We are experiencing 4 week turn-around time in review of submissions and resubmissions. We recommend commencing this process concurrently with your ethics submission and allowing at least 8 weeks for registration to be completed from date of first submission. We currently do not have the capacity to expedite reviews.

Note also there are delays to review of updates. We appreciate your patience.

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been endorsed by the ANZCTR. Before participating in a study, talk to your health care provider and refer to this information for consumers
Trial registered on ANZCTR


Registration number
ACTRN12613000924752
Ethics application status
Approved
Date submitted
29/07/2013
Date registered
21/08/2013
Date last updated
15/05/2019
Date data sharing statement initially provided
29/01/2019
Date results information initially provided
29/01/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
ANZ 1103 Study of Olaparib Clinical Effect in Patients with Breast Cancer or Ovarian Cancer
Scientific title
ANZ 1103 (SOLACE) - Patients with metastatic BRCA-associated breast cancer, triple negative breast cancer or serous ovarian cancer receiving Olaparib (a PARP inhibitor) in combination with metronomic cyclophosphamide in a Phase I study to determine the maximum tolerated dose of this treatment combination
Secondary ID [1] 273258 0
Nil
Universal Trial Number (UTN)
Trial acronym
SOLACE
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Metastatic triple negative breast cancer 279021 0
Metastatic BRCA-associated breast cancer 279022 0
High grade serous epithelial ovarian cancer 279023 0
Condition category
Condition code
Cancer 279208 279208 0 0
Breast
Cancer 279209 279209 0 0
Ovarian and primary peritoneal

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Dose level 1: Olaparib 300mg oral tablet twice per day + Cyclophosphamide 50 mg oral tablet once per day on Day 1, 3, 5 of each week of a 21 day cycle for up to 8 cycles

Dose level 2: Olaparib 300mg oral tablet twice per day + Cyclophosphamide 50 mg oral tablet once per day on Day 1 to 5 of each week of a 21 day cycle for up to 8 cycles

Dose level 3: Olaparib 300mg oral tablet twice per day + Cyclophosphamide 50 mg oral tablet once per day each day of a 21 day cycle for up to 8 cycles

Dose level -1: Olaparib 250mg oral tablet twice per day + Cyclophosphamide 50mg oral tablet once per day on Day 1, 3, 5 of a 21 day cycle for up to 8 cycles

Dose level -2: Olabarib 200mg oral tablet twice per day + Cyclophosphamide 50mg oral tablet once per day on Day 1, 3, 5 of a 21 day cycle for up to 8 cycles

If the maximum tolerated dose (MTD) is found to be Dose Level 3, extension cohort patients who experience no dose limiting toxicities at the MTD for 6 cycles may be treated as follows: Olaparib 300mg oral tablets twice per day on days 1-7, no olaparib days 8-14, olaparib 300mg oral tablets twice per day for days 15-21; cyclophosphamide 50mg oral tablet daily for 21 day cycle.

Patients receiving clinical benefit from treatment with no dose limiting toxicities may continue beyond Cycle 8 on maintenance chemotherapy at the discretion of the investigator.
Intervention code [1] 269599 0
Treatment: Drugs
Comparator / control treatment
n/a
Control group
Uncontrolled

Outcomes
Primary outcome [1] 279841 0
The primary outcome is to determine the maximum
tolerated dose and schedule of olaparib in combination with metronomic oral cyclophosphamide. The outcome is assessed using the "Escalation Decision Rule" along with Dose Limiting Toxicity. Toxicity grading will be according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Any of the following events that occur during the first 2 cycles will be considered a Dose Limiting Toxicity:
* ANC <0.5 x 109/L without fever and lasting for more than 5 days
* ANC >0.5 × 109/L but less than 1.5 × 109/L with fever >=38.5oC and neutropenic sepsis
* Platelets <25 x 109/L * Any grade 3 or 4 non-haematological adverse event with the exception of fatigue, nausea, vomiting, diarrhoea, myalgia or arthralgia, unless appropriate measures have been undertaken to treat these symptoms
* Any AE not otherwise described that results in treatment delay of >21 consecutive days * Any grade 3 or 4 toxicity considered, in the opinion of the investigator, to be dose limiting
* Requirement for repeated blood transfusions within the first 2 cycles.

