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Trial registered on ANZCTR


Registration number
ACTRN12618000686202
Ethics application status
Approved
Date submitted
27/03/2018
Date registered
27/04/2018
Date last updated
1/04/2019
Date data sharing statement initially provided
22/02/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Study evaluating the efficacy of:
1. Olaparib and cyclophosphamide followed by olaparib and durvalumab, or
2. Olaparib followed by olaparib and durvalumab, or
3. Olaparib in ovarian cancer patients.
Scientific title
A Phase II randomised trial comparing immune priming by low dose oral cyclophosphamide plus olaparib versus priming by olaparib alone, prior to combination therapy with olaparib plus durvalumab, versus single agent olaparib alone, in asymptomatic platinum-sensitive recurrent ovarian, fallopian tube or primary peritoneal cancers with homologous recombination repair defects.
Secondary ID [1] 294421 0
CTC 0178 / ANZGOG 1723/2018
Universal Trial Number (UTN)
Trial acronym
SOLACE 2
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Ovarian cancer 307159 0
Fallopian tube cancer 307160 0
Peritoneal cancer 307161 0
Condition category
Condition code
Cancer 306278 306278 0 0
Ovarian and primary peritoneal

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Interventional

Treatment: Drugs - Olaparib is a PARP inhibitor, targeting DNA repair processes.
Treatment: Drugs - Cyclophosphamide is a chemotherapy that has been used for the treatment of ovarian cancers for many years.
Treatment: Drugs - Durvalumab is a PD-L1 inhibitor, an antibody (a type of human protein) that works by blocking a body substance called PD-L1. Blocking (inhibiting) PD-L1 helps the body’s immune system to attack cancer cells.

Patients will be randomised to:
A) Olaparib tablets 300mg orally twice daily for 12 weeks, followed in the absence of progression according to RECIST 1.1 by olaparib 300 mg twice daily plus durvalumab 1500mg IV every 4 weeks for 12 cycles, followed by olaparib alone until progression;
B) Olaparib 300mg twice daily plus oral cyclophosphamide 50mg daily for 5 out of 7 days a week (1000mg per 4 weeks), for 3 x four-weekly cycles over 12 weeks, followed in the absence of progression according to RECIST 1.1 by olaparib plus durvalumab (dosing schedule as above) for 12 cycles, followed by olaparib alone until progression;
C) Olaparib 300mg twice daily until progression.

Participant compliance with olaparib and cyclophosphamide will be determined at each clinic visit by reviewing patient diaries.
Intervention code [1] 300714 0
Treatment: Drugs
Comparator / control treatment
Olaparib 300mg twice daily until progression.
Control group
Active

Outcomes
Primary outcome [1] 305284 0
To determine in each treatment arm:
1) 36 week progression-free survival rate (36wPFS, death or PD by RECIST 1.1 criteria at 36 weeks)
Timepoint [1] 305284 0
36 weeks post enrolment.
Secondary outcome [1] 344710 0
Objective response (OR = CR or PR) rate (ORR) by RECIST 1.1 or GCIG CA125 criteria. Objective response rate (ORR) is defined as the proportion of patients experiencing a complete response (CR) or partial response (PR) by RECIST 1.1 or GCIG CA125 criteria.
Timepoint [1] 344710 0
12 months post randomisation.
Secondary outcome [2] 344711 0
Progression free survival (PFS) by RECIST 1.1 or GCIG CA125 criteria.
Timepoint [2] 344711 0
12 months post randomisation.
Secondary outcome [3] 344712 0
Objective tumour response (OTR = CR or PR) rate (OTRR) and PFS by iRECIST. Objective tumour response rate (OTRR) in each arm is defined as the proportion of participants with an objective tumour response (OTR = CR + PR) divided by the total number of participants with measurable disease at baseline in that cohort.
Timepoint [3] 344712 0
12 months post randomisation.
Secondary outcome [4] 344713 0
Frequency and severity of adverse events (CTCAE v4.03) - composite outcome.
Examples may include: Drug toxicity, drug adverse reactions etc.
Timepoint [4] 344713 0
AEs will be recorded from the first dose of study treatment until 90 days after cessation of study treatment.
Secondary outcome [5] 344714 0
Aspects of health related quality of life (EORTC QLQ-C30, OV28 and MOST)
Timepoint [5] 344714 0
Collected at baseline then 4 weekly until up to 60 weeks then 12 weekly until progression and 4 weeks post progression.

Secondary outcome [6] 344715 0
Time to starting first subsequent therapy (TFST) or death.
Timepoint [6] 344715 0
12 months post randomisation.

Secondary outcome [7] 344716 0
Time to development of symptoms associated with progression, specifically abdominal/gastrointestinal symptoms including: abdominal pain/discomfort/cramps; changes in bowel habits; indigestion/heartburn; nausea; vomiting; bloating.
This outcome will be assessed by review of patient completed questionnaires including EORTC QLQ-C30, OV28 and MOST.
Timepoint [7] 344716 0
Collected at baseline then 4 weekly until up to 60 weeks then 12 weekly until progression and 4 weeks post progression.
Secondary outcome [8] 345105 0
Number of responders to PARPi and/or LDCy combination and/or immune therapy determined using a Cyclophosphamide-UPregulation (CUP) test.

Timepoint [8] 345105 0
Blood for tertiary correlative studies at study entry, pre-treatment, every 2 weeks for 12 weeks, then every 4 weeks for 24 weeks, and at progression.
Secondary outcome [9] 345108 0
Exploratory assessment of ctDNA in available plasma samples.
Timepoint [9] 345108 0
Blood for tertiary correlative studies at study entry, pre-treatment, every 2 weeks for 12 weeks, then every 4 weeks for 24 weeks, and at progression.

Eligibility
Key inclusion criteria
1. Women, aged 18 years and older, with histologically confirmed high-grade serous carcinoma of the ovary, fallopian tube or primary peritoneum.
2. Undergone adequate debulking surgery and 1 line of platinum-based chemotherapy. Patients who received bevacizumab as part of first-line treatment are eligible.
3. Known germline BRCA1 and BRCA2 status. Both BRCA mutant and BRCA wild-type patients are eligible. For patients who are BRCA wild-type, they must have:
• Initial diagnosis of high-grade serous carcinoma at less than 70 years of age;
• Normalisation of CA125 to less than upper limit of normal (ULN) by the end of cycle 4 of first-line chemotherapy.
4. First CA125 GCIG progression after first-line treatment, occurring 6 months or more following the last dose of chemotherapy, defined as CA125 readings twice the upper limit of normal on 2 occasions at least 1 week apart.
5. Patients can have either RECIST measurable or non-measurable disease or no disease
6. No symptoms of cancer progression.
7. No indication for immediate chemotherapy or secondary debulking surgery.
8. ECOG performance status of 0-1
9. Confirmation of the availability of tumour tissue (FFPE) for translational studies (a cell pellet from ascites or pleural fluid is not acceptable). If no tissue is available, patients will not be eligible for this study.
10. Adequate bone marrow function (measured within 28 days prior to registration and with values within the ranges specified below):
• Absolute neutrophil count equal to or greater than 1.5 x 109 /L
• Platelet count equal to or greater than 100 x 109 /L
• Haemoglobin equal to or greater than 100 g/L with no blood transfusion in the past 28 days
• Peripheral blood smear must not show any features suggestive of myelodysplastic syndrome/acute myeloblastic leukaemia.
11. Adequate liver function, as follows:
• Total bilirubin equal to or less than 1.5 x institutional upper limit of normal (ULN)
• Alkaline phosphatase (ALP), equal to or less than 2.5 x ULN (or equal to or less than 5 x ULN if liver metastases AST (SGOT), ALT (SGPT are present)
12. Adequate renal function, as follows:
• Serum creatinine equal to or less than 1.5 x ULN, or
• Creatinine clearance greater than 50mL/min (Cockcroft-Gault Formula)
13. Willing and able to comply with all study requirements, including treatment, timing and/or nature of required assessments.
14. Signed, written informed consent prior to any study specific procedures.
Minimum age
18 Years
Maximum age
No limit
Gender
Females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Previous enrolment or randomization in the present study.
2. Any previous treatment with a PARP inhibitor, including olaparib.
3. Any previous treatment with durvalumab, or any other anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibodies or any other antibody or drug specifically targeting T cell co-stimulation or immune checkpoint pathways.
4. Concomitant use of known strong CYP3A inhibitors (e.g. itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (e.g. ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The required washout period prior to starting olaparib is 2 weeks.
5. Concomitant use of known strong (e.g. phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John’s Wort) or moderate CYP3A inducers (e.g. bosentan, efavirenz, modafinil). The required washout period prior to starting olaparib is 5 weeks for enzalutamide or phenobarbital and 3 weeks from the last study dose for other agents.).
6. Treatment with any investigational product during the last 14 days (or a longer period depending on the defined characteristics of the agents used).
7. Patients receiving any systemic anti-cancer treatment (including endocrine therapy, chemotherapy or VEGF-targeted agents) or 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).
8. 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).
9. Suspected brain or leptomeningeal metastases, untreated brain metastases or current clinical or radiological progression of known brain metastases, or requirement for steroid therapy for brain metastases. Patients with treated brain metastases are eligible if they have been stable and off steroids for equal to or greater than 3 weeks.
10. Patients with known haemorrhagic cystitis.
11. History of another malignancy within 5 years prior to registration, except curatively treated cervical carcinoma in situ, non-melanomatous carcinoma of the skin, DCIS of the breast, or Stage 1 Grade 1 endometrial cancer. Patients who have been free of other solid tumours (including lymphomas without bone marrow involvement) malignancies for equal to or greater than 5 years prior to registration are eligible for this study. Patients with triple-negative breast cancer treated with curative therapy which was completed more than three years before are eligible.
12. History of known or suspected auto-immune disease other than vitiligo, type 1 diabetes, residual hypothyroidism due to an autoimmune condition requiring only hormone replacement, or psoriasis not requiring systematic treatment within the last 2 years.
13. Prior allogeneic organ transplant, double umbilical cord blood transplantation, inflammatory bowel disease (e.g. Crohn’s disease, ulcerative colitis), pneumonitis, tuberculosis, or primary immunodeficiency.
14. 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.
15. Current or prior use of immunosuppressive medication within 28 days before the first dose of durvalumab, with the exception of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone or an equivalent corticosteroid. In the case of short term use of systemic corticosteroids (less than 24 hours within 28 days) of greater than 10 mg/day of prednisone or an equivalent corticosteroid, the required washout period prior to starting the first dose of durvalumab is 7 days.
16. Receipt of live attenuated vaccination within 30 days before the first dose of durvalumab.
17. Whole blood transfusions in the last 120 days prior to entry to the study (packed red blood cells and platelet transfusions are acceptable outside of 28 days prior to registration).
18. Patients who are known to be serologically positive for human immunodeficiency virus (HIV), Hepatitis B and/or Hepatitis C.
19. 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.
20. 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, symptomatic congestive heart failure, uncontrolled hypertension, uncontrolled ventricular arrhythmia, recent (within 3 months) myocardial infarction, unstable angina pectoris, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, extensive interstitial bilateral lung disease on High Resolution Computed Tomography (HRCT) scan, active peptic ulcer disease or gastritis, active bleeding diathesis, or any psychiatric disorder/social situation that would limit compliance with study requirements or compromise the ability of the subject to give written informed consent.
21. Major surgical procedure within 14 days prior to study treatment, or still recovering from any effects of major surgery.
22. Any unresolved toxicity NCI CTCAE Grade >1 from previous anticancer therapy. Subjects with Grade equal to or less than 2 neuropathy or Grade equal to or less than 2 alopecia are exceptions to this criterion.
23. Patients with known hypersensitivity to cyclophosphamide or any excipients of olaparib, cyclophosphamide or durvalumab.
24. Life expectancy of less than 12 months.
25. Pregnancy, lactation, or inadequate contraception. Most patients would have undergone prior oophorectomy and hysterectomy as part of surgical treatment for ovarian cancer. For women who have ovaries and uterus in situ, they must be post-menopausal, infertile, or use a reliable means of contraception. Women of childbearing potential must have a negative pregnancy test done within 7 days prior to registration.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Central randomisation by computer.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Site/Institution
Minimisation will be used to allocate patients equally to each of the 3 treatment arms (1:1:1), with stratification factors as follows:
1. Platinum-free interval (6-12 months versus greater than 12 months)
2. CA-125 (less than 100 U/mL versus equal to or greater than 100 U/mL)
3. Measureable disease (yes versus none)
4. Germline BRCA mutation status (mutant versus wild-type).
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?



The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
The choice of PFS rate at the 36-week (9-month) time-point from randomization is considered optimal for providing the best possible data to address the primary hypothesis.

Using Fleming’s single stage design, with 95% confidence and 80% power, 38 patients per arm will be required in order to exclude at 36 weeks an uninteresting PFS rate of 47% in favour of a more clinically meaningful PFS rate of 67%. Additionally as there are 3 groups a total of 114 patients will also allow (using the selection design of Simon, Wittes, and Ellenberg) a minimum of 15% difference from the best performing regimen to be detected with a probability greater than 0.80.

The primary endpoint progression-free survival (PFS) will be analysed using time-to-event methods. The PFS rate at 36 weeks will be calculated using Kaplan-Meier estimates, with corresponding 95% confidence intervals (CIs).

The secondary endpoints will be analysed by the proportions of patients achieving objective responses will be calculated with appropriate 95% confidence intervals. Proportions of patients suffering grade 3 or worst toxicity will be reported by treatment arm. Comparisons of proportions between treatment arms will be performed using chi-squared or exact tests.

The primary Quality of Life endpoint change in QLQ-C30 global score from baseline to 36 weeks will be analysed using regression methods including adjustment for baseline variables and other appropriate statistical methods. Amongst progressors the time to clinically significant increase in abdominal/gastrointestinal symptom scores will be analysed using the Kaplan-Meier method and described using the median with 95% CI. Abdominal/gastrointestinal scores at progression and prior to progression will be compared using the paired t-test.

Time to starting first subsequent therapy or death will be analysed using time-to-event methods, similarly as for PFS above, and characterised in terms of the median (with 95% CI).

Recruitment
Recruitment status
Recruiting
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,QLD,SA,TAS
Recruitment hospital [1] 10482 0
St George Hospital - Kogarah
Recruitment hospital [2] 13226 0
Newcastle Private Hospital - New Lambton Heights
Recruitment hospital [3] 13227 0
Prince of Wales Hospital - Randwick
Recruitment postcode(s) [1] 22195 0
2217 - Kogarah
Recruitment postcode(s) [2] 22196 0
3050 - Parkville
Recruitment postcode(s) [3] 25783 0
2305 - New Lambton Heights
Recruitment postcode(s) [4] 25784 0
2031 - Randwick

Funding & Sponsors
Funding source category [1] 299050 0
Commercial sector/Industry
Name [1] 299050 0
AstraZeneca
Address [1] 299050 0
Cambridge Biomedical Campus
1 Francis Crick Ave, Cambridge CB2 0RE
Country [1] 299050 0
United Kingdom
Primary sponsor type
University
Name
The University of Sydney
Address
NSW 2006
Country
Australia
Secondary sponsor category [1] 298285 0
None
Name [1] 298285 0
Address [1] 298285 0
Country [1] 298285 0
Other collaborator category [1] 280043 0
Other Collaborative groups
Name [1] 280043 0
Australia New Zealand Gynaecological Oncology Group
Address [1] 280043 0
Level 6, Chris O’Brien Lifehouse
119-143 Missenden Road, CAMPERDOWN NSW 2050
Country [1] 280043 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 299985 0
Sydney Local Health District Human Research Ethics Committee - RPAH Zone
Ethics committee address [1] 299985 0
Research Development Office
Royal Prince Alfred Hospital
Missenden Road
CAMPERDOWN NSW 2050
Ethics committee country [1] 299985 0
Australia
Date submitted for ethics approval [1] 299985 0
18/04/2018
Approval date [1] 299985 0
31/05/2018
Ethics approval number [1] 299985 0

Summary
Brief summary
Study purpose
The purpose of this study is to test new combinations of drugs for ovarian cancer that has come back after first-line treatment. The new combinations of treatment include olaparib given by itself, olaparib given with an antibody (durvalumab), or olaparib given with chemotherapy (cyclophosphamide) and then with an antibody (durvalumab). These new combinations may slow the progression of the cancer and delay the time until chemotherapy treatment is needed.

Who is it for?
You may be eligible for this study if you are a female aged over 18 years and have a histologically proven diagnosis of high-grade serous or carcinoma of the ovary, fallopian tube or peritoneum, at first asymptomatic CA125 progression which responded to platinum-based chemotherapy.

Study details
Participants will be randomly assigned (by chance) to one of three treatment groups.
One group will receive two medications, olaparib taken by mouth twice a day, followed by durvalumab given into a vein and at the same time olaparib, then olaparib only.

The second group will receive three medications, olaparib taken by mouth twice a day and at the same time cyclophosphamide taken by mouth once daily for 5 days of every week, followed by durvalumab given into a vein and at the same time olaparib, then olaparib only.

The third group will receive one medication, olaparib taken by mouth twice a day.

Participants will attend a number of hospital visits to give blood and answer questionnaires about their quality of life.

It is hoped that this research may help people in the future who have the same kind of cancer as you have.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 82166 0
A/Prof Clare Scott
Address 82166 0
c/o SOLACE 2 Study Team
NHMRC Clinical Trials Centre
Locked Bag 77
Camperdown, NSW 1450
Country 82166 0
Australia
Phone 82166 0
+61 2 9562 5000
Fax 82166 0
Email 82166 0
scottc@wehi.edu.au
Contact person for public queries
Name 82167 0
Miss SOLACE 2 Trial Coordinator
Address 82167 0
c/o SOLACE 2 Study Team
NHMRC Clinical Trials Centre
Locked Bag 77
Camperdown, NSW 1450
Country 82167 0
Australia
Phone 82167 0
+61 2 9562 5000
Fax 82167 0
Email 82167 0
solace2@ctc.usyd.edu.au
Contact person for scientific queries
Name 82168 0
A/Prof Clare Scott
Address 82168 0
c/o SOLACE 2 Study Team
NHMRC Clinical Trials Centre
Locked Bag 77
Camperdown, NSW 1450
Country 82168 0
Australia
Phone 82168 0
+61 2 9562 5000
Fax 82168 0
Email 82168 0
solace2@ctc.usyd.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
What supporting documents are/will be available?
Study protocol
Summary results
No Results