| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Unresectable Non-Small Cell Lung Cancer (NSCLC). |
|
| E.1.1.1 | Medical condition in easily understood language |
| Unresectable Non-Small Cell Lung Cancer (NSCLC). |
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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 | 18.0 |
| 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 evaluate the antitumor activity as progression-freesurvival at four months (PFS4) of PM01183 alone or in combination with gemcitabine as second-line treatment in unresectable NSCLC patients, using single agent docetaxel as a reference in the control arm as current standard of care. |
|
| E.2.2 | Secondary objectives of the trial |
*To analyze the following in each of the three treatment arms:
- Time-to-event endpoints, such as: progression-free survival (PFS), overall survival (OS), overall survival rate at 1-year (OS12) and duration of response (DR).
- Antitumor activity, as response rate (RR) evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.
- Safety and efficacy profiles of PM01183 alone and in combination with gemcitabine, to be preliminary compared with docetaxel.
- Patients’ quality of life (QoL) assessment.
- To explore the feasibility and safety of a PM01183 maintenance dose in non-progressing NSCLC patients.
- Pharmacokinetics (PK) of PM01183.
- PK/PD (pharmacokinetic/pharmacodynamic)
correlation in PM01183-based treated patients, whenever possible.
*Pharmacogenomics (PGx): To explore potential correlations between molecular parameters found in previous available tumor samples and clinical outcomes
achieved with PM01183-based treatment. |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
| Pharmacogenomic sub-study. |
|
| E.3 | Principal inclusion criteria |
1) Voluntary written IC of the patient obtained before any study-specific procedure.
2) Histologically or cytologically confirmed unresectable NSCLC.
3) Patients must have failed one prior line of CT-based therapy for unresectable disease.
4) Age between 18 and 75 years, both inclusive.
5) Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 1.
6) Adequate hematological, renal, metabolic and hepatic function:
a) Hemoglobin ≥ 9 g/dl (patients may have received prior red blood cell [RBC] transfusion up to 48 hours before
treatment start, if clinically indicated), absolute neutrophil count (ANC) ≥ 2.0 x 109/l, and platelet count ≥ 100 x 109/l.
b) Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3.0 x upper limit of normal (ULN).
c) Total bilirubin ≤ ULN.
d) Albumin ≥ 3.0 g/dl.
e) Calculated creatinine clearance (CrCl) ≥ 30 ml/minute (using Cockcroft and Gault’s formula).
f) Creatine phosphokinase (CPK) ≤ 2.5 x ULN.
7) At least four weeks (if the patient received a total dose ≥ 30 Gy)/two weeks (if the patient received a total dose < 30 Gy) since the last prior therapy, at least four weeks since completion of any prior radiotherapy and recovery to grade ≤ 1 from any adverse event (AE) derived from previous anticancer treatment, except alopecia, sensory neuropathy, anemia or asthenia (all of which must have recovered to grade ≤ 2) according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE, v.4).
8) Pre-menopausal women must have a negative pregnancy test before treatment start and not be breast feeding. Both women and men must agree to use a medically acceptable method of contraception throughout the treatment period and for at least six months after treatment discontinuation. Acceptable methods of contraception include intrauterine device (IUD), oral contraceptive,
subdermal implant, double barrier and/or complete abstinence (non-periodic). |
1) Obtention du consentement éclairé écrit du patient avant le début de toute procédure spécifique de l'étude.
2) CBNPC non résécable confirmé par histologie ou cytologie.
3) Les patients doivent être en échec d’une première ligne de chimiothérapie.
4) Âgé(e) de 18 à 75 ans.
5) Indice de performance (PS; « performance status ») ECOG (« Eastern Cooperative Oncology Group ») ≤ 1.
6) Fonctions hématologique, rénale, métabolique et hépatique adéquates.
a) Hémoglobine ≥ 9 g/dL (les patients peuvent avoir reçu une transfusion de globules rouges [GR] jusqu'à 48 heures avant le début du traitement, si cliniquement indiqué), nombre absolu de polynucléaires neutrophiles (PNN) ≥ 2,0 x 109 /L, et nombre de plaquettes ≥ 100 x 109/L.
b) Alanine aminotransférase (ALAT) et aspartate aminotransférase (ASAT) ≤ 3,0 x LSN (Limite Supérieure de la Normale).
c) Bilirubine totale ≤ LSN.
d) Albumine ≥ 3,0 g/dL.
e) Clairance de la créatinine calculée (ClCr) ≥ 30 mL/minute (à l'aide de la formule de Cockcroft et Gault).
f) Créatine phosphokinase (CPK) ≤ 2,5 × LSN.
7) Délai d’au moins trois semaines après la dernière chimiothérapie, et d’au moins quatre semaines (si le patient a reçu une dose totale d’irradiation ≥ 30 Gy) / deux semaines (si le patient a reçu une dose totale d’irradiation < 30 Gy) après la fin de la dernière radiothérapie, et récupération jusqu’à un grade≤1 de tout évènement indésirable (EI) survenu lors du traitement anticancéreux précédent, à l'exception de l'alopécie, de la neuropathie sensorielle, de l'anémie ou de l'asthénie (desquels il faudra avoir récupéré jusqu’à un grade ≤ 2) selon le « National Cancer Institute Common Terminology Criteria for Adverse Events » (NCI-CTCAE, version 4).
8) Les femmes en âge de procréer doivent avoir un test de grossesse négatif avant le début du traitement et ne pas allaiter. Les patients hommes et femmes doivent accepter d'utiliser une contraception appropriée pendant toute la durée de participation à l'étude et pendant au moins six semaines après la dernière dose de PM01183. Les méthodes de contraception appropriée comprennent l’utilisation de dispositif intra-utérin (DIU), la contraception orale, l’implant contraceptif sous-cutané, la double barrière et/ou l’abstinence totale (pas seulement périodique). |
|
| E.4 | Principal exclusion criteria |
1) Concomitant diseases/conditions:
a) History (within the last year) or presence of unstable angina, myocardial infarction, symptomatic congestive heart failure or asymptomatic with left ventricular ejection fraction (LVEF) ≤ 50% (assessed by multiple-gated acquisition scan [MUGA] or equivalent by ultrasound [US]) or clinically significant valvular heart disease.
b) Patients with dyspnea at rest or requiring any oxygen support within the last four weeks.
c) Known infection by human immunodeficiency virus (HIV), including seropositive patients without AIDs.
d) Chronic active hepatitis or cirrhosis. For Hepatitis B, this includes positive tests for both Hepatitis B surface antigen and Hepatitis B quantitative polymerase chain
reaction (qPCR). For Hepatitis C, this includes positive tests for both Hepatitis C antibody and Hepatitis C qPCR.
e) Active uncontrolled infection; patients undergoing active antibiotherapy for an ongoing infection must have finished treatment at least one week before treatment start.
f) Pleural or pericardial effusions requiring invasive management procedures.
g) Known myopathy of any cause.
h) Limitation of the patient’s ability to comply with the treatment or to follow-up the protocol.
I) Any other major illness that, in the Investigator’s judgment, will substantially increase the risk associated with the patient’s participation in this study.
2) More than one prior line of CT for advanced or unresectable disease.
3) Histological features of neuroendocrine or bronchioalveolar differentiation.
4) Unknown epidermal growth factor receptor (EGFR) mutation status or previously known EGFR mutated status in patients with adenocarcinoma.
5) Prior or concurrent invasive malignant disease, unless in complete remission for more than three years. Exceptions are completely resected or definitively treated squamous cell carcinoma of the cervix or head and neck without lymphatic spread, cutaneous basal cell carcinoma or superficial transitional cell carcinoma of the bladder.
6) Significant cancer-related weight loss (≥10%) within four weeks prior to treatment start.
7) Prior treatment with gemcitabine or docetaxel-containing therapy (one full infusion at least completed).
8) Symptomatic, steroid-requiring or progressive CNS involvement. If there is prior or current, known or suspected CNS involvement, clinical stability and lack of radiological progression of lesions should be demonstrated for at least the immediate six weeks before study entry.
