Phase 2 Multicenter Randomized Open-label Study of Ifinatamab Deruxtecan in Pretreated Extensive-stage Small Cell Lung Cancer

Trial ID: 2024-512368-79-00
Sponsor: Daiichi Sankyo Inc.

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Diseases & Conditions

Small cell lung cancer extensive stage

Objectives

The primary objective of this Phase 2, multicenter, randomized, open-label study is to assess the **antitumor activity** of Ifinatamab Deruxtecan (I-DXd), a B7-H3 antibody drug conjugate, in subjects with pretreated extensive-stage small cell lung cancer (ES-SCLC). This objective is clinically relevant as it aims to evaluate the efficacy of I-DXd in a patient population with limited treatment options, potentially offering a new therapeutic avenue for those with advanced disease stages.

Participants

The clinical trial involves a total of **129 participants** diagnosed with **Extensive-stage Small Cell Lung Cancer (ES-SCLC)**. The study population includes both male and female subjects aged 18 years and older. Participants were selected based on their prior treatment history, specifically those who have undergone at least one platinum-based line of systemic therapy for extensive-stage disease. The trial does not include a vulnerable population. Participants are required to have a documented radiological disease progression on or after their most recent systemic therapy and must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. Lifestyle considerations such as diet and physical activity are not specified. The selection criteria ensure that participants have a life expectancy of at least three months and meet specific laboratory and health status requirements, including adequate organ function and the ability to comply with study procedures.

Plans and Procedures

The clinical trial is a Phase II, multicenter, randomized, open-label study designed to evaluate the **antitumor activity** of Ifinatamab deruxtecan, an antibody-drug conjugate, in subjects with pretreated extensive-stage small cell lung cancer (ES-SCLC). The trial is expected to run from January 9, 2023, to November 15, 2025. Participants will be randomly assigned to receive the investigational product, administered as a **solution for infusion** via intravenous use. The study aims to assess the objective response rate, defined as the proportion of subjects with a best overall response of confirmed complete response or confirmed partial response, as evaluated by blinded independent central review based on RECIST v1.1 criteria.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, including laboratory tests and medical history. The treatment period will involve regular follow-up visits to monitor the safety and efficacy of the investigational product, with assessments including laboratory tests, imaging studies, and physical examinations. The end-of-study visit will occur after the completion of the treatment period or upon early termination from the study. The expected length of participant involvement is up to 36 weeks, with conditions for early termination including disease progression, unacceptable toxicity, or withdrawal of consent.

Inclusion criteria require participants to have histologically or cytologically documented ES-SCLC, at least one measurable lesion, and prior therapy with at least one platinum-based line of systemic therapy. Participants must be at least 18 years old, with an Eastern Cooperative Oncology Group performance status of 0 or 1, and a life expectancy of at least three months. Exclusion criteria are not explicitly detailed in the provided data. The study emphasizes compliance with scheduled visits, drug administration plans, and other study procedures. Participants must also adhere to specific contraceptive measures during and after the study period to prevent pregnancy.

Treatment

The clinical trial involves the administration of **Ifinatamab deruxtecan**, an experimental medication classified as an **Antibody Drug Conjugate**. This investigational product is provided in the form of a **solution for infusion** and is intended for **intravenous use**. The active substance, **ifinatamab deruxtecan**, is a protein-based compound developed by Daiichi Sankyo, Inc. The dosing regimen for this trial specifies a maximum daily dose of 12 mg/kg, with a total maximum dose of 624 mg/kg over the course of the treatment. The maximum treatment period is set at 36 weeks. The administration of the drug will be closely monitored to ensure participant compliance and adherence to the dosing schedule.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The focus is solely on evaluating the antitumor activity of Ifinatamab deruxtecan in subjects with pretreated extensive-stage small cell lung cancer (ES-SCLC). Participants' adherence to the treatment protocol will be monitored throughout the trial to ensure the integrity of the study data and the safety of the participants.

Efficacy

The efficacy of Ifinatamab Deruxtecan in the clinical trial will be assessed primarily through the **Objective Response Rate (ORR)**. This endpoint is defined as the proportion of subjects achieving a Best Overall Response (BOR) of confirmed Complete Response (CR) or confirmed Partial Response (PR). The assessment will be conducted by a Blinded Independent Central Review (BICR) based on the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. The trial is designed to evaluate the antitumor activity of Ifinatamab Deruxtecan in subjects with pretreated extensive-stage small cell lung cancer (ES-SCLC).

Inclusion and Exclusion Criteria

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Inclusion Criteria

Sign and date the ICF prior to the start of any study- specific qualification procedures
Subject must have at least one lesion, not previously irradiated, amenable to core biopsy and must consent to provide a pretreatment biopsy tissue sample and on-treatment biopsy. Fresh pretreatment biopsy may be waived for subjects who consent to provide archival tumor tissue from a biopsy performed within 6 months of consent and performed after treatment with their most recent cancer therapy regimen. If, after all efforts have been made, the fresh pretreatment biopsy is not feasible or the procedure is unsuccessful and an appropriate archival sample is not available, the subject may be considered for study eligibility only after discussion with the Sponsor
Male or female subjects aged ≥18 years
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 prior platinum-based line as systemic therapy for extensive-stage disease with at least two cycles of therapy (except in case of early objective PD) and, beginning with protocol version 3.0, a minimum of two previous lines of systemic therapy. Subjects with or without prior immune-checkpoint inhibitor therapy are eligible. Subject must not have received more than three previous lines of systemic therapy (rechallenge with platinum chemotherapy will be considered as one separated prior line of therapy). Subjects treated with a platinum-based line of therapy for prior limited stage (LS)-SCLC may be eligible for the study if the disease has progressed on treatment or within 6 months from treatment completion: the platinum-based line of therapy will count as one prior line of therapy. One line of therapy will be defined as 1 or more drugs received prior to newly documented disease progression in the locally advanced or metastatic setting. Any switch between carboplatin and cisplatin for toxicity reasons will be regarded as one line overall.
Documentation of radiological disease progression on or after most recent systemic therapy
ECOG PS of 0 or 1
Life-expectancy ≥3 months
Required baseline local laboratory data (within 7 days prior to Cycle 1 Day 1): a. ALT and AST: - ≤3 × ULN in subjects with no liver metastasis or - ≤5.0 × ULN in subjects with liver metastasis b. Total bilirubin ≤1.5 × ULN if no liver metastases or ≤3 × ULN in the presence of documented Gilbert's syndrome (undocumented hyperbilirubinemia) or liver metastases at baseline c. ANC ≥1.5 × 109/L (hematopoietic growth factors [eg, G-CSF, GM-CSF] support allowed up to 14 days before screening laboratory tests) d. Platelet count ≥100 × 109/L (platelet transfusion is allowed up to 14 days before screening laboratory tests) e.Hemoglobin ≥8.5 g/dL (transfusion and/or growth factor support allowed up to 14 days before screening laboratory tests) f. Creatinine clearance ≥30 mL/min, as calculated using the CockcroftGault equation g. International normalized ratio (INR)/prothrombin time (PT) and either partial thromboplastin time (PTT) or activated partial thromboplastin time (aPTT) ≤1.5 × ULN, except for subjects receiving anti vitamin K derivative anticoagulant therapy who must have prothrombin time international normalization ratio within the therapeutic range as deemed appropriate by the investigator.
If the subject is a female of childbearing potential, she must have a negative serum pregnancy test within 7 days before the first dose of study drug and must be willing to use a highly effective birth control upon enrollment, during the Treatment Period, and for 7 months following the last dose of study drug. A female is considered of childbearing potential following menarche and until becoming postmenopausal (no menstrual period for a minimum of 12 months) unless permanently sterile (undergone a hysterectomy, bilateral salpingectomy or bilateral oophorectomy) with surgery at least 1 month before the first dose or confirmed by FSH test.
If male, the subject must be surgically sterile or willing to use highly effective birth control upon enrollment, during the Treatment Period, and for 4 months following the last dose of study drug.
Male subjects must not freeze or donate sperm starting at enrollment, throughout the Treatment Period, and for at least 4 months following the last dose of the study drug. Preservation of sperm may be considered prior to enrollment in this study.
Female subjects must not donate, or retrieve for their own use, ova from the time of enrollment and throughout the Treatment Period, and for at least 7 months following the last dose of the study drug. They should refrain from breastfeeding throughout this time. Preservation of ova may be considered prior to enrollment in this study.
Is willing and able to comply with scheduled visits, drug administration plan, laboratory tests, other study procedures, and study restrictions.

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Exclusion Criteria

Prior treatment with orlotamab, enoblituzumab, or other B7-H3 targeted agents including I-DXd
Prior discontinuation of an ADC that consists of an exatecan derivative (eg, trastuzumab deruxtecan)
Inadequate washout period before randomization, defined as: a. Major surgery (placement of vascular access will not be regarded as a major surgery) <4 weeks; surgery for low invasive cases (eg, colostomy, <4 weeks) b. Radiation therapy to the lung >30 Gy <6 months; palliative radiotherapy affecting lung areas at lower dose <3 weeks; any other palliative radiotherapy <2 weeks c. Cranial irradiation, including WBRT and SRS, ≤2 weeks d. Any systemic anticancer therapy <3 weeks or 5 half-lives whichever is longer and <6 weeks for nitrosoureas or mitomycin C e. Antibody-based anticancer therapy <3 weeks f. Chloroquine or hydroxychloroquine ≤14 days g. Hormonal therapy <2 weeks
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 another arterial thromboembolic event.
Clinically significant corneal disease
Uncontrolled or significant cardiovascular disease including: a. Corrected QT interval (by Fridericia's formula) >470 ms (females) or >450 ms (males) based on average of the screening triplicate 12-lead ECG determinations. b. Diagnosed or suspected long QT syndrome or known family history of long QT syndrome. c. History of clinically relevant ventricular arrhythmias, such as ventricular tachycardia, ventricular fibrillation or Torsade de Pointes d. Bradycardia of less than 50 bpm unless the subject has a pacemaker. e. History of second-or third-degree heart block f. Acute myocardial infarction within 6 months prior to screening g. Uncontrolled angina pectoris within 6 months prior to screening h. CHF defined as NYHA Class II to IV i. Coronary/peripheral artery bypass graft or any coronary/peripheral angioplasty within 6 months prior to screening j. Grade ≥3 hypertension k. Complete left or right bundle branch block l.LVEF <50% by either an ECHO or a MUGA scan
History of (non-infectious) 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 including, but not limited to, any underlying pulmonary disorder, and potential pulmonary involvement caused by any autoimmune, connective tissue or inflammatory disorders, prior complete pneumonectomy, or requirement for supplemental oxygen.
Chronic steroid treatment (dose of 10 mg daily or more 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 GI 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 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.
Has active or uncontrolled hepatitis B or C infection; subject is positive for hepatitis B or C virus within 28 days of enrolment.
Active, known, or suspected autoimmune disease. The following examples may be enrolled as an exception: a. Type I diabetes mellitus, hypothyroidism only requiring hormone replacement b. Skin disorders not requiring systemic treatment, or c. Conditions not expected to recur in the absence of an external trigger.
Any evidence of severe or uncontrolled systemic diseases or other factors that, in the investigator's opinion, make it undesirable for the subject to participate in the study or would jeopardize compliance with the protocol.
Has received a live vaccine within 30 days prior to the first dose of study drug.
Female who is pregnant or breastfeeding 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 investigators opinion, could affect the safety of the subject; alter the absorption, distribution, metabolism or excretion of the study drug; or confound the assessment of study results.
Known HIV infection that is not well controlled.