| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Ovarian, fallopian tube or primary peritoneal cancer of clear cell, endometrioid or high grade serous subtype or carcinosarcoma |
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| E.1.1.1 | Medical condition in easily understood language |
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| 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 | PT |
| E.1.2 | Classification code | 10033128 |
| E.1.2 | Term | Ovarian cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10052171 |
| E.1.2 | Term | Peritoneal carcinoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| 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 | 10016180 |
| E.1.2 | Term | Fallopian tube cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| 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 |
| To compare the effectiveness of TAK228 plus weekly paclitaxel with weekly paclitaxel alone as treatments for women with advanced/recurrent ovarian, fallopian tube or primary peritoneal cancer resistant to platinum chemotherapy, based on progression free survival (PFS). PFS is the length of time during and after a treatment that each patient lives with the cancer but it does not grow significantly. In a clinical trial, measuring the progression-free survival is one way to see how well each treatment works. |
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| E.2.2 | Secondary objectives of the trial |
To compare the effectiveness of TAK228 plus weekly paclitaxel and weekly paclitaxel alone as treatments for women with advanced/recurrent ovarian, fallopian tube or primary peritoneal cancer resistant to platinum chemotherapy, based on the following:
- Progression free survival (PFS) at 24 weeks
- Overall response rate (ORR). This means the proportion of patients for whom the cancer significantly shrinks (called partial response) or disappears completely (called complete response) after a treatment.
- Duration of response (DoR), meaning that in patients with partial or complete response, the length of time between that response and the cancer significantly growing
- Time to progression (TTP). This means the length of time measured from a patient entering the study and the cancer growing significantly or spreading to other parts of the body
- Clinical Benefit Rate (CBR). This is similar to ORR but also includes patients for whom the cancer neither significantly grows or shrinks (ca |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Signed and dated written informed consent prior to admission to the study and initiation of any study procedures in accordance with ICH-GCP 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/MDT 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 disease (recurrence within 6 months of last platinum treatment), Patients having received at least one prior line of chemotherapy. Carboplatin and weekly paclitaxel are permitted as first line therapy
5. Measurable disease as per Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1 (Appendix A) by CT or MRI
6. Fresh tumour biopsy during screening is compulsory if judged technically feasible by radiologist
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 (IHC) and tissue microarray (TMA) or, if no block is available, 20 ordinary unstained slides (5µm sections) will be acceptable
9. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0‐2
10. Adequate organ and bone marrow function:
a. Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
b. Platelets ≥ 100 x 109/L
c. Haemoglobin ≥ 9 g/dL
d. Total bilirubin ≤ 1.5 x upper limit of normal (ULN) (< 2 x ULN in cases of Gilbert’s syndrome)
e. Aspartate aminotransferase/serum glutamic oxaloacetic transaminase [AST/SGOT] ≤ 2.5 x ULN (< 5 x ULN if liver metastases are present)
f. Alanine aminotransferase/serum glutamic pyruvic transaminase [ALT/SGPT]) ≤ 2.5 x ULN (< 5 x ULN if liver metastases are present)
g. Creatinine clearance ≥ 50 mL/min based on Cockcroft-Gault estimate, Wright Formula or urine collection (12 or 24 hour)
h. Fasting serum glucose ≤ 7 mmol/L (≤ 126 mg/dL)
i. Fasting triglycerides ≤ 3.38 mmol/L (≤ 300 mg/dL)
11. For 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. Permitted methods of contraception are specified in section 6.7.2
ii) Practice true abstinence where this is in line with the preferred and usual lifestyle of the patient.
Periodic abstinence [e.g. calendar, ovulation, symptothermal, postovulation methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male condoms should not be used together
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
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| E.4 | Principal 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 (CNS) 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. CRO) 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 (GI) surgery, GI disease, or for an unknown reason that may alter the absorption of TAK228. In addition, patients with enteric 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 (NYHA) Class III or IV heart failure (See Appendix B)
f. Pulmonary embolism
17. Significant active cardiovascular or pulmonary disease including:
a. Uncontrolled hypertension (i.e., systolic blood pressure > 180 mm Hg, diastolic blood pressure > 95 mm Hg). Use of anti-hypertensive agents to control hypertension before first dose of study treatment is allowed
b. Pulmonary hypertension
c. Uncontrolled asthma or O2 saturation < 90% by arterial blood gas analysis or pulse oximetry on room air
d. Significant valvular disease; severe regurgitation or stenosis by imaging independent of symptom control with medical intervention, or history of valve replacement
e. Medically significant (symptomatic) bradycardia
f. History of arrhythmia requiring an implantable cardiac defibrillator
g. Baseline prolongation of the rate-corrected QT interval (QTc) (e.g., repeated demonstration of QTc interval > 480 milliseconds, or history of congenital long QT syndrome, or additional risk factors for torsades de pointes (e.g. hypokalaemia, family history of long QT syndrome) and patients who use concomitant medications that prolong the QT/QTc interval
18. Patients receiving systemic corticosteroids (either 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
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Progression free survival (PFS; as assessed by RECIST v1.1), defined as time in months from randomisation to first evidence of disease progression or death due to any cause
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Every 8 weeks/2 treatment cycles, then at end of treatment and 3 monthly during follow up until progressive disease (PD) as documented by RECIST v1.1 (or death, if this occurs sooner) |
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| E.5.2 | Secondary end point(s) |
1. Progression Free Survival (PFS; as assessed by RECIST v1.1) at 24 weeks, defined as time in months from randomisation to first evidence of disease progression or death due to any cause.
2. Overall Response Rate (ORR; as assessed by RECIST v1.1) defined by complete response (CR) or partial response (PR). The best overall response will be used.
3. Duration of response (DOR), defined as time in months from randomisation to change in response from CR or PR to stable disease (SD) or progressive disease (PD) (as assessed by RECIST v1.1).
4. Time to progression (TTP), defined as time in months from randomisation to first evidence of disease progression or death due to any cause.
5. Clinical Benefit Rate (CBR; as assessed by RECIST v1.1) defined as CR, PR or SD for at least 4 months
6. Response according to CA125 levels (response has occurred if there is at least a 50% reduction in CA125 levels from a pretreatment sample. The response must be confirmed and maintained for at least 28 days. Patients can be evaluated according to CA125 only if they have a pretreatment sample that is at least twice the upper limit of normal and within 2 weeks prior to starting treatment
7. Overall Survival (OS) defined as time in months from randomisation to death due to any cause or to study termination
8. Safety and tolerability as assessed by adverse events according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03
9. Quality of Life as assessed by EORTC QLQ-C30 and EORTC QLQ-OV28
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. 24 weeks/after 6 treatment cycles
2. As per E5-1
3. As per E5-1
4. As per E5-1
5. As per E5-1
6. Day 1 of each treatment cycle, then at end of treatment visit and 3 monthly during follow up until progression or death (whichever occurs first)
7. Every protocol visit until death
8. As per 7 above
9. Day 1 of each treatment cycle, then at end of treatment visit |
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| 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 | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| 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 | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 25 |
| 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 | Yes |
| 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
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| 6 months after the last DICE patient stops study treatment, or up to 18 months after the last DICE patient is randomised, whichever is sooner. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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