Efficacy and Safety Evaluation of Ifinatamab Deruxtecan in Recurrent or Metastatic Solid Tumors: A Phase 1b/2 Open-Label Study

Trial ID: 2023-509632-26-00
Protocol: DS7300-203
Sponsor: Daiichi Sankyo Inc.

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Diseases & Conditions

Endometrial cancer Adenocarcinoma gastric Colorectal cancer Oesophageal adenocarcinoma

Objectives

The primary objective of this study is to evaluate the **efficacy** of Ifinatamab deruxtecan (I-DXd) as measured by the Objective Response Rate (ORR) in subjects with recurrent or metastatic solid tumors who have target lesions per RECIST v1.1. Additionally, the study aims to assess the safety and tolerability of I-DXd in subjects with hepatocellular carcinoma (HCC). This is clinically relevant as it seeks to determine the therapeutic potential and safety profile of I-DXd in a diverse group of solid tumors, which could inform treatment strategies and improve patient outcomes.

Secondary objectives include: - Assessing the safety and tolerability of I-DXd in subjects with relapsed or recurrent disease in the locally advanced or metastatic setting. - Further evaluating the efficacy of I-DXd as measured by Duration of Response (DoR), Progression-Free Survival (PFS), Overall Survival (OS), and Disease Control Rate (DCR) by investigator assessment. - Evaluating the pharmacokinetics (PK) of I-DXd. - Assessing the immunogenicity of I-DXd.

Participants

The clinical trial involves a total of **320 participants** diagnosed with **recurrent or metastatic solid tumors**, including endometrial cancer, head and neck squamous cell carcinoma, pancreatic ductal adenocarcinoma, colorectal cancer, hepatocellular carcinoma, adenocarcinoma of the esophagus, gastroesophageal junction, and stomach, urothelial carcinoma, ovarian cancer, cervical cancer, biliary tract cancer, HER2-low breast cancer, HER2 IHC 0 breast cancer, and cutaneous melanoma. The study population comprises both **male and female subjects** aged 18 years and older, adhering to local regulatory requirements for the legal age of consent. Participants were selected based on specific inclusion criteria, ensuring they have measurable lesions per RECIST v1.1 and adequate organ function. The trial includes individuals with 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. The study considers lifestyle factors such as previous treatments and the presence of actionable target tumor mutations, which may have influenced prior therapy decisions. The trial population includes vulnerable groups, ensuring comprehensive representation across different demographics and health statuses.

Plans and Procedures

The clinical trial is designed as a **Phase 1b/2** open-label study to evaluate the efficacy and safety of **ifinatamab deruxtecan** in subjects with recurrent or metastatic solid tumors. The trial will assess the overall response rate (ORR) and safety profile of the investigational drug, administered as a **solution for infusion** via **intravenous use**. The study will include participants with various types of solid tumors, including endometrial cancer, head and neck squamous cell carcinoma, pancreatic ductal adenocarcinoma, colorectal cancer, hepatocellular carcinoma, adenocarcinoma of the esophagus, gastroesophageal junction, and stomach, urothelial carcinoma, ovarian cancer, cervical cancer, biliary tract cancer, HER2-low breast cancer, HER2 IHC 0 breast cancer, and cutaneous melanoma.

The trial is expected to commence recruitment on January 1, 2025, and conclude by January 1, 2027. Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, such as age, disease progression, and prior treatment history. Subsequent visits will involve the administration of the study drug, monitoring of adverse events, and assessment of tumor response according to RECIST v1.1 criteria. Follow-up visits will be scheduled to evaluate the duration of response (DoR), progression-free survival (PFS), and overall survival (OS). The end-of-study visit will mark the completion of the participant's involvement, during which final assessments will be conducted.

Participant involvement is anticipated to last until the end of the study or until disease progression, unacceptable toxicity, or withdrawal of consent occurs. Conditions that may lead to early termination from the study include significant adverse events, non-compliance with study procedures, or any other reason deemed necessary by the investigator. The trial will adhere to rigorous safety monitoring, with adverse events graded according to the NCI-CTCAE v5.0. The study aims to provide valuable insights into the therapeutic potential of ifinatamab deruxtecan for patients with challenging oncological conditions.

Treatment

The clinical trial involves the administration of **Ifinatamab deruxtecan**, an experimental medication classified as an **antibody-drug conjugate (ADC)**. This investigational product is provided in the form of a **solution for infusion**. The administration route is **intravenous use**, ensuring direct delivery into the bloodstream. The frequency and specific dosing schedule are determined by the study protocol, which is designed to evaluate the efficacy and safety of the drug in subjects with recurrent or metastatic solid tumors. The active substance, **ifinatamab deruxtecan**, is a protein-based compound, specifically categorized under "Protein - Other". The product is not formulated for pediatric use and holds an orphan drug designation, indicating its potential use in treating rare conditions.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The focus remains solely on the investigational product, Ifinatamab deruxtecan. Participant compliance with the dosing regimen is monitored throughout the trial to ensure adherence to the protocol and to accurately assess the drug's efficacy and safety profile. The study is conducted under the sponsorship of Daiichi Sankyo, Inc., which is responsible for the development and provision of the investigational product.

Efficacy

The efficacy of the investigational drug **Ifinatamab deruxtecan** (I-DXd) in the clinical trial will be primarily assessed by the **Objective Response Rate (ORR)**. ORR is defined as the percentage of subjects who achieve a Best Overall Response (BOR) of confirmed Complete Response (CR) or confirmed Partial Response (PR) as evaluated by the investigator according to the RECIST v1.1 criteria. This assessment will be conducted in subjects with recurrent or metastatic solid tumors.

Secondary efficacy endpoints include the **Duration of Response (DoR)**, which measures the time from the first documentation of objective tumor response (CR or PR) to the first documentation of objective tumor progression or death from any cause. **Progression-Free Survival (PFS)** is defined as the time from the first dose of the study drug to the date of disease progression or death from any cause. **Overall Survival (OS)** is the time from the first dose of the study drug to death from any cause. Additionally, the **Disease Control Rate (DCR)**, which includes the percentage of subjects with a BOR of confirmed CR, confirmed PR, or Stable Disease (SD), will be evaluated.

