Malignant Melanoma, Squamous Cell Carcinoma of Skin
Conditions
Brief summary
Primary Objective: -To determine the antitumor activity of SAR444245 in combination with cemiplimab. Secondary Objectives: * To determine the recommended phase 2 dose and to assess the safety profile of SAR444245 when combined with cemiplimab * To assess other indicators of antitumor activity * To assess the concentrations of SAR444245 when given in combination with cemiplimab * To assess the immunogenicity of SAR444245 * To assess active concentrations of cemiplimab when given in combination with SAR444245
Detailed description
The duration of the study for an individual patient will start from the signature of the main informed consent and include a screening period of up to 28 days, a treatment period \[max 35 cycles or until PD\], an end-of-treatment visit 30 days + 7 days following the last administration of study drug (or until the patient receives another anticancer therapy, whichever is earlier), and a follow-up visit 3 months after treatment discontinuation and every 3 months following, until disease progression, or initiation of another antitumor treatment, or final cohort cut-off, whichever is earlier
Interventions
DRUGTHOR-707
Solution for infusion: intravenous infusion
DRUGCemiplimab
Solution for infusion: intravenous infusion
Sponsors
Sanofi
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Participant must be ≥18 years of age (or country's legal age of majority if \>18 years), at the time of signing the informed consent. * Participants with: * Cohort A: Histologically confirmed unresectable locally advanced or metastatic melanoma that are not amenable to local therapy * Cohort B: Histologically confirmed metastatic CSCC or locally advanced * CSCC that are not candidates for curative surgery or radiation. Special considerations for the following categories: Participants with tumors arising on the cutaneous hair (non-glabrous) bearing lip with extension onto dry red lip (vermillion) may be eligible after communication with and approval from the Sponsor Participants with the primary site is nose are only eligible if the primary site was skin, not nasal mucosa with outward extension to skin (the Investigator confirmed) Participants with mixed histology in which the predominant histology is invasive CSCC may be eligible after communication with and approval from the Sponsor * Participants in both cohorts must have at least one measurable lesion * Provision of tumor tissue: For participants in the dose escalation: 16 µg/kg: at screening, biopsy is optional but highly recommended; and on-treatment not required 24 µg/kg: at screening, biopsy is mandatory and on-treatment, optional but highly recommended * For the other participants : Mandatory baseline biopsy for the participants to enroll in cohort A with skin metastasis and in cohort B. Mandatory on-treatment biopsy for participants in Cohort A with skin metastasis and participants in Cohort B. * Females are eligible to participate if they are not pregnant or breastfeeding, not a woman of childbearing potential (WOCBP) or are a WOCBP that agrees: to use approved contraception method and submit to regular pregnancy testing prior to treatment and for at least 180 days after discontinuing study treatment and to refrain from donating or cryopreserving eggs for 180 days after discontinuing study treatment. * Males are eligible to participate if they agree to refrain from donating or cryopreserving sperm, and either abstain from heterosexual intercourse OR use approved contraception during study treatment and for at least 210 days after discontinuing study treatment. * Capable of giving signed informed consent
Exclusion criteria
* Participants are excluded from the study if any of the following criteria apply: * Eastern Cooperative Oncology Group (ECOG) performance status of ≥2 * Poor organ function * Participants with baseline SpO2 ≤92% * Active brain metastases or leptomeningeal disease. * History of allogenic tissue/solid organ transplant. * Last administration of prior antitumor therapy or any investigational treatment within 28 days or less than 5 times the half-life, whichever is shorter; major surgery or local intervention within 28 days. * History of lung disease * Comorbidity requiring corticosteroid therapy * Antibiotic use (excluding topical antibiotics) ≤14 days prior to first dose of IMP * Severe or unstable cardiac condition within 6 months prior to starting study treatment * Active, known, or suspected autoimmune disease that has required systemic treatment in the past 2 years * Known second malignancy either progressing or requiring active treatment within the last 3 years For both cohorts: * Prior immune checkpoint inhibitors except in the context of adjuvant or neoadjuvant; Participants who were on control arm of a study with an investigational anti-PD-1/PD-L1 are eligible. * Received adjuvant or neoadjuvant therapy during the 6 months prior to development of metastatic disease. * For Cohort A: any prior systemic treatment for advanced/metastatic disease * For Cohort B: \>2 prior lines of any systemic treatment for advanced/metastatic disease * Inability to undergo any contrast-enhanced radiologic response assessment * Receipt of a live-virus vaccination within 28 days of planned treatment start. Seasonal flu vaccines that do not contain live virus are permitted The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| All Cohorts: Objective Response Rate (ORR) | From first dose of study treatment administration (Day 1) up to approximately 25 months (Cohorts A and B) | The ORR was defined as the percentage of participants who had best overall response (BOR) as confirmed complete response (CR) or partial response (PR) as per Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1 or modified world health organization (WHO) response criteria. CR was defined as the disappearance of all target lesions, any pathological lymph nodes (whether target or non-target) with reduction in short axis to \<10 millimeter (mm) (\<1 centimeter \[cm\]). PR was defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| All Cohorts: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) | From first dose of study treatment (Day 1) up to 30 days after the last dose of study treatment; approximately 27 months (Cohorts A and B) | An AE was any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. An SAE was any AE that at any dose: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect or was an important medical event. TEAEs were defined as AEs that developed, worsened (according to the investigator's opinion) or became serious during the TE period. |
| All Cohorts: Number of Participants With Dose Limiting Toxicities (DLTs) | From Day 1 to Day 21 of Cycle 1 (each cycle is 21 days: Cohorts A and B) | Selected events that occurred during the DLT observation period were considered as DLT unless due to PD or to a cause obviously unrelated to pegenzileukin. Selected events included: any grade 4 neutropenia irrespective of duration; any febrile neutropenia; grade 3 thrombocytopenia associated with transfusion in addition to bleeding and any grade 4 thrombocytopenia; grade 3 or above: alanine aminotransferase or aspartate aminotransferase, vascular leak syndrome, hypotension, cytokine release syndrome, and AE that did not resolve to grade \<=2 within 7 days of starting accepted standard of care medical management; and grade 4 laboratory abnormalities. |
| All Cohorts: Complete Response (CR) Rate | From first dose of study treatment administration (Day 1) up to maximum exposure of study treatment, approximately 26 months (Cohorts A and B) | The CR rate was defined as the percentage of participants who had a confirmed CR as per RECIST v 1.1 or modified WHO response criteria. CR was defined as the disappearance of all target lesions, any pathological lymph nodes (whether target or non-target) with reduction in short axis to \<10 mm (\<1 cm). |
| All Cohorts: Time to Complete Response | From first dose of study treatment administration (Day 1) up to maximum exposure of study treatment, approximately 26 months (Cohorts A and B) | The time to CR was defined as the time from the first administration of study treatment to the first tumor assessment at which the overall response was recorded as CR that was subsequently confirmed as per RECIST v 1.1 or modified WHO response criteria. CR was defined as the disappearance of all target lesions, any pathological lymph nodes (whether target or non-target) with reduction in short axis to \<10 mm (\<1 cm). |
| All Cohorts: Time to Response (TTR) | From first dose of study treatment administration (Day 1) up to maximum exposure of study treatment, approximately 26 months (Cohorts A and B) | The TTR was defined as the time from the first study treatment administration to the first tumor assessment at which the overall response was recorded as PR or CR that was subsequently confirmed as per RECIST v 1.1 or modified WHO response criteria. CR was defined as the disappearance of all target lesions, any pathological lymph nodes (whether target or non-target) with reduction in short axis to \<10 mm (\<1 cm). PR was defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. |
| All Cohorts: Duration of Response (DOR) | From first dose of study treatment administration (Day 1) up to maximum exposure of study treatment, approximately 26 months (Cohorts A and B) | The DOR was defined as the time from the first tumor assessment at which the overall response was recorded as CR or PR that was subsequently confirmed until documented PD before the initiation of any subsequent anti-cancer therapy or death due to any cause, whichever occurred first, as per RECIST v 1.1 or modified WHO response criteria. CR was defined as the disappearance of all target lesions, any pathological lymph nodes (whether target or non-target) with reduction in short axis to \<10 mm (\<1 cm). PR was defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. PD was defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this included the baseline sum if that was the smallest on study), in addition to the relative increase of 20%, the sum must have also demonstrated an absolute increase of at least 5 mm (0.5 cm). |
