| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced nonsquamous non-small cell lung cancer (NSCLC). |
| Tratamiento de segunda línea del CPNM no escamoso avanzado |
|
| E.1.1.1 | Medical condition in easily understood language |
| Advanced nonsquamous non-small cell lung cancer (NSCLC). |
| Tratamiento de segunda línea del CPNM no escamoso avanzado |
|
| 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 | 17.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10061873 |
| E.1.2 | Term | Non-small cell lung cancer |
| 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 efficacy of nab-paclitaxel administered intravenously (IV) on Days 8 and 15 with epigenetic modifying therapy of CC-486 once daily (QD) on Days 1 to 14 every 21 days, and nab-paclitaxel monotherapy administered IV on Days 1 and 8 every 21 days as second-line treatment for advanced nonsquamous NSCLC, and the relative efficacy of these two treatment regimens. |
| Valorar la eficacia de nab-paclitaxel administrado por vía intravenosa (IV) en los días 8 y 15 con el modificador epigenético CC-486 una vez al día (1 v/d) en los días 1 y 14 cada 21 días, y de nab-paclitaxel en monoterapia, administrado IV en los días 1 y 8 cada 21 días como tratamiento de segunda línea del CPNM no escamoso avanzado, y la eficacia relativa de estos dos regímenes de tratamiento. |
|
| E.2.2 | Secondary objectives of the trial |
| To evaluate the safety and tolerability of nab-paclitaxel administered IV on Days 8 and 15 in combination with epigenetic modifying therapy of CC-486 once daily (QD) on Days 1 to 14 every 21 days, and nab-paclitaxel monotherapy administered IV on Days 1 and 8 every 21 days as second-line treatment for advanced nonsquamous NSCLC. |
| Evaluar la seguridad y la tolerabilidad de nab-paclitaxel administrado IV en los días 8 y 15 combinado con el modificador epigenético CC-486 una vez al día (1 v/d) en los días 1 a 14 cada 21 días, y de nab-paclitaxel en monoterapia, administrado IV en los días 1 a 8 cada 21 días como tratamiento de segunda línea del CPNM no escamoso avanzado |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subjects must satisfy the following criteria to be randomized in the study:
1.Age ? 18 years the time of signing the Informed Consent Form (ICF).
2.Understand and voluntarily provide written informed consent prior to the conduct of any study related assessments/procedures.
3.Able to adhere to the study visit schedule and other protocol requirements
4.Histologically or cytologically confirmed advanced nonsquamous NSCLC.
5.No other current active malignancy requiring anticancer therapy.
6.Radiographically documented measurable disease (defined by the presence of ? 1 radiographically documented measurable lesion).
7.One prior platinum-containing chemotherapy for the treatment of advanced disease.
8.Absolute neutrophil count (ANC) ? 1500 cells/mm3.
9.Platelets ? 100,000 cells/mm3.
10.Hemoglobin (Hgb) ? 9 g/dL.
11.Aspartate transaminase (AST/serum glutamic oxaloacetic transaminase [SGOT]) and alanine transaminase (ALT/serum glutamic pyruvic transaminase [SGPT]) ? 2.5 × upper limit of normal range (ULN) or ? 5.0 × ULN if liver metastases.
12.Total bilirubin ? 1.5 ULN (unless there is a known history of Gilberts Syndrome).
13.Serum creatinine ? 1.5 x ULN, or calculated creatinine clearance ? 60 mL/min (if renal impairment is suspected 24-hour urine collection for measurement is required).
14.Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
15.Females of childbearing potential [defined as a sexually mature woman who (1) have not undergone hysterectomy (the surgical removal of the uterus) or bilateral oophorectomy (the surgical removal of both ovaries) or (2) have not been naturally postmenopausal for at least 24 consecutive months (ie, has had menses at any time during the preceding 24 consecutive months)] must:
a.Have a negative pregnancy test (ß-hCG) as verified by the study doctor within 72 hours prior to starting study therapy. She must agree to ongoing pregnancy testing during the course of the study, and after end of study therapy. This applies even if the subject practices true abstinence* from heterosexual contact.
b.Either commit to true abstinence* from heterosexual contact or agree to use, and be able to comply with, effective contraception without interruption, 28 days prior to starting investigational product (IP), during the study therapy (including dose interruptions), and for 3 months after discontinuation of study therapy.
Male subjects must:
a.Practice true abstinence* or agree to use a condom during sexual contact with a pregnant female or a female of childbearing potential while participating in the study, during dose interruptions and for at least 6 months following IP discontinuation, even if he has undergone a successful vasectomy.