Plasma pharmacokinetic (PK) parameters such as Tmax, t1/2, Cmax, Ctrough, and AUC for I-DXd, total anti-B7-H3 antibody, and DXd will be measured. The presence of Anti-Drug Antibodies (ADA) will be assessed using a validated assay to determine ADA prevalence and incidence, as well as titer and neutralizing antibodies when ADA is positive.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Subjects ages ≥18 years (follow local regulatory requirements if the legal age of consent for study participation is >18 years).
At least 1 measurable lesion on computed tomography (CT) or magnetic resonance imaging (MRI) according to RECIST v1.1, as assessed by the investigator.
Documentation of radiological disease progression on or after the previous standard of care regimen in the advanced/metastatic setting. a. Subjects who experience disease progression during treatment or within a time frame of up to 6 months (180 days) after the completion of neoadjuvant/adjuvant treatment are considered eligible if they meet all other criteria and the prior treatment is defined as a line of therapy.
Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
Has adequate organ function within 7 days before the start of study drug. Transfusion (red blood cell or platelet) or granulocyte-colony stimulating factor (G-CSF) administration is not allowed within 2 weeks prior to screening laboratory assessments. Adequate organ function is defined as follows: - Platelet count ≥100 × 109/L - Hemoglobin ≥8.5 g/dL - Absolute neutrophil count ≥1.5 × 109/L - Creatinine clearance ≥30 mL/min, as calculated using the Cockcroft-Gault equation - Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST): ≤3 × upper limit of normal (ULN) in subjects with no liver metastasis or ≤5.0 × ULN in subjects with liver metastasis or primary liver tumor - Total bilirubin (TBL): ≤1.5 × ULN if no liver metastases or ≤3 × ULN in the presence of documented Gilbert’s syndrome (unconjugated hyperbilirubinemia) or liver metastases at Baseline. For HCC, please refer to the additional inclusion criteria for HCC subjects. - International normalized ratio (INR)/prothrombin time and either partial thromboplastin time (PTT) or activated PTT (aPTT): ≤1.5 × ULN. Note: Except for subjects receiving anti-vitamin K derivative anticoagulant therapy who must have prothrombin time-INR within therapeutic range as deemed appropriate by the investigator.
For EC Subjects: Pathologically or cytologically documented EC of any histological carcinoma subtype or endometrial carcinosarcoma, irrespective of MSI or MMR status.
For EC Subjects: Relapse or progression after a platinum-containing systemic treatment and an ICI containing regimen (combined or sequential). Subjects with actionable target tumor mutation should have been previously treated with targeted therapy, ), with a maximum of 3 prior lines of therapy for endometrial carcinoma or carcinosarcoma. Neoadjuvant/adjuvant therapy may count as 1 line of therapy if the subject progressed within 6 months after completion of therapy.
For HNSCC Subjects: Pathologically or cytologically documented unresectable or metastatic squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx, excluding nasopharynx, nasal cavity and paranasal sinuses, and unknown primary.
For HNSCC Subjects: Has disease progression after platinum-based and ICI treatment, whether administered in combination or separately. Subjects with actionable target tumor mutation should have been previously treated with targeted therapy, with a maximum of 2 prior therapy lines for unresectable or metastatic HNSCC.
For HNSCC Subjects: Subjects without radiographic evidence of major blood vessel invasion/infiltration or tumor demonstrating a >90-degree abutment or encasement of a major blood vessel.
For HNSCC Subjects: Subjects with no prior history of Grade ≥3 bleeding as per the National Cancer Institute – Common Terminology Criteria for Adverse Events (NCI-CTCAE) v5.0 within 28 days prior to the start of study drug related to the current head and neck cancer may be included in the study.
For PDAC Subjects: Pathologically or cytologically documented unresectable or metastatic pancreatic adenocarcinoma that has relapsed or progressed after 1 prior line of gemcitabine-based systemic therapy in the locally advanced/metastatic setting or after 2 lines of therapy if the subject has actionable target tumor mutation and has been previously treated with targeted therapy. a. No prior treatment with topoisomerase I inhibitors, such as irinotecan or topotecan.
For CRC Subjects: Pathologically or cytologically documented unresectable or metastatic CRC with MSS status.
For CRC Subjects: Relapse or progression after 1 prior line of systemic therapy including a fluoropyrimidine plus oxaliplatin with or without anti-vascular endothelial growth factor (VEGF) mAb or anti-EGFR mAb therapy, as clinically indicated, or relapse or progression after 2 lines of therapy if the subject has received targeted therapy. Note: Prior adjuvant/neoadjuvant systemic cytotoxic chemotherapy will count as 1 line of prior systemic therapy if there is documented disease progression during therapy or within 6 months of chemotherapy completion.
For CRC Subjects: No prior treatment with topoisomerase I inhibitors, such as irinotecan or topotecan.
For HCC Subjects: Pathologically or cytologically documented unresectable or metastatic HCC (fibrolamellar and mixed hepatocellular/cholangiocarcinoma subtypes are not eligible) or noninvasive diagnosis of HCC as per the American Association for the Study of Liver Diseases (AASLD) criteria in subjects with a confirmed diagnosis of cirrhosis.
For HCC Subjects: Relapse or progression after 1 prior line of an ICI-containing regimen (combination or monotherapy) in the locally advanced/metastatic setting , with a maximum of 2 prior lines. Subjects with actionable target tumor mutation should have been previously treated with targeted therapy.
