| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Platinum-Resistant Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
| Ovarian and other gynecologic cancers |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The primary objective of this trial is to evaluate the objective response rate (ORR) of AZD1775 in combination with carboplatin, paclitaxel, gemcitabine, or pegylated liposomal doxorubicin (PLD) in patients with platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer. |
|
| E.2.2 | Secondary objectives of the trial |
Secondary objectives:
1. Evaluate the DoR of AZD1775 + carboplatin, paclitaxel, gemcitabine, or PLD..
2. Evaluate the safety and tolerability of AZD1775 + carboplatin, paclitaxel, gemcitabine, or PLD in patients with platinum-resistant epithelial ovarian,fallopian tube, or primary peritoneal cancer.
3. Evaluate DCR of AZD1775 + carboplatin, paclitaxel, gemcitabine, or PLD in patients with platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer.
4. Evaluate the Cancer Antigen-125 (CA-125) response of AZD1775 + carboplatin, paclitaxel, gemcitabine, or PLD in patients with platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer.
5. Characterise the pharmacokinetic (PK) parameters of AZD1775 + carboplatin, AZD1775 + paclitaxel, and AZD1775 + gemcitabine, and AZD1775 + PLD.
6. Assess the drug interaction between AZD1775 + carboplatin, AZD1775 + paclitaxel, AZD1775 + gemcitabine, and AZD1775 + PLD. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Has read and understands the informed consent form (ICF) and has given written consent.
2. Histologic or cytologic diagnosis of epithelial ovarian, fallopian tube, or primary peritoneal cancer.
3. Progressed within 6 months of completing at least 4 cycles of a first-line platinum-containing regimen for Stage III/IV disease. Patients with refractory disease (progression during platinum-containing therapy) are ineligible.
4. No more than 2-4 prior treatment regimens for Stage III/IV disease, defined as investigational, chemotherapy, hormonal, biologic, or targeted therapy.
5. Prior doxorubicin (or other anthracycline) at a cumulative dose of ≤ 360 mg/m² or cumulative epirubicin dose of ≤ 720 mg/m² (calculated using doxorubicin equivalent doses: 1 mg of doxorubicin = 1 mg PLD = 0.3 mg mitoxantrone = 0.25 mg idarubicin). Subjects without any prior anthracycline exposure can also be included (applies to Arm D only).
6. At least 1 measurable lesion according to RECIST v1.1.
7. Any prior palliative radiation therapy must be completed at least 7 days prior to start of study treatment and patients must have recovered from any acute adverse effects prior to start of study treatment.
8. ECOG Performance Status (PS) score of 0 - 1.
9. Baseline Laboratory Values within 7 days of starting study drugs:
a) ANC ≥1500/μL
b) HgB ≥ 9 g/dL with no blood transfusions in the past 28 days
c) Platelets ≥ 100,000/μL
d) ALT & AST ≤ 3 x ULN or ≤ 5 x ULN if known hepatic metastases
e) Serum bilirubin within normal limits (WNL) or ≤1.5 x ULN in patients with liver metastases; or total bilirubin ≤ 3.0 x ULN with direct bilirubin WNL in patients with well documented Gilbert’s Syndrome.
f) Serum creatinine ≤1.5 x ULN OR measured creatinine clearance (CrCl) ≥ 45 mL/min by the Cockcroft-Gault method.
10. Left ventricular ejection fraction (LVEF) WNL of the institution, as determined by multiple uptake gated acquisition (MUGA) or echocardiography (ECHO) (applies to Arm D only).
11. Female patients who are not of childbearing potential and fertile female patients of
childbearing potential who agree to use adequate contraceptive measures from 2
weeks prior to the study and until 1 month after study treatment discontinuation,
who are not breastfeeding, and who have a negative serum or urine pregnancy test
within 3 days prior to start of study treatment
12. Predicted life expectancy ≥ 12 weeks
13. Must be ≥18 years of age.
14. Willingness and ability to comply with study and follow-up procedures. |
|
| E.4 | Principal exclusion criteria |
1. Participation in another clinical investigational study within the previous 28 days.
2. Use of a study drug (approved or investigational drug therapy) ≤ 21 days or 5 half-lives
(whichever is shorter) prior to the first dose of study treatment. For study drugs for which 5 half-lives is ≤ 21 days, a minimum of 10 days between termination of the study drug and administration of study treatment is required.
3. Major surgical procedures ≤ 28 days of beginning study treatment, or minor surgical
procedures ≤ 7 days. No waiting required following port-a-cath placement, or any other central venous access placement.
4. No other chemotherapy, immunotherapy, hormonal anti-cancer therapy, radiotherapy (except for palliative local radiotherapy), biological therapy or other novel agent is permitted while the patient is receiving study medication.
5. Grade >1 toxicity from prior therapy (except alopecia or anorexia).
6. Known malignant CNS disease other than neurologically stable, treated brain metastases – defined as metastasis having no evidence of progression or haemorrhage after treatment for at least 2 weeks (including brain radiotherapy). Must be off any systemic corticosteroids for the treatment of brain metastases for at least 14 days prior to enrolment.
7. Any prescription or non-prescription drugs or other products (i.e. grapefruit juice) known to be sensitive CYP3A4 substrates or CYP3A4 substrates with a narrow therapeutic index, or to be moderate to strong inhibitors or inducers of CYP3A4, which cannot be discontinued 2 weeks prior to Day 1 of dosing and withheld throughout the study until 2 weeks after the last dose of study drug.
8. Any of the following cardiac diseases currently or within the last 6 months as defined by New York Heart Association (NYHA) ≥ Class 2:
a) Unstable angina
b) Congestive heart failure
c) Acute myocardial infarction
d) Conduction abnormality not controlled with pacemaker or medication
e) Significant ventricular or supraventricular arrhythmias (patients with chronic rate controlled atrial fibrillation in the absence of other cardiac abnormalities are eligible).
9. AZD1775 should not be given to patients with a history of Torsades de pointes unless all risk factors that contributed to Torsades have been corrected. AZD1775 has not ben studied in patients with ventricular arrhythmias or recent myocardial infarction.
10. Corrected QT interval (QTc) >470 msec at study entry or congenital long QT syndrome. QTc interval will be calculated using Fridericia's formula (per institutional standards) obtained from 3 ECGs performed 2-5 minutes apart at study entry.
11.Pregnant or lactating.
12. Serious active infection upon enrolment, or other serious underlying medical condition that would impair the patient's ability to receive study treatment.
13. Presence of other active cancers, or history of treatment for invasive cancer within the last 3 years. Patients with Stage I cancer who have received definitive local treatment within the last 3 years, and whom are considered unlikely to recur, are eligible. All patients with previously treated in-situ carcinoma (i.e., non-invasive) are eligible, as are patients with prior non-melanoma skin cancers.
14. Psychological, familial, sociological, or geographic conditions that do not permit compliance with the protocol. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoint of this study is ORR for the arms included in the efficacy assessment, defined as the proportion of patients achieving a complete or partial tumour response according to Response
Evaluation Criteria in Solid Tumours (RECIST) v1.1. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Baseline, every 8 weeks (every 6 weeks for carboplatin arm only) from the first dose (every 12 weeks for patients on study > 1 year) until progression, death or until the study is terminated by the sponsor. Follow-up assessments will start 12 weeks from the date of last tumour and response assessment. |
|
| E.5.2 | Secondary end point(s) |
Secondary Endpoints:
1) DoR, defined as the time from first documented tumour response until the date of documented
progression or death from any cause.
2) Treatment emergent adverse events (TEAEs), serious adverse events (SAEs), and deaths; clinically significant changes in safety-related laboratory parameters according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE v4.03) and abnormal vital signs.
3) Disease Control Rate (DCR), defined as the proportion of patients achieving a complete response (CR), partial response (PR), or stable disease (SD) according to RECIST v1.1 criteria.
4) Gynaecologic Cancer Intergroup (GCIG) CA-125 response, defined as the proportion of patients achieving a 50% reduction in CA-125 levels from baseline, if baseline level is ≥ 2 x ULN within 2 weeks prior to starting treatment. Response must be confirmed and maintained for at least 28 days.
5) Plasma PK parameters of AZD1775 plus carboplatin, AZD1775 plus paclitaxel, and AZD1775 plus gemcitabine, and AZD1775 plus PLD. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Timepoints of Evaluation of Secondary Endpoints:
1) Baseline, every 8 weeks (every 6 weeks for carboplatin arm) from first dose (every 12 weeks for patients on study > 1 year) until progression, death or until the study is terminated by the sponsor.
2) Safety and tolerability is assessed from time of informed consent until the end of the study.
3) Baseline, every 8 weeks (every 6 weeks for carboplatin arm) from first dose (every 12 weeks for patients on study > 1 year) until progression, death or until the study is terminated by the sponsor.
4) CA-125 serum sample collected at baseline (within 14 days prior to first study treatment), Day 1 of each cycle, and end-of-study treatment visit.
5) Blood samples are collected pre and post dose. |
|
| 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 | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| 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 | 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) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| 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.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 3 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Canada |
| Netherlands |
| United Kingdom |
| United States |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
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