Ifinatamab deruxtecan for Endometrial cancer | Head and neck squamous cell carcinoma | Pancreatic ductal adenocarcinoma | Colorectal cancer | Hepatocellular carcinoma | Esophageal adenocarcinoma | Gastroesophageal junction adenocarcinoma | Gastric adenocarcinoma | Urothelial carcinoma | Ovarian cancer | Cervical cancer | Biliary tract cancer | Breast cancer (HER2-low) | Breast cancer (HER2 IHC 0) | Cutaneous melanoma

Inclusion criteria

• {"criterion_text":"- Subjects ages ≥18 years (follow local regulatory requirements if the legal age of consent for study participation is >18 years).\n- At least 1 measurable lesion on computed tomography (CT) or magnetic resonance imaging (MRI) according to RECIST v1.1, as assessed by the investigator.\n- Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.\n- 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: -\tPlatelet count ≥100 × 109/L -\tHemoglobin ≥8.5 g/dL -\tAbsolute neutrophil count ≥1.5 × 109/L -\tCreatinine clearance ≥30 mL/min, as calculated using the Cockcroft-Gault equation -\tAlanine 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 -\tTotal 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. -\tInternational 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.\n- Documentation of radiological disease progression on or after the previous standard of care regimen in the advanced/metastatic setting. a.\tSubjects 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.\n- 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.\n- 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.\n- 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.\n- 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.\n- 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.\tNo prior treatment with topoisomerase I inhibitors, such as irinotecan or topotecan.\n- For CRC Subjects: Pathologically or cytologically documented unresectable or metastatic CRC with MSS status.\n- 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.\n- For CRC Subjects: No prior treatment with topoisomerase I inhibitors, such as irinotecan or topotecan.\n- 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.\n- 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.\n- For HCC Subjects: Barcelona Clinic Liver Cancer (BCLC) Stage B or C.\n- 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.\n- 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.\tSubjects 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.\n- 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.\n- 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.\n- 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.\tAt least 1 line of therapy should include enfortumab vedotin in countries where enfortumab vedotin is approved and available. b.\tPerioperative systemic therapies will be counted as 1 line of therapy. c.\tTo meet inclusion criteria requirement of prior ICI-containing therapy, use in the perioperative or metastatic setting will suffice. d.\tSubjects with actionable target tumor mutation should have been previously treated with targeted therapy. e.\tThe same regimen administered twice in different disease settings will be counted as 1 line of prior therapy.\n- 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.\n- 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.\n- 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.\n- 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.\n- For BTC Subjects: Pathologically or cytologically documented unresectable or metastatic BTC (intra- or extrahepatic cholangiocarcinoma or gallbladder carcinoma).\n- 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.\n- For HER2-Low BC Subjects: Pathologically or cytologically documented unresectable or metastatic BC.\n- 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.\n- For HER2-Low BC Subjects: Progression on or after treatment with T-DXd.\n- 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.\n- For HER2 IHC 0 BC Subjects: Pathologically or cytologically documented unresectable or metastatic BC.\n- 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.\n- 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.\n- For Cutaneous (Acral and Non-acral) Melanoma Subjects: Histologically or cytologically confirmed cutaneous (acral and non-acral) melanoma.\n- 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."}

Exclusion criteria

• {"criterion_text":"- Prior treatment with orlotamab, enoblituzumab, or other B7-H3-targeted agents, including I-DXd.\n- Prior discontinuation of an ADC that consists of an exatecan derivative (eg, T-DXd) due to treatment-related toxicities.\n- 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.\n- Inadequate treatment washout period before enrollment, defined as follows: -\tMajor surgery (placement of vascular access will not be regarded as a major surgery) (washout period <4 weeks) -\tSurgery for low-invasive cases (eg, colostomy) (washout period <2 weeks) -\tRadiation therapy (washout period <4 weeks) -\tPalliative stereotactic radiation therapy without abdominal radiation (washout period ≤2 weeks) -\tCranial irradiation, including whole brain radiation therapy and stereotactic radiosurgery (washout period ≤2 weeks) -\tRadiation therapy to the lung >30 Gy (washout period <6 months) -\tPalliative radiotherapy affecting lung areas at lower dose (washout period <3 weeks) -\tAny systemic anticancer therapy (including immunotherapy [other than antibodies] and investigational drugs) (washout period <3 weeks or 5 half-lives, whichever is longer) -\tHormonal therapy (except for luteinizing hormone-releasing hormone [LHRH] agonists/antagonists) (washout period <2 weeks) -\tLocoregional therapy (chemoembolization, radioembolization) (washout period <4 weeks) -\tNitrosoureas or mitomycin C (washout period <6 weeks) -\tAntibody-based anticancer therapy (washout period <3 weeks) -\tChloroquine/hydroxychloroquine (washout period ≤14 days)\n- Clinically significant corneal disease.\n- History of (noninfectious) ILD/pneumonitis that required corticosteroids, current ILD/pneumonitis, or suspected ILD/pneumonitis that cannot be ruled out by imaging at Screening.\n- 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.\n- 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)\tChemotherapy-induced neuropathy b)\tFatigue c)\tEndocrinopathies, which may include hypothyroidism, hyperthyroidism, type I diabetes, hyperglycemia, adrenal insufficiency, and/or adrenalitis d)\tSkin hypopigmentation (vitiligo)"}

Primary endpoints

• {"endpoint_text":"- ORR is defined as the percentage of subjects with a BOR of confirmed CR or confirmed PR as assessed by the investigator per RECIST v1.1.","definition_or_measurement_approach":"ORR is measured as the percentage of subjects with a best overall response (confirmed CR or PR) assessed by investigator per RECIST v1.1."}
• {"endpoint_text":"- DLTs and TEAEs graded according to the NCI-CTCAE v5.0, including deaths and other relevant safety endpoints.","definition_or_measurement_approach":"Dose-limiting toxicities (DLTs) and treatment-emergent adverse events (TEAEs) are graded by NCI-CTCAE v5.0; includes capturing deaths and other safety parameters as defined in protocol."}

Secondary endpoints

• {"endpoint_text":"- Incidence of TEAEs, SAEs, and AESIs graded according to the NCI-CTCAE v5.0, including deaths, changes from baseline in vital signs, clinical laboratory results, ECGs, ECHO/MUGA, ophthalmologic findings, and other relevant safety endpoints.","definition_or_measurement_approach":"Incidence measured as counts/rates of events graded per NCI-CTCAE v5.0; includes laboratory and clinical assessments as listed."}
• {"endpoint_text":"- DoR is defined as the time from the date of the first documentation of objective tumor response (CR or PR), subsequently confirmed by investigator assessment, to the first documentation of objective tumor progression (confirmed by investigator assessment) or to death from any cause, whichever occurs first.","definition_or_measurement_approach":"Duration of Response measured from first documented objective response (CR/PR) to documented progression or death; confirmed by investigator assessment."}
• {"endpoint_text":"- PFS is defined as the time interval from the date of the first dose of study drug to the date of disease progression as assessed by the investigator per RECIST v1.1 or death from any cause.","definition_or_measurement_approach":"Progression-free survival measured from first dose to investigator-assessed RECIST v1.1 progression or death."}
• {"endpoint_text":"- OS is defined as the time interval from the date of the first dose of study drug to the date of death from any cause.","definition_or_measurement_approach":"Overall survival measured from first dose to death from any cause."}
• {"endpoint_text":"- DCR is defined as the percentage of subjects with a BOR of confirmed CR, confirmed PR, or SD as assessed by the investigator per RECIST v1.1.","definition_or_measurement_approach":"Disease control rate measured as percentage of subjects with confirmed CR, PR, or stable disease (SD) by investigator per RECIST v1.1."}
• {"endpoint_text":"- Plasma PK parameters (eg, Tmax, t1/2, Cmax, Ctrough, AUC) for I-DXd, total anti-B7-H3 antibody, and DXd.","definition_or_measurement_approach":"Pharmacokinetic parameters measured in plasma for I-DXd, total anti-B7-H3 antibody and DXd; standard PK sampling and validated assays."}
• {"endpoint_text":"- ADA as measured in the plasma via a validated assay. ADA prevalence: defined as the proportion of subjects who are ADA positive at any point in time (including pre-existing ADA at baseline and treatment-emergent ADA). ADA incidence: defined as the proportion of subjects having treatment-emergent ADA. Titer and neutralizing antibodies will be determined when the ADA is positive.","definition_or_measurement_approach":"Anti-drug antibodies measured in plasma with validated assays; prevalence and incidence as defined; titers and neutralizing activity assessed if ADA positive."}

Methods

• Physician referral letters (K2_Physician Referral Letter) — channel: letter/email from referring physician to investigator/clinic; target audience: treating physicians and potential referring clinicians; country-specific versions present in multiple countries.
• Dr-to-Patient letters (K2_Dr-to-Patient Letter) — channel: letter from treating physician to potential participants; target audience: patients; available as country/language-specific versions (e.g., EN, DE, FR, NL, PL, ES).
• Patient brochures and flyers (K2_Patient Brochure, K2_Patient Flyer) — channel: printed or digital patient-facing materials distributed at sites; target audience: potential participants; available in multiple language versions per country.
• Site posters (K2_Site Poster) — channel: on-site posters at participating centres to inform patients and site visitors; target audience: patients attending clinics; country/language-specific materials available.
• Site-facing materials (Site Study Information Slides, Investigator Welcome Letter, Chart Review Checklist, Eligibility Criteria Booklet/Cards) — channel: materials provided to site staff to aid identification and pre-screening of eligible patients; target audience: site investigators, clinical staff.
• Patient study guides, patient ID cards and emergency/ILD cards (L2 materials) — channel: on-site distribution to enrolled participants; target audience: participants (for retention and safety information).
• Sub-study email templates and telephone scripts — channel: electronic outreach (email) and telephone outreach for sub-study recruitment; target audience: potential participants identified for sub-studies.

Italy

Earliest CTIS Part Ii Submission Date

14-11-2024

Latest Decision Or Authorization Date

03-11-2025

Processing Time Days

354

Number Of Sites

6

Number Of Participants

35

France

Earliest CTIS Part Ii Submission Date

18-11-2024

Latest Decision Or Authorization Date

03-11-2025

Processing Time Days

350

Number Of Sites

12

Number Of Participants

40

Poland

Earliest CTIS Part Ii Submission Date

18-11-2024

Latest Decision Or Authorization Date

04-11-2025

Processing Time Days

351

Number Of Sites

5

Number Of Participants

30

Germany

Earliest CTIS Part Ii Submission Date

14-11-2024

Latest Decision Or Authorization Date

05-11-2025

Processing Time Days

356

Number Of Sites

8

Number Of Participants

25

Spain

Earliest CTIS Part Ii Submission Date

13-11-2024

Latest Decision Or Authorization Date

14-11-2025

Processing Time Days

366

Number Of Sites

8

Number Of Participants

50

Belgium

Earliest CTIS Part Ii Submission Date

13-11-2024

Latest Decision Or Authorization Date

31-10-2025

Processing Time Days

352

Number Of Sites

6

Number Of Participants

26

Ireland

Earliest CTIS Part Ii Submission Date

12-11-2024

Latest Decision Or Authorization Date

31-10-2025

Processing Time Days

353

Number Of Sites

5

Number Of Participants

10

Portugal

Earliest CTIS Part Ii Submission Date

15-11-2024

Latest Decision Or Authorization Date

03-11-2025

Processing Time Days

353

Number Of Sites

5

Number Of Participants

30

Netherlands

Earliest CTIS Part Ii Submission Date

15-11-2024

Latest Decision Or Authorization Date

03-11-2025

Processing Time Days

353

Number Of Sites

5

Number Of Participants

20

Primary sponsor

Full Name

Daiichi Sankyo Inc.

Organisation Type

Pharmaceutical company

Country Of Registered Address

United States

Contract research organisations

Name

IQVIA Limited

Responsibilities

multiple site and study services (codes listed in sponsor data: 1,10,11,12,13,2,5,9)

Name

PPD Development LP

Responsibilities

PK/ADA Analysis

Name

Almac Clinical Services Limited

Responsibilities

Import, Storage, & Investigational Product (IP) Shipment

Name

Suvoda LLC

Responsibilities

eClinical / study systems (code: 3)

Name

Medidata Solutions Inc.

Responsibilities

Electronic data capture / study platform (code: 7)

Name

WCG Clinical Inc.

Responsibilities

Regulatory/ethics submission support (code: 8)

Third parties

• {"country":"United States","full_name":"Fisher Bioservices Inc.","duties_or_roles":"Long term storage of samples","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Eresearchtechnology Inc.","duties_or_roles":"Central Imaging, ILD Adjudication","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Ventana Medical Systems Inc.","duties_or_roles":"Archival Tumor Tissue Sample; Fresh Tumor Biopsy Sample","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"PPD Development LP","duties_or_roles":"PK/ADA Analysis","organisation_type":"Pharmaceutical company"}
• {"country":"United Kingdom","full_name":"IQVIA Limited","duties_or_roles":"codes: 1,10,11,12,13,2,5,9","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Mosaic Laboratories LLC","duties_or_roles":"Archival Tumor Tissue Sample, Fresh Tumor Biopsy Sample","organisation_type":"Pharmaceutical company"}
• {"country":"Japan","full_name":"Daiichi Sankyo Co. Ltd.","duties_or_roles":"Archival Tumor Tissue Samples, Fresh Tumor Biopsy Sample","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Suvoda LLC","duties_or_roles":"code: 3","organisation_type":"Non-Pharmaceutical company"}
• {"country":"United Kingdom (Northern Ireland)","full_name":"Almac Clinical Services Limited","duties_or_roles":"Import, Storage, & Investigational Product (IP) Shipment","organisation_type":"Pharmaceutical company"}
• {"country":"United Kingdom","full_name":"Q Squared Solutions Limited","duties_or_roles":"code: 4","organisation_type":"Non-Pharmaceutical company"}
• {"country":"United States","full_name":"WCG Clinical Inc.","duties_or_roles":"code: 8","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Medidata Solutions Inc.","duties_or_roles":"code: 7","organisation_type":"Non-Pharmaceutical company"}
• {"country":"United States","full_name":"Fisher Bioservices Inc. (address contact)","duties_or_roles":"Long term storage of samples (contact: brandi.adams@thermofisher.com)","organisation_type":"Pharmaceutical company"}