E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Locally advanced, metastatic or locally recurrent non-small cell lung cancer (NSCLC).
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E.1.1.1 | Medical condition in easily understood language |
Advanced malignant solid tumours. |
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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 | LLT |
E.1.2 | Classification code | 10007050 |
E.1.2 | Term | Cancer |
E.1.2 | System Organ Class | 100000004864 |
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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 establish the maximum tolerated dose and dose-limiting toxicities of DTX-SPL8783 given intravenously (IV).
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E.2.2 | Secondary objectives of the trial |
• To characterise the safety and tolerability profile of DTX-SPL8783 in patients with advanced cancer • To characterise the pharmacokinetics of DTX-SPL8783 in blood and tumour tissue samples • To define a recommended dose for clinical studies of DTX-SPL8783 dosed intravenously (IV) • To assess the safety of DTX-SPL8783 and nintedanib combination therapy • To explore preliminary anti-tumour efficacy |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Signed informed consent form. 2. At least 18 years old. 3. Histologically or cytologically confirmed advanced or metastatic cancer for which no standard or curative therapy exists. For patients selected to be treated with the nintedanib combination, they should have locally advanced, metastatic or locally recurrent non-small cell lung cancer (NSCLC) of adenocarcinoma tumour histology after first-line chemotherapy. 4. No taxane chemotherapy (eg. docetaxel, paclitaxel) in the previous 6 months. 5. Measurable or evaluable disease per RECIST version 1.1 or applicable radiological or biochemical assessment. 6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 7. Life expectancy of greater than 12 weeks. 8. Reproductive inclusion criteria : a) If of childbearing potential, willing to use an effective form of contraception (see below) during chemotherapy treatment and for at least six months thereafter. Such methods include (if using hormonal contraception this method must be supplemented with a barrier method, preferably male condom): combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation: o oral o intravaginal o transdermal progestogen-only hormonal contraception associated with inhibition of ovulation: o oral o injectable o implantable intrauterine device (IUD) intrauterine hormone-releasing system (IUS) bilateral tubal occlusion vasectomised partner true sexual abstinence when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods), declaration of abstinence for the duration of a trial, and withdrawal are not acceptable methods of contraception. b) Women must have a negative pregnancy test at study entry. c) Men who are truly sexually abstinent when this is in line with the preferred and usual lifestyle of the subject or vasectomized or willing to ensure that their female sexual partners use a highly-effective means of contraception with female sexual partners (i.e.: as outlined in Inclusion criterion 8.a) for the duration of study therapy and 6 months afterwards. In addition, men must be willing to use a condom during sexual intercourse from the first dose of DTX-SPL8783 until 6 months after their final dose, so as to protect their partner from exposure to study drug. |
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E.4 | Principal exclusion criteria |
1. Uncontrolled brain metastases or spinal cord compression. Patients who were treated with surgical resection or radiation therapy completing at least 4 weeks prior to enrolment are not excluded if they are neurologically stable, not taking glucocorticoids and have a follow-up MRI scan performed within the previous 4 weeks showing no tumour progression. 2. Inadequate bone marrow reserve as demonstrated by an absolute neutrophil count (ANC) < 1.5 × 109/L or platelet count < 100 × 109/L (cannot be post-transfusion) or haemoglobin < 9 g/dL (can be post- transfusion). 3. Serum bilirubin > upper limit of normal (ULN). 4. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level > 1.5 × ULN in conjunction with alkaline phosphatase > 2.5 × ULN; or AST or ALT > 2.5 × ULN irrespective of alkaline phosphatase level. 5. Serum creatinine > 1.5 × ULN; however, an exception can be made if the calculated (by the Cockcroft-Gault formula) or measured creatinine clearance is > 50 mL/min. 6. International normalized ratio (INR) or activated partial thromboplastin time (aPTT) > 1.5 × ULN. 7. Use of therapeutic anticoagulation, with the exception of treatment with a low molecular weight heparin. 8. History of a bleeding diathesis. 9. Allergy to docetaxel, other components of study therapy or compounds of similar chemical composition. 10. Hypersensitivity to nintedanib, peanut or soya, or to any of the excipients listed in the SPC. 11. Congenital long-QT syndrome. 12. Myocardial infarction within 6 months of enrolment, congestive heart failure of New York Heart Association class > II, unstable angina or unstable cardiac arrhythmias. 13. Other uncontrolled intercurrent illness, including active infection. 14. A history of infection with HIV or hepatitis B or C viruses. 15. Participation in a study of an investigational agent within 30 days prior to first study therapy. 16. Anti-tumour therapy (including chemotherapy, radiation therapy, targeted therapeutics or hormonal therapy) within the 30 days prior to first study therapy. Permitted exceptions are concurrent use of GnRH agonists for prostate cancer and radiation to bone metastases completed > 14 days prior to first study therapy. 17. Unresolved toxicity from prior anti-tumour therapy, defined as toxicities (excluding alopecia) that have not resolved to < grade 2 as scored using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Exceptions may be allowed for stable toxicities after discussion with the investigator and sponsor. 18. Peripheral neuropathy of grade 2 or higher due to any cause other than the cancer under investigation. 19. Patients with diabetes with signs or symptoms of peripheral neuropathy or other end organ damage or those at a higher risk of peripheral neuropathy (eg: history of poor diabetes control or non-compliance with anti-diabetic medication). 20. Concurrent or planned treatment with strong inhibitors (e.g. ketoconazole, itraconazole, clarithromycin, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) or inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital) of cytochrome P450 3A4/5. Concurrent or planned treatment with St John’s Wort. Concurrent or planned treatment with Organic Anion-Transporting-Polypeptide OATP1B1 substrates (e.g, statins, valsartan, repaglinide, amlodipine and other calcium channel blockers of the same class) should be avoided during DTX-SPL8783 treatment where possible. A 1-week washout period is necessary for patients already on any of these treatments. 21. Major surgery within 30 days of commencing first study therapy. 22. Pregnant or breast-feeding women. 23. Ascites of ≥ grade 2, pericardial effusions of ≥ grade 3 or pleural effusions of ≥ grade 2 (CTCAE version 4.03). 24. Any concurrent condition which, in the Investigator's opinion, makes it undesirable for the subject to participate in this study or which would jeopardize compliance with the protocol.
Note: The patient’s overall clinical picture should be considered, and special caution exercised, if a patient has, for example: received previous treatment with several neurotoxic agents, diabetes (Type I or II), a history of or baseline neuropathy or neurological disorder. |
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E.5 End points |
E.5.1 | Primary end point(s) |
14.3.1 Safety endpoints
Toxicity will be graded using the NCI CTCAE v4.0. Safety assessments will include medical review of AEs and the results of vital sign measurements, physical examinations, ECGs and clinical laboratory tests.
14.3.2 Pharmacokinetic Endpoints
Plasma concentrations of free and total docetaxel versus time will be analysed using non-compartmental methods and a validated PK analysis program to generate the following PK parameters for each patient: Cmax: Maximum observed plasma concentration Tmax: Time to maximum observed plasma concentration AUC: Area under the concentration-time curve t1/2: Apparent terminal half-life
14.3.3 Efficacy Endpoints
RECIST 1.1 criteria will be used to classify tumour responses to DTX-SPL8783 into the following categories: (1) complete response; (2) partial response; (3) stable disease; or (4) progressive disease. The following efficacy variables will be derived: - Objective Response Rate (ORR) based on RECIST 1.1 - Progression free survival (PFS) which equals time from enrolment to progression or death whichever comes first - Overall Survival (OS) which equals time from enrolment to death - Duration of responses best overall response - Duration of stable disease If progression or death are not observed then the time will be censored at the last tumour assessment for PFS, and at the last observation for survival. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Please refer to the study protocol. |
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E.5.2 | Secondary end point(s) |
There are no secondary endpoints. |
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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 | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
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) | Yes |
E.7.1.1 | First administration to humans | Yes |
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
| 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 | No |
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 |
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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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Last patient, last visit in the study. |
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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 | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 3 |