Ifinatamab Deruxtecan (I-DXd) in Subjects With Pretreated Extensive-Stage Small Cell Lung Cancer (ES-SCLC)

Study Overview
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Brief Summary
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This study intends to define the recommended Phase 2 dose of ifinatamab deruxtecan (I-DXd) based on the efficacy, safety, and pharmacokinetics (PK) results observed in participants with Extensive-stage Small Cell Lung Cancer (ES-SCLC) who received at least 1 prior line of platinum-based chemotherapy and a maximum 3 prior lines of therapy and to investigate I-DXd anti-tumor activity in this population.

Detailed Description
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In this study, eligible participants will be randomized in a 1:1 ratio to receive one of the two dose levels of I-DXd. Randomization will be stratified by: Prior receipt or of an anti-programmed death-ligand 1 (PD-[L]1) antibody (yes/no) The chemotherapy-free interval (CTFI) from completion of the first-line therapy to the date of documented radiological Progressive Disease of <90 days vs. ≥90 days in second-line participants as well as the number of previous lines. Thus, the stratification factor includes three categories: (1) second-line participants with CTFI <90 days, (2) second-line participants with CTFI ≥90 days, and (3) third- and fourth-line participants.

Official Title
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A Phase 2, Multicenter, Randomized, Open-label Study of DS-7300a, a B7-H3 Antibody Drug Conjugate (ADC), in Subjects With Pretreated Extensive-stage Small Cell Lung Cancer (ES-SCLC)

Conditions
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Extensive-stage Small-cell Lung Cancer

Intervention / Treatment
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* Drug: Ifinatamab Deruxtecan (I-DXd)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants must meet all the following criteria to be eligible for enrollment into the study: Sign and date the informed consent form (ICF) prior to the start of any study-specific qualification procedures. Participant must have at least one lesion, not previously irradiated, amenable to core biopsy. Male or female subjects aged ≥18 years (follow local regulatory requirements if the legal age of consent for study participation is >18 years old). Histologically or cytologically documented ES-SCLC. At least one measurable lesion according to RECIST v1.1 as assessed by the investigator. Prior therapy with at least one platinum-based line as systemic therapy for extensive-stage disease with at least two cycles of therapy (except in the case of early objective PD). Documentation of radiological disease progression on or after most recent systemic therapy. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1. Exclusion Criteria: Participants who meet any of the following criteria will be disqualified from entering the study: Prior treatment with orlotamab, enoblituzumab, or other B7-H3 targeted agents. Prior treatment with an antibody drug conjugate (ADC) that consists of an exatecan derivative (eg, trastuzumab deruxtecan). Clinically active brain metastases, spinal cord compression or leptomeningeal carcinomatosis, defined as untreated or symptomatic, or requiring therapy with steroids or anticonvulsants to control associated symptoms. Any of the following conditions within the past 6 months: cerebrovascular accident, transient ischemic attack, or arterial thromboembolic event. Clinically significant corneal disease. Uncontrolled or significant cardiovascular disease. History of (non-infectious) interstitial lung disease (ILD)/pneumonitis that required corticosteroids, current ILD/pneumonitis, or suspected ILD/pneumonitis that cannot be ruled out by imaging at screening. Clinically severe pulmonary compromise resulting from intercurrent pulmonary illnesses, Chronic steroid treatment (maximum dose of 10 mg daily prednisone equivalent), except for low-dose inhaled steroids (for asthma/COPD) or topical steroids (for mild skin conditions) or intra-articular steroid injections. History of malignancy other than SCLC within the 3 years prior to enrollment, except adequately resected non-melanoma skin cancer, curatively treated in situ disease, superficial gastrointestinal (GI) tract tumors and non-muscle invasive bladder cancer curatively resected by endoscopic surgery. History of allogeneic bone marrow, stem cell, or solid organ transplant. Unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to National Cancer Institute- Common Terminology Criteria for Adverse Events Version 5.0 (NCI-CTCAE V5.0), Grade ≤1 or baseline. History of hypersensitivity to the drug substances, inactive ingredients in the drug product or severe hypersensitivity reactions to other monoclonal antibodies. Evidence of ongoing uncontrolled systemic bacterial, fungal, or viral infection (including HIV infection). Active or uncontrolled hepatitis B or C infection. Active, known, or suspected autoimmune disease. Any evidence of severe or uncontrolled systemic diseases (including active bleeding diatheses, psychiatric illness/social situations, substance abuse). Has received a live vaccine within 30 days prior to the first dose of study drug. Female who is pregnant or breast-feeding or intends to become pregnant during the study. Prior or ongoing clinically relevant illness, medical condition, surgical history, physical finding, or laboratory abnormality that, in the investigator's opinion, could affect the safety of the participant.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ifinatamab Deruxtecan (8 mg/kg)<br>Participants will be randomized to receive I-DXd at 8 mg/kg. | Drug: Ifinatamab Deruxtecan (I-DXd)<br>* I-DXd will be administered as an intravenous (IV) infusion on Day 1 of each 21-day cycle (every Q3W).<br>* Other names: DS-7300a;|
| Experimental: Ifinatamab Deruxtecan (12 mg/kg)<br>Participants will be randomized to receive I-DXd at 12 mg/kg. | Drug: Ifinatamab Deruxtecan (I-DXd)<br>* I-DXd will be administered as an intravenous (IV) infusion on Day 1 of each 21-day cycle (every Q3W).<br>* Other names: DS-7300a;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Objective Response Rate (ORR) Based on Blinded Independent Central Review (BICR) Following Treatment With I-DXd in Participants With Pretreated ES-SCLC | ORR was defined as the percentage of participants who achieved a best overall response (BOR) of confirmed Complete Response (CR) or Partial Response (PR), assessed by BICR based on RECIST version 1.1. CR was defined as a disappearance of all target lesions and PR was defined as at least a 30% decrease in the sum of diameters of target lesions. | Up to approximately 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) Following Treatment With I-DXd in Participants With Pretreated ES-SCLC | TEAEs are defined as new adverse events (AEs) that occur after the dose of study drug or as AEs that were present prior to the dose of study drug but which worsened in severity after the start of study drug. | Up to approximately 24 months | 
| Progression-Free Survival (PFS) Following Treatment With I-DXd in Participants With Pretreated ES-SCLC | PFS is defined as the time interval from the date of enrollment to the date of disease progression based on RECIST v1.1 criteria or death due to any cause. PFS will be assessed by BICR and investigator. | From enrollment until disease progression or death (whichever occurs first), up to approximately 24 months | 
| Duration of Response (DoR) Following Treatment With I-DXd in Participants With Pretreated ES-SCLC | DoR is defined as the time from the date of first documentation of objective tumor response (CR or PR) to the first documentation of objective tumor progression based on RECIST v1.1 criteria or to death due to any cause, whichever occurs first. DoR will be assessed by BICR and investigator. | From enrollment until disease progression or death (whichever occurs first), up to approximately 24 months | 
| Overall Survival (OS) Following Treatment With I-DXd in Participants With Pretreated ES-SCLC | OS is defined as the time interval from the date of enrollment to the date of death due to any cause or last contact follow-up, whichever occurs first. | From enrollment until death, up to approximately 24 months | 
| Time to Response (TTR) Following Treatment With I-DXd in Participants With Pretreated ES-SCLC | TTR is defined as the time from the date of enrollment to the first documentation of objective tumor response (CR or PR) based on RECIST v.1.1 criteria. TTR will be assessed by BICR and investigator. | From enrollment until disease progression or death (whichever occurs first), up to approximately 24 months | 
| Percentage of Participants With Objective Response Rate (ORR) Based on Investigator Assessment Following Treatment With I-DXd in Participants With Pretreated ES-SCLC | ORR was the defined as the percentage of participants who achieved a best overall response (BOR) of confirmed Complete Response (CR) or Partial Response (PR), assessed by investigator based on RECIST version 1.1. CR was defined as a disappearance of all target lesions and PR was defined as at least a 30% decrease in the sum of diameters of target lesions. | Up to approximately 24 months | 
| Disease Control Rate (DCR) Following Treatment With I-DXd in Participants With Pretreated ES-SCLC | DCR is defined as percentage of participants with BOR of CR, PR, or stable disease, according to RECIST v1.1 criteria. | Up to approximately 24 months | 
| Maximum Plasma Concentration (Cmax) Following Treatment With I-DXd in Participants With Pretreated ES-SCLC | Cmax will be calculated using noncompartmental methods. Cmax will be assessed for I-DXd, total anti-B7-H3 antibody, and MAAA-1181a. | Cycle 1: Predose, end of infusion (EOI), 3, 6, & 24 hours post start of infusion (SOI), Days 4, 8, 15, & 22; Cycle 2: Predose & EOI; Cycle 3: Predose, EOI, 3 & 6 hours post SOI; Cycle 4, 5 & every 2 cycles up to 24 months: Predose (each cycle is 21 days) | 
| Time to Reach Maximum Serum Concentration (Tmax) Following Treatment With I-DXd in Participants With Pretreated ES-SCLC | Tmax will be calculated using noncompartmental methods. Tmax will be assessed for I-DXd, total anti-B7-H3 antibody, and MAAA-1181a. | Cycle 1: Predose, end of infusion (EOI), 3, 6, & 24 hours post start of infusion (SOI), Days 4, 8, 15, & 22; Cycle 2: Predose & EOI; Cycle 3: Predose, EOI, 3 & 6 hours post SOI; Cycle 4, 5 & every 2 cycles up to 24 months: Predose (each cycle is 21 days) | 
| Minimum Observed Concentration (Ctrough) Following Treatment With I-DXd in Participants With Pretreated ES-SCLC | Ctrough will be calculated using noncompartmental methods. Ctrough will be assessed for I-DXd, total anti-B7-H3 antibody, and MAAA-1181a. | Cycle 1: Predose, end of infusion (EOI), 3, 6, & 24 hours post start of infusion (SOI), Days 4, 8, 15, & 22; Cycle 2: Predose & EOI; Cycle 3: Predose, EOI, 3 & 6 hours post SOI; Cycle 4, 5 & every 2 cycles up to 24 months: Predose (each cycle is 21 days) | 
| Area Under the Curve (AUC) Following Treatment With I-DXd in Participants With Pretreated ES-SCLC | AUC will be calculated using noncompartmental methods. AUC will be assessed for I-DXd, total anti-B7-H3 antibody, and MAAA-1181a. | Cycle 1: Predose, end of infusion (EOI), 3, 6, & 24 hours post start of infusion (SOI), Days 4, 8, 15, & 22; Cycle 2: Predose & EOI; Cycle 3: Predose, EOI, 3 & 6 hours post SOI; Cycle 4, 5 & every 2 cycles up to 24 months: Predose (each cycle is 21 days) | 
| Terminal Half-Life (T1/2) Following Treatment With I-DXd in Participants With Pretreated ES-SCLC | T1/2 will be calculated using noncompartmental methods. T1/2 will be assessed for I-DXd, total anti-B7-H3 antibody, and MAAA-1181a. | Cycle 1: Predose, end of infusion (EOI), 3, 6, & 24 hours post start of infusion (SOI), Days 4, 8, 15, & 22; Cycle 2: Predose & EOI; Cycle 3: Predose, EOI, 3 & 6 hours post SOI; Cycle 4, 5 & every 2 cycles up to 24 months: Predose (each cycle is 21 days) | 
| Percentage of Participants Who Have Treatment-Emergent Antidrug Antibodies (ADA) Following Treatment With I-DXd in Participants With Pretreated ES-SCLC | The immunogenicity of I-DXd will be assessed. | Cycle 1, Cycle 2, Cycle 3 and Cycle 4 Day 1: Predose; Cycle 5 Day 1 & every 2 cycles thereafter up to approximately 24 months: Predose; End of Termination Visit; 40-day Follow-up Visit (each cycle is 21 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Relapsed/Refractory Extensive-stage Small-cell Lung Cancer, DS-7300a, B7-H3 Antibody Drug Conjugate, Ifinatamab Deruxtecan, I-DXd