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Trial registered on ANZCTR


Registration number
ACTRN12618000109202
Ethics application status
Approved
Date submitted
16/01/2018
Date registered
24/01/2018
Date last updated
5/06/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
A Phase II Study of Durvalumab and Tremelimumab in combination with Neoadjuvant Carboplatin and Paclitaxel in newly diagnosed women with advanced high grade Serous Ovarian, Fallopian Tube and Peritoneal Cancers “iPRIME”.
Scientific title
A Phase II Study of Durvalumab and Tremelimumab in combination with Neoadjuvant Carboplatin and Paclitaxel in newly diagnosed women with advanced high grade Serous Ovarian, Fallopian Tube and Peritoneal Cancers “iPRIME”.
Secondary ID [1] 293780 0
Nil known
Universal Trial Number (UTN)
U1111-1207-7229
Trial acronym
iPRIME
Linked study record
Not applicable.

Health condition
Health condition(s) or problem(s) studied:
Ovarian cancer 306175 0
Fallopian tube cancer 306283 0
Peritoneal cancer 306284 0
Condition category
Condition code
Cancer 305289 305289 0 0
Ovarian and primary peritoneal

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Participants will be randomised in the ratio of 2:1 between the Arms:

Arm 1: Carboplatin, paclitaxel combined with durvalumab and tremelimumab (Du-T-NACT), followed by maintenance durvalumab and tremelimumab
a) Carboplatin: AUC 5 via intravenous infusion on Day 1 of each 21 day cycle, for a total of 18 weeks
b) Paclitaxel: 175 mg/m2 via intravenous infusion on Day 1 of each 21 day cycle, for a total of 18 weeks
c) Durvalumab: 1500mg via intravenous infusion on Day 1 of each 21 day cycle, for a total of 36 weeks
d) Tremelimumab: 75mg via intravenous infusion on Day 1 of each 21 day cycle, for a total of 36 weeks

Following completion of 3 cycles of neoadjuvant treatment, patients in both arms who are suitable for interval debulking surgery (IDS) should undergo debulking surgery with the goal of optimal cytoreduction by a certified gynaecological oncologist. Surgery should be performed at least 21 days after cycle 3 day 1 (C3D22) but before day 36 (C3D36) provided adequate haematological and clinical recovery.

Patients in Arm 1 who continue to respond will receive maintenance therapy with durvalumab and tremelimumab. Maintenance treatment should commence 4 weeks ± 3 days following the last dose of adjuvant treatment in cycle 6 and continue for 36 weeks or until disease progression, unacceptable toxicity, withdrawal of consent, or another discontinuation criterion is met. Maintenance immunotherapy will consist of:
a) Durvalumab: 1500mg via intravenous infusion on Day 1 of each 21 day cycle, for a total of 36 weeks
b) Tremelimumab: 75mg via intravenous infusion on Day 1 of each 21 day cycle, for a total of 36 weeks

Intervention code [1] 300033 0
Treatment: Drugs
Intervention code [2] 300097 0
Treatment: Surgery
Comparator / control treatment
Arm 2: Carboplatin and paclitaxel (NACT) followed by observation for 36 weeks:
a) Carboplatin: AUC 5 via intravenous infusion on Day 1 of each 21 day cycle, for a total of 18 weeks
b) Paclitaxel: 175 mg/m2 via intravenous infusion on Day 1 of each 21 day cycle, for a total of 18 weeks.

The observation period should commence 4 weeks ± 3 days following the last dose of adjuvant treatment in cycle 6 and continue for a total of 36 weeks. The following assessments take place during the observation period:
- CT scan of the chest, abdomen and pelvis (week 1 only and then as clinically indicated)
- CA-125 assessment (every 4 weeks)
- Quality of Life questionnaire (Week 9, 21 and 33 only)
Control group
Active

Outcomes
Primary outcome [1] 304452 0
The proportion of participants who achieved a complete pathological response (CRS 3) after 3 cycles of neo-adjuvant durvalumab and tremelimumab, as assessed by Clinical Response Score, in patients who underwent interval debulking surgery (composite primary outcome).
Timepoint [1] 304452 0
9 weeks after treatment commencement and post surgery.
Secondary outcome [1] 342011 0
Progression free survival, defined as the time from randomisation to first documented disease progression by RECIST 1.1 or death from any cause,
Timepoint [1] 342011 0
12 months after treatment commencement.
Secondary outcome [2] 342012 0
The safety of neoadjuvant durvalumab and tremelimumab treatment, determined according to CTCAE 4.03 criteria.
Timepoint [2] 342012 0
Week 3, 6, 9, 12, 15, 18, then 4-weekly thereafter, until 30 days after the last dose of treatment.
Secondary outcome [3] 342013 0
The proportion of interval debulking surgery performed, assessed in terms of surgery completion rates.
Timepoint [3] 342013 0
Between week 10 and 11 after treatment commencement.
Secondary outcome [4] 342219 0
To describe Heath-Related Quality of Life (HRQoL) in patients treated with Du-T-NACT, and compare with NACT alone, as assessed from the Functional Assessment of Cancer Therapy for Ovarian Cancer (FACT-O) questionnaire.
Timepoint [4] 342219 0
Baseline, Cycles 1 through to 6 during the neo-adjuvant phase, then weeks 9, 21 and 33 during maintenance/observation phase.

Eligibility
Key inclusion criteria
1. Signed, written informed consent obtained from the patient prior to performing any protocol-related procedures, including screening evaluations
2. Age greater than or equal to 18 years at the time of screening
3. Has a life expectancy of at least 12 weeks
4. Histologically or cytologically confirmed high grade serous ovarian carcinoma
5. FIGO stage IIIC or IV disease:
- A diagnosis of stage IIIC requires evidence of macroscopic, extra-pelvic, peritoneal metastasis > 2 cm ± positive retroperitoneal lymph nodes. Includes extension to capsule of liver/spleen. based on either laparoscopic or radiological assessment
- Stage IV disease is defined as either IVA: pleural effusion with positive cytology, or IVB: hepatic and/or splenic parenchymal metastasis, metastasis to extraabdominal organs (including inguinal lymph nodes and lymph nodes outside of the abdominal cavity)
6. Agree to undergo a pre-treatment biopsy either radiologically (core-needle) or via laparoscopy. Fine needle aspirate (FNA) alone is not acceptable.
7. Measurable disease according to RECIST 1.1 criteria
8. Considered to be both medically fit to receive NACT, and a suitable surgical candidate for interval debulking surgery by both the study investigator and the treating gynaecologic oncologist
9. ECOG performance status 0-1
10. Adequate normal organ and marrow function as defined below:
- Haemoglobin greater than or equal to 90g/L
- Absolute neutrophil count (ANC) greater than or equal to 1.5 x 109/L
- Platelet count greater than or equal to 100 x 109/L
- Serum bilirubin less than or equal to 1.5 x institutional upper limit of normal (ULN). This will not apply to patients with confirmed Gilberts syndrome (persistent or recurrent hyperbilirubinaemia that is predominantly unconjugated in the absence of haemolysis or hepatic pathology, who will be allowed only in consultation with the CPI
- AST (SGOT)/ALT (SGPT) less than or equal to 2.5 x ULN unless liver metastases are present, in which case it must be less than or equal to 5 x ULN
- Measured creatinine clearance (CL) >40mL/min or Calculated creatinine clearance >40mL/min by the Cockcroft-Gault formula or by 24-hour urine collection for determination of creatinine clearance
- Evidence of post-menopausal status or negative urinary or serum pregnancy test for pre-menopausal patients. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause.
11. Patient is willing and able to comply with the protocol for the duration of the study including undergoing biopsies, treatment, and scheduled visits and examination including follow up
12. Body weight >30 kg
Minimum age
18 Years
Maximum age
No limit
Gender
Females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Previous chemotherapy, radiotherapy or surgery for ovarian cancer
2. Prior exposure to immune-mediated therapy including, but not limited to, other anti-CTLA-4, anti PD 1, anti-PD-L1, or anti-PD-L2 antibodies, including therapeutic anticancer vaccines.
3. Prior omentectomy
4. Patients with disease that is considered inoperable and in the opinion of the treating gynaecological oncologist is unlikely to become operable post NACT
5. Participation in another clinical study with an investigational product during the last 6 months
6. Concurrent enrolment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study
7. Any unresolved toxicity NCI CTCAE Grade greater than or equal to 2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria
- Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab or tremelimumab may be included only after consultation with the CPI
8. Any other concurrent chemotherapy, biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non–cancer-related conditions (e.g., hormone replacement therapy) is acceptable
9. Major surgical procedure within 28 days prior to randomisation. A diagnostic laparoscopy or laparotomy is acceptable provided a debulking has not been performed.
10. History of allogenic organ transplantation
11. Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g., ulcerative colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc.]). The following are exceptions to this criterion:
- Patients with vitiligo or alopecia
- Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement
- Any chronic skin condition that does not require systemic therapy
- Patients without active disease in the last 5 years may be included but only after consultation with the CPI
- Patients with coeliac disease controlled by diet alone
12. Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent
13. History of another primary malignancy except for
- Malignancy treated with curative intent and with no known active disease greater than or equal to 5 years before the randomisation and of low potential risk for recurrence
- Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
- Adequately treated carcinoma in situ without evidence of disease
14. History of leptomeningeal carcinomatosis
15. Brain metastases or spinal cord compression. Patients with suspected brain metastases at screening should have an MRI (preferred) or CT each preferably with IV contrast of the brain prior to randomisation
16. History of active primary immunodeficiency
17. Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice), hepatitis B (known positive HBV surface antigen (HBsAg) result), hepatitis C, or human immunodeficiency virus (positive HIV 1/2 antibodies). Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA positive, or Hepatitis C antibody (anti-HCV) positive (except if HCV-RNA negative)
18. Current or prior use of immunosuppressive medication within 14 days before randomisation. The following are exceptions to this criterion:
- Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection)
- Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent
- Steroids as premedication for hypersensitivity reactions (e.g. CT scan premedication)
19. Receipt of live attenuated vaccine, inactive vaccines including annual influenza vaccine within 30 days prior to randomisation. Note: Patients, if enrolled, should not receive live vaccine whilst receiving study drugs and up to 30 days after the last dose of study drugs
20. Patients who are pregnant or breastfeeding or of reproductive potential who are not willing to employ effective birth control from screening to 180 days after the last dose of durvalumab and tremelimumab combination therapy
21. Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients
22. Prior randomisation or treatment in a previous durvalumab and/or tremelimumab clinical study regardless of treatment Arm assignment..


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)
Eligible patients will be randomised electronically using the online iPRIME electronic data capture (EDC) system. Confirmation of randomisation and randomisation Arm assigned will be provided electronically (via email) as well as, a unique 6-digit patient identification number. Participants will be randomised in the ratio of 2:1 between the Arms, stratified according to Stage (IIIC vs. IV).
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by computer software (i.e. computerised sequence generation). Participants will be randomised in the ratio of 2:1 between the Arms, stratified according to Stage (IIIC vs. IV).
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
Baseline characteristics and treatment details will be described by Arm using descriptive statistics such as minimum, maximum, median, mean and standard deviation for quantitative variables. Qualitative variables will be described in tabular form as counts and percentages.

No imputation for missing values and no adjustment for multiplicity is intended.

The primary endpoint for this trial is the rate of CRS 3 after 3 cycles of neoadjuvant therapy. The CRS 3 rate will be reported as a binomial proportion with exact two-sided 90% confidence interval in the subset of patients treated with Du-T-NACT who underwent surgery (most patients are expected to have surgery). A second analysis of CRS rate will be performed considering all patients randomised to Du-T-NACT with patients not proceeding to surgery due to not responding to treatment being considered as non-responders for CRS 3.

A cut-off date for follow-up will be determined at the time of analysis, generally taken as the date of the earliest follow-up on all participants alive and not lost to follow-up. The cut-off date will be chosen to enable data on follow-up to that date to be collected, where possible, on all living participants. All events occurring after this date will be ignored in the analysis in order to minimise reporting bias. Progression free survival will be described for each Arm using Kaplan-Meier methods. Estimates at key time points will be provided with 95% confidence intervals. The stratified log-rank test will be used to compare the curves between Arms.

Pre-operative response rate, CA-125 response rate, CRS response rate and surgery completion rate will be estimated for each Arm with corresponding exact 95% confidence interval and will be compared between Arms using Fisher’s exact test. The surgery delay time will be described in each Arm using descriptive statistics.

All AEs observed from the beginning of treatment until 30 days after the last dose is administered will be recorded for each participant and the maximum AE grade per participant of each adverse event will be derived and presented in table format according to Arm. The analysis of AE’s will be conducted twice: once for all AE’s, regardless of relatedness to treatment and once considering only AE’s related to the treatment (i.e. classified as possibly, probably or definitely related). Rate of grade 3+ toxicities will be compared between Arms using Fisher’s exact test. Serious AEs and other significant AEs will be listed.

HRQoL will be analysed using linear mixed models (LMM) with time (as factor), Arm and interaction of time and Arm included as a fixed effect and patient included as a random effect. No within-group correlations will be assumed, with the model being fitted by maximizing the restricted log-likelihood (REML). No imputation for missing values is intended. Means and 95% confidence intervals will be estimated from the LMM contrasts for each Arm and each time point. HRQoL trajectory will be described graphically.

An analysis of measured biomarkers will be performed to assess association with disease activity, effects of study drug and clinical outcomes in order to detect potentially prognostics or predictive biomarkers that may be of interest for further research. Biomarkers analysis methods and report will be separate from the main study.

A statistical analysis plan (SAP) will be written for the trial. Any deviations from the planned analysis will be described in a protocol amendment or updated SAP.

The proposed primary endpoint is complete pathological response (CRS 3) after 3 cycles of neoadjuvant chemotherapy. The expected rate of CRS 3 from the primary and validation cohorts of chemotherapy response scoring was 27-33%. For patients treated with Du-T-NACT , the null hypothesis is that the true rate of CRS 3 is 30% and would be of no further interest, whereas a CRS 3 rate of greater than or equal 50% is of interest for further development. With 80% power, 0.05 alpha, 1-sided exact test, the required sample size of patients treated with Du-T-NACT is 43 patients. The primary endpoint will be assessed on patients who underwent surgery, therefore 50 patients will be recruited to allow at least 43 to be assessable for primary the endpoint.

A control group of 25 patients treated with NACT alone will be recruited to provide a contemporary estimate of the CRS 3 rate in this population. This will allow for further validation studies if the control group is found to have a CRS 3 rate higher than the expected 30%. Patients will be randomised at a 2:1 ratio between Du-T-NACT and NACT alone.

Recruitment of the 75 patients will occur over a two-year period and patients will be followed until 2 years after last participant commenced treatment

Recruitment
Recruitment status
Not yet 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,WA,VIC
Recruitment hospital [1] 9773 0
Peter MacCallum Cancer Centre - Melbourne
Recruitment hospital [2] 9774 0
Monash Medical Centre - Clayton campus - Clayton
Recruitment hospital [3] 9775 0
Mater Adult Hospital - South Brisbane
Recruitment hospital [4] 9776 0
Royal Brisbane & Womens Hospital - Herston
Recruitment hospital [5] 9777 0
St George Hospital - Kogarah
Recruitment hospital [6] 9778 0
Westmead Hospital - Westmead
Recruitment hospital [7] 9779 0
Newcastle Private Hospital - New Lambton Heights
Recruitment hospital [8] 9780 0
Prince of Wales Hospital - Randwick
Recruitment hospital [9] 9781 0
St John of God Hospital, Subiaco - Subiaco
Recruitment hospital [10] 9782 0
Linear Clinical Research - Nedlands
Recruitment postcode(s) [1] 18551 0
3000 - Melbourne
Recruitment postcode(s) [2] 18552 0
3168 - Clayton
Recruitment postcode(s) [3] 18553 0
4101 - South Brisbane
Recruitment postcode(s) [4] 18554 0
4029 - Herston
Recruitment postcode(s) [5] 18555 0
2217 - Kogarah
Recruitment postcode(s) [6] 18556 0
2145 - Westmead
Recruitment postcode(s) [7] 18557 0
2305 - New Lambton Heights
Recruitment postcode(s) [8] 18558 0
2031 - Randwick
Recruitment postcode(s) [9] 18559 0
6008 - Subiaco
Recruitment postcode(s) [10] 18560 0
6009 - Nedlands

Funding & Sponsors
Funding source category [1] 298397 0
Other Collaborative groups
Name [1] 298397 0
Australia New Zealand Gynaecological Oncology Group (ANZGOG)
Address [1] 298397 0
Level 6, Chris O’Brien Lifehouse
119-143 Missenden Road
CAMPERDOWN NSW 2050
Country [1] 298397 0
Australia
Primary sponsor type
Other Collaborative groups
Name
Australia New Zealand Gynaecological Oncology Group (ANZGOG)
Address
Level 6, Chris O’Brien Lifehouse
119-143 Missenden Road
CAMPERDOWN NSW 2050
Country
Australia
Secondary sponsor category [1] 297536 0
None
Name [1] 297536 0
Address [1] 297536 0
Country [1] 297536 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 299390 0
Peter MacCallum Cancer Centre
Ethics committee address [1] 299390 0
C/O HREC Secretariat
Victorian Comprehensive Cancer Centre
305 Grattan Street
Melbourne VIC 3000
Ethics committee country [1] 299390 0
Australia
Date submitted for ethics approval [1] 299390 0
12/02/2018
Approval date [1] 299390 0
22/03/2018
Ethics approval number [1] 299390 0
HREC/17/PMCC/289
Ethics committee name [2] 299400 0
Bellberry Limited
Ethics committee address [2] 299400 0
29 Glen Osmond Road
Eastwood South Australia 5063
Ethics committee country [2] 299400 0
Australia
Date submitted for ethics approval [2] 299400 0
12/02/2018
Approval date [2] 299400 0
14/05/2018
Ethics approval number [2] 299400 0
2018-02-133
Ethics committee name [3] 299401 0
St John of God
Ethics committee address [3] 299401 0
St John of God Health Care Human Research Ethics Committee
C/o St John of God Subiaco Hospital
12 Salvado Road
Subiaco Western Australia 6008
Ethics committee country [3] 299401 0
Australia
Date submitted for ethics approval [3] 299401 0
08/05/2018
Approval date [3] 299401 0
Ethics approval number [3] 299401 0

Summary
Brief summary
Ovarian cancer is the second most common gynaecological malignancy and the most common cause of gynaecological cancer death in Australia. The majority of women are diagnosed with advanced disease, where standard treatment includes surgery followed by six cycles of adjuvant platinum-based chemotherapy.

The purpose of this research project is to test how safe and effective the combination treatment of durvalumab and tremelimumab in combination with standard chemotherapy is as a treatment for patients with ovarian, fallopian tube or peritoneal cancers.

Who is it for?
You may be eligible to join this study if you are a female aged 18 years or older with a confirmed diagnosis of stage III or IV high grade serous ovarian, fallopian tube, or peritoneal carcinoma, and a life expectancy of at least 12 weeks.

Study details
Participants in this study will be randomly allocated (by chance) to one of two groups. Participants in one group will receive [18 weeks/6 cycles] of treatment with Carboplatin, paclitaxel combined with durvalumab and tremelimumab (Du-T-NACT) administered intravenously (i.e. directly into the vein). This will then be followed by maintenance therapy with Durvalumab (every 4 weeks) and Tremelimumab (every 12 weeks) for 36 weeks or until disease progression, unacceptable toxicity, withdrawal of consent, or another discontinuation criterion is met. Durvalumab and tremelimumab are new drugs which are designed to increase the body’s immune response. Participants in the other group will receive [18 weeks/6 cycles] of chemotherapy with Carboplatin and paclitaxel only, followed by an observation period, which involves 4 weekly CA-125 assessments. Participants in both groups may also undergo interval debulking surgery after 3 cycles of treatment, if suitable.

All participants will be monitored regularly for up to 12 months post treatment in order to assess clinical response and treatment safety. It is hoped that that durvalumab and tremelimumab will stimulate the immune cells to be able to prevent or slow down cancer growth.

The study aims to recruit 75 patients (50 patients to receive adjuvant treatment and 25 to receive neoadjuvant treatment at a 2:1 ratio), across 10 Australian sites over a 2 year recruitment period.
Trial website
https://www.anzgog.org.au/
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 80254 0
Dr Tarek Meniawy
Address 80254 0
Linear Clinical Research
B Block
Hospital Avenue
Nedlands WA 6009
Country 80254 0
Australia
Phone 80254 0
+61 8 6457 3841
Fax 80254 0
+61 8 6547 3390
Email 80254 0
Tarek.Meniawy@health.wa.gov.au
Contact person for public queries
Name 80255 0
Dr Tarek Meniawy
Address 80255 0
Linear Clinical Research
B Block
Hospital Avenue
Nedlands WA 6009
Country 80255 0
Australia
Phone 80255 0
+61 8 6457 3841
Fax 80255 0
+61 8 6547 3390
Email 80255 0
Tarek.Meniawy@health.wa.gov.au
Contact person for scientific queries
Name 80256 0
Dr Tarek Meniawy
Address 80256 0
Linear Clinical Research
B Block
Hospital Avenue
Nedlands WA 6009
Country 80256 0
Australia
Phone 80256 0
+61 8 6457 3841
Fax 80256 0
+61 8 6547 3390
Email 80256 0
Tarek.Meniawy@health.wa.gov.au

No data has been provided for results reporting
Summary results
Not applicable