| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with advanced/metastatic non-small cell lung cancer (NSCLC) with no documented targetable alterations (EGFR mutation, ALK translocation, ROS1 mutation if available or MET exon 14 skipping mutation if available) |
| Patients avec un cancer du poumon non à petites cellules (CPNPC) à l’état localement avancé/métastatique n’ayant pas d’altérations cibles connues (mutation EGFR, translocation de ALK, mutation ROS1 si disponible, mutation de MET par le saut de l’exon si disponible) |
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| E.1.1.1 | Medical condition in easily understood language |
| Lung cancer |
| cancer du poumon |
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| 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 determine the safety of the tested 3-drug combination therapy based on NCI CTCAE v4.03 June 14, 2010,
•To assess activity parameters, including response rate (RR) by RECIST 1.1, duration of response, progression-free survival (PFS), overall survival (OS),
•To correlate clinical outcome with the predicted SIMS matching through a retrospective study.
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•Déterminer l’innocuité de la thérapie combinant les 3 médicaments testés en fonction des Critères Communs de Terminologie pour des Evénements Indésirables de l’Institut National du Cancer (National Cancer Institute Common Terminology Criteria for Adverse Events ) - NCI CTCAE v4.03 June 14, 2010,
•Evaluer les paramètres d’activité, incluant le taux de réponse (response rate, RR) à l’aide des critères RECIST version 1.1, la durée de la réponse, la survie sans-progression (Progression-Free Survival, PFS), la survie globale (Overall Survival, OS),
•Corréler la réponse clinique avec la prédiction d’efficacité de l’algorithme SIMS au cours d’une étude rétrospective.
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| E.2.2 | Secondary objectives of the trial |
•Describe any safety issues related to biopsy acquisition or tri-therapy,
•Describe genomic/transcriptomic aberrations seen in NSCLC.
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•Décrire tous les cas d’innocuité liés aux procédures de la biopsie ou de la trithérapie.
•Décrire les anomalies génomiques/transcriptomiques observées dans le CPNPC.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Age: Men and women aged >18 years,
2.Signed written informed consent,
3.Any histologic type of locally advanced or metastatic NSCLC,
4.Life expectancy of ≥ 12 weeks,
5.Measurable or evaluable (cytologically or radiologically detectable disease such as ascites, peritoneal deposits, or lesions which do not fulfill RECIST 1.1 criteria for measurable disease) lesions according to RECIST v1.1 criteria for phase 1 portion. For phase 2, all patients must have RECIST 1.1 measurable disease,
6.Physiologic function:
-Hematologic: Absolute neutrophil count (ANC) ≥ 1.5 × 109/L, platelet count ≥ 100 × 109/L, and hemoglobin ≥ 9 g/dL (may have been transfused),
-Hepatic: Total bilirubin level ≤ 1.5 × the upper limit of normal (ULN) range and AST and ALT levels ≤ 2.5 × ULN,
-Renal: Estimated creatinine clearance ≥ 30 mL/min according to the Cockcroft-Gault formula (or local institutional standard method).
7.Pregnancy and contraception:
-Pregnancy test: Negative serum or urine pregnancy test at screening for women of childbearing potential,
-Contraception: Highly effective contraception for both male and female subjects throughout the study and for at least 90 days after avelumab treatment administration if the risk of conception exists.
8.Ability to comply with protocol requirements,
9.Willingness to consent and ability to undergo a trucut biopsy to obtain tumor tissue from metastasis or primary tumor in case no adequate tumor tissue is available, and to undergo a bronchoscopy in order to obtain normal bronchial mucosa,
10.No serious or medically uncontrolled concomitant conditions that are likely to make the patient unfit for SPRING combination therapy, as per investigator assessment,
11.ECOG performance status of 0 to 1.
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| E.4 | Principal exclusion criteria |
-Patients with documented oncogenic aberrations at enrollment: EGFR, ALK, ROS1 when available, MET exon 14 skipping when available.
Note: For Phase 1 portion, all patients with adenocarcinoma histology must have documentation of results for druggable oncogenic aberrations (EGFR mutations, ALK rearrangements, and ROS1 when available) prior to enrollment on the study.
-For Phase 1 portion, >2 lines of prior therapy in the metastatic setting.
-For the dose escalation phase of the study or until the MTD for the combination regimen has been determined, patients with moderate hepatic impairment defined as AST, ALT, ALP >5 times ULN, which would be grade 3 or higher. However patients with liver metastases with AST/ALT ≤ 5 x ULN can be included in the study.
-For Phase 2 portion, any prior therapy in the metastatic setting.
Clinical exclusion criteria for Phase 1 and Phase 2 studies:
1.Documented untreated central nervous system metastases (indicated by clinical symptoms, cerebral edema, steroid requirement, or progressive disease in the prior four weeks),
2.Participants with a history of myocardial infarction within the last 2 years or with significant cardiac arrhythmias uncontrolled by medication or pacemaker,
3.Participants with any history of interstitial lung disease,
4.Prior clinically significant toxicities from anticancer agents or radiotherapy which have not regressed to Grade ≤ 1 severity (NCI-CTCAE version 4.03) apart from peripheral neuropathy and alopecia,
5.History of any second malignancy in the last two years; patients with prior history of in-situ cancer or basal or squamous cell skin cancer are eligible. Patients with a history of other malignancies are eligible if they have been continuously disease-free for at least two years,
6.Autoimmune condition requiring medical intervention,
7.Uncontrolled concomitant illness, active infection requiring i.v. antibiotics,
8.Participants who are at risk for, or who have a history of arterial thromboembolic events within the past 12 months and/or venous thromboembolic events within the past 6 months, or have had any recent active gastrointestinal bleeding,
9.Prior > G3 hemoptysis, major blood vessel involvement, and/or central cavitations,
10.Known or suspected drug hypersensitivity to any drug used in the combination,
11.Difficulty swallowing, malabsorption or other chronic gastrointestinal disease, or conditions that may hamper compliance and/or absorption of the oral drugs,
12.Any condition (e.g., known or suspected poor compliance, psychological instability, geographical location, etc.) that, in the judgment of the investigator may affect the patient’s ability to sign the informed consent and undergo study procedures,
13.Taking another experimental drugs within 28 days prior to day 1 of the protocol medications in this study,
14.Pregnant or breast-feeding women,
15.Both male and female patients of reproductive potential must agree to use a reliable method of birth control, during the study and for 3 months following the last dose of study drug,
16.Patients currently taking strong CYP3A4 inducers and inhibitors.
17.Patients currently taking proton pump inhibitors due to their impact on the disposition of palbociclib during the dose escalation phase,
18.Other anticancer agents and anticoagulants are excluded (except for low doses of anticoagulants used for access lines),
19.A time period of at least three weeks or five drug half-lives, whichever is shorter must have elapsed from last non-investigational therapy before 1 day of treatment on this study,
Specific exclusion criteria for administration of avelumab, in combination:
20.IMMUNOSUPRESSANTS: Current use of immunosuppressive medication, with exceptions detailed in protocol.
21.AUTOIMMUNE DISEASE: Active autoimmune disease that might deteriorate when receiving an immuno-stimulatory agent, with exceptions detailed in protocol.
22.ORGAN TRANSPLANTATION: Prior organ transplantation including allogenic stem-cell transplantation.
23.INFECTIONS: Active infection requiring systemic therapy.
24.HIV/AIDS: Known history of testing positive for HIV or known acquired immunodeficiency syndrome.
25.HEPATITIS: Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening.
26.VACCINATION: Vaccination within 4 weeks of the first dose of avelumab and while on trials is prohibited except for administration of inactivated vaccines.
27.HYPERSENSITIVITY TO STUDY DRUG.
28.CARDIOVASCULAR DISEASE: Clinically significant (i.e., active) cardiovascular disease.
29.OTHER PERSISTING TOXICITIES: Persisting toxicity related to prior therapy (NCI CTCAE v. 4.03 Grade > 1) with exceptions detailed in protocol.
30.Other severe acute or chronic medical conditions or psychiatric conditions or laboratory abnormalities.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
•To determine the safety of the tested 3-drug combination therapy based on NCI CTCAE v4.03 June 14, 2010, patients with advanced/metastatic NSCLC with no documented targetable alterations (EGFR, ROS1, MET exon 14 skipping mutation or ALK translocation) will receive a tri-therapy associating avelumab, axitinib and palbociclib. During the Phase 1, the tri-therapy will be tested at different doses following a specific dose-escalation scheme in order to establish the safety and identify the recommended dose (RP2D) for the Phase 2. The phase 2 will confirm the safety and will assess the efficacy of the tri-therapy approach in the treatment of advanced/metastatic NSCLC. Endpoints related to safety include an evaluation of Dose-Limiting Toxicities (DLTs), overall safety and parameters related to the optimal biological dose with RP2D. The Maximal Tolerated Dose (MTD) evaluation will be based on the DLT evaluable population. The optimal biological dose will be determined based upon analysis of all subject data, including safety and response data Endpoints for safety profile include assessments of AEs, SAEs, laboratory evaluations, vital signs, and physical examinations. Toxicities will be carefully monitored following the investigator brochure of each drug and the recommendations detailed in the protocol for dose modification or discontinuation. A data safety monitoring board will review the overall patient safety during the trial, starting from the phase 2.
The occurrence of AEs, abnormal laboratory values, and SAEs reported from the signing of an informed consent through 90 days after the last administration of the treatment will be summarized for all subjects who received at least one dose of the study treatment (safety population).
To determine the drug levels in blood and their interaction in combination, blood collections will be performed on Day 15’s visit (corresponding to the second injection of avelumab) of each cycle during phase 1, for each dose level and every two cycles during the phase 2. The apparition of auto-antibodies against avelumab will be monitored during the phase 2 at day 15 every two cycles.
•To assess the efficacy, evaluation will be based on following assessments according to RECIST 1.1 criteria: Best Overall Response, 6-month Response, Progression-Free Survival and Overall Survival (date of death of the patient will be collected). Patients will be considered evaluable if they received at least one cycle of treatment and had their baseline scan within 28 days of the start of therapy and follow-up scans about every 8 weeks (+/- 7 days) thereafter.
•To correlate clinical outcome with the predicted SIMS matching a retrospective study will be conducted.
The trial will be considered as meeting its primary endpoint if a 6-month response rate (% of patients achieving RECIST 1.1 complete or partial response within 6 months of treatment start) of 50% is achieved for patients who are fully matched according to the SIMS retrospective analysis and is superior to the partially matched arms. With a type I error of 10% and a power of 94%, 20 patients fully matched will be enough to demonstrate the usefulness of the approach assuming a null response rate of 20% based on the one-sided Fisher’s exact test. This would require a cohort of 200 patients treated. Nevertheless, we intend to treat an initial cohort of 100 patients as an exploratory observational study. Pending clinical activity, the study could be extended to an additional 100 patients treated in order to attain sufficient statistical power to support the validity of the approach.
SIMS will show clinical utility: If the proportion of patients fully matched to the combination versus partially matched estimated using SIMS (20/80) is similar to the observed proportion in the SPRING cohort (maximum coefficient variability allowed 20%) and if fully matched patients show significantly better clinical outcomes than the partially matched ones and the fully or partially matched ones show significantly better clinical outcomes than the non-matched ones.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Safety endpoints related to the phase 1 part will be analyzed through the study until the end of the phase 1. Analysis will continue during the phase 2 until the end.
Efficacy endpoints will be analyzed according to the stopping rules described in the protocol. An interim analyses will be perform once 50 treated patients has been reached. Final analysis will be done at the end of the study.
Correlation of the clinical outcome with the SIMS algorithm will be performed at the end of the study.
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| E.5.2 | Secondary end point(s) |
•Describe any safety issues related to biopsy acquisition or tri-therapy,
•Describe genomic/transcriptomic aberrations seen in NSCLC.
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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 | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Test of the Simplified Interventional Mapping System (SIMS) algorithm using genomic and transcriptomic data. |
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| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| Safety and efficacy of a treament combination |
| tolérabilité et efficacité d'une combinaison de traitement |
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| 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 | No |
| 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.8.3 |
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 | 5 |
| 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 |
| France |
| Israel |
| Luxembourg |
| Spain |
| United States |
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| 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
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| The last patient 90-day follow-up visit after end of study treatment is defined as the last patient last visit. |
| la dernière visite du dernier patient est la visite du dernier patient pour un suivi à 90 jours après la fin du traitement de l'étude. |
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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 | 5 |
| 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 | 5 |
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