Cancer Patients With Germline BRCA1/2 Mutations
This is an open-label study to assess the safety, tolerability and efficacy of olaparib in combination with carboplatin. There are two parts in this study: Part A, a dose escalation in patients with advanced Human Epidermal Growth Factor 2 (HER-2) negative breast cancer and Part B, a dose expansion in the neoadjuvant treatment of HER-2 negative breast cancer patients with germline Breast Cancer Susceptibility Gene (BRCA)1/2 mutations.
Read the detailed description
In Part A up to 36 evaluable patients with advanced breast cancer will be enrolled across 6 cohorts. The total number of patients will depend on the number of dose escalations necessary to enable a decision to be made on the recommended dose to take forward into Part B of the study.
The planned dose escalation will start with cohort 1, where patients will receive carboplatin (AUC5) on day 1 of cycle 1, and will start dosing with olaparib tablets at the dose of 50 mg twice daily (bd) on day 4 until day 19 of cycle 1 inclusive (a total of 16 days per cycle). Patients will receive carboplatin on day 1 of each 3 weeks cycle in combination with olaparib for a total of 4 cycles. Provided that there are no safety concerns after assessment of 6 evaluable patients in the first cohort, patients in subsequent cohorts may be dosed following Safety Review Committee (SRC) approval. Dose escalation scheme may be adjusted during the study on the basis of emerging safety, efficacy and pharmacokinetic data. Those patients in Part A who tolerate the combination up to and including cycle 4 may remain on treatment, either continuing with the combination, with carboplatin alone at the same AUC or with olaparib alone at the dose of 300 mg bd, if in the opinion of the treating Investigator, a patient is deemed to be deriving clinical benefit from treatment. In these cases, a patient may remain on treatment until progression, unacceptable toxicity or until other discontinuation criteria are met. Beyond cycle 4, patients will undergo assessments in line with the clinical protocol. Once the maximum tolerated dose (MTD) and/or recommended dose (RD) has been defined in Part A, a dose expansion phase, Part B will begin and this will include up to 21 patients with HER2 negative breast cancer, with a deleterious or suspected deleterious germlineBRCA1/2 (gBRCA1/2) mutation, who are deemed eligible for neoadjuvant therapy.
Part B will explore the safety, tolerability and efficacy of the combination of olaparib and carboplatin in terms of pathological complete response (pCR) rate. Neoadjuvant systemic therapy will consist of the following anti-cancer drugs for a total of 8 cycles of treatment:
- The first 4 cycles (cycle 1 to cycle 4: 12 weeks) will be based on combination of olaparib, at the defined RD and schedule from Part A, with carboplatin. It is expected that a cycle of treatment would be 3 weeks.
- Another 4 cycles (cycle 5 to cycle 8) will be based on a combination of an anthracycline and cyclophosphamide (AC). The choice of the AC regimen will be up to local Investigator following international guidelines (National Comprehensive Cancer Network (NCCN), European Society for Medical Oncology (ESMO), and St Gallen).
The tumour response will be assessed through careful clinical examination and also with radiological examinations between cycle 4 and 5 and at the end of neoadjuvant part, before surgery. Additionally, tumour biopsy will be performed within 7 days before cycle 5 day 1, after completion of carboplatin and olaparib combination therapy and early pathological response assessed by local pathologist. Curative-intent surgery should be performed following completion of neoadjuvant treatment in all patients, 3 to 5 weeks after day 1 of the last cycle of neoadjuvant treatment.
A decision has been made to stop recruitment after Part A cohort 2, and to not start Part B of the study. The protocol has been amended to define that the collection of clinical data will stop once the final patient from cohort 2 of Part A has completed 4 cycles or all patients from cohort 2 of Part A discontinue prior to end of cycle 4 to enable data analysis and reporting. The database would close at this time point, however AstraZeneca commits to providing study treatment to ongoing patients that continue to receive clinical benefit, in Investigator's judgment. Patients who remain on study treatment after this time point will be monitored according to routine clinical practice as defined by the Investigator and no clinical data will be collected, other than SAEs and drug dispensing/accountability.
- Conditions
- Breast Cancer
- Being tested
- Olaparib, Carboplatin, Anthracycline, Cyclophosphamide
- Keywords
- breast cancer
- Medical subject headings
- Breast Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
OlaparibDrug
tablets taken orally twice daily
CarboplatinDrug
intravenous injections on day one of each cycle
AnthracyclineDrug
The choice of anthracycline and cyclophosphamide (AC) regimen in Part B will be up to local Investigator following international guidelines
CyclophosphamideDrug
The choice of anthracycline and cyclophosphamide (AC) regimen in Part B will be up to local Investigator following international guidelines
| Study group | Role | What they receive |
|---|---|---|
| Arm 1 | Experimental | Part A: ascending doses of olaparib in combination with carboplatin will be administered to investigate safety and tolerability and to define the MTD and/or RD for part B. Patients will be treated with this combination up to cycle 4, after cycle 4 they can continue with combination or monotherapy (carboplatin or olaparib). Cohorts will be started sequentially, based on SRC recommendation. Part B will start after MTD/RD identification in part A. Patients will receive olaparib and carboplatin combination for first 4 cycles (21 days per cycle), at the dose, frequency and schedule recommended from Part A. This will be followed by another 4 cycles of standard cancer therapy consisting of anthracycline and cyclophosphamide regimen. Total of 8 treatment cycles will be given before final surgery Receives: Drug: Olaparib; Drug: Carboplatin; Drug: Anthracycline; Drug: Cyclophosphamide |
What is being measured
The primary outcome is the main question the study is designed to answer.
