| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Squamous Non-Small Cell Lung Cancer |
| Cáncer de Pulmón Amicrocítico Escamoso |
|
| E.1.1.1 | Medical condition in easily understood language |
| Non-Small Cell Lung Cancer |
| Cáncer de Pulmón Amicrocítrico |
|
| 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 the efficacy of the combination of AZD2014 and weekly paclitaxel in patients with squamous NSCLC by evaluation of objective response rate (ORR) |
Evaluar la eficacia del tratamiento combinado de AZD2014 y de paclitaxel semanal en pacientes con cáncer de pulmón amicrocítico escamoso mediante la evaluación
de la tasa de respuesta objetiva (ORR) |
|
| E.2.2 | Secondary objectives of the trial |
To assess the safety and tolerability of the combination of AZD2014 and weekly paclitaxel in patients with squamous NSCLC
To investigate the efficacy of the combination of AZD2014 and weekly paclitaxel in patients with squamous NSCLC by evaluation of tumour response and overall survival (OS)
To determine the effect of co-administration of intravenous paclitaxel on the PK of AZD2014 dosed orally and to determine the effect of co-administration of oral dosing of AZD2014 on the PK of intravenous paclitaxel (Group A)
To estimate exposure to AZD2014 when co-administered with weekly paclitaxel (Group B) |
Evaluar la seguridad y la tolerabilidad del tratamiento combinado de AZD2014 y de
paclitaxel semanal en pacientes con cáncer de pulmón amicrocítico escamoso.
Investigar la eficacia del tratamiento combinado de AZD2014 y de paclitaxel semanal en pacientes con cáncer de pulmón amicrocítico escamoso mediante la evaluación de la respuesta del tumor y la supervivencia global (SG) Determinar el efecto de la administración conjunta de paclitaxel intravenoso sobre la FC de AZD2014 administrado por vía oral y determinar el efecto de la administración
conjunta de AZD2014 oral sobre la FC de paclitaxel intravenoso (grupo A) Calcular
la exposición a AZD2014 cuando se administra junto con paclitaxel semanal (grupo
B) |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Histologically or cytologically proven squamous non-small cell lung cancer (NSCLC) where treatment with weekly paclitaxel is an appropriate treatment option.
2. Relapsed or refractory disease after at least one line of prior therapy. Subjects must have previously received appropriate lines of standard of care (SOC) treatment.
3. Measurable disease by RECIST v1.1 criteria
4. Life expectancy of at least 12 weeks.
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
6. Adequate hematologic function independent of transfusion and growth factor support for at least 7 days prior to screening (with the exception of pegylated G-CSF (pegfilgrastim) and darbopoeitin which require at least 14 days prior to screening), defined as:
? Absolute neutrophil count ?? 1500 cells/mm3 (1.5 x 109/L)
? Platelet count ? ?100,000 cells/mm3 (100 x 109/L)
? Haemoglobin ? ?9.0 g/dL
7. Adequate hepatic and renal function defined as:
? Serum aspartate transaminase (AST) or alanine transaminase (ALT) ?? 2.5 x upper limit of normal (ULN) if no demonstrable liver metastases or ?? 5 x ULN in the presence of liver metastases
? Alkaline phosphatase (ALP) < 5 x ULN
? Serum bilirubin ?? 1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin)
? Estimated Creatinine Clearance ? ? 50 ml/min (Cockroft Gault) or serum creatinine ?? 1.5 x ULN
8. PT/INR <1.5 x ULN and PTT (aPTT) <1.5 x ULN
9. Fasting glucose ?? 125 mg/dL (7 mmol/L) and erythrocyte-HbA1c ?? 59 mmol/mol
10. Men and women ? ? 18 years of age
11. Female patients must fulfil either of the 2 following main criteria:
? Not of childbearing potential, defined as:
? Post-menopausal women: Either women aged more than 50 years and amenorrhoeic for at least 12 months following cessation of all exogenous hormonal treatments, or, women under 50 years old who have been amenorrhoeic for at least 12 months following the cessation of exogenous hormonal treatments, and have serum follicle-stimulating hormone (FSH) and luteininzing hormone (LH) levels in the postmenopausal range for the institution.
Or
? Have documentation of irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation
? Have a negative pregnancy test prior to start of dosing, shoudl not be breastfeeding, and willing to use two forms of highly effective contraception (per institution standards) from the time of screening until 4 weeks after discontinuing study treatment (see Section 3.8)
12. Male patients must use an effective barrier method of contraception during the study and for 16 weeks following the last dose if sexually active with a female of childbearing potential
13. Able to swallow and retain oral medication
14. Written (signed and dated) informed consent (including provision of consent for collection of formalin fixed paraffin-embedded blocks or slides from archival histology or cytology samples, where available) and be capable of co-operating with treatment and follow up
Inclusion in biopsy research
For inclusion in the biopsy research of the study, patients must fulfil the following additional criterion:
? Provision of signed, written and dated informed consent for biomarker sampling analyses. Sampling will include the provision of tumour biopsies . If a patient declines to participate in this research, there will be no penalty or loss of benefit to the patient. The patient will not be excluded from other aspects of the study described in this Clinical Study Protocol, so long as they consent
Inclusion in the genetic component of the study
For inclusion in the genetic component of the study, patients must fulfil the following additional criteria:
? Provision of signed, written and dated informed consent for genetic research. If a patient declines to participate in the genetic component of the study, there will be no penalty or loss of benefit to the patient. The patient will not be excluded from other aspects of the study described in this Clinical Study Protocol, so long as they consent
? No history of non-autologous bone marrow transplant
Any whole blood transfusion given within 120 days of genetic sample collection should be leukocyte depleted |
|
| E.4 | Principal exclusion criteria |
1. Radiotherapy (except for palliative reasons), chemotherapy, endocrine therapy, or immunotherapy during the previous 3 weeks (4 weeks for investigational medicinal products and 6 weeks for nitrosoureas and Mitomycin-C) before treatment .
2. Ongoing toxic manifestations of previous treatments. Exceptions to this are alopecia or Grade 1 toxicities, which in the opinion of the Investigator should not exclude the patient.
3. Known leptomeningeal involvement, brain metastases or spinal cord compression.
4. History of hypersensitivity (> Grade 2) to active or inactive excipients of AZD2014, drugs containing Cremophor, taxanes or structurally/chemically similar drugs
5. Current refractory nausea and vomiting, chronic gastrointestinal disease, inability to swallow formulated product or previous significant bowel resection that would preclude adequate absorption of AZD2014
6. Patients with Diabetes Type I or uncontrolled Type II (HbA1c > 59 mmol/mol assessed locally) as judged by the investigator
7. Major surgery within 4 weeks prior to entry to the study (excluding placement of vascular access), or minor surgery within 2 weeks of entry into the study and from which the patient has not yet recovered
8. Treatment with warfarin. Patients on warfarin for DVT/PE can be converted to LMWH.
9. Exposure to potent or moderate inhibitors or inducers of CYP3A4/5 if taken within the stated washout periods before the first dose of study treatment (see Appendix G)
10. Exposure to potent or moderate inhibitors or inducers of CYP2C8 if taken within the stated washout periods before the first dose of study treatment (see Appendix G)
11. Exposure to sensitive or narrow therapeutic range substrates of the drug metabolising enzymes CYP2C8, CYP2C9, CYP2C19, CYP2D6 or the drug transporters Pgp (MDR1), BCRP, OATP1B1, OATP1B3, OCT1 and OCT2 within the appropriate wash-out period (a minimum of 5 times reported elimination half-life) before the first dose of study treatment (see Appendix G)
12. At high medical risk because of non-malignant systemic disease including active uncontrolled infection e.g. interstitial lung disease, severe hepatic impairment, uncontrolled chronic renal disease
13. Known to be serologically positive for hepatitis B, hepatitis C or human immunodeficiency virus (HIV)
14. Patients who have experienced any of the following procedures or conditions currently or in the preceding 12 months:
? coronary artery bypass graft
? angioplasty
? vascular stent
? myocardial infarction (MI)
? uncontrolled angina pectoris
? congestive heart failure NYHA Grade 2
? ventricular arrhythmias requiring continuous therapy
? supraventricular arrhythmias including AF, which are uncontrolled
? Torsades de Pointes
? haemorrhagic or thrombotic stroke, including transient ischaemic attacks or any other central nervous system bleeding
