Clinical trial NCT04524689: Tusamitamab Ravtansine (SAR408701) in Combination With Pembrolizumab and Tusamitamab Ravtansine (SAR408701) in Combination With Pembrolizumab and Platinum-based Chemotherapy With or Without Pemetrexed in Patients With NSQ NSCLC
Official title: Open-label, Phase 2 Study of Tusamitamab Ravtansine (SAR408701) Combined With Pembrolizumab and Tusamitamab Ravtansine (SAR408701) Combined With Pembrolizumab and Platinum-based Chemotherapy With or Without Pemetrexed in Patients With CEACAM5 Positive Expression Advanced/Metastatic Non-squamous Non-small-cell Lung Cancer (NSQ NSCLC)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Non-squamous Non-small-cell Lung Cancer (NSQ NSCLC)
Lead sponsor: Sanofi
Sponsor class: INDUSTRY
First posted: 2020-08-24
Enrollment: 57
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Primary Objective:

* Safety run-in part: to assess the tolerability and to determine the recommended doses of tusamitamab ravtansine in combination with pembrolizumab and tusamitamab ravtansine in combination with pembrolizumab and platinum-based chemotherapy with or without pemetrexed to be tested in the expansion part of the study in the NSQ NSCLC population
* Expansion part (including participants treated at the recommended dose for expansion \[RDE\] from the Safety Run-in part): to assess the antitumor activity of several dose levels (DLs; if applicable) of tusamitamab ravtansine in combination with pembrolizumab and of several DLs of tusamitamab ravtansine in combination with pembrolizumab, platinum-based chemotherapy, and pemetrexed in the NSQ NSCLC population

Secondary Objectives:

* To assess the safety and tolerability of several DLs (if applicable) of tusamitamab ravtansine in combination with pembrolizumab and of 1 DL of tusamitamab ravtansine in combination with pembrolizumab and platinum-based chemotherapy, and of several DLs of tusamitamab ravtansine in combination with pembrolizumab, and platinum-based chemotherapy with pemetrexed in the NSQ NSCLC population
* To assess the antitumor activity of several DLs (if applicable) of tusamitamab ravtansine in combination with pembrolizumab and of 1 DL of tusamitamab ravtansine in combination with pembrolizumab and platinum-based chemotherapy, and of several DLs of tusamitamab ravtansine in combination with pembrolizumab, platinum-based chemotherapy, and pemetrexed in the NSQ NSCLC population
* To assess the durability of the response to treatment with several DLs (if applicable) of tusamitamab ravtansine in combination with pembrolizumab and of 1 DL of tusamitamab ravtansine in combination with pembrolizumab and platinum-based chemotherapy, and of several DLs of tusamitamab ravtansine in combination with pembrolizumab and platinum-based chemotherapy, and pemetrexed in the NSQ NSCLC population
* To assess the antitumor activity of tusamitamab ravtansine in combination with pembrolizumab and platinum-based chemotherapy in the NSQ NSCLC population
* To assess the pharmacokinetics (PK) of tusamitamab ravtansine, pembrolizumab, pemetrexed, cisplatin, and carboplatin, each when given in combination as a doublet (tusamitamab ravtansine + pembrolizumab) or a triplet (tusamitamab ravtansine + pembrolizumab + platinum-based chemotherapy) or a quadruplet (tusamitamab ravtansine + pembrolizumab + platinum-based chemotherapy + pemetrexed)
* To assess the immunogenicity of tusamitamab ravtansine in combination with pembrolizumab and tusamitamab ravtansine in combination with pembrolizumab and platinum based chemotherapy with or without pemetrexed

Detailed description: The expected duration of study intervention for participants may vary, based on disease progression date; median expected duration of study per participant is estimated at 10 months (up to 1 month for screening, a median of 6 months for treatment, a median of 1 month for EOT, and follow-up visit 90 days after the last IMP administration).

Eligibility criteria: Inclusion criteria :

* Histologically- or cytologically-confirmed diagnosis of advanced or metastatic NSQ NSCLC with no EGFR sensitizing mutation or BRAF mutation or ALK/ROS alterations.
* No prior systemic chemotherapy for the treatment of the participant's advanced or metastatic disease (treatment with chemotherapy and/or radiation as part of neoadjuvant/adjuvant therapy is allowed as long as completed at least 6 months prior to diagnosis of advanced or metastatic disease).
* Expression of CEACAM5 as demonstrated prospectively by a centrally assessed Immunohistochemistry (IHC) assay of ≥2+ in intensity involving at least 1% of the tumor cell population in archival tumor sample (or if not available fresh biopsy sample).
* Measurable disease based on RECIST 1.1.
* Eastern Cooperative Oncology Group (ECOG) performance status 0-1
* Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies
* Life expectancy of at least 3 months

Exclusion criteria:

* Medical condition requiring concomitant administration of a medication with a strong CYP3A inhibitor.
* Uncontrolled brain metastases and history of leptomeningeal disease.
* Significant concomitant illness, including any severe medical condition that, in the opinion of the investigator or Sponsor, 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.
* History of known acquired immunodeficiency syndrome (AIDS) related illnesses or known HIV disease requiring antiretroviral treatment, or active hepatitis A, B, or C infection.
* 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 randomization or active tuberculosis.
* Interstitial lung disease or history of pneumonitis that has required oral or IV steroids
* Non-resolution of any prior treatment-related toxicity to \< Grade 2 according to NCI CTCAE V5.0, with the exception of alopecia, vitiligo, or active thyroiditis controlled with hormone replacement therapy.
* Unresolved corneal disorder or any previous corneal disorder considered by an ophthalmologist to predict higher risk of drug-induced keratopathy. The use of contact lenses is not permitted.
* Symptomatic herpes zoster within 3 months prior to screening.
* Significant allergies to humanized monoclonal antibodies.
* Clinically significant multiple or severe drug allergies, intolerance to topical corticosteroids, or severe post-treatment hypersensitivity reactions (including, but not limited to, erythema multiforme major, linear immunoglobulin A \[IgA\] dermatosis, toxic epidermal necrolysis, and exfoliative dermatitis).
* Concurrent treatment with any other anticancer therapy.
* Have received prior chemotherapy treatment for advanced/metastatic NSCLC.
* The patient is a candidate for a curative treatment with either surgical resection and/or chemoradiation
* Washout period before the first administration of study intervention of less than 3 weeks or less than 5 times the half-life, whichever is shorter, for any investigational treatment).
* Any prior therapy targeting CEACAM5.
* Any prior treatment with any other anti-PD-1, or PD-L1 or programmed death ligand 2 (PD-L2), anti-CD137, or anti-cytotoxic T-lymphocyte-associated antigen-4.
* Any prior maytansinoid treatment (DM1 or DM4 ADC).
* Is receiving systemic steroid therapy ≤3 days prior to the first dose of study therapy or receiving any other form of immunosuppressive medication. Daily steroid replacement therapy or any corticosteroid premedication if applicable are allowed.
* 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.
* Any major surgery within the preceding 3 weeks of the first study intervention administration.

Prior/concurrent clinical study experience

* Current participation in any other clinical study involving an investigational study treatment or any other type of medical research.
* Poor organ function

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

Primary outcomes:
measure: All Cohorts: Number of Participants With Study Drug-Related Dose-Limiting Toxicities (DLTs)
timeFrame: Cycle 1 Day 1 up to Cycle 1 Day 21 (cycle duration=3 weeks)
measure: Doublet Cohort: Objective Response Rate (ORR)
timeFrame: Tumor assessments performed at baseline, then every 6 weeks for first 24 weeks, and every 9 weeks thereafter, approximately 155.4 weeks
measure: Quadruplet Cohort: Objective Response Rate
timeFrame: Tumor assessments performed at baseline, then every 6 weeks for first 24 weeks, and every 9 weeks thereafter, approximately 108.4 weeks
Secondary outcomes:
measure: All Cohorts: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)
timeFrame: From first dose of study treatment (Day 1) up to 30 days post last dose of study treatment, approximately 159.4 weeks (doublet), 117 weeks (triplet), and 112.4 weeks (quadruplet)
measure: Doublet and Quadruplet Cohorts: Progression-free Survival (PFS)
timeFrame: Tumor assessments performed at baseline, then every 6 weeks for first 24 weeks, and every 9 weeks thereafter, approximately 155.4 weeks (doublet) and 108.4 weeks (quadruplet)
measure: All Cohorts: Disease Control Rate (DCR)
timeFrame: Tumor assessments performed at baseline, then every 6 weeks for first 24 weeks, and every 9 weeks thereafter, approximately 155.4 weeks (doublet), 113 weeks (triplet), and 108.4 weeks (quadruplet)
measure: All Cohorts: Duration of Response (DOR)
timeFrame: Tumor assessments performed at baseline, then every 6 weeks for first 24 weeks, and every 9 weeks thereafter, approximately 155.4 weeks (doublet), 113 weeks (triplet), and 108.4 weeks (quadruplet)
measure: Triplet Cohort: Objective Response Rate
timeFrame: Tumor assessments performed at baseline, then every 6 weeks for first 24 weeks, and every 9 weeks thereafter, approximately 113 weeks
measure: All Cohorts: Trough Concentration (Ctrough) of Tusamitamab Ravtansine
timeFrame: Pre-dose on Day 1 of Cycle 2 (cycle duration=3 weeks)
measure: All Cohorts: Ctrough of Pembrolizumab
timeFrame: Pre-dose on Day 1 of Cycle 2 (cycle duration=3 weeks)
measure: Quadruplet Cohort: Plasma Concentration of Pemetrexed
timeFrame: 30 minutes post-dose on Day 1 of Cycle 1 (cycle duration=3 weeks)
measure: Triplet and Quadruplet Cohorts: Total Plasma Concentration Observed at the End of Infusion (Ceoi) of Cisplatin
timeFrame: At end of infusion on Day 1 of Cycle 1 (cycle duration=3 weeks)
measure: Triplet and Quadruplet Cohorts: Total Plasma Concentration Observed at the End of Infusion of Carboplatin
timeFrame: At end of infusion on Day 1 of Cycle 1 (cycle duration=3 weeks)
measure: All Cohorts: Number of Participants With Treatment-emergent Anti-Therapeutic Antibodies (ATAs) Against Tusamitamab Ravtansine
timeFrame: From first dose of study treatment (Day 1) up to 30 days post last dose of study treatment, approximately 159.4 weeks (doublet), 117 weeks (triplet), and 112.4 weeks (quadruplet)
Other outcomes:
Locations:
city: Westwood
country: United States
facility: KU Medical Center_Investigational Site Number :8400002
state: Kansas
city: Natal
country: Brazil
facility: Centro Avancado de Oncologia CECAN - Liga Contra o Cancer Site Number : 0760004
state: Rio Grande Do Norte
city: Temuco
country: Chile
facility: Centro de Investigacion y Desarrollo Oncologico (CIDO) Hochstetter 599 of. 602-603-1001, Temuco_Investigational Site Number :1520005
state: La Araucanía
city: Viña del Mar
country: Chile
facility: ONCOCENTRO APYS Av. La Marina 1702, 2do piso, Viña del Mar_Investigational Site Number :1520003
state: Valparaíso
city: Santiago
country: Chile
facility: Orlandi Oncologia General Salvo 159, Providencia_Investigational Site Number :1520002
city: Santiago
country: Chile
facility: ICEGCLINIC Avenida Serafín Zamora 190 Torre B, piso 4. La Florida_Investigational Site Number :1520006
city: Olomouc
country: Czechia
facility: Fakultní nemocnice Olomouc Onkologická klinika I.P. Pavlova 6_Site Number :2030001
city: Ostrava - Vitkovice
country: Czechia
facility: Nemocnice AGEL Ostrava - Vitkovice Plicní oddělení Zalužanského 2214/35_Site Number :2030002
city: Avignon
country: France
facility: Institut Sainte-Catherine 250 Chemin de Baigne-Pieds_Investigational Site Number :2500005
city: Brest
country: France
facility: CHRU BREST 5 Avenue Foch_Investigational Site Number :2500003
city: Pessac
country: France
facility: Centre François Magendie Hôpital du Haut Lévèque Av.de Magellan_Investigational Site Number :2500001
city: Poitiers Cedex
country: France
facility: Pôle régional de Cancérologie 2 rue de la Milèterie BP 577_Investigational Site Number :2500004
city: Budapest
country: Hungary
facility: Országos Onkológiai Intézet Ráth György u. 7_Investigational Site Number :3480002
city: Farkasgyepü
country: Hungary
facility: Veszprém Megyei Tüdőgyógyintézet 049/2 Hrsz_Investigational Site Number :3480004
city: Ramat Gan
country: Israel
facility: Investigational Site Number : 3760001
city: Tel Aviv
country: Israel
facility: Investigational Site Number : 3760002
city: La Coruña
country: Spain
facility: Investigational Site Number : 7240005
state: A Coruña [La Coruña]
city: Oviedo
country: Spain
facility: Investigational Site Number : 7240007
state: Asturias
city: Badalona
country: Spain
facility: Investigational Site Number : 7240006
state: Catalunya [Cataluña]
city: Las Palmas
country: Spain
facility: Investigational Site Number : 7240002
city: Madrid
country: Spain
facility: Investigational Site Number : 7240004
city: Madrid
country: Spain
facility: Investigational Site Number : 7240001
Study officials:
affiliation: Sanofi
name: Clinical Sciences & Operations
role: STUDY_DIRECTOR
References: