E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Non-small cell lung cancer metastatic |
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E.1.1.1 | Medical condition in easily understood language |
Non-small cell lung cancer metastatic |
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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 | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10059515 |
E.1.2 | Term | Non-small cell lung cancer metastatic |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 |
• Part 1 (safety run-in):
To assess the tolerability and to confirm the recommended dose of SAR408701 in combination with ramucirumab in the NSQ NSCLC population.
• Part 2:
To assess the antitumor activity of SAR408701 in combination with ramucirumab in the NSQ NSCLC population.
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E.2.2 | Secondary objectives of the trial |
To assess the safety and tolerability of SAR408701 in combination with ramucirumab
To assess the durability of the response to treatment with SAR408701 in combination with ramucirumab
To assess efficacy of SAR408701 in combination with ramucirumab on progression free survival
To assess the pharmacokinetic (PK) profile of SAR408701 and ramucirumab when given in combination
To assess the immunogenicity of SAR408701 when given in combination with ramucirumab
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Histologically or cytologically proven diagnosis of non-squamous NSCLC with metastatic disease progression
a) After one prior line of chemotherapy in a metastatic setting. Development of metastatic disease during or within 6 months of an adjuvant/neoadjuvant treatment (to be considered as first-line treatment).
b) After or during one platinum-based chemotherapy and one immune checkpoint inhibitor (whatever the order)..
• Participants with carcinoembryonic antigen-related cell adhesion molecule (CEACAM) 5 expression of ≥2+ in archival tumor sample (or if not available, fresh biopsy sample) involving at least 50 % of the tumor cell population as demonstrated prospectively by central laboratory via immune histochemistry (IHC).
• At least one measurable lesion by RECIST v1.1.
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1.
• A female participant who agrees to use effective contraceptive methods during and for at least 7 months after the last dose of study intervention.
• A male participant who agrees to use effective contraception methods during and for at least 4 months after the last dose of study intervention
• Signed informed consent
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E.4 | Principal exclusion criteria |
Participants are excluded from the study if any of the following criteria apply:
• Patients with untreated brain metastases and history of leptomeningeal disease.
• Significant concomitant illnesses that would impair the patient’s participation in the study or interpretation of the results.
• History within the last 3 years of an invasive malignancy other than the one treated in this study, with the exception of resected/ablated basal or squamous-cell carcinoma of the skin or carcinoma in situ of the cervix, or other local tumors considered cured by local treatment.
• Non-resolution of any prior treatment related toxicity to < grade 2 according to NCI CTCAE V5.0, except for alopecia, vitiligo and active thyroiditis controlled with hormonal replacement therapy
• History of known acquired immunodeficiency syndrome (AIDS) related illnesses or known HIV disease requiring antiretroviral treatment, or unresolved viral hepatitis
• Previous history of and/or unresolved corneal disorders. The use of contact lenses is not permitted.
• Radiographic evidence of major airway or blood vessel invasion or intratumor cavitation
• History of uncontrolled hereditary or acquired thrombotic disorder or history of aneurism.
• Major surgery within 28 days prior to Day 1/first IMP infusion,. Postoperative bleeding complications or wound complications from a surgical procedure performed in the last 2 months.
• History of gross hemoptysis within 2 months before the first administration of study intervention.
• Clinically relevant congestive heart failure (CHF; NYHA II-IV) or symptomatic or poorly controlled cardiac arrhythmia.
• Any arterial thrombotic event within 6 months before the first administration of study intervention.
• Uncontrolled arterial hypertension (systolic ≥150 mmHg or diastolic ≥90 mmHg) despite standard medical management.
• Serious or nonhealing wound, skin ulcer, or bone fracture within 28 days before the first administration of study intervention.
• Gastrointestinal (GI) perforation and/or fistulae within 6 months prior to first administration of study intervention.
• Significant bleeding disorders, vasculitis, or Grade 3-4 gastrointestinal (GI) bleeding within 3 months before the first administration of study intervention.
• Bowel obstruction, history or presence of inflammatory enteropathy or extensive intestinal resection Crohn's disease, ulcerative colitis, or chronic diarrhea.
• Medical condition requiring concomitant administration of a medication with a narrow therapeutic window and metabolized by CYP450 or a strong CYP3A inhibitor
• Concurrent treatment with any other anticancer therapy
• No more than 1-line previous chemotherapy in metastatic setting
• Prior treatment with ramucirumab or docetaxel
• Prior therapy targeting CEACAM5 or maytansinoid treatment (DM1 or DM4 antibody-drug conjugate)
• Contraindication to use of corticosteroid premedication
• Current therapeutic anticoagulation with warfarin, low-molecular-weight heparin, or similar agents. Patients receiving prophylactic, low-dose anticoagulation therapy are eligible
• Previous enrollment in this study, current participation in any other clinical study involving an investigational study treatment, or any other type of medical research
• Poor bone marrow, liver or kidney functions
• Urine dipstick or routine analysis indicating proteinuria of 2+ or higher, unless a 24 hour urine collection demonstrates <1000 mg of protein.
• Sensitivity to any of the study interventions, or components thereof, or drug or other allergy that, in the opinion of the Investigator, contraindicates participation in the study.Most important exclusion criteria for potential participants
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E.5 End points |
E.5.1 | Primary end point(s) |
Part 1: Incidence of study drug-related dose-limiting toxicity (DLT) at Cycle 1 and Cycle 2 - Drug-related dose-limiting toxicity (DLT) as oserved during DLT-observation period tolerability in order to confirm the recommended dose of SAR408701 in combination with ramucirumab for the Part 2.
Part 2: Objective response rate - Objective response rate defined as proportion of participants with confirmed complete response (CR) or partial response (PR) as best overall response determined per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Part 1. - baseline up to Cycle 2 (approximatively 1 month
Part 2. - Baseline up to 6 months after the last patient treated |
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E.5.2 | Secondary end point(s) |
1. Incidence of treatment emergent adverse events (TEAEs) and serious adverse events (SAEs) - Incidence of TEAEs and SAEs and laboratory abnormalities according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) V5.0.
2. Duration of response (DOR) - Duration of response (DOR) is defined as the time from first documented evidence of CR or PR until progressive disease (PD) determined per RECIST v.1.1 or death from any cause, whichever occurs first.
3. Progression-free survival (PFS) - Progression-free survival (PFS) is defined as the time from the first investigational medicinal product (IMP) administration to the date of the first documented disease progression or death due to any cause, whichever comes first.
4. PK:
-Cmax Maximum concentration of SAR408701 observed after SAR408701 1st infusion
-AUC0-14d Area under the plasma SAR408701 concentration versus time curve calculated using the trapezoidal method from time 0 to 14 days after SAR408701 1st infusion.
-Ctrough Concentration observed of SAR408701 just before SAR40870 treatment administration during repeated dosing
-Ctrough Concentration observed of ramucirumab just before ramucirumab treatment administration during repeated dosing
5. Incidence of anti-therapeutic antibodies (ATAs) against SAR408701 - Incidence of anti-therapeutic antibodies (ATAs) against SAR408701. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Baseline up to 90 days after the last study treatment administration
2. Baseline up to 6 months after the last patient treated
3. Baseline up to 6 months after the last patient treated
4. Baseline up to cycle 13 (approximatively 6 months)
5. Baseline up to end of study (approximately 2 years) |
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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 | 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 | 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 | 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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 21 |
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 |
Bulgaria |
Czech Republic |
Italy |
Korea, Republic of |
Portugal |
Spain |
United States |
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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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 8 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 8 |