| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Platinum-Resistant Ovarian Cancer
|
|
| E.1.1.1 | Medical condition in easily understood language |
Ovarian Cancer that has not responded to treatment with platinum containing chemotherapy.
|
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | SOC |
| E.1.2 | Classification code | 10029104 |
| E.1.2 | Term | Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10066697 |
| E.1.2 | Term | Ovarian cancer recurrent |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The trial is trying to find out if it is safe to treat women who have advanced ovarian cancer and are at risk of developing malignant bowel obstruction (bowel blockage due to advanced cancer) with a weekly dose of standard chemotherapy (paclitaxel) plus a new oral tablet medication (cediranib). |
|
| E.2.2 | Secondary objectives of the trial |
The trial will also find out if the trial treatments:
1. Can reduce the number of women with advanced ovarian cancer who are hospitalised due to malignant bowel obstruction.
2. Are tolerable for participants i.e. do participants take the cediranib tablets.
3. Cause more our fewer side-effects than standard chemotherapy.
4.Can shrink the tumours and how long any tumour shrinkage lasts.
5. Can increase the number of months that the participants are expected to live without their disease worsening.
6. Offer any long- term survival benefit to participants.
Additionally, the trial will find out if switching from cediraib and paclitaxel treatment to treatment with cediranib plus a new tablet medication (olaparib):
1. Is tolerable for participants i.e. do participants take the olaparib and cediranib tablets.
2. Causes more our fewer side-effects than standard chemotherapy.
3. Can shrink the tumours and how long any tumour shrinkage lasts.
4. Can increase the number of months that the partic |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
There are two sets of inclusion criteria: one for treatment with paclitaxel and cediranib, and one for when patients switch treatment to cediranib and olaparib.
INITIAL TREATMENT (paclitaxel and cediranib):
1) Histologically confirmed, progressive, platinum-resistant or refractory, high-grade ovarian, fallopian tube or primary peritoneal cancer for which weekly paclitaxel would be a potential treatment option.
2) Aged 16 years or over.
3) Patients who are at risk of bowel obstruction are eligible for the trial. Features that are compatible with this diagnosis include increasing abdominal pain and swelling, borborygmi, change in bowel habit, extensive serosal disease or dilated or tethered bowel on radiological investigation. It is anticipated that one or more of these should be present in eligible patients. Previous bowel obstruction is permitted providing patients can take oral medication and there is no concern about absorption of oral medication. Recto sigmoid involvement is permitted.
4) Adequate haematological function: Hb ≥ 100 g/l, Neutrophils ≥ 1.5 x 109/l, Platelets ≥ 100 x 109/l; coagulation: INR <1.4 (unless therapeutically anti-coagulated) and/or APPT ratio <1.4
5) Adequate renal function defined as GFR ≥50ml/min and Creatinine clearance ≥50 mL/min using modified Wright or Cockcroft-Gault formula.
6) Adequate liver function: bilirubin ≤ 1.5 xULN, transaminases ≤ 3 xULN.
7) Any number of previous anti-cancer treatments permitted including weekly paclitaxel in the first-line setting.
8) Controlled hypertension permitted. Patients must have a blood pressure (BP) of ≤ Systolic BP (SBP) :150/ Diastolic BP (DBP) 90 mmHg, with or without anti-hypertensive medication. BP measurements must be taken in the clinic setting by a medical professional within 2 weeks prior to starting study. A maximum of 3 anti-hypertensive medications are permitted and it is strongly recommended that patients who are on 3 anti-hypertensive medications be followed by a cardiologist or a primary care physician for management of BP while on study.
9) ECOG performance status 0-2 and life expectancy of over 12 weeks.
10) Adequately controlled thyroid function, with no symptoms of thyroid dysfunction.
11) Measurable disease by RECIST 1.1.
12) Previous bevacizumab is permitted but patients cannot have been treated with VEGF RTKi previously.
13) Written informed consent.
14) Able to swallow and retain oral medications and without gastrointestinal (GI) illnesses that would preclude absorption of cediranib or olaparib.
SECOND TREATMENT (cediranib and olaparib):
1) Radiological evidence of PD that is measurable per RECIST v1.1.
2) Adequate haematological function: Hb ≥ 100 g/l, Neutrophils ≥ 1.5 x 10⁹/l, Platelets ≥ 100 x 109/l; coagulation: INR <1.4 (unless therapeutically anti-coagulated) and/or APPT ratio <1.4.
3) Adequate renal function defined as GFR ≥50ml/min and Creatinine clearance ≥50 mL/min using modified Wright or Cockcroft-Gault formula
4) Adequate liver function: bilirubin ≤1.5xULN, transaminases≤3xULN.
5) Controlled hypertension permitted. Patients must have a blood pressure (BP) of ≤ SBP:150/ DBP 90 mmHg, with or without anti-hypertensive medication. BP measurements must be taken in the clinic setting by a medical professional within 2 weeks prior to starting study. A maximum of 3 anti-hypertensive medications are permitted and it is strongly recommended that patients who are on 3 anti-hypertensive medications be followed by a cardiologist or a primary care physician for management of BP while on study.
6) ECOG performance status 0-2 and life expectancy of over 12 weeks.
7) Adequately controlled thyroid function, with no symptoms of thyroid dysfunction.
8) No contra-indications to receive cediranib or olaparib.
9) Able to swallow and retain oral medications and without gastrointestinal (GI) illnesses that would preclude absorption of cediranib or olaparib.
|
|
| E.4 | Principal exclusion criteria |
There are two sets of exclusion criteria: one for treatment with paclitaxel and cediranib, and one for when patients switch treatment to cediranib and olaparib. The criteria have been edited from the Protocol to stay within the character limit.
INITIAL TREATMENT (paclitaxel and cediranib):
1) Patients with known hypersensitivity to olaparib, cediranib or paclitaxel or any of the excipients of the products.
2) Concurrent medical illness that would impact on compliance with the protocol including myelodysplastic syndrome (MDS)/ acute myeloid leukaemia (AML) or with features suggestive of MDS/AML.
3) Uncontrolled brain metastases or seizures. A scan to confirm the absence of brain metastases is not required.
4) Known positivity for Hep B, Hep C or HIV.
5) Resting ECG with QTc > 470msec or family history of long QT syndrome.
6) Concomitant use of known strong CYP3A4/5 inhibitors such as such as ketoconazole, itraconazole, ritonavir, indinavir, saquinavir, telithromycin, clarithromycin and nelfinavir. Concomitant use of inducers or inhibitors (e.g., phenobarbital, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's Wort) is also excluded. The required washout period prior to starting olaparib is 2 weeks.
7) 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 for other agents.
8) Another cancer, active within the previous 5 years, except for adequately treated cone-biopsied in situ carcinoma of the cervix uteri and basal or squamous cell carcinoma of the skin and no evidence of recurrence of other malignancy.
9) Pregnant or lactating. Pregnancy status in women of child bearing potential will be confirmed via a serum or urine pregnancy test prior to randomisation, monthly during the treatment period, and at the end of treatment assessment. In addition, women of child bearing potential MUST be willing to ensure they use effective contraception for four weeks before entering the trial, throughout the treatment period and for six months following the end of treatment. Acceptable methods of contraception are listed in Protocol.
10) Patients who are planning to receive maintenance bevacizumab.
11) Radiotherapy, surgery or tumour embolization within 28 days before cediranib.
12) Additional concurrent anti-cancer therapy.
13) Malabsorption e.g. uncontrolled diarrhoea or poorly controlled stoma.
14) Patients who have or have had prior leukoencephalopathy, recent arterial thromboembolic event (MI/CVA within previous 6 months), previous or concurrent fistula, previous or concurrent GI perforation, concurrent intra-abdominal abscess, previous VEGF RTKi or clinically relevant proteinuria.
15) Inability to comply with the protocol.
16) Major surgery within two weeks of starting study treatment and patients must have recovered from any effects of any major surgery.
17) Patients considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection.
18) Patients unable to swallow oral medication or with gastrointestinal disorders likely to interfere with absorption of study medication.
19) Patients receiving any systemic chemotherapy or radiotherapy (except for palliative reasons) within 3 weeks prior to study treatment.
20) Persisting ≥Grade 2 CTCAE toxicity (except alopecia and Grade 2 peripheral neuropathy) from previous anti-cancer treatment(s).
21) No prior allogeneic bone marrow transplant or double umbilical cord blood transplantation.
SECOND TREATMENT (cediranib and olaparib):
As for initial stage but for these differences:
• Patients will not be excluded if another cancer has become active, or if they are receiving concurrent anti-cancer therapy (as they will be receiving cediranib).
• Patients will be excluded if they have had major surgery within 6 weeks.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary outcome is the number of patients who are free of grade III-V gastrointestinal perforation or fistula, which is causally related to cediranib or the cediranib olaparib combination, during cediranib treatment and for up to 4 weeks after stopping cediranib. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| For each participant: 4 weeks after stopping treatment with cediranib. |
|
| E.5.2 | Secondary end point(s) |
The secondary outcome measures are:
1) Proportion of participants hospitalised for bowel obstruction.
2) Grade III or more toxicities excluding gastrointestinal perforation/ fistula as assessed by CTCAE 4.03
3) Treatment compliance, as assessed by the dose intensity of paclitaxel, cediranib and, expressed as the {[total delivered dose/actual time taken to complete therapy]/[standard dose/planned time to complete therapy]} x (actual number of cycle /planned number of cycles) , and the dose intensity of cediranib and olaparib treatment, expressed as [number of days drug was taken correctly x 100/ number of days for which drug was prescribed].
4) Investigator-determined objective response rate (ORR) assessed by RECIST 1.1 within 18 weeks of starting paclitaxel.
5) Progression free survival (PFS), where PFS is measured as the time from date of registration to date of investigator-assessed objective progression via RECIST v1.1 or death from any cause in the absence of progression
6) Overall survival (OS) defined as the time from date of registration to date of death.
The exploratory outcome measures are:
1) Association between prior treatment with bevacizumab and toxicities, ORR, PFS and OS
2) After switching to from paclitaxel/cediranib to olaparib/cediranib at first progression:
a. Grade III or more toxicities as assessed by CTCAE 4.03
b. Association between BRCA status and grade III or more toxicities, ORR, PFS and OS
c. ORR and time to further progression from the date of switching to olaparib
3) The feasibility of capturing quality of life using the QLQ-c30, administered every 3 weeks during both treatment components of the trial and until disease progression.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Secondary outcome timepoints for each participant:
1) 28 days post-treatment
2) 28 days post-treatment
3) End of trial treatment
4) 18 weeks after starting paclitaxel
5) End of trial treatment
6) Trial closure
Exploratory outcome timepoints for each participant:
1) Trial closure
2)
a. 28 days post-treatment
b. Trial closure
c. End of trial treatment
3) 28 days post-treatment
|
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The end of the trial is defined as the date of final data capture to meet the trial endpoints. In this case end of trial is defined as 28 days after the last participant’s last treatment visit. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 1 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 1 |
Print
