E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Non-small cell lung cancer |
|
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10061873 |
E.1.2 | Term | Non-small cell lung cancer |
|
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 determine the efficacy of deforolimus in patients with KRAS mutant NSCLC who have progressed after two prior chemotherapy regimens compared to placebo by progression free survival analysis of randomized patients who have stable disease after an 8-week lead-in treatment with deforolimus. |
|
E.2.2 | Secondary objectives of the trial |
In patients with KRAS mutant NSCLC who receive deforolimus after failing two prior chemotherapy regimens, to: • Evaluate the safety profile of deforolimus. • Evaluate the best overall response rate. • Evaluate the overall duration of progression-free survival. • Estimate overall survival. • Estimate whether continuing therapy with deforolimus improves survival in patients who have experienced stable disease after 8 weeks of therapy with deforolimus.
|
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1.Patient has histologically confirmed stage IIIB/IV non-small cell lung cancer. 2.Patient has a documented mutation of the KRAS gene in tumor tissue. a.Patients with a known KRAS mutation must have documentation in the source documents, and are strongly encouraged to submit archival tissue material for central confirmation of mutation status. b.Patients without a previously documented mutation in the KRAS gene must submit a paraffin block or unstained slides for mutation testing and only those patients who test positive for a KRAS mutation will be eligible (see Study Operations Manual). 3.Patient has measurable disease by protocol-specific RECIST criteria (see the IIOM). 4.Patient has evidence of disease progression following 2 prior chemotherapy regimens, one of which was a platinum doublet. No more than 2 prior chemotherapy regimens for treatment of locally advanced or metastatic disease are allowed. Adjuvant (or neoadjuvant) chemotherapy given less than one year before disease recurrence is considered a prior chemotherapy regimen, but one additional prior cytotoxic chemotherapy regimen is allowed if it was given as adjuvant or neoadjuvant therapy more than one year before recurrence or progression to advanced disease. a.A prior chemotherapy regimen is defined as a drug regimen used for treatment of lung cancer that contains at least one conventional cytotoxic chemotherapy agent. b.Prior kinase inhibitor therapy and prior monoclonal antibody therapy are allowed, alone or in combination with chemotherapy. There is no limit on prior non-cytotoxic agents or regimens. 5.A minimum of 4 weeks has elapsed between prior chemotherapy and day 1 of study treatment. A minimum of 14 days has elapsed since prior kinase inhibitor therapy or radiotherapy, and a minimum of 6 weeks has elapsed since prior monoclonal antibody therapy (e.g. cetuximab or bevacizumab). 6.Patient has performance status ≤2 on ECOG Performance Scale (Appendix, 6.1). 7.Patient voluntarily agreed to participate by giving written informed consent. 8.Patient is ≥18 years of age on day of signing informed consent. 9.Women of childbearing potential (WOCBP) must have a negative serum pregnancy test within 7 days prior to start of therapy and must use an approved contraceptive method for the entire duration of the study, from the time of study enrollment until 30 days after the last dose of study drug. a.Approved contraceptive methods include hormonal contraception, intra-uterine device, diaphragm with spermicide, cervical cap with spermicide, or female condom with spermicide (spermicides alone are not an acceptable method of contraception.) b.WOCBP are defined as women who are not surgically sterile or who are not post-menopausal. Post-menopausal women who have been amenorrheic for less than one year are considered to be WOCBP unless they have a documented FSH value in the post-menopausal range. 10.Male partners of WOCBP agree to use approved methods of contraception for the entire duration of the study. 11.Patient must be available for periodic blood sampling, study related assessments, and management at the treating institution for the duration of the study.
|
|
E.4 | Principal exclusion criteria |
1.Patient is known to have active brain metastases. Patients with previously treated brain metastases that are stable for > 3 months are eligible if a current brain MRI (within 28 days of day 1 of study treatment) shows no edema or evidence of progression compared to a prior study at least 3 months ago. 2.Patient is currently participating or has participated in a study with an investigational compound in or device within 30 days or 5 half lives of the investigational compound (which ever is greater) of initial dosing with study drug. 3.Patient has previously received rapamycin or rapamycin analogs, including deforolimus, everolimus, or temsirolimus. 4.Patient is receiving corticosteroids administered at doses greater than those used for normal replacement therapy. 5.Patient has a history of prior malignancy except for basal cell carcinoma of the skin, carcinoma in situ of the cervix; or any patient who has undergone potentially curative therapy for malignancy with no evidence of that disease for five years or who is deemed at low risk for recurrence by his treating physician. 6.Patient has known severe hypersensitivity to macrolide antibiotics (ie: clarithomycin, erythromycin, or azythromycin). 7.Patient has NYHA Class III or IV congestive heart failure or any other significant history of cardiac disease including: myocardial infarction within the last 6 months; ventricular arrhythmia or acute congestive heart failure within the last 3 months; uncontrolled angina or uncontrolled hypertension. 8.Patient is known to be HIV positive or has a known history of Hepatitis B or C. 9.Patient has a psychiatric disorder that would interfere with cooperation with the requirements of the trial, is a regular user of illicit drugs (including "recreational use"), or has a recent history (within the last year) of drug or alcohol dependence. 10.Patient is pregnant or breastfeeding, or expecting to conceive within the projected duration of the study. 11.Patient has an active infection requiring prescribed intervention. 12.Patient has a requirement for concurrent treatment with medications that are strong inducers or inhibitors of cytochrome P450 (CYP3A) (see Appendix 6.2). Patients should be off these medications for at least 2 weeks prior to the first dose of deforolimus. Concomitant medications that are metabolized by CYP3A are allowed (e.g., simvastatin or atorvastatin). 13.Patient has newly diagnosed (within 3 months before enrollment) or poorly controlled Type 1 or 2 diabetes. Poorly controlled diabetes is defined as a fasting glucose >160 mg/dL during screening or being known to have a HbA1C > 8%. 14.Patient has a history or current evidence of any condition, therapy, or lab abnormality that might confound the results of the study or interfere with the patient's participation for the full duration of the study, or it is not in the best interest of the patient to participate.
|
|
E.5 End points |
E.5.1 | Primary end point(s) |
Primary Efficacy endpoint: Progression-free Survival (PFS) in the randomized population: is defined, in the randomized population, as the time from randomization to progressive disease or death, whichever is earlier. Patients without an event at the time of analysis will be censored at the date of the last tumor assessment.
Secondary endpoints: Overall survival (OS) in the randomized population: is defined, in the randomized population, as the time from randomization to death due to any cause. Patients without documented death at the time of analysis will be censored at the date last known to be alive. Overall response rate (ORR) in the FAS population: is defined, in the FAS population, as the proportion of patients whose best response is PR or CR at Week 8. Progression Free Survival (PFS) in the FAS population: is defined, in the FAS population, as the time from entry to the study to progressive disease or death, whichever is earlier. Patients without an event at the time of analysis will be censored at the date of the last tumor assessment. Overall survival (OS) in the FAS population: is defined, in the FAS population, as the time from entry to the study to death due to any cause. Patients without documented death at the time of analysis will be censored at the date last known to be alive.
Exploratory endpoint: EQ-5D, a validated instrument for the assessment of overall quality of life (QoL): the questionnaire consists of 5 questions, pertaining to a specific dimension of quality of life: (1) mobility, (2) self-care, (3) usual activities, (4) pain/discomfort and (5) anxiety/depression. Additionally, a sixth question, called the Health State Thermometer, measures a patient's current health state.
Safety Endpoints: Safety and tolerability will be assessed by a clinical review of all relevant adverse experiences and monitoring variables related to laboratory measurements, ECG, ECOG performance status, physical examinations, and vital signs.
|
|
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 | 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 | Yes |
E.8.1.7.1 | Other trial design description |
Randomized Discontinuation Trial |
|
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.8.3 |
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 | 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 | Information not present in EudraCT |
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
| |
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 | 0 |
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 | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |