Clinical trial NCT04394624: Tusamitamab Ravtansine (SAR408701) in Combination With Ramucirumab or Ramucirumab and Pembrolizumab in Pretreated Patients With NSQ NSCLC (CARMEN-LC04)
Official title: 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Non-small Cell Lung Cancer Metastatic
Lead sponsor: Sanofi
Sponsor class: INDUSTRY
First posted: 2020-05-19
Enrollment: 31
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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

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)

Eligibility criteria: 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
* 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

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.

Primary outcomes:
measure: Doublet Cohort - Part 1: Number of Participants With Study Drug-Related Dose-Limiting Toxicity (DLT)
timeFrame: From Cycle 1 Day 1 up to Cycle 2 Day 14, approximately 28 days
measure: Doublet Cohort - Part 2: Objective Response Rate (ORR)
timeFrame: Tumor assessments performed at baseline, and every 8 weeks +/-7 days thereafter, approximately 130 weeks
measure: Triplet Cohort: Number of Participants With Study Drug-Related Dose-Limiting Toxicity
timeFrame: From Cycle 1 Day 1 up to Cycle 1 Day 21
Secondary outcomes:
measure: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
timeFrame: From first dose of study drug (Day 1) up to Day 30 post last dose of study drug, approximately 134 weeks
measure: Number of Participants With Potentially Clinically Significant Abnormalities: Hematology
timeFrame: From first dose of study drug (Day 1) up to Day 30 post last dose of study drug, approximately 134 weeks
measure: Number of Participants With Potentially Clinically Significant Abnormalities: Metabolism
timeFrame: From first dose of study drug (Day 1) up to Day 30 post last dose of study drug, approximately 134 weeks
measure: Number of Participants With Potentially Clinically Significant Abnormalities: Electrolytes
timeFrame: From first dose of study drug (Day 1) up to Day 30 post last dose of study drug, approximately 134 weeks
measure: Number of Participants With Potentially Clinically Significant Abnormalities: Renal Function
timeFrame: From first dose of study drug (Day 1) up to Day 30 post last dose of study drug, approximately 134 weeks
measure: Number of Participants With Potentially Clinically Significant Abnormalities: Liver Function
timeFrame: From first dose of study drug (Day 1) up to Day 30 post last dose of study drug, approximately 134 weeks
measure: Number of Participants With Potentially Clinically Significant Abnormalities: Electrocardiogram (ECG)
timeFrame: From first dose of study drug (Day 1) up to Day 30 post last dose of study drug, approximately 134 weeks
measure: Number of Participants With Potentially Clinically Significant Abnormalities: Urinalysis
timeFrame: From first dose of study drug (Day 1) up to Day 30 post last dose of study drug, approximately 134 weeks
measure: Doublet Cohort: Duration of Response (DOR)
timeFrame: Tumor assessments performed at baseline, and every 8 weeks +/-7 days thereafter, approximately 130 weeks
measure: Doublet Cohort: Progression-Free Survival (PFS)
timeFrame: Tumor assessments performed at baseline, and every 8 weeks +/-7 days thereafter, approximately 130 weeks
measure: Doublet Cohort: Disease Control Rate (DCR)
timeFrame: Tumor assessments performed at baseline, and every 8 weeks +/-7 days thereafter, approximately 130 weeks
measure: Triplet Cohort: Objective Response Rate
timeFrame: Tumor assessments performed at baseline, and every 8 weeks +/-7 days thereafter, approximately 130 weeks
measure: Doublet Cohort: Maximum Observed Concentration (Cmax) of Tusamitamab Ravtansine
timeFrame: Day 1 of Cycles 1 and 4
measure: Doublet Cohort: Area Under the Plasma Concentration Versus Time Curve From Time 0 to 14 Days (AUC0-14d) of Tusamitamab Ravtansine
timeFrame: Day 1 of Cycles 1 and 4
measure: Doublet Cohort: Concentration Observed Before Treatment Administration During Repeated Dosing (Ctrough) of Ramucirumab
timeFrame: Cycle 2 Day 1
measure: Number of Participants With Anti-Therapeutic Antibodies (ATAs) Against Tusamitamab Ravtansine
timeFrame: From first dose of study drug (Day 1) up to Day 30 post last dose of study drug, approximately 134 weeks
Other outcomes:
Locations:
city: Detroit
country: United States
facility: Henry Ford Hospital Site Number : 8400005
state: Michigan
city: Buffalo
country: United States
facility: Roswell Park Cancer Institute Site Number : 8400003
state: New York
city: Waco
country: United States
facility: McClinton Cancer Center Site Number : 8400002
state: Texas
city: Plovdiv
country: Bulgaria
facility: Investigational Site Number : 1000001
city: Ostrava - Vitkovice
country: Czechia
facility: Investigational Site Number : 2030001
city: Praha 2
country: Czechia
facility: Investigational Site Number : 2030002
city: Seoul
country: Korea, Republic of
facility: Investigational Site Number : 4100001
state: Seoul-teukbyeolsi
city: Seoul
country: Korea, Republic of
facility: Investigational Site Number : 4100002
state: Seoul-teukbyeolsi
city: Porto
country: Portugal
facility: Investigational Site Number : 6200001
city: Barcelona / Sabadell
country: Spain
facility: Investigational Site Number : 7240001
state: Catalunya [Cataluña]
city: Madrid
country: Spain
facility: Investigational Site Number : 7240005
state: Madrid, Comunidad De
city: Madrid
country: Spain
facility: Investigational Site Number : 7240004
city: Zaragoza
country: Spain
facility: Investigational Site Number : 7240003
Study officials:
affiliation: Sanofi
name: Clinical Sciences & Operations
role: STUDY_DIRECTOR
References: