Tusamitamab Ravtansine (SAR408701) in Combination With Ramucirumab or Ramucirumab and Pembrolizumab in Pretreated Patients With NSQ NSCLC (CARMEN-LC04) (CARMEN-LC04)

February 28, 2024 updated by: Sanofi

Open-label, Single-arm Trial to Evaluate Antitumor Activity, Safety, and Pharmacokinetics of Tusamitamab Ravtansine (SAR408701) Used in Combination With Ramucirumab or Ramucirumab and Pembrolizumab in Metastatic, Non-squamous, Non Small-cell Lung Cancer (NSQ NSCLC) Patients With CEACAM5-positive Tumors, Previously Treated With Platinum-based Chemotherapy and an Immune Checkpoint Inhibitor

Primary Objectives:

Doublet Cohort

Part 1 (safety run-in):

To assess the tolerability and to confirm the recommended dose of tusamitamab ravtansine in combination with ramucirumab in the NSQ NSCLC population.

Part 2:

To assess the antitumor activity of tusamitamab ravtansine in combination with ramucirumab in the NSQ NSCLC population.

Triplet cohort

To assess the tolerability and to confirm the recommended dose of tusamitamab ravtansine in combination with ramucirumab and pembrolizumab in the NSQ NSCLC population.

Secondary Objectives:

Doublet Cohort

To assess the safety and tolerability of tusamitamab ravtansine in combination with ramucirumab.

To assess the durability of the response to treatment with tusamitamab ravtansine in combination with ramucirumab.

To assess anti-tumor activity of tusamitamab ravtansine in combination with ramucirumab on progression free survival (PFS) and disease control rate (DCR).

To assess the pharmacokinetic (PK) profiles of tusamitamab ravtansine (SAR408701) and ramucirumab when given in combination.

To assess the immunogenicity of tusamitamab ravtansine (SAR408701) when given in combination with ramucirumab.

Triplet cohort

To assess the safety and tolerability of tusamitamab ravtansine in combination with ramucirumab and pembrolizumab

To assess the antitumor activity of tusamitamab ravtansine in combination with ramucirumab and pembrolizumab in the NSQ NSCLC population.

To assess the immunogenicity of tusamitamab ravtansine when given in combination with ramucirumab and pembrolizumab

Study Overview

Status

Active, not recruiting

Conditions

Intervention / Treatment

Detailed Description

The expected duration of the study intervention for participants may vary, based on progression date ; median expected duration of study per participant is estimated 11 months (up to 1 month for screening, a median of 6 months for treatment, and a median of 4 months for end-of-treatment assessments and safety follow-up visit)

Study Type

Interventional

Enrollment (Actual)

31

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

  • Name: Trial Transparency email recommended (Toll free number for US & Canada)
  • Phone Number: option 6 800-633-1610
  • Email: contact-us@sanofi.com

Study Locations

  • Bulgaria
      • Plovdiv, Bulgaria, 4004
        • Investigational Site Number : 1000001
  • Czechia
      • Ostrava - Vitkovice, Czechia, 703 84
        • Investigational Site Number : 2030001
      • Praha 2, Czechia, 12808
        • Investigational Site Number : 2030002
  • Korea, Republic of
    • Seoul-teukbyeolsi
      • Seoul, Seoul-teukbyeolsi, Korea, Republic of, 03080
        • Investigational Site Number : 4100001
      • Seoul, Seoul-teukbyeolsi, Korea, Republic of, 03722
        • Investigational Site Number : 4100002
  • Portugal
      • Porto, Portugal, 4200-162
        • Investigational Site Number : 6200001
  • Spain
      • Madrid, Spain, 28040
        • Investigational Site Number : 7240004
      • Zaragoza, Spain, 50009
        • Investigational Site Number : 7240003
    • Catalunya [Cataluña]
      • Barcelona / Sabadell, Catalunya [Cataluña], Spain, 08208
        • Investigational Site Number : 7240001
    • Madrid, Comunidad De
      • Madrid, Madrid, Comunidad De, Spain, 28046
        • Investigational Site Number : 7240005
  • United States
    • Michigan
      • Detroit, Michigan, United States, 48202
        • Henry Ford Hospital Site Number : 8400005
    • New York
      • Buffalo, New York, United States, 14263
        • Roswell Park Cancer Institute Site Number : 8400003
    • Texas
      • Waco, Texas, United States, 76712
        • McClinton Cancer Center Site Number : 8400002

