| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Metastatic, Gastric or Gastro-oesophageal Junction Cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
| Metastatic, Gastric or Gastro-oesophageal Junction, Cancer |
|
| 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 | 14.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10071114 |
| E.1.2 | Term | Metastatic gastric adenocarcinoma |
| 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 |
| To assess the relative efficacy of AZD8931 plus paclitaxel compared with paclitaxel alone by comparison of the change in tumour size at 8 weeks |
|
| E.2.2 | Secondary objectives of the trial |
· To assess the relative efficacy of AZD8931 plus paclitaxel compared with paclitaxel alone by assessment of progression-free survival (PFS)
· To investigate the efficacy of AZD8931 plus paclitaxel compared with paclitaxel alone by assessment of objective response rate (ORR)
· To assess the efficacy of AZD8931 plus paclitaxel compared with paclitaxel alone by assessment of the percentage of patients without progressive disease (i.e. patients with CR, PR or SD) at 8 weeks
· To assess the efficacy of AZD8931 plus paclitaxel compared with paclitaxel alone by assessment of overall survival (OS)
· To compare and assess the safety and tolerability of AZD8931 plus paclitaxel compared with paclitaxel alone
· To investigate the pharmacokinetics (PK) of AZD8931 and AZD8931 O-desmethyl metabolite in a metastatic, gastric or gastro-oesophageal junction, cancer patient population.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Provision of signed, written informed consent prior to any study specific procedures
2. Male or female aged 18 years or older (20 years or older in Japan)
3. Histological diagnosis of gastric adenocarcinoma (including adenocarcinoma of the gastro-oesophageal junction)
4. Patients must have radiologically confirmed progression following 1st line fluoropyrimidine and platinum based treatment for metastatic gastric cancer (the date of progression and start of first line treatment to be captured on the database)
5. Suitable for paclitaxel therapy
6. At least one lesion, not previously irradiated and not chosen for a mandatory fresh tumour biopsy during the study screening period, that can be accurately measured at baseline as ≥10mm in longest diameter (except lymph nodes which must have short axis ≥15mm) by computed tomography (CT) or magnetic resonance imaging (MRI) and is suitable for accurate repeat assessment i.e. the tumour site chosen for mandatory biopsy will not be deemed measurable and will be classed as a non-target lesion at baseline RECIST 1.1 assessment.
7. World Health Organisation (WHO) performance status 0-1, minimum life expectancy of 12 weeks from proposed first dose date, no deterioration within 2 weeks of screening and first dose. Investigator has discretion to exclude rapidly progressive gastric cancer (such as those patients with rapid deterioration of performance status, requiring repeated drainage of ascites, patients with low or rapidly decreasing albumin or patients requiring feeding assistance with devices such as PEG)
8. Ineligible for trastuzumab treatment by local assessment. This should include IHC analysis to determine HER2 status with further testing by FISH/CISH for IHC 2+ patients. Eligible patients are those defined as; HER2 IHC 0, HER2 IHC 1+, or HER2 IHC 2+ (FISH –ve)
9. Collection of the original archival diagnostic (or more recent archival) tumour sample for retrospective central HER2 assessment, followed by exploratory retrospective biomarker analysis. Both primary lesion and metastatic sites are acceptable.
10. Women should be using adequate contraceptive measures (see Appendix J), should not be breast feeding and must have a negative pregnancy test prior to start of dosing if of child bearing potential, or must have evidence of non-child bearing potential by fulfilling one of the following criteria at screening:
· Post menopausal defined as:
- Aged ≥ 50 years and amenorrhoeic for at least 12 months following cessation of all exogenous hormonal treatments
- Aged <50 years and amenorrhoeic for at least 12 months following cessation of all exogenous hormonal treatments and with luteinising hormone and follicular stimulating hormone levels in the post menopausal range
· Documentation of irreversible surgical sterilization by hysterectomy, and/or bilateral oophorectomy and/or bilateral salpingectomy but excludes bilateral tubal ligation
For inclusion in the optional PGx sample collection:
11. Provision of informed consent for PGx sample collection
For inclusion in the optional fresh tumour biopsy upon RECIST 1.1 defined progression:
12. Provision of informed consent for tumour sample collection
If a patient declines to participate in the optional components of the study (PGx or additional tumor sample collection) there will be no penalty or loss of benefit to the patients. The patient will not be excluded from other aspects of the study to which they have consented.
13. Patients must provide fresh baseline (pre-treatment) excisional or core needle tumour biopsies from a suitable and accessible site (other than from a key target lesion site chosen for the primary efficacy assessment [see inclusion criteria 6]). |
|
| E.4 | Principal exclusion criteria |
1.Have received more than 1 prior chemotherapy regimen for metastatic gastric cancer. (chemotherapy as adjuvant treatment is permitted).
2.Any prior taxane therapy (at any time from diagnosis of gastric cancer)
3.Any prior therapy with an inhibitor of ErbB1 or ErbB2 (eg, lapatinib)
4.Inadequate bone marrow reserve as demonstrated by an absolute neutrophil count <1.5 x 109/L or platelet count <100 x 109/L
5.Moderate or severe renal impairment.
6.Haemoglobin ≤9 g/dL (5.59 mmol/L), any blood transfusion must be >14 days prior to the determination of the haemoglobin levels
7.Inadequate liver function defined in protocol;
8.Resting ECG with measurable QTc(F) interval of >480 msec at 2 or more time points within a 24 hour period
9.Cardiac ejection fraction outside institutional range of normal or ≤50% (whichever is higher) as measured by echocardiogram
10.Known uncontrolled or symptomatic angina, arrhythmias or congestive heart failure, evidence of transmural infarction on ECG, poorly controlled hypertension (systolic >180 mmHg or diastolic >100 mmHg), significant valvular disease or history of high risk dysrrhythmia (such as ventricular fibrillation or ventricular tachycardia [includes ventricular triplets])
11.Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis which required steroid treatment, or any evidence of clinically active interstitial lung disease
12.Active or uncontrolled systemic disease which in the investigator’s / delegate’s opinion makes it undesirable for the patient to participate in the trial or which would jeopardise compliance with the protocol
13.History or repeated unexplained episodes of syncope/dizziness
14.Medical diagnosis of acne rosacea, psoriasis, severe atopic eczema
15.Concurrent second primary malignancy (except in situ carcinoma of the cervix). Patients with a prior cancer are eligible if they are disease-free with no evidence of recurrence or relapse in the past 5 years
16.Unresolved toxicity >CTCAE grade 2 (except alopecia) from previous anti-cancer therapy
17.Unable to discontinue medication with agents designated as having a risk of Torsades de Pointes due to QT prolongation.
18.Unable to discontinue any medication or herbal supplement with known moderate or potent inhibitory effect on CYP3A4, or potent inducing effects on CYP3A4. Such drugs must have been discontinued for an appropriate period prior to starting AZD8931. Guidance on medicines to avoid and on washout periods is given in Appendix G to this protocol
19.Known hypersensitivity to AZD8931
20.Involvement in the planning and/or conduct of the study
21.Receipt of investigational drug within 30 days or five half lives, whichever is longer, of the first dose of IP
22.Prior diagnosis of dry eye syndrome, eyelid or eyelash abnormalities
23.History or current evidence of any of the following:
-Any eye injury in the previous 3 months or a prior eye injury still associated with persistent or recurrent symptoms or impairment of vision
-Corneal surgery (laser refractive surgery performed more than 3 months prior to the start of the study is allowed and should be recorded in surgical history)
-Orbital irradiation
-Collagen vascular, chronic inflammatory or degenerative disease with eye involvement (eg, rheumatoid, Sjögren’s syndrome, systemic lupus erythematosus )
-Clinically significant ocular surface disease ie, diseases of the conjunctiva and cornea (including atopic keratoconjunctivitis, Stevens-Johnson syndrome, ocular cicatricial pemphigoid or chemical burns, herpes simplex or herpes zoster virus eye disease)
24.History of maculopathy in patients with impaired visual acuity. (Impaired visual acuity is defined as best corrected near visual acuity <0.4 or best corrected distance visual acuity (including with pinhole) <0.7) Note: patients with cataracts are allowed. No eye symptoms must be present on Day 1 of AZD8931 dosing
25.Last dose of prior anticancer therapy (chemotherapy, radiation therapy, surgery, immunotherapy, targeted therapy, biologic therapy, or tumour embolisation) received within 14 days (within 6 weeks for nitrosurea or mitomycin C) prior to the first dose of treatment with investigational product (IP) (AZD8931 or placebo). If sufficient wash-out time has not occurred due to schedule or PK properties, a longer wash-out period will be required, as agreed by AZ and the investigator / delegate
For optional PGx component only:
26.Previous allogenic bone marrow transplant
27.Non-leukocyte depleted whole blood transfusion in 120 days of genetic sample collection.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Efficacy- Change in tumour size at 8 weeks
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Change in tumour size at 8 weeks |
|
| E.5.2 | Secondary end point(s) |
Efficacy-
-Progression Free Survival (PFS)
-Overall survival (OS)
-Objective response rate (ORR)
-Percentage of patients without progressive disease at 8 weeks (i.e. patients with CR, PR or SD)
Safety- Adverse Events
- Deaths
- Laboratory findings (clinical chemistry, haematology, urinalysis)
- Vital signs
- Physical Examination
- Ophthalmic assessments
Pharmacokinetic
- Plasma concentrations of AZD8931 and AZD8931 O-desmethyl metabolite
- Pharmacokinetic parameters including (but not restricted to):
AZD8931: AUCss, Css,max, Css,min,tssmax, CLss/F and tlast
AZD8931 O-desmethyl metabolite : AUC0-t, Cmax, tmax and AUC0-t metabolite:parent ratio
- Cardiac assessments (ECG, ECHO/MUGA)
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Assessment made during trial |
|
| 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 | No |
| 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 | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| 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 | Yes |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 9 |
| 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 |
| China |
| Italy |
| Japan |
| Korea, Republic of |
| Spain |
| Taiwan |
| United Kingdom |
|
| 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
|
Patients may continue to receive AZD8931 as long as they are continuing to show clinical benefit, as judged by the investigator, and in the absence of discontinuation
criteria |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
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