9) Ongoing symptomatic paraneoplastic syndromes.
|
1) Maladies concomitantes :
a) Antécédents (au cours de la dernière année) ou présence d’un angor instable, infarctus du myocarde, insuffisance cardiaque congestive symptomatique ou asymptomatique avec fraction d’éjection du ventricule gauche (FEVG) ≤ 50 % [évaluée par ventriculographie radio-isotopique « multiple-gated acquisition scan » (MUGA) ou équivalent par ultrasons (US)] ou maladie cardiaque valvulaire cliniquement significative.
b) Les patients ayant souffert de dyspnée au repos ou nécessitant un apport d'oxygène au cours des quatre dernières semaines.
c) Infection connue par le virus de l'immunodéficience humaine (VIH), y compris les patients séropositifs sans sida.
d) Hépatite chronique active ou cirrhose. Pour l’hépatite B, cela comprend des tests positifs par détection de l’antigène de surface et par réaction en chaîne par polymérase quantitative (qPCR). Pour l’hépatite C, cela comprend des tests positifs par dosage des anticorps anti-hépatite C et par réaction en chaîne par polymérase quantitative (qPCR).
e) Infection active non contrôlée ; les patients sous antibiothérapie active pour une infection en cours doivent avoir terminé le traitement au moins une semaine avant le début du traitement.
f) Épanchements pleuraux ou péricardiques nécessitant des procédures de prise en charge invasives
g) Myopathie connue, quelle qu’en soit la cause.
h) Patient difficilement capable de se conformer au traitement et au suivi du protocole.
i) Toute autre maladie importante qui, de l’avis de l’investigateur, augmentera de façon significative le risque associé à la participation du patient à l’étude.
2) Plus d'une ligne antérieure de chimiothérapie pour un cancer avancé ou non résécable.
3) Caractéristiques histologiques de différenciation neuro-endocrine ou broncho-alvéolaire.
4) Statut de la mutation du récepteur du facteur de croissance épithélial (EGFR) inconnu ou mutation de l'EGFR précédemment établie chez les patients atteints d'un adénocarcinome.
5) Affection maligne invasive antérieure ou simultanée, à moins qu'elle ne soit en rémission complète depuis plus de trois ans. Les exceptions incluent le carcinome épidermoïde du col de l'utérus, de la tête et du cou complètement réséqué ou traité de manière définitive et sans propagation lymphatique, un carcinome basocellulaire ou un carcinome cellulaire transitoire superficiel de la vessie.
6) Perte de poids importante liée au cancer (≥10 %) au cours des quatre semaines avant le début du traitement.
7) Un traitement préalable par thérapie incluant le docétaxel (au moins une perfusion complète réalisée).
8) Implication progressive ou symptomatique du SNC, nécessitant des stéroïdes. En cas d'implication antérieure ou actuelle du SNC, connue ou suspectée, la stabilité clinique et l'absence de progression radiologique des lésions doivent être démontrées pendant au moins six semaines avant l'entrée dans l'étude.
9) Syndromes paranéoplasiques symptomatiques en cours. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Progression-free survival rate at four months (PFS4), defined as the rate estimate of the percentage of patients
who are alive and progression-free at 16 weeks (~4 months) after randomization. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
| Overall response rate (ORR), Duration of response (DR), Progression-Free Survival (PFS), Overall Survival (OS), Overall Survival rate at 1 year (OS12), Treatment Safety, Quality of Life (QoL), Non-compartmental (NCA) PK parameters, Pharmacogenomics (PGx). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | 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 | Yes |
| E.8.1.1 | Randomised | Yes |
| 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 | Yes |
| E.8.2.3.1 | Comparator description |
|
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 15 |
| 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 |
|
| 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
|
| Nine months after the last treatment discontinuation of the last patient, or twelve months after accrual of the last evaluable patient (whichever occurs first), provided all patients who are still alive have had at least 12 months survival follow-up. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| 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 | 4 |
| 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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