| All Cohorts: Clinical Benefit Rate (CBR) | From first dose of study treatment administration (Day 1) up to maximum exposure of study treatment, approximately 26 months (Cohorts A and B) | The CBR was defined as the percentage of participants with clinical benefit: confirmed CR or PR as BOR, or stable disease (SD) lasting at least 6 months, as per RECIST v 1.1 or modified WHO response criteria. CR was defined as the disappearance of all target lesions, any pathological lymph nodes (whether target or non-target) with reduction in short axis to \<10 mm (\<1 cm). PR was defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. BOR was defined as the best response observed from the start of the study treatment until PD, death, cut-off date or initiation of post-treatment anti-cancer therapy, whichever occurred first. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. |
| All Cohorts: Progression Free Survival (PFS) | From first dose of study treatment administration (Day 1) up to maximum exposure of study treatment, approximately 26 months (Cohorts A and B) | The PFS was defined as the time from the date of first study treatment administration to the date of the first documentation of objective PD, or death due to any cause, whichever occurred first, as per RECIST v 1.1 or modified WHO response criteria. PD was defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this included the baseline sum if that was the smallest on study), in addition to the relative increase of 20%, the sum must have also demonstrated an absolute increase of at least 5 mm (0.5 cm). |
| All Cohorts: Plasma Concentrations of Pegenzileukin | Cycle 1 Days 2 and 3 (each cycle is 21 days) | Blood samples were collected at specified timepoints for the assessment of plasma concentrations of pegenzileukin. |
| All Cohorts: Number of Participants With Anti-Drug Antibodies (ADAs) Against Pegenzileukin | From first dose of study treatment (Day 1) up to 30 days after the last dose of study treatment; approximately 27 months (Cohorts A and B) | Blood samples were collected at specified timepoints to assess the presence of ADAs against pegenzileukin. Treatment-emergent ADA was defined as at least one treatment-induced or treatment-boosted ADA. Treatment-induced ADA was defined as ADA that developed during the TE period and without pre-existing ADA (including participants without pre-treatment samples). Treatment-boosted ADA was defined as pre-existing ADA that was boosted during the TE period to a significant higher titer than the baseline. Number of participants with treatment-emergent ADA is presented. |
| All Cohorts: Concentration Observed Just Before Study Treatment Administration During Repeated Dosing (Ctrough) of Cemiplimab | Cycles 1, 2, 4, 7, 10, and 15 (each cycle is 21 days) | Blood samples were collected at specified timepoints for the assessment of Ctrough of cemiplimab. The PK population consisted of all participants from exposed population with at least one PK concentration available after the first dose of study treatment. Only participants with data collected at specified timepoints are reported. |
| All Cohorts: Concentration at End of Infusion (Ceoi) of Cemiplimab | Cycles 1, 2, 4, 7, 10, and 15 (each cycle is 21 days) | Blood samples were collected at specified timepoints for the assessment of Ceoi of cemiplimab. The PK population consisted of all participants from exposed population with at least one PK concentration available after the first dose of study treatment. Only participants with data collected at specified timepoints are reported. |
Countries
Australia, Chile, France, Germany, Italy, Spain, United States
Participant flow
Recruitment details
This study was conducted at 21 centers (corresponds to number of sites which screened at least one participant) in 7 countries. Out of 61 participants who were screened from 15 July 2021 to 25 October 2022, 46 participants were enrolled in the study.
Pre-assignment details
The study was terminated based on strategic sponsor decision not driven by any safety concerns. Note: Reason for not completed = Reason for permanent full intervention discontinuation.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 61.1 years STANDARD_DEVIATION 11.7 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 20 Participants |
| Sex: Female, Male Female | 7 Participants |
| Sex: Female, Male Male | 31 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 5 / 20 | 2 / 7 | 2 / 16 | 0 / 3 |
| other Total, other adverse events | 19 / 20 | 7 / 7 | 16 / 16 | 3 / 3 |
| serious Total, serious adverse events | 11 / 20 | 4 / 7 | 8 / 16 | 1 / 3 |
Outcome results
None listed