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion criteria :

  • Metastatic disease progression fulfilling both of the following 2 criteria:

    1. Having progressive disease during or after platinum-based chemotherapy (at least 2 cycles). Maintenance therapy following platinum-based chemotherapy is not considered as a separate regimen. Adjuvant/neoadjuvant treatment for a patient who had a relapse with metastatic disease during or within 6 months of completing treatment will be considered as first-line treatment.

      AND

    2. Having progressive disease during or after 1 immune checkpoint inhibitor (anti-PD1/PD-L1); this could be given as monotherapy or in combination with platinum-based chemotherapy (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

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 arterial 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 LVEF less than 50%) 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
  • 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

Triplet cohort exclusions

  • History of active autoimmune disease that has required systemic treatment in the past 2 years.
  • History of allogeneic tissue/solid organ transplantation.
  • Active infection requiring IV systemic therapy within 2 weeks prior to first study intervention administration or active tuberculosis.
  • Interstitial lung disease or history of pneumonitis that has required oral or IV steroids.
  • Symptomatic herpes zoster within 3 months prior to screening.
  • Significant allergies to humanized monoclonal antibodies.
  • Any radiation therapy to lung >30 Gy within 6 months of first study intervention administration.
  • Has received or will receive a live vaccine within 30 days prior to the first study intervention administration.
  • Thyroid-stimulating hormone (TSH) out of normal limits. If TSH is not within normal limits at baseline, the subject may still be eligible if T3 and free T4 are within the normal limits

The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Non-Randomized
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Ramucirumab + SAR408701
Ramucirumab will be administered intravenously prior to intravenously adminstration of SAR408701 every two 2 weeks.
Drug: SAR408701
Pharmaceutical form:concentrate for solution for injection Route of administration: intravenous infusion
Drug: ramucirumab
Pharmaceutical form: concentrate for solution for injection Route of administration: intravenous infusion
Experimental: Ramucirumab + pembrolizumab +SAR408701
Participants will be treated with tusamitamab ravtansine and ramucirumab and pembrolizumab to assess the tolerability of the combination
Drug: SAR408701
Pharmaceutical form:concentrate for solution for injection Route of administration: intravenous infusion
Drug: ramucirumab
Pharmaceutical form: concentrate for solution for injection Route of administration: intravenous infusion
Drug: pembrolizumab
Pharmaceutical form: concentrate for solution for injection Route of administration: intravenous infusion

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Doublet Cohort - Part 1: Number of Participants With Study Drug-Related Dose-Limiting Toxicity (DLT)
Time Frame: From Cycle 1 Day 1 up to Cycle 2 Day 14, approximately 28 days

The following AEs occurred during the first 2 cycles of treatment, unless due to disease progression or to a cause obviously unrelated to study drug, were considered DLTs:

  • Grade 4 neutropenia for 7 or more consecutive days.
  • Grade 3 to 4 neutropenia complicated by fever.
  • Grade >=3 thrombocytopenia.
  • Elevated urine protein >=3 gram(g)/24 hour.
  • Grade 4 non-hematologic AE.
  • Grade >=3 keratopathy.
  • Grade 4 or refractory hypertension. In addition, any other AE that the Investigators and sponsor deemed to be dose limiting, regardless of its grade, was also considered as DLT.
From Cycle 1 Day 1 up to Cycle 2 Day 14, approximately 28 days
Doublet Cohort - Part 2: Objective Response Rate (ORR)
Time Frame: Tumor assessments performed at baseline, and every 8 weeks +/-7 days thereafter, approximately 106 weeks
The ORR is defined as percentage of participants with confirmed complete response (CR) or partial response (PR) as best overall response (BOR) determined per Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1. The CR is defined as disappearance of all target lesions. The PR is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
Tumor assessments performed at baseline, and every 8 weeks +/-7 days thereafter, approximately 106 weeks
Triplet Cohort: Number of Participants With Study Drug-Related Dose-Limiting Toxicity
Time Frame: From Cycle 1 Day 1 up to Cycle 1 Day 21

The following AEs occurred during the first cycle of treatment, unless due to disease progression or to a cause obviously unrelated to study drug, were considered DLTs:

  • Grade 4 neutropenia for 7 or more consecutive days.
  • Grade 3 to 4 neutropenia complicated by fever.
  • Grade >=3 thrombocytopenia.
  • Elevated urine protein >=3 g/24 hour.
  • Grade 4 non-hematologic AE.
  • Grade >=3 keratopathy.
  • Grade 4 or refractory hypertension. In addition, any other AE that the Investigators and sponsor deemed dose limiting, regardless of its grade, was also considered as DLT.
From Cycle 1 Day 1 up to Cycle 1 Day 21

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Doublet and Triplet Cohorts: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
Time Frame: From first dose of study drug (Day 1) up to Day 30 post last dose of study drug, approximately 110 weeks
An AE is any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of study drug, whether or not considered related to the study drug. A SAE is defined as any untoward medical occurrence that, at any dose: results in death or life-threatening or requires inpatient hospitalization or prolongation of existing hospitalization or results in persistent disability/incapacity or congenital anomaly/birth defect. TEAE is defined as AEs that develop, worsen, or become serious during the treatment period.
From first dose of study drug (Day 1) up to Day 30 post last dose of study drug, approximately 110 weeks
Doublet and Triplet Cohorts: Number of Participants With Potentially Clinically Significant Abnormalities in Clinical Laboratory Parameters
Time Frame: From first dose of study drug (Day 1) up to Day 30 post last dose of study drug, approximately 110 weeks
Blood samples were collected to determine the clinical chemistry laboratory abnormalities.
From first dose of study drug (Day 1) up to Day 30 post last dose of study drug, approximately 110 weeks
Doublet and Triplet Cohorts: Number of Participants With Potentially Clinically Significant Abnormalities in Electrocardiogram (ECG)
Time Frame: From first dose of study drug (Day 1) up to Day 30 post last dose of study drug, approximately 110 weeks
A single 12-lead ECG was recorded using an ECG machine that automatically calculates the heart rate and measures PR, QRS, and QT intervals.
From first dose of study drug (Day 1) up to Day 30 post last dose of study drug, approximately 110 weeks
Doublet and Triplet Cohorts: Number of Participants With Potentially Clinically Significant Abnormalities in Urinalysis
Time Frame: From first dose of study drug (Day 1) up to Day 30 post last dose of study drug, approximately 110 weeks
Urine samples were collected to determine the clinical chemistry laboratory abnormalities.
From first dose of study drug (Day 1) up to Day 30 post last dose of study drug, approximately 110 weeks
Doublet Cohort: Duration of Response (DOR)
Time Frame: Tumor assessments performed at baseline, and every 8 weeks +/-7 days thereafter, approximately 106 weeks
The DOR is defined as the time from first documented evidence of CR or PR until progressive disease (PD) determined per RECIST v1.1 or death from any cause, whichever occurs first. The PD is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study.
Tumor assessments performed at baseline, and every 8 weeks +/-7 days thereafter, approximately 106 weeks
Doublet Cohort: Progression-Free Survival (PFS)
Time Frame: Tumor assessments performed at baseline, and every 8 weeks +/-7 days thereafter, approximately 106 weeks
The PFS is defined as the time from the first study drug administration to the date of the first documented disease progression or death due to any cause, whichever comes first.
Tumor assessments performed at baseline, and every 8 weeks +/-7 days thereafter, approximately 106 weeks
Doublet Cohort: Disease Control Rate (DCR)
Time Frame: Tumor assessments performed at baseline, and every 8 weeks +/-7 days thereafter, approximately 106 week
The DCR is defined as the percentage of participants who achieved confirmed CR, confirmed PR or stable disease (SD) as per RECIST v1.1. The SD is defined as neither sufficient shrinkage from the baseline study to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.
Tumor assessments performed at baseline, and every 8 weeks +/-7 days thereafter, approximately 106 week
Triplet Cohort: Objective Response Rate
Time Frame: Tumor assessments performed at baseline, and every 8 weeks +/-7 days thereafter, approximately 106 weeks
The ORR is defined as percentage of participants with confirmed CR or PR as BOR determined per RECIST v1.1.
Tumor assessments performed at baseline, and every 8 weeks +/-7 days thereafter, approximately 106 weeks
Doublet Cohort: Maximum Observed Concentration (Cmax) of Tusamitamab Ravtansine and Ramucirumab
Time Frame: Tusamitamab ravtansine: At start of every infusion for each cycle up to Cycle 13; Ramucirumab: At start of infusion at Cycle 7
Blood samples were collected for the measurement of Cmax of tusamitamab ravtansine and ramucirumab concentrations. Cmax of tusamitamab ravtansine will be calculated using non-compartmental method.
Tusamitamab ravtansine: At start of every infusion for each cycle up to Cycle 13; Ramucirumab: At start of infusion at Cycle 7
Doublet Cohort: Area Under the Plasma Concentration Versus Time Curve From Time 0 to 14 Days (AUC0-14d) of Tusamitamab Ravtansine and Ramucirumab
Time Frame: Tusamitamab ravtansine: At start of every infusion for each cycle up to Cycle 13; Ramucirumab: At start of infusion at Cycle 7
Blood samples were collected for the measurement of AUC0-14d of tusamitamab ravtansine and ramucirumab concentrations. AUC0-14d will be calculated using the trapezoidal method from time 0 to 14 days and non-compartmental method.
Tusamitamab ravtansine: At start of every infusion for each cycle up to Cycle 13; Ramucirumab: At start of infusion at Cycle 7
Doublet Cohort: Concentration Observed Before Treatment Administration During Repeated Dosing (Ctrough) of Tusamitamab Ravtansine and Ramucirumab
Time Frame: Tusamitamab ravtansine: At start of every infusion for each cycle up to Cycle 13; Ramucirumab: At start of infusion at Cycle 7
Blood samples were collected for the measurement of Ctrough of tusamitamab ravtansine and ramucirumab concentrations. Ctrough of tusamitamab ravtansine was calculated using non-compartmental method.
Tusamitamab ravtansine: At start of every infusion for each cycle up to Cycle 13; Ramucirumab: At start of infusion at Cycle 7
Doublet and Triplet Cohorts: Number of Participants With Anti-Therapeutic Antibodies (ATAs) Against Tusamitamab Ravtansine
Time Frame: From first dose of study drug (Day 1) up to Day 30 post last dose of study drug, approximately 110 weeks
Blood samples were collected to assess the presence of ATA against tusamitamab ravtansine in plasma from all participants.
From first dose of study drug (Day 1) up to Day 30 post last dose of study drug, approximately 110 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sanofi

Investigators

  • Study Director: Clinical Sciences & Operations, Sanofi

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

August 31, 2020

Primary Completion (Actual)

March 6, 2023

Study Completion (Estimated)

March 29, 2024

Study Registration Dates

First Submitted

May 14, 2020

First Submitted That Met QC Criteria

May 14, 2020

First Posted (Actual)

May 19, 2020

Study Record Updates

Last Update Posted (Actual)

March 28, 2024

Last Update Submitted That Met QC Criteria

February 28, 2024

Last Verified

February 1, 2024

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • ACT16525
  • 2019-003914-15 (EudraCT Number)
  • U1111-1244-1585 (Registry Identifier: ICTRP)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

Qualified researchers may request access to patient level data and related study documents including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan, and dataset specifications. Patient level data will be anonymized and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi's data sharing criteria, eligible studies, and process for requesting access can be found at: https://vivli.org

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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