E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients with histological confirmation of E-cadherin negative, previously treated advanced lobular breast cancer or diffuse gastric cancer |
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E.1.1.1 | Medical condition in easily understood language |
Patients with histological negative confirmation of the cell adhesion molecule called E-cadherin, previously treated advanced lobular breast cancer or diffuse gastric cancer the cell adhesion molecule |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
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 confirmed response rate by RECIST 1.1 of crizotinib and fulvestrant in the breast cohort
To assess confirmed response rate by RECIST 1.1 of crizotinib monotherapy in the diffuse gastric cancer cohort |
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E.2.2 | Secondary objectives of the trial |
To assess the overall safety and tolerability of crizotinib with fulvestrant in the breast cancer cohort and as monotherapy in the gastric cancer cohort
To assess the clinical benefit rate (response and stable disease lasting at least 24 weeks) in the breast cancer cohort
To assess progression-free survival in each cohort |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Patients with histologically or Histological diagnosis of inoperable or metastatic diffuse gastric cancer or recurrent inoperable locally advanced ER positive/HER2 negative lobular breast cancer. Assessment of ER and HER2 status as per local assessment.
• Previously treated with at least one prior line of therapy for advanced disease, but no more than three prior lines of chemotherapy for advanced disease. Patients with breast cancer must have received at least one prior line of hormone therapy for advanced disease Measurable disease (RECIST 1.1)
• Haematological and biochemical indices within the ranges shown in the protocol. These measurements must be performed within one week (Day -7 to Day 1) before the patient goes in the trial.
• Female patients with child-bearing potential must have a negative urine or serum pregnancy test within 7 days prior to start of trial. Both male and female patients of reproductive potential must agree to use two forms of highly effective contraception throughout the treatment period and for 90 days after discontinuation of treatment. The oral contraceptive pill may be ineffective when taken with crizotinib so is not an acceptable means of contraception during this study.
• 18 years of age or over with written (signed and dated) informed consent and be capable of co-operating with treatment and follow-up.
• Eastern Cooperative Oncology Group (ECOG) performance status 0,1 or 2
• Estimated life expectancy of at least 3 months in the opinion of the investigator
• Pre-/peri-menopausal breast cancer patients must be willing to receive gosarelin injections every 28 days.
• Signed and dated informed consent.
• Patients willing and able to comply with scheduled visits, treatment plans, laboratory tests, and other procedures |
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E.4 | Principal exclusion criteria |
• Systemic chemotherapy or investigational medicinal products during the previous four weeks, or hormonal therapy within 7 days except luteinizing hormone-releasing hormone (LHRH) analogues for ovarian suppression. Bisphosphonates or RANK ligand antagonists are permitted for the management of bone metastases.
• Previous treatment with fulvestrant or any agent that inhibits ROS1
• Mixed ductal/lobular breast cancer, unless both ductal and lobular components are CDH1 negative by local assessment
• Major surgery (excluding minor procedures, e.g. placement of vascular access) within 4 weeks or radiation therapy within 14 days prior to study entry
• Patients with known symptomatic brain metastases requiring steroids, untreated brain metastases or spinal cord compression
• Any of the following within 12 months prior to study entry: myocardial infarction, uncontrolled angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident, or transient ischemic attack. Uncontrolled hypertension or cardiac dysrhythmia including atrial fibrillation
• QT interval, corrected >470 ms or the use of bradycardic agents, drugs which prolong the QT interval and/or anti-arrhythmic agents within 12 days before the first dose of crizotinib or during study treatment.
• Use of drugs that are known potent cytochrome P450 (CYP) 3A4 inhibitors or moderate or strong CYP 3A4 inducers within 12 days before the first dose of crizotinib. Us of CYP3A4 substrates with a narrow therapeutic index (such as ciclosporin) is also not permitted within 12 days prior or during the study treatment,.
• Patients on warfarin. Patients requiring anticoagulation for rate-controlled AF or previous venous thromboembolism should be switched to low-molecular weight heparin.
• Known HIV or AIDS-related illness, active infection requiring systemic therapy, or positive HBV or HCV test indicating acute or chronic infection
• Inability or unwillingness to swallow pills, or (for patients receiving fulvestrant) receive IM injections.
• Other severe acute or chronic medical condition or psychiatric condition, recent or active suicidal ideation or behaviour, or end stage renal disease on haemodialysis, or laboratory abnormality that may increase the risk associated with study participation or investigational products administration or may interfere with the interpretation of results and, in the judgment of the Investigator, would make the patient inappropriate study entry
• Persisting toxicity related to prior therapy >Grade 1 (except for stable peripheral neuropathy grade ≤2 or alopecia grade ≤2).
• Pregnancy or lactation.
• Diagnosis of other malignancy within 5 years, except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of the breast or cervix, or low-grade (Gleason ≤6) prostate cancer
• Is a participant or plans to participate in another interventional clinical trial, whilst taking part in this study. Participation in an observational trial would be acceptable.
• Immunocompromised status due to current known active infection with HIV or due to the use of immunosuppressive therapies for other conditions
• Known prior or suspected hypersensitivity to investigational products
• Any other condition which in the Investigator’s opinion would not make the patient a good candidate for the clinical trial.
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E.5 End points |
E.5.1 | Primary end point(s) |
Compare the response rate, by RECIST 1.1, of crizotinib and fulvestrant in advanced E-cadherin negative, ER positive lobular breast cancer.
Compare the response rate, by RECIST 1.1, of crizotinib in advanced E-cadherin negative, diffuse gastric cancer. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
Secondary Endpoints:
Toxicities will be presented as frequencies and proportions for each cohort separately.
Clinical benefit rate will be presented as the proportion of patients with a best over response of CR, PR or SD maintained for a minimum of 6 months, with the 95% CI.
Progression free survival will be calculated using Kaplan Meier methods. This will be defined from the date 1 of study treatment to date of radiological disease progression or death from any cause. Any progression free surviving patients will be censored at last follow up.
Exploratory Endpoints
The objective response rate in each cohort will be presented in patients with centralised confirmed E-cadherin negative and CDH1 mutated tumours. The objective response rate will also be presented in patients with PIK3CA, ESR1 and CDH1 mutations and other biomarkers. These will be presented with 95% CIs. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | No |
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
| 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 | 6 |
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
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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 | 2 |
E.8.9.1 | In the Member State concerned months | 5 |
E.8.9.1 | In the Member State concerned days | 30 |
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 | 5 |
E.8.9.2 | In all countries concerned by the trial days | 30 |