15. Resting ECG with measurable QTcF interval of >470 msec at 2 or more time points within a 24 hour period.
16. Concomitant medications known to prolong QT interval, or with factors that increase the risk of QTc prolongation or risk of arrhythmic events (such as heart failure, hypokalaemia, congenital long QT syndrome, family history of long QT syndrome), or unexplained sudden death under 40 years of age. Inability to discontinue medication with agents designated as having a risk of Torsades de Pointes due to QT prolongation
17. Left ventricular (LV) dysfunction (LVEF outside institutional range of normal) by MUGA or Echocardiogram
18. Current malignancies of other types, with the exception of adequately treated cone-biopsied in situ carcinoma of the cervix uteri and basal or squamous cell carcinoma of the skin. Cancer survivors, who have undergone potentially curative therapy for a prior malignancy, have no evidence of that disease for three years or more and are deemed at negligible risk for recurrence, are eligible for the trial.
19. Prior bone marrow transplant or have had extensive radiotherapy to greater than 25% of bone marrow within eight weeks of starting trial
20. Patients participating in or planning to participate in another interventional clinical trial whilst on this study. Participation in an observational trial is acceptable
21. Any other condition which in the Investigator's opinion would not make the patient a good candidate for the clinical trial. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Objective response rate |
| Tasa de respuesta objetiva (ORR) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| RECIST assessments will be performed every 7 weeks |
| Las evaluaciones de RECIST se llevarán a cabo cada 7 semanas. |
|
| E.5.2 | Secondary end point(s) |
AEs/SAEs
Vital signs
Clinical chemistry/haematology/coagulation
ECGs
Best objective response
Duration of response
Disease control rate
Change in tumour size
Progression free survival
Overall survival
PK parameters for each drug in the presence and absence of the other (Group A)
PK parameters for AZD2014 (Group B) |
AA/AAG
Constantes vitales
Bioquímica clínica/hematología/coagulación
ECG
Mejor respuesta objetiva
Duración de la respuesta
Índice de control de la enfermedad Cambio en el tamaño del tumor Supervivencia libre de progresión
Los parámetros FC de cada uno de los medicamentos en presencia y ausencia del otro (Grupo A)
Parámetros FC para AZD2014 (Grupo B) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
AEs continually monitored
Vital signs - Screening and at Day 1 of each week
Safety labs - Screening and at Day 1 of each week
ECG - Screening and at Day 1 of each cycle
Best Objective Response, duration of response, disease control rate, change in tumur size and progression free survival - every 7 weeks
PK parameters- Group A - Paclitaxel - Day 1 or 2 and Day 8 or 9 of Cycle 1 (in the presence or absence of the other)
PK parameters AZD2014 - Day 3 or 4 and Day 8 (in the presence or absence of the other)
PK parameters Group B - AZD2014 - Day 1 and 3 of Cycle 1
Overall Survival - every 12 weeks following progression |
Control continuo de los AAs
Constantes vitales - Revisión y en el Día 1 de cada semana
Laboratorios de seguridad - Revisión y el día 1 de cada semana
ECG - Revisión y el día 1 de cada ciclo
Mejor respuesta objetiva, duración de la respuesta, índice de
control de la enfermedad, cambio en el tamaño del tumor y supervivencia libre de progresión- cada 7 semanas
Parámetros FC - Grupo A - Paclitaxel - Día 1 o 2 y el Día 8 o 9 del Ciclo 1 (en presencia o ausencia de la otra)
Parámetros FC AZD2014 - Día 3 o 4 y el Día 8 (en presencia o ausencia de la otra)
Parámetros FC Grupo B - AZD2014 - Día 1 y 3 del Ciclo 1
Supervivencia global - cada 12 semanas después de la progresión |
|
| 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 | Yes |
| 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 | 1 |
| 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 | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 10 |
| 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 |
| Belgium |
| Germany |
| Spain |
| 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
|
| LVLS |
| Última visita del último paciente |
|
| 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 | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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