Patients with documented response beyond cycle 2 who experience dose limiting toxicity related to the study drugs as listed above are allowed to continue with the study after appropriate dose modifications. The occurrence of any of the above dose limiting toxicities beyond cycle 2 for the current or previous dose levels will also be considered by the Trial Management Committee at the time of any decision to escalate or expand recruitment for a dose level.

AEs that are considered unrelated to the study drugs should be managed as clinically indicated, but will NOT be considered dose limiting. Patients who require dose omission or dose delay of >7 days due to adverse events that are considered unrelated to study drugs in the period evaluable for DLT (first 42 days of treatment), will be regarded as non-evaluable for DLT. They may continue on study, but will be replaced to fulfill the aims of the study. When the relationship between an adverse event and the study drugs is clinically uncertain, the event should be considered possibly related to the study drugs.

After cycle 2, patients may have the cyclophosphamide dose reduced because of toxicity and remain on treatment with olaparib provided, in the opinion of the investigator, they are continuing to benefit from treatment. However, the patient should be considered for discontinuation from the study drugs if:
* The patient is required to stop treatment due to unacceptable toxicity, or
* The patient would receive cyclophosphamide 50mg for less than 3 days per week over the 21-day cycle, and/or
* The patient would receive olaparib at a dose less than 200mg twice per day over the 21-day cycle.
Timepoint [1] 279841 0
Maximum of 8 cycles of treatment (1 cycle = 21 days)
Secondary outcome [1] 294558 0
To obtain preliminary evidence of clinical efficacy (response rate, progression free survival, overall survival) for this treatment combination using RECIST Criteria
Timepoint [1] 294558 0
Maximum of 8 cycles of treatment (1 cycle = 21 days)
Secondary outcome [2] 294559 0
To investigate the role of novel biomarkers as predictors for treatment
Timepoint [2] 294559 0
Archival tumour samples at the beginning of the study. On-study fresh tumour samples at Baseline, Week 6, Week 15 and at end of study.

Eligibility
Key inclusion criteria
1. All patients must be aged >= 18 years and:
a) Male or female with histologically confirmed, metastatic triple negative breast cancer: ER-negative, PR-negative (for ER- and PR-negative: <1% tumour staining by IHC), and HER-2 non-overexpressing (IHC score 0 or 1 or ISH-negative) OR
b) Male or female with histologically confirmed, metastatic breast cancer and documented BRCA1 or BRCA2 germline mutation, regardless of tumour steroid hormone receptor or HER-2 status OR
c) Female with histologically confirmed high grade serous epithelial ovarian cancer (EOC) (including fallopian tube cancer or primary peritoneal cancer) with or without a documented BRCA1 or BRCA2 germline mutation

2. Patients can have disease that is measurable or non-measurable.
*Patients with high grade EOC with CA125 elevation alone are eligible if they meet the criteria of disease progression from previous systemic treatment as according to Gynecologic Cancer InterGroup (GCIG) criteria for tumour response and progression

3. Patients meeting eligibility criteria 1a or 1b (breast cancer cohort):
* must have received prior treatment with an anthracycline and taxane in either the adjuvant or metastatic setting
*must not have received more than 3 prior chemotherapy regimens for metastatic/recurrent disease
*may have received prior platinum-based regimens

4. Patients meeting eligibility 1c (ovarian cancer cohort):
* must not have received more than 3 lines of subsequent chemotherapy regimens for metastatic/recurrent disease
* must have received at least one prior platinum-based regimen for their disease
* may have platinum ‘sensitive’ (disease relapse more than 6 months after last platinum based chemotherapy) or platinum ‘resistant or refractory’ disease (disease relapse less than 6 months after last platinum based chemotherapy or primary progressive disease during first line platinum based chemotherapy)

5. The last dose of systemic treatment, inclusive of chemotherapy or hormonal agents must have been administered more than 14 days prior to registration into the study. The last dose of bevacizumab must have been administered 6 weeks or more before registration

6. Prior radiation therapy must be limited to <30% of bone marrow producing areas. Radiation therapy with curative intent must be completed at least 14 days prior to registration

7. Patients must have normal organ and bone marrow function measured within 7 days prior to administration of study treatment as defined below:
a) Haematological function, as follows:
* Haemoglobin >= 100 g/L
* White blood cells (WBC) > 3x109/L or absolute neutrophil count (ANC) >= 1.5 x 109/L
* Platelet count >= 100 x 109/L
* Peripheral blood smear must not show any features suggestive of MDS/AML
b) Hepatic function, as follows:
* Total bilirubin <= 1.5 x institutional upper limit of normal (ULN)
* Alkaline phosphatase (ALP), AST (SGOT)/ALT (SGPT) <= 2.5 x ULN unless liver metastases are present in which case it must be <= 5 x ULN. In the presence of bone metastases, ALP <= 5 x ULN is allowed.
c) Renal function, as follows:
* Serum creatinine <= 1.5 x ULN, or
* creatinine clearance > 60mL/min

8. Within 28 days of registration, patients must have two ECG assessments within a 24 hour period. Patients must not have a resting ECG with a QTc interval of >470 msec or a family history of long QT syndrome

9. Patients on study with reproductive potential must use an effective barrier contraceptive method during the trial and for 3 months after the last dose of study drugs 10. Evidence of non-childbearing status for women of childbearing potential, or postmenopausal status:
* negative urine or serum pregnancy test within 28 days of study treatment, confirmed prior to treatment on day 1 of cycle 1. Postmenopausal status is defined as: - Amenorrheic for 1 year or more following cessation of exogenous hormonal treatments, - LH and FSH levels in the post-menopausal range for women under 50, - radiation-induced oophorectomy with last menses >1 year ago, - chemotherapy-induced menopause with >1 year interval since last menses, - or surgical sterilisation (bilateral oophorectomy or hysterectomy)

11. ECOG Performance Status <=2

12. Estimated life expectancy of at least 16 weeks

13. Patients have signed informed consent and are willing and able to comply with the protocol for the duration of the study, including undergoing treatment and scheduled visits and examinations.
* Patients must also consent for donation of archival diagnostic tumour specimens, if available, for further correlative science research as specified in the protocol and Participant Information Sheet and Consent Form
* Patients will also have the opportunity to consent to additional, optional tissue collection (blood and serum for DNA testing, fresh tissue and ascitic fluid [if applicable]) for further correlative science research as specified in the protocol and Participant Information Sheet and Consent Form

14. Patients must be treated and followed at the institution where they are registered, unless otherwise agreed by the Trial Management Committee
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Any one of the following is regarded as criterion for exclusion from the trial:

1. Any previous treatment with a PARP inhibitor, including olaparib

2. Treatment with any investigational product during the last 14 days (or a longer period depending on the defined characteristics of the agents used). These cases must be referred to the study chair prior to patient registration

3. Patients receiving any systemic chemotherapy, radiotherapy (except for palliative reasons), within 14 days from the last dose prior to study treatment (or a longer period depending on the defined characteristics of the agents used). The patient can receive a stable dose of bisphosphonates for bone metastases, before and during the study as long as these were started at least 4 weeks prior to study treatment

4. Patients with symptomatic uncontrolled brain metastases. A scan to confirm the absence of brain metastases is not required. The patient can receive a stable dose of corticosteroids for brain metastasis, before and during the study, as long as these were started at least 4 weeks prior to treatment

5. Patients who are pregnant or currently breast-feeding

6. Patients who are unable to swallow orally administered medication or have gastrointestinal disorders likely to interfere with absorption of the study medication (e.g. including but not limited to partial bowel obstruction or chronic malabsorption syndrome, Crohn’s disease and ulcerative colitis)

7. Patients with uncontrolled seizures

8. Patients with known interstitial lung disease

9. Patients with known haemorrhagic cystitis

10. Patients with another active second primary cancer, except: - adequately treated non-melanoma skin cancer - curatively treated in-situ cancer of the cervix, or - other solid tumours curatively treated with no evidence of disease for >= 5 years

11. Patients with prior diagnosis of myelodysplastic syndrome or acute myeloid leukaemia. Any abnormal blood films at baseline need to be reviewed to exclude these conditions

12. Patients must not have had a blood transfusion within 28 days prior to registration

13. Patients who are known to be serologically positive for human immunodeficiency virus (HIV), Hepatitis B and/or Hepatitis C

14. Patients receiving the following classes of inhibitors of CYP3A4:
- Azole antifungals
- Macrolide antibiotics
- Protease inhibitors

15. Toxicities (>CTCAE grade 2) caused by previous cancer therapy

16. Patients considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection. Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 3 months) myocardial infarction, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, or any psychiatric disorder that prohibits obtaining informed consent

17. If patient has a major surgery within 14 days of starting study treatment, patient must have recovered from any effects of major surgery

18. Patients with a known hypersensitivity to cyclophosphamide or any of the excipients of olaparib and cyclophosphamide

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Potential participants are identified from patients attending a participating site and are pre-registered to the ANZ 1103 registration system. The Trial Management Committee will authorise a patient to proceed to registration. Written informed consent is obtained, eligibility verified, baseline assessments completed and registration via the ANZ 1103 registration system is performed. The patient is assigned a Trial Registration Number. Patients will enter the study as a cohort of 3 patients per dose level and will receive study drugs as per the dose escalation plan.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other design features
Phase
Phase 1
Type of endpoint(s)
Safety
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,VIC
Recruitment postcode(s) [1] 4655 0
2217
Recruitment postcode(s) [2] 4656 0
3000
Recruitment postcode(s) [3] 5822 0
2031

Funding & Sponsors
Funding source category [1] 284084 0
Other Collaborative groups
Name [1] 284084 0
Breast Cancer Trials
Address [1] 284084 0
PO Box 283
The Junction NSW 2291
Country [1] 284084 0
Australia
Primary sponsor type
Other Collaborative groups
Name
Breast Cancer Trials
Address
PO Box 283
The Junction NSW 2291
Country
Australia
Secondary sponsor category [1] 269050 0
None
Name [1] 269050 0
Address [1] 269050 0
Country [1] 269050 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 272041 0
Cancer Institute NSW Clinical Research Ethics Committee
Ethics committee address [1] 272041 0
Ethics committee country [1] 272041 0
Australia
Date submitted for ethics approval [1] 272041 0
12/11/2012
Approval date [1] 272041 0
11/01/2013
Ethics approval number [1] 272041 0
2012C/12/CIC/206
Ethics committee name [2] 291155 0
South Eastern Sydney Local Health District HREC
Ethics committee address [2] 291155 0
Room B71 East Wing
Edmund Blacket Building
Prince of Wales Hospital
Randwick NSW 2031
Ethics committee country [2] 291155 0
Australia
Date submitted for ethics approval [2] 291155 0
10/02/2014
Approval date [2] 291155 0
10/03/2014
Ethics approval number [2] 291155 0
HREC/13/POWH/531

Summary
Brief summary
This aim of this study is to determine the maximum tolerated dose of Olaparib combined with cyclophosphamide in patients with breast cancer or ovarian cancer.
Who is it for?
You may be eligible to join this study if you are aged 18 years or above and have been diagnosed with either metastatic BRCA-associated breast cancer, triple negative breast cancer or serous ovarian cancer.
Trial details
Olaparib is a highly active agent when used as a single therapy in a standard dose of 400mg twice a day. However, olaparib frequently results in suppression of the immune system when combined with chemotherapy.