16.Females must abstain from breastfeeding during study participation and 3 months after IP discontinuation.
*True abstinence is acceptable when this is in line with the preferred and usual lifestyle of the subject. [Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception]. |
- Edad >= 18 años en el momento de la firma del ICI.
- CPNM no escamoso avanzado confirmado histológica o citológicamente
- Ausencia de otro proceso maligno activo que exija tratamiento antineoplásico
- Enfermedad mensurable comprobada radiológicamente (definida por la presencia de >= 1 lesión mensurable comprobada radiológicamente).
- Una quimioterapia previa que contenía platino para el tratamiento de la enfermedad
avanzada.
- Recuento absoluto de neutrófilos (RAN) >= 1500/mm3.
- Recuento de plaquetas >= 100.000/mm3.
- Hemoglobina (Hb) >= 9 g/dl.
- Aspartato transaminasa (AST/transaminasa glutamicooxaloacética sérica [SGOT]) y
alanina aminotransferasa (ALT/transaminasa glutamicopirúvica sérica) [SGPT]) <= 2,5 ×
límite superior normal (LSN) o <= 5,0 × LSN si hay metástasis hepáticas.
- Bilirrubina total <= 1,5 LSN (a menos que existan antecedentes conocidos de síndrome de
Gilbert).
- Creatinina sérica <=1,5 x LSN, o aclaramiento de creatinina calculado >= 60 ml/min (si se
sospecha deterioro renal, hay que recoger la orina de 24 horas para determinación).
- Estado funcional 0 o 1 del Eastern Cooperative Oncology Group (ECOG).
- Las mujeres con capacidad fértil deben seguir los criterios embarazo y lactancia
- Los varones y las mujeres en edad fértil deben seguir los criterios de anticoncepción |
|
| E.4 | Principal exclusion criteria |
The presence of any of the following will exclude a subject from enrollment:
1.Squamous cell NSCLC.
2.Prior taxane therapy.
3.Evidence of active brain metastases, including leptomeningeal involvement (prior evidence of brain metastasis are permitted only if asymptomatic and clinically stable for at least 8 weeks following completion of therapy). MRI of the brain (or CT scan w/contrast) is preferred.
4.Only evidence of disease is non-measurable.
5.Known EGFR mutation.
6.Known EML4-ALK mutation.
7.Preexisting peripheral neuropathy of Grade > 2 (per NCI CTCAE v4.0).
8.Venous thromboembolism within 1 month prior to Cycle 1 Day 1.
9.Current congestive heart failure (New York Heart Association Class II-IV).
10.History of the following within 6 months prior to Cycle 1 Day 1: a myocardial infarction, severe/unstable angina pectoris, coronary/peripheral artery bypass graft, New York Heart Association (NYHA) Class III-IV heart failure, uncontrolled hypertension, clinically significant cardiac dysrhythmia or clinically significant electrocardiogram (ECG) abnormality, cerebrovascular accident, transient ischemic attack, or seizure disorder.
11.Known hepatitis B or C virus (HBV/HCV) infection, known history of human immunodeficiency virus (HIV) infection, or receiving immunosuppressive or myelosuppressive medications that would in the opinion of the investigator, increase the risk of serious neutropenic complications.
12.Active, uncontrolled bacterial, viral, or fungal infection(s) requiring systemic therapy, defined as ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics, antiviral therapy, and/or other treatment.
13.History of interstitial lung disease, sarcoidosis, silicosis, idiopathic pulmonary fibrosis, or pulmonary hypersensitivity pneumonitis.
14.Subject has a clinically significant malabsorption syndrome, persistent diarrhea, or known sub-acute bowel obstruction > NCI CTCAE Grade 2, despite medical management.
15.Treatment with any investigational product within 28 days prior to signing the ICF.
16.History of or suspected allergy to nab-paclitaxel, azacitidine, human albumin or mannitol.
17.Currently enrolled in any other clinical protocol or investigational trial that involves administration of experimental therapy and/or therapeutic devices.
18.Any other clinically significant medical condition, psychiatric illness, and/or organ dysfunction that will interfere with the administration of the therapy according to this protocol or which, in the views of investigator, preclude combination chemotherapy.
19.Any other malignancy within 5 years prior to randomization, or advanced malignant hepatic tumors, with the exception of adequately treated squamous cell carcinoma of the skin, in-situ carcinoma of the cervix, uteri, non-melanomatous skin cancer, carcinoma in situ of the breast, or incidental histological finding of prostate cancer (TNM Classification of Malignant Tumours (TNM) stage of T1a or T1b). (All treatment of which should have been completed 6 months prior to signing ICF).
20.Any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study.
21.Any medical condition that confounds the ability to interpret data from the study.
22.Pregnant or breastfeeding females. |
- CPNM de células escamosas.
- Tratamiento previo con taxanos.
- Evidencia de metástasis cerebrales activas, incluida afectación leptomeníngea (sólo se
permiten la evidencia previa de metástasis cerebral si es asintomática y clínicamente estable durante al menos 8 semanas después de completarse el tratamiento).
- Los únicos indicios de enfermedad no son mensurables.
- Mutación conocida del EGFR y de EML4-ALK.
- Neuropatía periférica preexistente de grado >2 (según los CTCAE del NCI v4.0).
- Antecedentes de convulsiones o problemas cardiovascular clínicamente significativos en los 6 meses previos al día 1 del ciclo 1
- Infección conocida por el virus de la hepatitis B o C (VHB/VHC), antecedentes conocidos de infección por el virus de la inmunodeficiencia humana (VIH), estado de inmunosupresión, infecciones activas
- Antecedentes de neumopatía intersticial, sarcoidosis, silicosis, fibrosis pulmonar
idiopática o neumonitis por hipersensibilidad pulmonar
- El sujeto sufre un síndrome de malabsorción de importancia clínica, diarrea persistente u
obstrucción intestinal subaguda conocida
- Cualquier otro proceso maligno en los 5 años previos a la aleatorización, o los tumores
hepáticos malignos avanzados
- Embarazo o lactancia materna |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Progression free survival |
| Supervivencia Libre de Progressión |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The time from the date of randomization to the date of disease progression or death (any cause) on or prior to the data cutoff date for analyses, whichever occurs first. |
| Tiempo desde la fecha de aleatorización hasta la de progresión de la enfermedad o fallecimiento (por cualquier causa) en o antes de la fecha de corte de los datos para los análisis, lo que antes ocurra. |
|
| E.5.2 | Secondary end point(s) |
Efficacy
- Disease control rate
- Overall response rate
- Overall survival
Safety
- The type, frequency, and severity of AEs and SAEs graded using National Cancer
Institute Common Terminology Criteria for Adverse Events (Version 4.0).
- Discontinuation rate
- The median dose intensity
- The incidence of dose reduction |
Eficacia
- Tasa de control de la enfermedad
- Tasa de respuesta global
- Supervivencia global
Seguridad
- El tipo, la frecuencia y la intensidad de los AA y los AAG. graduados mediante los Criterios terminológicos comunes para acontecimientos adversos (CTCAE, versión 4.0) del National Cancer Institute (NCI).
- La tasa de retiradas.
- La mediana de intensidad de la dosis.
- La incidencia de reducciones de la dosis. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Disease control rate, OS, and ORR will be evaluated within each treatment arm and between the treatment arms at the time of the final analysis of the PFS endpoint when approximately 120 PFS events have been observed. |
| Tasa de control de la enfermedad, SG, y TRG se evaluarán para cada brazo de tratamiento y entre brazos de tratamiento en el momento del análisis final del criterio de valoración SLP cuando se hayan obervado aproximadamente 120 episodios de SSP |
|
| 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 | No |
| 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 | Information not present in EudraCT |
| E.8.1.2 | Open | Information not present in EudraCT |
| E.8.1.3 | Single blind | Information not present in EudraCT |
| E.8.1.4 | Double blind | Information not present in EudraCT |
| E.8.1.5 | Parallel group | Information not present in EudraCT |
| E.8.1.6 | Cross over | Information not present in EudraCT |
| E.8.1.7 | Other | Information not present in EudraCT |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 18 |
| 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 |
| Canada |
| France |
| Germany |
| Italy |
| Netherlands |
| Spain |
| United States |
|
| 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
|
The End of Trial is defined as either the:
- date of the last visit of the last subject to complete the study, or
- the date of receipt of the last data point from the last subject that is required for primary, secondary and/or exploratory analysis, as pre-specified in the protocol and/or the Statistical Analysis Plan, whichever is the later date. |
El final del ensayo se define como:
- la fecha de la última visita del último sujeto que complete el estudio, o
- la fecha de recepción del último punto de datos del último sujeto que se precise para
análisis principal, secundario o exploratorio, preestablecida en el protocolo o en el plan de análisis estadístico (PAE), la que sea posterior. |
|
| 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 |
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