For HCC Subjects: Barcelona Clinic Liver Cancer (BCLC) Stage B or C.
For HCC Subjects: Liver function status should be Child-Pugh (CP) Class A. CP status should be calculated based on clinical findings and laboratory results during the Screening Period.
For Ad-eso/GEJ/Gastric Subjects: Pathologically or cytologically documented unresectable or metastatic Ad eso/GEJ/Gastric that has relapsed or progressed after 1 prior line of systemic therapy in the locally advanced/metastatic setting. a. Subjects with PD-(L)1+ or MSI-H/dMMR should receive ICI treatment if ICIs are standard of care in the country, unless the subject is ineligible for ICI treatment.
If the subject has known history of HER2 positivity (defined by IHC 3+ or IHC 2+ and ISH+, as classified by ASCO-CAP) or other actionable target, the subject must have been previously treated with a targeted therapy.
For UC Subjects: Pathologically or cytologically documented unresectable or metastatic UC of the bladder, renal pelvis, ureter, or urethra. Subjects with histological variants are allowed if urothelial histology is predominant. Small cell/neuroendocrine tumors are not allowed even if mixed histology.
For UC Subjects: Relapse or progression after at least 1 prior line of ICI-containing systemic therapy, and 1 prior line of systemic chemotherapy, given in combination with other anticancer therapy or separately , with a maximum of 3 prior therapy lines. a. At least 1 line of therapy should include enfortumab vedotin in countries where enfortumab vedotin is approved and available. b. Perioperative systemic therapies will be counted as 1 line of therapy. c. To meet inclusion criteria requirement of prior ICI-containing therapy, use in the perioperative or metastatic setting will suffice. d. Subjects with actionable target tumor mutation should have been previously treated with targeted therapy. e. The same regimen administered twice in different disease settings will be counted as 1 line of prior therapy.
Histologically confirmed unresectable or metastatic CC that was previously treated with ≥1 prior line of systemic therapy in the locally advanced or metastatic setting. Subjects with actionable target tumor mutation should have been previously treated with targeted therapy.
For OVC Subjects: Histologically confirmed high-grade serous OVC, high-grade endometrioid OVC, primary peritoneal cancer, or fallopian tube cancer that was previously treated with at least 1 line of platinum-based therapy and bevacizumab unless the subject is ineligible for treatment with bevacizumab.
For OVC Subjects: Subject is no longer considered eligible for platinum-based therapy per the investigator’s opinion or has progressed less than 180 days after the last dose of platinum therapy.
For OVC Subjects: Subject is not considered primary platinum refractory and has not progressed during platinum treatment or within 4 weeks after the completion of platinum treatment.
For BTC Subjects: Pathologically or cytologically documented unresectable or metastatic BTC (intra- or extrahepatic cholangiocarcinoma or gallbladder carcinoma).
For BTC Subjects: Relapse or progression after at least 1 prior line of systemic therapy, or 2 prior lines of systemic therapy if the subject has an actionable target and has received targeted therapy.
For BTC Subjects: Histological subtypes other than ampullary cancer, small cell cancer, lymphoma, sarcoma, neuroendocrine tumors, mixed tumor histology, and/or mucinous cystic neoplasms (Please note that the histological subtypes listed here are not allowed.)
For HER2-Low BC Subjects: Pathologically or cytologically documented unresectable or metastatic BC.
For HER2-Low BC Subjects: Low HER2 expression, defined as IHC 2+/ISH- or IHC 1+ (ISH- or untested) according to ASCO-CAP 2018 HER2 testing guidelines, based on most recent testing, regardless of hormonal status.
For HER2-Low BC Subjects: Progression on or after treatment with T-DXd.
For HER2-Low BC Subjects: Relapse or progression after at least 2 and a maximum of 3 prior lines of systemic therapy. Subjects with metastatic HR+ BC who have received endocrine-based therapy and have received at least 2 and a maximum of 3 prior lines of additional systemic therapy in the metastatic setting. Subjects with actionable target tumor mutation should have been previously treated with targeted therapy.
For HER2 IHC 0 BC Subjects: Pathologically or cytologically documented unresectable or metastatic BC.
For HER2 IHC 0 BC Subjects: Negative for HER2 expression, defined as IHC 0 (ISH- or untested) according to ASCO CAP 2018 HER2 testing guidelines, based on the most recent testing, regardless of hormonal status.
For HER2 IHC 0 BC Subjects: Relapse or progression after at least 2 and a maximum of 3 prior lines of systemic therapy. Subjects with metastatic HR+ BC who have received endocrine-based therapy and have received at least 2 and a maximum of 3 prior lines of additional systemic therapy in the metastatic setting. Subjects with actionable target tumor mutation should have been previously treated with targeted therapy.
For Cutaneous (Acral and Non-acral) Melanoma Subjects: Histologically or cytologically confirmed cutaneous (acral and non-acral) melanoma.
For Cutaneous (Acral and Non-acral) Melanoma Subjects: Disease progression while on or after having received treatment with ≥1 prior line of ICI based therapy. Prior anti-PD-(L)1 therapy in the adjuvant setting may be counted as 1 line if there is recurrence within 12 weeks of the last dose. If the subject had BRAF mutated melanoma or other actionable target tumor mutation, they must have had disease progression on targeted therapy as well.

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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, T-DXd) due to treatment-related toxicities.
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. Subjects with clinically inactive or treated brain metastases who are asymptomatic (ie, without neurologic signs or symptoms and not requiring treatment with corticosteroids or anticonvulsants) may be included in the study. Subjects must have a stable neurologic status for at least 2 weeks prior to C1D1. Note: For melanoma and BC subjects, a contrast-enhanced MRI (preferred) or CT of the brain should be included at baseline. For all other subjects, brain MRI or CT is required only in cases of pre-existing or suspected central nervous system tumor lesions.
Inadequate treatment washout period before enrollment, defined as follows: - Major surgery (placement of vascular access will not be regarded as a major surgery) (washout period <4 weeks) - Surgery for low-invasive cases (eg, colostomy) (washout period <2 weeks) - Radiation therapy (washout period <4 weeks) - Palliative stereotactic radiation therapy without abdominal radiation (washout period ≤2 weeks) - Cranial irradiation, including whole brain radiation therapy and stereotactic radiosurgery (washout period ≤2 weeks) - Radiation therapy to the lung >30 Gy (washout period <6 months) - Palliative radiotherapy affecting lung areas at lower dose (washout period <3 weeks) - Any systemic anticancer therapy (including immunotherapy [other than antibodies] and investigational drugs) (washout period <3 weeks or 5 half-lives, whichever is longer) - Hormonal therapy (except for luteinizing hormone-releasing hormone [LHRH] agonists/antagonists) (washout period <2 weeks) - Locoregional therapy (chemoembolization, radioembolization) (washout period <4 weeks) - Nitrosoureas or mitomycin C (washout period <6 weeks) - Antibody-based anticancer therapy (washout period <3 weeks) - Chloroquine/hydroxychloroquine (washout period ≤14 days)
Clinically significant corneal disease.
History of (noninfectious) 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 (eg, pulmonary emboli within 3 months of the study enrollment, severe asthma, severe chronic obstructive pulmonary disease [COPD], restrictive lung disease, pleural effusion, etc) and any autoimmune, connective tissue, or inflammatory disorders with potential pulmonary involvement (eg, rheumatoid arthritis, Sjögren’s syndrome, sarcoidosis, etc), prior pneumonectomy, or requirement for supplemental oxygen.
Unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to NCI-CTCAE v5.0 Grade ≤1 or baseline. Note: Subjects may be enrolled with chronic, stable Grade 2 toxicities (defined as no worsening to Grade >2 for at least 3 months prior to enrollment and managed with standard-of-care treatment) that the investigator deems related to previous anticancer therapy, following discussion with the Sponsor, such as the following: a) Chemotherapy-induced neuropathy b) Fatigue c) Endocrinopathies, which may include hypothyroidism, hyperthyroidism, type I diabetes, hyperglycemia, adrenal insufficiency, and/or adrenalitis d) Skin hypopigmentation (vitiligo)

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Belgium	Recruiting	01 Jan 2025	26
France	Recruiting	01 Jan 2025	60
Germany	Recruiting	01 Jan 2025	25
Ireland	Recruiting	01 Jan 2025	25
Italy	Recruiting	01 Jan 2025	35
The Netherlands	Recruiting	01 Jan 2025	—
Poland	Recruiting	01 Jan 2025	30
Portugal	Recruiting	01 Jan 2025	30
Spain	Recruiting	01 Jan 2025	60
Netherlands	—	—	20