Part A: Number of Subjects Reporting Adverse Events (AEs)
Treatment-emergent AEs (TEAEs) defined as events occurring on or after cycle 1, day 1 up to and including 30 days after last dose (approximately 114 days).
Measured: From day 1 cycle 1, up to and including 30 days after last dose
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted28 Sep 2015 (estimated)
- Study start6 Nov 2015
- Primary completion30 Sep 2016
- Study completion1 Feb 2017
Why it stopped: This decision was based upon strategic considerations impacting the clinical development of olaparib in this indication.
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Breast CancerStudies of the same condition, open and under way.
- More trials run by AstraZenecaThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 15 participants (actual)
Sponsor and investigators
- Lead sponsor
- AstraZeneca
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Judith Balmana, Principal investigator, Hospital Vall d'Hebron, Barcelona, SpainTiffany Traina, Principal investigator, Memorial Sloan Kettering Cancer Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02561832
- Sponsor's protocol ID
- D081EC00001
- Status last verified
- Oct 2018
- First submitted
- 13 Aug 2015
- Last updated
- 20 Feb 2019
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
Study at a glance
From the registry record, last updated by the sponsor on 20 Feb 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase I, Open-Label, 2 Part Multicentre Study to Assess the Safety, Tolerability and Efficacy of Olaparib in Combination With Carboplatin: Part A: Dose Escalation of Olaparib in Combination With Carboplatin in Patients With Advanced HER-2 Negative Breast Cancer; Followed by Part B: an Expansion Phase of Olaparib in Combination With Carboplatin in the Neoadjuvant Treatment of HER-2 Negative Breast Cancer Patients With Germline BRCA1/2 Mutations
- ClinicalTrials.gov ID
- NCT02561832
- Acronym / sponsor ID
- D081EC00001
- Conditions
- Breast Cancer
- Keywords
- breast cancer
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: This decision was based upon strategic considerations impacting the clinical development of olaparib in this indication.
- Enrolment
- 15 participants (actual)
- Lead sponsor
- AstraZenecaIndustry (pharma, biotech, devices)
- Study start
- 6 Nov 2015 (actual)
- Primary completion
- 30 Sep 2016 (actual)
- Study completion
- 1 Feb 2017 (actual)
- First posted
- 28 Sep 2015 (estimated)
- Results
- Posted 20 Feb 2019
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This is an open-label study to assess the safety, tolerability and efficacy of olaparib in combination with carboplatin. There are two parts in this study: Part A, a dose escalation in patients with advanced Human Epidermal Growth Factor 2 (HER-2) negative breast cancer and Part B, a dose expansion in the neoadjuvant treatment of HER-2 negative breast cancer patients with germline Breast Cancer Susceptibility Gene (BRCA)1/2 mutations.
Detailed description
In Part A up to 36 evaluable patients with advanced breast cancer will be enrolled across 6 cohorts. The total number of patients will depend on the number of dose escalations necessary to enable a decision to be made on the recommended dose to take forward into Part B of the study.
The planned dose escalation will start with cohort 1, where patients will receive carboplatin (AUC5) on day 1 of cycle 1, and will start dosing with olaparib tablets at the dose of 50 mg twice daily (bd) on day 4 until day 19 of cycle 1 inclusive (a total of 16 days per cycle). Patients will receive carboplatin on day 1 of each 3 weeks cycle in combination with olaparib for a total of 4 cycles. Provided that there are no safety concerns after assessment of 6 evaluable patients in the first cohort, patients in subsequent cohorts may be dosed following Safety Review Committee (SRC) approval. Dose escalation scheme may be adjusted during the study on the basis of emerging safety, efficacy and pharmacokinetic data. Those patients in Part A who tolerate the combination up to and including cycle 4 may remain on treatment, either continuing with the combination, with carboplatin alone at the same AUC or with olaparib alone at the dose of 300 mg bd, if in the opinion of the treating Investigator, a patient is deemed to be deriving clinical benefit from treatment. In these cases, a patient may remain on treatment until progression, unacceptable toxicity or until other discontinuation criteria are met. Beyond cycle 4, patients will undergo assessments in line with the clinical protocol. Once the maximum tolerated dose (MTD) and/or recommended dose (RD) has been defined in Part A, a dose expansion phase, Part B will begin and this will include up to 21 patients with HER2 negative breast cancer, with a deleterious or suspected deleterious germlineBRCA1/2 (gBRCA1/2) mutation, who are deemed eligible for neoadjuvant therapy.
Part B will explore the safety, tolerability and efficacy of the combination of olaparib and carboplatin in terms of pathological complete response (pCR) rate. Neoadjuvant systemic therapy will consist of the following anti-cancer drugs for a total of 8 cycles of treatment:
- The first 4 cycles (cycle 1 to cycle 4: 12 weeks) will be based on combination of olaparib, at the defined RD and schedule from Part A, with carboplatin. It is expected that a cycle of treatment would be 3 weeks.
- Another 4 cycles (cycle 5 to cycle 8) will be based on a combination of an anthracycline and cyclophosphamide (AC). The choice of the AC regimen will be up to local Investigator following international guidelines (National Comprehensive Cancer Network (NCCN), European Society for Medical Oncology (ESMO), and St Gallen).
The tumour response will be assessed through careful clinical examination and also with radiological examinations between cycle 4 and 5 and at the end of neoadjuvant part, before surgery. Additionally, tumour biopsy will be performed within 7 days before cycle 5 day 1, after completion of carboplatin and olaparib combination therapy and early pathological response assessed by local pathologist. Curative-intent surgery should be performed following completion of neoadjuvant treatment in all patients, 3 to 5 weeks after day 1 of the last cycle of neoadjuvant treatment.
A decision has been made to stop recruitment after Part A cohort 2, and to not start Part B of the study. The protocol has been amended to define that the collection of clinical data will stop once the final patient from cohort 2 of Part A has completed 4 cycles or all patients from cohort 2 of Part A discontinue prior to end of cycle 4 to enable data analysis and reporting. The database would close at this time point, however AstraZeneca commits to providing study treatment to ongoing patients that continue to receive clinical benefit, in Investigator's judgment. Patients who remain on study treatment after this time point will be monitored according to routine clinical practice as defined by the Investigator and no clinical data will be collected, other than SAEs and drug dispensing/accountability.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Arm 1 | Experimental | Drug: Olaparib, Drug: Carboplatin, Drug: Anthracycline, Drug: CyclophosphamidePart A: ascending doses of olaparib in combination with carboplatin will be administered to investigate safety and tolerability and to define the MTD and/or RD for part B. Patients will be treated with this combination up to cycle 4, after cycle 4 they can continue with combination or monotherapy (carboplatin or olaparib). Cohorts will be started sequentially, based on SRC recommendation. Part B will start after MTD/RD identification in part A. Patients will receive olaparib and carboplatin combination for first 4 cycles (21 days per cycle), at the dose, frequency and schedule recommended from Part A. This will be followed by another 4 cycles of standard cancer therapy consisting of anthracycline and cyclophosphamide regimen. Total of 8 treatment cycles will be given before final surgery |
Who may qualify
- Ages
- 18 to 130 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (31 listed)
- Male or female aged ≥18 years
- Normal organ and bone marrow function, measured within 28 days prior to administration of study treatment
- Eastern Cooperative Oncology Group performance status of 0-1
- Postmenopausal or evidence of non-childbearing status for women of childbearing potential.
- Additional for patients participating in Part A only
Key exclusion criteria (0 listed)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Olaparibtablets taken orally twice daily | Drug | Arm 1 |
| Carboplatinintravenous injections on day one of each cycle | Drug | Arm 1 |
| AnthracyclineThe choice of anthracycline and cyclophosphamide (AC) regimen in Part B will be up to local Investigator following international guidelines | Drug | Arm 1 |
| CyclophosphamideThe choice of anthracycline and cyclophosphamide (AC) regimen in Part B will be up to local Investigator following international guidelines | Drug | Arm 1 |
Primary outcome
Part A: Number of Subjects Reporting Adverse Events (AEs)
Time frame: From day 1 cycle 1, up to and including 30 days after last dose
Treatment-emergent AEs (TEAEs) defined as events occurring on or after cycle 1, day 1 up to and including 30 days after last dose (approximately 114 days).
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 20 Feb 2019.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Judith Balmana principal investigator
Hospital Vall d'Hebron, Barcelona, Spain
Tiffany Traina principal investigator
Memorial Sloan Kettering Cancer Center
7 sites in 2 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Olaparib, Carboplatin and Anthracycline in people with Breast Cancer, run by AstraZeneca at 7 sites in 2 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 31 inclusion and 0 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 20 Feb 2019. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 7 sites in Spain, United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 20 Feb 2019). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Part A: Number of Subjects Reporting Adverse Events (AEs) (time frame: From day 1 cycle 1, up to and including 30 days after last dose). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 20 Feb 2019.