Cyclophosphamide is a DNA-damaging agent widely used in breast cancer and epithelial ovarian cancer in metronomic (low dose, continuous therapy) doses and does not have significant suppression of the immune system. It is suggested that combining full-dose olaparib with metronomic cyclophosphamide might result in better treatment of cancers without causing extra difficulties with the immune system.

In this study, participants will be administered olaparib as 300mg tablets twice per day in combination with Cyclophosphamide, which will be administered as 50mg tablets at a pre-specified schedule (the schedule will differ slightly for each dose level). Patients will enter the study as a cohort of 3 patients per dose level. Each dose level cohort will be assessed for toxicity until the maximum tolerated dose (MTD) is determined.

Two extension cohorts will be treated at the MTD. Each cohort will consist of nine or more patients: one cohort of patients with breast cancer, the other cohort of patients with ovarian cancer.

Treatment duration will be up to a maximum of 8 x 21 day cycles. All participants will be regularly monitored throughout treatment to evaluate toxicity, and to assess response rate, progression free survival, and overall survival.
Trial website
www.breastcancertrials.org.au
Trial related presentations / publications
Lee CK, Scott CL, Lindeman GJ, Gibbs E, Badger HD, Paterson RJ, Macnab L, Kwan EM, Boyle FM, Friedlander M, on behalf of the Australia and New Zealand Breast Cancer Trials Group. Phase I study of olaparib (O), in combination with oral cyclophosphamide (C), in patients (pts) with metastatic triple negative breast cancer (TNBC) and recurrent high grade serous ovarian cancer (OVCA). Journal of Clinical Oncology. 2017; 35, (suppl; abst 1104).[ASCO Annual Meeting].
Public notes
Breast Cancer Trials formerly known as Australia & New Zealand Breast Cancer Trials Group.

Contacts
Principal investigator
Name 33299 0
Dr Chee Khoon Lee
Address 33299 0
NHMRC Clinical Trials Centre
University of Sydney
Medical Foundation Building
92-94 Parramatta Road
Camperdown NSW 2050
Country 33299 0
Australia
Phone 33299 0
+61 2 9562 5365
Fax 33299 0
Email 33299 0
chee.lee@ctc.usyd.edu.au
Contact person for public queries
Name 16546 0
Ms Corinna Beckmore
Address 16546 0
BCT
PO Box 283
The Junction NSW 2291
Country 16546 0
Australia
Phone 16546 0
+61 2 4925 5235
Fax 16546 0
Email 16546 0
corinna.beckmore@bctrials.org.au
Contact person for scientific queries
Name 7474 0
Dr Chee Khoon Lee
Address 7474 0
NHMRC Clinical Trials Centre University of Sydney Medical Foundation Building 92-94 Parramatta Road Camperdown NSW 2050
Country 7474 0
Australia
Phone 7474 0
+61 (02) 9562-5365
Fax 7474 0
Email 7474 0
chee.lee@ctc.usyd.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No/undecided IPD sharing reason/comment
What supporting documents are/will be available?
Summary results
Have study results been published in a peer-reviewed journal?
Yes
Journal publication details
Publication date and citation/details [1] 1184 0
Lee CK, Scott C, Lindeman GJ, Hamilton A, Lieschke E, Gibbs E, Asher R, Badger H, Paterson R, Macnab L, Kwan EM, Francis PA, Boyle F, Friedlander M. Phase 1 trial of olaparib and oral cyclophosphamide in BRCA breast cancer, recurrent BRCA ovarian cancer, non-BRCA triple-negative breast cancer, and non-BRCA ovarian cancer. British Journal of Cancer. 2019; epub 17 January 2019, https://doi.org/10.1038/s41416-018-0349-6.
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary