Study setting {9}
Participating hospital research sites in the UK and Germany. A list of study sites can be obtained from the trial registration listing.
Eligibility criteria {10}
Inclusion criteria:
1. Signed and dated written informed consent prior to admission to the study and initiation of any study procedures in accordance with The International Council for Harmonisation Good Clinical Practice guidelines and to the local legislation
2. Females ≥ 18 years of age
3. Pathological diagnosis of ovarian, fallopian tube or primary peritoneal cancer, of clear cell, endometrioid or high grade serous subtype or carcinosarcoma. Local tumour board/multi-disciplinary team histological review is required and in mixed tumours more than 50% endometrioid, clear cell or high grade serous elements are required to define the predominant histology
4. Platinum-resistant (recurrence within 6 months of platinum treatment), or platinum refractory disease (recurrence during platinum treatment), patients having received at least one prior line of chemotherapy. Carboplatin and weekly paclitaxel are permitted as first line therapy and/or as therapy for recurrent platinum sensitive disease i.e. prior to platinum resistant relapse
5. Measurable disease as per RECIST version 1.1 by computerised tomography (CT) or magnetic resonance imaging (MRI)
6. Fresh tumour biopsy during screening is compulsory, if judged technically feasible by radiologist, unless the local site is unable to collect the sample due to COVID-19 capacity restrictions
7. Patients with a history of brain metastasis are eligible as long as all the following criteria are met: brain metastases must have been treated, have no evidence of progression or haemorrhage after treatment, have been off dexamethasone for 4 weeks prior to first study treatment, and no ongoing requirement for dexamethasone or anti‐epileptic drugs
8. Available blocks for immunohistochemistry and tissue microarray or, if no block is available, 20 ordinary unstained slides (5μm sections) will be acceptable
9. Eastern Cooperative Oncology Group (ECOG) performance status 0‐2
10. Adequate organ and bone marrow function
11. Female patients who:
a. Are postmenopausal for > 1 year before the screening visit OR
b. Are surgically sterile OR
c. If of childbearing potential, patient agrees to practice one of the following from informed consent to 90 days after the last dose of study treatment (or longer, as mandated by local labelling [e.g. Summary of Product Characteristics]):
i. Practice 1 highly effective method of contraception and 1 additional effective barrier method at the same time OR
ii. Practice true abstinence where this is in line with the preferred and usual lifestyle of the patient
12. For women of child‐bearing potential, negative blood serum pregnancy test within 14 days prior to the first study treatment
13. Able to swallow oral medication
Exclusion criteria:
1. Previous treatment with PI3K, AKT, dual PI3K/mTOR inhibitors, mTORC1/2 inhibitors or mTORC1 inhibitors
2. Prior weekly single agent paclitaxel
3. Known allergy to paclitaxel and/or any excipients of investigational medicinal products that, in the investigator’s opinion, precludes study treatment on clinical and/or safety grounds
4. Treatment with strong inhibitor/s and/or inducer/s of cytochrome P450 (CYP) 3A4 or CYP2C8 within 7 days of study treatment
5. Central nervous system metastasis, for patients who have brain metastases, they will be eligible if their brain metastases must have been treated, have no evidence of progression or haemorrhage after treatment, have been off dexamethasone for 4 weeks prior to first study drug administration, and no ongoing requirement for dexamethasone or anti‐epileptic drugs
6. Other clinically significant co-morbidities, such as uncontrolled pulmonary disease, active central nervous system disease, active infection, or any other condition that could compromise the patient’s participation in the study
7. Known human immunodeficiency virus infection
8. Known hepatitis B surface antigen-positive, or known or suspected active hepatitis C infection
9. Any serious medical or psychiatric illness that could, in the investigator’s opinion, potentially interfere with the completion of treatment according to this protocol
10. German sites only: Unable to be regularly followed up for any reason (geographic, familiar, social, psychological, housed in an institution e.g. prison because of a court agreement or administrative order)
11. German sites only: Subjects that are dependent on the sponsor (and/or contracted body e.g. contract research organisation) or investigational site as well as on the investigator
12. Diagnosed or treated for another malignancy within 2 years before administration of the first dose of study treatment, or previously diagnosed with another malignancy and evidence of residual disease. Patients with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection
13. Breast feeding or pregnant
14. Manifestations of malabsorption due to prior gastrointestinal surgery, gastrointestinal disease, or for an unknown reason that may alter the absorption of TAK228. In addition, patients with enteric small bowel stomata are also excluded
15. Treatment with any investigational products, chemotherapy or radiotherapy within 28 days, or major surgery within 21 days of study treatment
16. History of any of the following within the last 6 months before administration of the first dose of study treatment:
a. Ischemic myocardial event, including angina requiring therapy and artery revascularisation procedures
b. Ischemic cerebrovascular event, including transient ischemic attack and artery revascularisation procedures
c. Requirement for inotropic support (excluding digoxin) or serious (uncontrolled) cardiac arrhythmia (including atrial flutter/fibrillation, ventricular fibrillation or ventricular tachycardia)
d. Placement of a pacemaker for control of rhythm
e. New York Heart Association Class III or IV heart failure
f. Pulmonary embolism
17. Significant active cardiovascular or pulmonary disease
18. Patients receiving systemic corticosteroids (either intravenous (IV) or oral steroids, excluding inhalers or low-dose hormone replacement therapy) within 1 week before administration of the first dose of study treatment
19. Daily or chronic use of a proton pump inhibitor (PPI) and/or having taken a PPI within 7 days before receiving the first dose of study treatment
20. Poorly controlled diabetes mellitus defined as glycosylated haemoglobin (HbA1c) > 7%; patients with a history of transient glucose intolerance due to corticosteroid administration may be enrolled in this study if all other inclusion/exclusion criteria are met
Who will take informed consent? {26a}
Informed consent will be obtained by appropriately trained and delegated investigator at an outpatient clinic appointment within the relevant participating hospital research site with the following assurances for each consented participant:
- full and adequate oral and written information about the study including the background, purpose and risks/benefits of participation;
- notification that they are free to withdraw from the study at any time;
- opportunity to ask questions, allowed sufficient time to read and understand the information sheet, and given at least 24 hours to decide whether or not to take part;
- storage of the signed, dated Informed Consent Form in the participant’s medical records and also the Investigator Site File;
- the participant receives a copy of the signed, dated Informed Consent Form
Additional consent provisions for collection and use of participant data and biological specimens {26b}
The study wide Informed Consent Form is inclusive of all relevant use of participant for collection and use of participant data to include personal data; the mandatory collection of relevant biological specimens e.g. archival tissue, tissue biopsy at screening if judged technically feasible, blood sample during screening, treatment and end of treatment.
Interventions
Explanation for the choice of comparators {6b}
The comparator or control arm of this study is weekly paclitaxel, which is a standard treatment option in women with ovarian cancer that is resistant to platinum-based chemotherapy.
Intervention description {11a}
Arm 1: weekly paclitaxel
Treatment according to 4 week/28 day cycles within administration at 80mg/m2 full dose IV on days 1, 8 and 15 per cycle.
Arm 2: weekly paclitaxel plus TAK228
Paclitaxel as per arm 1.
TAK228 administration at 4mg full dose orally on days 2-4, 9-11, 16-18 and 23-25 per cycle.
Criteria for discontinuing or modifying allocated interventions {11b}
Protocol treatment discontinuation criteria as follows:
- Confirmed disease progression and/or death
- Significant adverse events or unacceptable toxicities, including but not limited to significant adverse events or unacceptable toxicities that require discontinuation of study treatment according to the relevant dose modification algorithm
- Allergic reaction to study treatment
- Participant decision
- If the Investigator considers that a participant's health will be compromised due to adverse events or concomitant illness that develop after entering the study
- Severe non-compliance to this protocol as judged by the Investigator
- Pregnancy and/or breast feeding/lactation
With respect to modification of randomised treatment by one or a combination of dose delay, omission or reduction, these are permitted with in stipulated instances of the following adverse events:
- Neutropaenia
- Febrile neutropaenia
- Thrombocytopaenia
- Elevated serum creatinine
- Elevated liver function tests i.e. bilirubin, alanine transaminase or aspartate transaminase
- Elevated clotting screen times i.e. prothrombin and activated partial thromboplastin
- Hypersensitivity / allergic reaction
- Poorly controlled nausea, vomiting, diarrhoea, constipation
- Neuropathy
- Pneumonitis
- Hyperglycaemia
- Hyperlipidaemia
- Oral mucositis
- Rash
- Left Ventricular Dysfunction
- Corrected QT Prolongation
- Other Non-Haematological Toxicities (e.g. asthenia, weakness and fatigue)
Strategies to improve adherence to interventions {11c}
Weekly paclitaxel chemotherapy is given in an outpatient setting and is a standard treatment in the participant population, meaning that there are no significant anticipated challenges in participant adherence and/or compliance.
With respect to TAK228, participants randomised to receive this treatment are given detailed information and counselled at screening, including provision of a treatment diary that they are encouraged to complete. Participants are instructed to bring their completed diary and capsule bottles with them to all protocol scheduled visits so that they can be checked by the medical team responsible for their care, and any queries or problems can be discussed and raised with the central sponsor study team as needed.
All study deviations, whether relating to adherence and/or compliance to study treatment are recorded on the central electronic study database, with corrective and preventative actions recorded and followed up in order to mitigate any deemed risk/s to participant safety and/or data integrity.
Relevant concomitant care permitted or prohibited during the trial {11d}
Guidance regarding concomitant medications:
Prophylactic use of anti-emetic, anti-nausea, and anti-diarrhoeal medications is encouraged and may be used prior to first dose of study treatment (paclitaxel +/- TAK228), and as needed throughout the study prior to each dosing of study treatment and as clinically indicated per standard practice. When selecting an anti-emetic agent, drugs that do not have an effect on the QT interval, such as palonosetron, are preferred.
Histamine H2 receptor antagonists may be allowed if needed, provided that the histamine H2 receptor antagonist is not taken < 12 hours before and < 6 hours after TAK228 administration (Arm 2). Participants receiving histamine H2 receptor antagonists before study entry must not receive such medications < 24 hours prior to their first dose of TAK228. It is important that this adhered to in relation to paclitaxel treatment. Examples of histamine H2 receptor antagonists include ranitidine, famotidine and nizatidine. Cimetidine, a moderate CYP1A2 inhibitor, is not recommended as a first choice H2 receptor antagonist.
Neutralising antacid preparations (acid neutralisers) and calcium supplements are permitted except from 4 hours before until 2 hours after TAK228 administration (Arm 2). Some anti-gas preparations may also have antacid properties, and should also not be permitted from 2 hours before until 2 hours after TAK228 administration.
Strong CYP1A2 inducers and/or inhibitors should only be administered with caution, at the discretion of the Investigator. Alternative treatment, if available, should be considered.
Paclitaxel should be administered with caution in participants receiving protease inhibitors as concomitant therapy. Post-chemotherapy supportive medications for paclitaxel, such as anti-emetics can be given as per local policy providing these are not contraindicated.
Prohibited medications (Arm 1 and 2):
- Strong inhibitor/s and/or inducer/s of cytochrome P450 (CYP) 3A4 or CYP2C8
Prohibited medications (Arm 2):
- Other investigational medicinal product/s including PI3K, AKT, dual PI3K/mTOR inhibitors, mTORC1/2 inhibitors or mTORC1 inhibitors
- Other anti-cancer therapies including chemotherapy i.e. additional to paclitaxel given according to study protocol, immunotherapy, radioimmunotherapy, targeted agents, radiation or surgery
- NB Palliative radiation for pain control of pre-existing lesions is allowed with sponsor approval. Bowel surgery and colostomy but not ileostomy are allowed
- Systemic corticosteroids (either IV or oral steroids, excluding inhalers or premedication with dexamethasone prior to paclitaxel administration), unless necessary for treatment of TAK228-related adverse events e.g. rash. Pre-medication for paclitaxel is required
- Anti-epileptic drugs for participants with treated brain metastasis
- Medications known to prolong the corrected QT interval e.g. clarithromycin, antipsychotics, citalopram, amitriptyline, ondansetron
- Concomitant administration of any protein pump inhibitor is not permitted during the study. Participants receiving such therapy before study entry must stop using the PPI > 7 days prior to their first dose of study treatment. Examples of PPIs include omeprazole, esomeprazole, pantoprazole, lansoprazole, and rabeprazole.
No dietary restrictions will be imposed on study participants other than daily fasting for glucose monitoring. Participants who show evidence of hyperglycaemia during the study should be encouraged to follow a low carbohydrate diet.
Provisions for post-trial care {30}
Post-trial care is at the discretion of the relevant investigator, and compensation to those who suffer harm from trial participation is available through the study sponsor and/or the relevant participating hospital research site.
Outcomes {12}
Primary:
PFS (median) assessed by RECIST, version 1.1 based on radiological imaging performed at baseline and then every 8 weeks during randomised treatment +/- at end of treatment and then every 3 months during follow up using CT or MRI scan. Defined as the time from study entry to first evidence of disease progression or death due to any cause.
This efficacy outcome has clinical relevance as the aim of treating platinum-resistant ovarian cancer is disease control rather than cure since women will inevitably die of the cancer. Prolongation of PFS to a statistically significant degree within the weekly paclitaxel plus TAK228 arm when compared to weekly paclitaxel alone would make this approach worthy of investigation in a larger randomised clinical trial.
Secondary:
- PFS at 24 weeks (median) assessed by RECIST, version 1.1 based on radiological imaging performed at baseline and then every 8 weeks during randomised treatment until 24 weeks. Defined as the time from study entry to first evidence of disease progression or death due to any cause;
- ORR (proportion) assessed by RECIST, version 1.1 based on radiological imaging performed at baseline and then every 8 weeks during randomised treatment +/- at end of treatment and then every 3 months during follow up using CT or MRI scan. Defined as a complete (CR) or partial response (PR) to treatment according to RECIST;
- DoR (median) assessed by RECIST, version 1.1 based on radiological imaging performed at baseline and then every 8 weeks during randomised treatment +/- at end of treatment and then every 3 months during follow up using CT or MRI scan. Defined as the time from study entry to change in response from CR or PR to stable disease (SD) or progressive disease (PD) according to RECIST;
- TTP (median) assessed by RECIST, version 1.1 based on radiological imaging performed at baseline and then every 8 weeks during randomised treatment +/- at end of treatment and then every 3 months during follow up using CT or MRI scan. Defined as the time from study entry to first evidence of disease progression or death due to any cause;
- CBR at 4 months (proportion) assessed by RECIST, version 1.1 based on radiological imaging performed at baseline and then every 8 weeks during randomised treatment +/- at end of treatment and then every 3 months during follow up using CT or MRI scan. Defined as CR, PR or SD for > 4 months;
- Response according to GCIG CA125 criteria (proportion) performed at baseline, during treatment, at end of treatment and then every 3 months during follow up. CA125 response according to GCIG criteria. A response according to CA125 has occurred if there is at least a 50% reduction in CA125 levels from a pre-treatment sample. The response must be confirmed and maintained for at least 28 days. Participants can be evaluated according to CA125 only if they have a pre-treatment sample that is at least twice the upper limit of normal and within 2 weeks prior to starting treatment;
- OS (median) assessed at baseline, throughout treatment and follow up and defined as time from study entry to death due to any cause or to study termination;
- Safety and tolerability (proportion) assessed at baseline and throughout treatment and follow up by adverse events according to the CTCAE version 4.03;
- Quality of life as a participant reported outcome assessed at baseline, during and at end of treatment by the EORTC validated questionnaires QLQ-C30 and QLQ-OV28.
Participant timeline {13}
Table 1 – Schedule of Assessments for Screening (all patients)
|
Time-point →
Assessments ↓
|
Screening / Baseline
|
|
Within 28 days
|
Within 14 days
|
|
Informed Consent
|
X
|
|
|
Inclusion/exclusion criteria
|
X
|
|
|
Demographics
|
X
|
|
|
Medical History
|
X
|
|
|
German sites only: screening for HIV and hepatitis
|
X
|
|
|
Vital signs
|
|
X
|
|
ECOG Performance Status
|
|
X
|
|
Complete Physical Examination
|
|
X
|
|
12-lead echocardiogram (ECG)
|
X
|
|
|
Haematology
|
|
X
|
|
Biochemistry
|
|
X
|
|
Coagulation
|
|
X
|
|
Fasting Serum Glucose
|
|
X
|
|
Glycosylated Haemoglobin (HbA1c)
|
|
X
|
|
Fasting Lipid Profile
|
|
X
|
|
Urinalysis
|
|
X
|
|
Creatinine clearance based on Cockcroft-Gault estimate, Wright Formula or urine collection
|
|
X
|
|
Blood Serum Pregnancy Test
|
|
X
|
|
Research Blood Sample for genomic DNA
|
|
X
|
|
Archival Tumour Tissue
|
X
|
|
|
Radiological imaging assessment (CT with contrast/MRI chest, abdomen and pelvis)
|
X
|
|
|
CA125
|
X
|
|
|
Research Fresh Tumour Biopsy, if judged technically feasible by radiologist, unless the local site is unable to collect the sample due to COVID-19 capacity restrictions
|
|
X
|
|
Quality of Life Questionnaires (EORTC QLQ-C30 and EORTC QLQ-OV28)
|
X
|
|
|
Adverse Events (NCI CTCAE version 4.03)
|
|
X
|
|
Concomitant Medications
|
|
X
|
|
Randomisation
|
|
X
|
Table 2 – Schedule of Assessments for Arm 1 patients
|
Time-point →
Assessments ↓
|
Each Treatment Cycle
|
End of Treatment Visit
|
Follow-up
|
|
Day 1
|
Day 8
|
Day 15
|
30 days post last treatment (±5 days)
|
Every 3 months
(±5 days)
|
|
Vital signs
|
X
|
X
|
X
|
X
|
|
|
ECOG Performance Status
|
X
|
X
|
X
|
X
|
|
|
Physical Examination
|
X
|
X
|
X
|
X
|
|
|
Haematology
|
X
|
X
|
X
|
X
|
|
|
Biochemistry
|
X
|
X
|
X
|
X
|
|
|
Urinalysis
|
X
|
|
X
Cycles 1 and 2 only
|
X
|
|
|
Pregnancy Test
|
X
|
|
|
X
|
|
|
Research Blood Sample for ctDNA
|
X
|
|
|
X
|
|
|
Radiological imaging assessment (CT with contrast/MRI chest, abdomen and pelvis)
|
Every 2 cycles/8 weeks
(± 7 days)
|
X
|
X
|
|
CA125
|
X
|
|
|
X
|
X
|
|
Paclitaxel Administration
|
X
|
X
|
X
|
|
|
|
Quality of Life Questionnaires (EORTC QLQ-C30 and EORTC QLQ-OV28)
|
X
|
|
|
X
|
|
|
Adverse Events (NCI CTCAE version 4.03)
|
X
|
X
|
X
|
X
|
X
|
|
Concomitant Medications
|
X
|
X
|
X
|
X
|
|
|
Record of Further Treatment
|
|
|
|
|
X
|
|
Record of Overall Survival
|
|
|
|
|
X
|
Table 3 – Schedule of Assessments for Arm 2 patients
|
Time-point →
Assessments ↓
|
Each Treatment Cycle
|
End of Treatment Visit
|
Follow-up
|
|
Day 1
|
Day 2(Cycles 1 & 2 only)
|
Day 8
|
Day 15
|
30 days post last treatment (±5 days)
|
Every 3 months
(±5 days)
|
|
Vital signs
|
X
|
|
X
|
X
|
X
|
|
|
ECOG Performance Status
|
X
|
|
X
|
X
|
X
|
|
|
Physical Examination
|
X
|
|
X
|
X
|
X
|
|
|
12-lead ECG
|
X
|
|
|
|
X
|
|
|
Haematology
|
X
|
|
X
|
X
|
X
|
|
|
Biochemistry
|
X
|
|
X
|
X
|
X
|
|
|
Coagulation
|
X
|
|
|
|
X
|
|
|
Fasting Serum Glucose
|
X
|
|
|
|
X
|
|
|
Glycosylated Haemoglobin (HbA1c)
|
X
|
|
|
|
|
|
|
Fasting Lipid Profile
|
X
|
|
|
|
X
|
|
|
Urinalysis
|
X
|
|
|
X
Cycles 1 and 2 only
|
X
|
|
|
Pregnancy Test
|
X
|
|
|
|
X
|
|
|
Research Blood Sample for ctDNA
|
X
|
|
|
|
X
|
|
|
Radiological imaging assessment (CT with contrast/MRI chest, abdomen and pelvis)
|
Every 2 cycles/8 weeks
(± 7 days)
|
X
|
X
|
|
CA125
|
X
|
|
|
|
X
|
X
|
|
In-Home Daily Fasting Glucose Monitoring
|
X
|
X
|
X
|
X
|
|
|
|
Paclitaxel Administration
|
X
|
|
X
|
X
|
|
|
|
TAK228 Administration / Compliance: administration at days 2-4, 9-11, 16-18 and 23-25 per cycle
|
X
|
X
|
X
|
X
|
|
|
|
Quality of Life Questionnaires (EORTC QLQ-C30 and EORTC QLQ-OV28)
|
X
|
|
|
|
X
|
|
|
Adverse Events (NCI CTCAE version 4.03)
|
X
|
X
|
X
|
X
|
X
|
X
|
|
Concomitant Medications
|
X
|
X
|
X
|
X
|
X
|
|
|
Record of Further Treatment
|
|
|
|
|
|
X
|
|
Record of Overall Survival
|
|
|
|
|
|
X
|
Sample size {14}
We hypothesise that the administration of TAK228 in combination with paclitaxel will increase median PFS by 2.15 months (i.e., from 4 to 6.15 months) when compared to the control therapy. Such an increase in median PFS corresponds to a 35% reduction in the risk of disease progression (i.e. target hazard ratio of 0.65). Based on a logrank test, we initially determined that a total of 97 progression events from among the two treatment arms were required to detect improvement in the investigational treatment arm compared to control with 80% power and type I error rate of 10% (one-sided). This equated to enrolment of 118 participants (59 per treatment arm) to achieve the required progression events assuming uniform enrolment over an 18-month period, no drop outs and a minimum 6 month follow-up per participant (sample size calculation performed using the Statistical Software Suite (SAS).
An interim analysis for futility was conducted to assess safety and futility when approximately 50% of the total progression events had occurred. The results of this analysis were reviewed by the independent data monitoring committee (IDMC). The sample size needed to be adjusted because of the statistical analysis method used at the interim analysis stage16-17. The group sequential method of O’Brien Fleming was used to select stopping rules for futility. It was estimated that, in order to maintain power for the final analysis, allowing for one interim analysis of futility and safety, the number of events will need to be 102 (Max information factor 1.05%, yielding 97*1.05 ≈ 102 events). In order to reach this number of events, the adjusted sample size due to interim analysis will be 124 participants (62 per treatment arm).
Patients who withdraw or are withdrawn before randomised treatment is administered will be replaced.
Recruitment {15}
Timely recruitment in line with projected accrual rate will be achieved by:
- Thorough selection and feasibility assessment of prospective participating hospital research sites;
- Close contact between central sponsor study team and participating hospital research sites to encourage discussion of progress and management of any perceived and/or actual recruitment barriers;
- Use of study newsletters and site meetings;
- Regular oversight of study progress including recruitment by trial management group and independent trial steering and data monitoring committees;
- Close and regular contact between the central sponsor study team and the study funder.
Assignment of interventions: allocation
Sequence generation {16a}
Randomisation will be on a 1:1 basis. It will be blocked with random block sizes and stratified by histology, the number of prior lines of chemotherapy, and prior taxane interval (< 6 months vs ³ 6 months or no prior taxane).
Concealment mechanism {16b}
Randomisation of each participant is implemented centrally using the study electronic case report form database in Inform. There is no option available for manual randomisation. Even though the study is not blinded, it is not possible to have knowledge of allocation before patient enrolment in the study and in the Inform database. Allocation is kept concealed to the study team. Only the study statistician was unblinded at the time of the interim analysis for the corresponding closed IDMC report.
Implementation {16c}
An independent statistician (external to the study team) will create the final randomisation list in accordance to the study protocol and the predefined sequence generation method (for stratification and blocks (section 16a)). The randomisation list will be sent with password-protection to the Inform team for embedding in the central system.
Baseline screening data for consented potential participants will be entered onto the central electronic study database and reviewed for eligibility by an appropriately trained and delegated member of the central sponsor study team. Eligible participants will be randomised within the database including randomised assignment of study treatment. Upon randomisation each patient will be allocated a unique subject number to be used throughout the study.
Assignment of interventions: Blinding
Who will be blinded {17a}
The study is open label with no blinding of participants, care providers, outcome assessors, data analysts etc.
Procedure for unblinding if needed {17b}
Not applicable, open label study.
Data collection and management
Plans for assessment and collection of outcomes {18a}
Collection and assessment of baseline and outcome data will occur according to the relevant outcome {12} and the participant timeline {13}.
Imaging data used for the assessment of relevant outcomes will be subject to independent external review to promote data quality.
The quality of life questionnaires used in the study are validated and thus reliable for the purposes of the relevant outcome analysis.
A copy of the data collection forms is held within the trial master file.
Plans to promote participant retention and complete follow-up {18b}
There are no specific plans to promote participant retention and/or follow up since treatment of ovarian cancer is based around outpatient visits to a secondary care hospital, and weekly paclitaxel i.e. control arm is a standard treatment approach in these women. Furthermore, the follow up frequency of the study i.e. 3 monthly outpatient visits is reflective of standard clinical practice.
Participants who discontinue and/or deviate from the protocol, whether in terms of treatment or otherwise, will all be followed up for outcome data. It is particularly crucial that participants who discontinue randomised treatment without their cancer significantly worsening (progressive disease) continue to be followed up according to the protocol’s radiological imaging schedule, in order to accrue for both the primary as well as various response based secondary endpoints.
Data management {19}
Processes relating to data entry, coding, security, and storage, as well as related processes to promote data quality are documented in a separate data management plan and associated study specific procedure manuals e.g. electronic case report form completion guidelines, pharmacovigilance manual etc.
Confidentiality {27}
Each participant will be identified by a unique subject number at randomisation. Month and year of birth will be collected along with ethnicity data. Individual patients will only ever be referred to by subject number and not identified in any trial related correspondence, to include any published results.
All relevant data will be collected and maintained according to applicable data protection legislation and guidelines.
Plans for collection, laboratory evaluation and storage of biological specimens for genetic or molecular analysis in this trial/future use {33}
The following biological specimens are collected from all participants as per the study wide informed consent form taken prior to any study specific procedures. Consent may be withdrawn by the participant at any time and any collected samples destroyed according to standard operating procedures:
- Baseline retrieval of archival tissue from ovarian cancer diagnosis / recurrence;
- Baseline biopsy from ovarian cancer – one ambient and two frozen tumour cores per participant – if judged technically feasible by interventional radiologists, unless there are local radiology capacity issues due to COVID-19;
- Baseline whole blood sample for analysis of genomic DNA;
- Plasma samples at the start and end of treatment for analysis of ct DNA.
In line with the aforementioned study wide informed consent, these biological specimens will be stored at Imperial College London and examined using genetic and molecular analysis in order to assess the exploratory endpoints.
Analyses will be undertaken by an accredited central laboratory. Results of these analyses will not be included in the Clinical Study Report, but reported separately according to standard ethical and regulatory guidelines.
Any residual biological specimen material will then be transferred to the Imperial College Healthcare Tissue Bank and retained for future use in ethically approved research.
Statistical methods
Statistical methods for primary and secondary outcomes {20a}
The statistical analysis will be detailed in the Statistical Analysis Plan (SAP).
All summaries and analysis will be conducted on the intention to treat population unless otherwise specified. All statistical tests will be two-tailed with a 5% significance level.
Primary endpoint: The primary inferential comparison between treatment arms will use the log-rank test adjusted by the stratification factors. Also, the hazard ratio will be estimated using a Cox proportional hazards model adjusted by age and the stratification factors.
Secondary endpoints: For the time to event secondary endpoints (PFS at 24 weeks, DoR, TTP and OS), the analysis will be performed using a two-sided stratified log-rank test for the comparison between treatment arms. Comparison of ORR and CBR between the 2 treatment groups will be made using the Cochran-Mantel Haenszel chi-square test.
Safety and tolerability summary statistics of vital signs, ECG, physical examination, laboratory parameters, adverse events and serious adverse events will be tabulated.
Multilevel models of each dimension of the quality of life overall score will be performed to investigate changes over time.
All the statistical analyses will be performed using STATA/SE 15.1.
The detailed SAP will be published separately.
Interim analyses {21b}
An interim analysis was performed to assess safety and futility after 49 (approximately 50%) PFS events had occurred. The results of this analysis were only accessible by the study statistician and reviewed by the IDMC, and the IDMC’s recommendations shared with the trial management group (TMG), trial steering committee (TSC) and study funder.
A detailed interim analysis plan will be published within the final analysis SAP.
Methods for additional analyses (e.g. subgroup analyses) {20b}
No additional analyses are planned.
Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c}
Non-adherence
Sensitivity Analysis will be used to handle non-adherence to treatment protocol. This analysis will exclude patients with protocol violation/deviation/s due to non-adherence to randomised treatment.
Missing data
Reasons for missingness of the primary outcome data and the relationship to the treatment will be investigated. There will be no data imputation for missing data for the primary endpoint.
To determine the effect of COVID-19, the baseline characteristics at randomisation will be summarised for the population recruited before and after COVID-19 and any protocol deviations/violations related to COVID-19 will be monitored. Missing data are expected for some patients as a consequence of the COVID-19 pandemic.
Plans to give access to the full protocol, participant level-data and statistical code {31c}
Not applicable, no current plans. Any future access will be subject to relevant standard operating procedures and contractual agreement between sponsor and funder.
Oversight and monitoring
Composition of the coordinating centre and trial steering committee {5d}
The TMG is composed of the Chief Investigator, Clinical Trial Coordinator, Clinical Trial Monitor, Operations Manager, Senior and Study Statistician, lead investigator in Germany, and the principal investigator at the top recruiting UK site. The role and responsibility of the TMG is to enable day to day support of the trial, to include safety review of adverse events and protocol deviations/violations. The TMG will ideally meet at least six monthly.
The TSC is composed of an Independent Chair, Independent Clinician, and Independent Patient Representative. The role and responsibility of the TSC is to provide independent support to the TMG, to include monitoring of recruitment, review of any significant substantial amendments, safety review of adverse events and protocol deviations/violations. The TSC is also executive to the IDMC, and ultimately has the power to recommend closure of the study if there are significant concerns around its delivery in a safe, scientifically viable and timely manner. The TSC will ideally meet at least annually. Each member signs a Charter held in the trial master file, including declaration of any conflicting interests.
Composition of the data monitoring committee, its role and reporting structure {21a}
The IDMC is composed of an Independent Chair Independent Clinician, and Independent Statistician. The role and responsibility of the IDMC is to independently review the safety and data quality aspects of the study, including interim analysis, and to provide recommendations to the TSC based on this independent review. The IDMC is independent from the sponsor and will ideally meet at least annually. Each member signs a Charter held in the trial master file, including declaration of any conflicting interests.
Adverse event reporting and harms {22}
Collection of adverse event data will occur according to the relevant outcome {12} and the participant timeline {13}.
Adverse events will be assessed according to CTCAE version 4.03.
Adverse events will be reported via the study database, the electronic case report form. Serious adverse events will be reviewed by the Chief Investigator.
Specific anticipated adverse events should be managed according to relevant guidance within the study protocol.
Frequency and plans for auditing trial conduct {23}
The study is subject to audit by the Imperial Clinical Trials Unit, specifically the Quality Assurance team). While part of the sponsor these processes are independent of the TMG, the core study team and study investigators, and according to relevant standard operating procedures.
Plans for communicating important protocol amendments to relevant parties (e.g. trial participants, ethical committees) {25}
Any important protocol amendments e.g. changes to eligibility criteria, outcomes, analyses etc will be subject to Research Ethics Committee, Health Research Authority and Regulatory Authority approvals and notified to investigators according to standard operating procedures. Such amendments may require updating of trial information held in public registries etc.
Where the amendment is likely to have a significant impact on participants, this will be communicated to the participants themselves in the form of a letter that has been ethically approved. In exceptional circumstances participants may need to be re-consented according to updated and ethically approved participant information.
Dissemination plans {31a}
Trial results will be disseminated as follows:
- Publication in a peer review journal article, and associated oral presentations to the scientific community where relevant
- Reporting on Clinicaltrials.gov and, where required, the European Medicines Agency database
- Lay summaries on charity websites e.g. Cancer Research UK, ovarian cancer specific charities. The content of these lay summaries may be subject to advice from a public focus group.
- To trial participants in the form of a lay summary or similar, with potential input from a public focus group
Dissemination must be according to the contractual agreement between sponsor and funder.