A Multicenter Study Evaluating the Safety, Efficacy, and Pharmacokinetics of IDE849 in Patients With DLL3-Expressing Tumors Including Small Cell Lung Cancer

Study Identifier:
IDE849-001
CT.gov Identifier:
NCT07174583
EudraCT Identifier:
202552343824
EU Trial (CTIS) Number:
2025-523438-24-00
Study Contact Information:
(210) 593-5651 or [email protected]
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Study Summary

This is Phase 1/2, multicenter, clinical study to evaluate the safety, efficacy, PK, and immunogenicity of IDE849 in subjects with DLL3-expressing tumors including SCLC.

To evaluate 3.5 mg/kg IV dose once every 3-weeks (Q3W). Next, to determine the recommended Phase 2 dose (RP2D)

The primary objective of Part 1 aims to test increasing doses of IDE849 (alone or with other drugs) to find the highest dose that is safe and well tolerated. The primary objective of Part 2 aims to further study the safety and anti-tumor activity of IDE849, alone or in combination, at or below the safe doses found in Part 1. Primary safety endpoints of Parts 1 & 2 include monitoring the number and severity of side effects and serious side effects and whether any dose-limiting toxicities (DLTs) occur — these are side effects that prevent further dose increases.

Medical Condition
The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.
Melanoma
Small Cell Lung
Neuroendocrine
Phase
The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
Phase I/II
Sex
Female & Male
Age
18+ years
Study Drug
N/A
Study Status
Indicates the current recruitment status or the expanded access status
Recruiting

Requirements information
Inclusion criteria
  • Are willing to participate in this clinical study, understand the study procedures, and are able to sign the written ICF.Subjects with histologically or cytologically confirmed ES- SCLC, neuroendocrine carcinoma (NEC), DLL3+ solid tumors, are eligible per protocol. Subjects must have radiologically progressed or recurred after previous standard treatment.For SCLC, this includes platinum-based therapy and programmed death-1/programmed death-ligand 1 inhibitors (except for subjects who refuse, or are judged by the Investigator to be unsuitable, or were intolerant to immunotherapy and chemotherapy may enroll to receive monotherapy or IDE161 combination.Subjects with NEC, this includesHigh-grade gastroenteropancreatic NECNEC of the prostateSmall cell NEC of any other organMerkel cell carcinomaTransformed non-small cell adenocarcinoma of the lung (including but not limited to epidermal growth factor receptor or Kirsten rat sarcoma viral oncogene homolog mutated adenocarcinoma of the lung post progression on targeted therapiesAny other NEC that does not meet any of the indications noted above.Subjects with other solid tumors demonstrated to express moderate/high expression of DLL3 including metastatic melanoma, Grade 3 gastrointestinal and pancreatic NETs, and pulmonary carcinoids.• metastatic melanomaSubjects will be required to provide blood/tumor tissue samples for biomarker testing.Have at least 1 measurable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.Have Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) score of 0 or 1.Have life expectancy > 3 months.Have adequate bone marrow and organ function within 7 days of the first dose (no use of any blood components and/or cell growth factors within 14 days prior to the start of the study treatment).Women of childbearing potential (WOCBP) must agree to take highly effective contraceptive measures from signing of consent through 8 months after the last dose of IDE849; men with partners of child-bearing potential must use effective contraception through 5 months after the last dose.
  • as per ctis:
  • Are willing to participate in this clinical study, understand the study procedures, and are able to sign the written ICF.
  • Are ≥ 18 years of age, male or female.
  • 3a. Have one of the following tumor types based on study Part or Arm: a. Part 1A Monotherapy Dose Escalation, Part 1B Arm 1 (IDE849 in combination with durvalumab) and Part 1B Arm 2 (IDE849 in combination with IDE161): Participants with histologically or cytologically confirmed extensive stage SCLC who have progressed or recurred after standard treatment, including platinum-based therapy and PD-1/PD-L1 inhibitors. No more than 3 total lines of systemic therapy for extensive stage disease. EXCEPTIONS: Participants who refuse or are judged by the Investigator to be unsuitable for immunotherapy and chemotherapy may enroll. Participants who were intolerant to platinum-based therapy and PD1/PD-L1 inhibitors may enroll; OR Participants with histologically or cytologically confirmed NEC who have progressed or recurred after standard treatment given in the locally advanced or metastatic setting, that includes the following: • High-grade gastroenteropancreatic neuroendocrine carcinoma • NEC of the prostate, de novo or transformed (eg, castrate resistant prostate cancer that has progressed on an androgen receptor pathway inhibitor/hormonal therapy) • Large cell neuroendocrine carcinoma of the lung • Small cell neuroendocrine carcinoma of “any other organ” • Merkel cell carcinoma • Transformed non-small cell adenocarcinoma of the lung (including but not limited to EGFR or KRAS mutated adenocarcinoma of the lung post progression on targeted therapies for these alterations by local testing) • Other NEC with moderate to high (2+ or greater by IHC) DLL3 expression by local testing (other detection or scoring methods may be submitted for eligibility with Medical Monitor discussion and approval) OR Participants with histologically or cytologically confirmed solid tumors (such as metastatic melanoma) shown to express moderate or high (2+ or greater by IHC) DLL3 expression by local testing who have progressed or recurred after standard treatment given in the locally advanced or metastatic setting (other detection or scoring methods may be submitted for eligibility with Medical Monitor discussion and approval). b. Part 2 Arm 3 and 4 Monotherapy Dose Expansion Participants with histologically or cytologically confirmed extensive stage SCLC who have progressed or recurred after standard treatment, including platinum-based therapy and PD-1/PD-L1 inhibitors. No more than 3 total lines of systemic therapy for extensive stage disease. EXCEPTIONS: Participants who refuse or are judged by the Investigator to be unsuitable for immunotherapy and chemotherapy may enroll.
  • 3b. Participants who were intolerant to platinum-based therapy and PD1/PD-L1 inhibitors may enroll c. Part 2 Arm 5 Monotherapy Dose Expansion in participants with NEC or DLL3-expressing solid tumors Participants with histologically or cytologically confirmed NEC who have progressed or recurred after standard treatment given in the locally advanced or metastatic setting, that includes the following: • High-grade gastroenteropancreatic neuroendocrine carcinoma • Neuroendocrine carcinoma of the prostate, de novo or transformed (eg, castrate resistant prostate cancer that has progressed on an androgen receptor pathway inhibitor/hormonal therapy) • Large cell neuroendocrine carcinoma of the lung • Small cell neuroendocrine carcinoma of any other organ • Merkel cell carcinoma • Transformed non-small cell adenocarcinoma of the lung (including but not limited to EGFR or KRAS mutated adenocarcinoma of the lung post progression on targeted therapies for these alterations) • Other NEC with moderate to high DLL3 expression by local testing; OR Participants with histologically or cytologically confirmed solid tumors shown to express moderate or high (2+ or greater by IHC) DLL3 expression by local testing who have progressed or recurred after standard treatment given in the locally advanced or metastatic setting (other detection or scoring methods may be submitted for eligibility with Medical Monitor discussion and approval). d. Part 2 Arm 6 (IDE849 in combination with durvalumab) and Arm 7 (IDE849 in combination with IDE161) Dose Expansion Participants with histologically or cytologically confirmed extensive stage SCLC who have radiologically progressed or recurred after standard treatment, including platinum based therapy and PD-1/PD-L1 inhibitors. No more than 3 total lines of systemic therapy for extensive stage disease. EXCEPTIONS: Participants who refuse or are judged by the Investigator to be unsuitable for immunotherapy and chemotherapy may enroll. Participants who were intolerant to platinum-based therapy and PD1/PD-L1 inhibitors may enroll
  • Participants will be required to provide tumor tissue samples for biomarker testing. Tumor tissue samples are required to be neutral formalin-fixed, paraffin-embedded tissue blocks or at least 20 unstained tumor tissue slices, fresh or archived, with fresh samples preferred. For participants who are unable to provide the above tumor tissue samples, the Investigator should discuss with the Sponsor to determine whether they can be enrolled
  • Have at least 1 measurable lesion according to RECIST version 1.1
  • Have ECOG PS score of 0 or 1
  • Have life expectancy > 3 months
  • Have adequate bone marrow and organ function (no use of any blood components and/or cell growth factors within 14 days prior to the start of study treatment) as follows: • Absolute neutrophil count ≥ 1.5 × 109/L (1500/mm3) • Platelets ≥ 100 × 109/L (100,000/mm3) • Hemoglobin ≥ 9.0 g/dL (90 g/L) • Albumin ≥ 3.0 g/dL (30 g/L) • ALT and AST ≤ 3 × ULN (ALT and/or AST ≤ 5 × ULN for participants with liver metastases) • Total bilirubin ≤ 1.5 × ULN (total bilirubin ≤ 3 × ULN for participants diagnosed with Gilbert’s syndrome) • Estimated creatinine clearance ≥ 60 mL/minute (calculated based on the Cockcroft-Gault formula). Participants with creatinine clearance of 50 to 60 mL/minute may be considered for eligibility with Medical Monitor discussion and approval. • International normalized ratio and activated partial thromboplastin time ≤ 1.5 × ULN; participants on stable doses of anticoagulants with coagulation tests within therapeutic range are allowed to enroll
  • Women of childbearing potential (WOCBP) must agree to take highly effective contraceptive measures (eg, with a failure rate of < 1% per year), preferably with low user dependency and avoid egg donation from the signing of the ICF to 8 months after the last dose of IDE849 (monotherapy or in any combination arm), have a negative serum pregnancy test within 24 hours before first study dose, and be nonlactating. Male participants whose partners are WOCBP must agree to take highly effective contraceptive measures (eg, abstinent from heterosexual intercourse on a long-term and persistent basis) and avoid sperm donation from the signing of the ICF to 5 months after the last dose of IDE849 (monotherapy or in any combination arm).
Exclusion criteria
  • Have mixed SCLC and NSCLC histology are not allowed (SCLC with components of large cell NEC are eligible). Participants with limited stage SCLC are ineligible.Subjects with locally untreated (radiotherapy or surgery) or active central nervous system (CNS) tumor metastasis.Have had other malignancies within 2 years prior to the first dose, except adequately treated carcinoma in situ (cervical, breast, or other), basal cell or squamous cell skin cancer, localized prostate cancer after curative therapy with no recurrence, or papillary thyroid cancer after curative resection; other prior or concurrent malignancies may be eligible with Medical Monitor review and approval.Have uncontrolled tumor-associated pain.Have severe cardiovascular and cerebrovascular diseaseHave history of clinically significant bleeding within 3 months before the first study dose.Have history of interstitial pneumonitis during previous treatment; current noninfectious pneumonitis requiring steroid therapy; known or suspected interstitial pneumonitis as seen on screening imaging; other moderate to severe lung diseases seriously affecting respiratory function within 3 months before the first dose, including, but not limited to, idiopathic pulmonary fibrosis and organizing pneumonia/obliterative bronchiolitis.Have history of immunodeficiency, with a positive human immunodeficiency virus (HIV) test at screening (HIV antibody positive and HIV-RNA above the lower limit of detection of the analytical method).Subjects with known or suspected viral hepatitis.Have a history of active tuberculosis within 1 year before enrollment.For participants enrolling to receive the combination with durvalumab, must not be deemed by the Investigator to be unsuitable to receive immunotherapy, or have had any prior intolerance to PD-1/PD-L1 inhibitor therapy, or have had any prior Grade 2 or higher myocarditis or any other Grade 3 or higher immune-related AE. If the participant has had a prior immune-related AE, must have recovered to Grade < 1.For participants enrolling to receive the combination with IDE161, must not have had prior GI or upper bowel removal or any other gastrointestinal disorder or defect (eg, malabsorption disorder such as Crohn's disease or ulcerative colitis), that would interfere with absorption of IDE161.For patients receiving a combination with carboplatin, be deemed by the Investigator to be unsuitable to receive platinum-based chemotherapy, or have had intolerance to platinum-based chemotherapyHave received chemotherapy within 3 weeks of first dose of IMP; immunotherapy or biologic targeted antitumor treatments within 2 weeks before the first dose of IMP; for small molecule treatments within 2 weeks before the first dose of the IMP or within 5 half lives of the drug (whichever is longer); other investigational products within 4 weeks or within 5 half-lives of the drug (whichever is longer) unless, in the opinion of the Investigator and Sponsor, the medication will not interfere with the study. Participants who received an immunotherapy agent (eg, PD-1/PD-L1 inhibitor) immediately prior to study enrollment must have documented radiologic disease progression as per the Investigator prior to the first dose of IMPAdministration of any of the following:Use of drugs that are inhibitors of P-gp, BCRP, and OATPIB1/OATP1B3Use of drugs with known risk of QT prolongation within 5 half-lives of their administration.For participants enrolling to receive the combination with IDE161:Use of drugs of narrow therapeutic index that are sensitive substrates of MATE2-K, BCRP, and P-gpUse of known moderate and strong CYP3A4/5 inducers and inhibitors is not permittedAdministration of PPIsUse of an H2 blocking agentUse of a local antacidUse of drugs with a known risk of QT prolongationHave prior treatment with DLL3 ADC with a Topo1 inhibitor payload (except for participants enrolling to receive the IDE161 combination).For participants enrolling to receive the combination with durvalumab, have history of prior intolerance to PD-1/PD-L1 inhibitors.Have received > 30 Gy of chest radiotherapy within 8 weeks prior to the first dose of the IMP, > 30 Gy of non-chest radiotherapy within 14 days prior to the first dose (subjects who have completed radiotherapy for brain metastases within 14 days prior to the first dose can be enrolled and palliative radiotherapy for other sites of ≤ 30 Gy is allowed if completed more than 14 days prior to the first dose).Have undergone major surgery or experienced significant trauma within 4 weeks prior to the first dose.Female subjects who are pregnant, lactating, or planning to become pregnant during the study period to 8 months after the last dose of the IMP.
  • As per ctis:
  • For participants with diagnosis of mixed SCLC and non-small cell lung cancer histology are not allowed (SCLC with components of large cell neuroendocrine carcinoma are eligible). Participants with LS SCLC are ineligible.
  • Participants with locally untreated (radiotherapy or surgery) or active CNS tumor metastasis. Participant with small asymptomatic CNS metastasis who do not require immediate local treatment (eg, without associated mass effect or vasogenic edema and not requiring steroids or anticonvulsant therapy) may be considered for enrollment after discussion with the Sponsor. Participants with a history of, or current leptomeningeal metastasis will be excluded. • Participants with treated CNS metastasis can be enrolled if the CNS tumor has received adequate local treatment (surgery or radiotherapy); no progression is observed from the end of local treatment to the imaging examination during the screening period; neurological symptoms are stable for at least 2 weeks before the first dose; and no glucocorticoid therapy or ≤ 10 mg/day prednisone (or equivalent) is needed.
  • Have had other malignancies within 2 years prior to the first dose, with the exception of adequately treated cervical carcinoma in situ, basal cell or squamous epithelial cell skin cancer, localized prostate cancer after prostatectomy or definitive radiation therapy with no evidence of recurrence including no biochemical recurrence, ductal or lobular carcinoma in situ of the breast after curative resection, and papillary thyroid cancer after curative resection; adequately treated carcinoma in situ of other types will also be eligible; other prior or concurrent malignancies may be eligible with Medical Monitor discussion and approval
  • Have uncontrolled tumor-associated pain as assessed by the Investigator. Those who require analgesics must have a stable analgesic treatment regimen at study entry; symptomatic lesions amenable to palliative radiotherapy should be treated prior to study entry.
  • Have severe cardiovascular and cerebrovascular disease, including, but not limited to the following: • Uncontrolled hypertension with SBP >150 mmHg or DPB > 100. • Severe cardiac rhythm or conduction abnormalities within 6 months before the first dose of the IMP, such as ventricular arrhythmia and first to second degree atrioventricular block requiring clinical intervention. Participants with cardiac rhythm device/pacemaker must be discussed with the Medical Monitor to judge eligibility. • Acute coronary syndrome, congestive heart failure (New York Heart Association cardiac function class ≥ 2), or aortic dissection within 6 months before the first dose of the IMP. • Venous thrombosis events within 6 months before the first dose of the IMP, such as cerebrovascular accidents (including transient ischemic attacks, cerebral hemorrhage, and cerebral stroke), and pulmonary embolism with hemodynamic consequences. Participants with a history of deep vein thrombosis who are on stable doses of anticoagulants, those with indwelling catheter related thrombosis or tumor related superior vena cava syndrome that is not currently active will be allowed to enroll. • Left ventricular ejection fraction < 50% within 28 days before the first dose of the IMP. Participants with a left ventricular ejection fraction between 45% and 50% with no symptoms of heart failure and on adequate treatment for left ventricular dysfunction, if needed, may be enrolled after discussion with the Medical Monitor. Mean corrected QT interval using Fridericia’s formula > 470 milliseconds on screening triplicate 12-lead electrocardiogram (ECG) at rest.
  • Have history of clinically significant bleeding within 3 months before the first study dose, with obvious hemoptysis of ≥ 2.5 mL of blood each time within 1 month before the first study dose
  • Have presence of uncontrolled pleural, peritoneal, or pericardial effusion within 2 weeks before the first study dose, requiring recurrent drainage procedures or an indwelling drainage catheter
  • Have history of interstitial pneumonitis during previous treatment; current noninfectious pneumonitis requiring steroid therapy; known or suspected interstitial pneumonitis as seen on screening imaging; other moderate to severe lung diseases seriously affecting respiratory function within 3 months before the first dose, including, but not limited to, idiopathic pulmonary fibrosis and organizing pneumonia/obliterative bronchiolitis
  • Have history of severe infections within 4 weeks prior to the start of study treatment, including but not limited to bacteremia, severe pneumonia, or other serious infectious complications requiring hospitalization; CTCAE Grade ≥ 2 active infections requiring systemic antibiotics within 2 weeks before the first dose
  • Have history of immunodeficiency, with a positive HIV test at screening (HIV antibody positive and HIV-RNA above the lower limit of detection of the analytical method). Human immunodeficiency virus seropositive participants without detectable HIV-RNA and cluster of differentiation 4 (CD4) counts ≥ 200/μL who are stable on an antiviral regimen may be enrolled after discussion with the Medical Monitor based on current and past CD4 and T cell counts, history (if any) of acquired immunodeficiency syndrome defining conditions (eg, opportunistic infections), and status of HIV treatment. Also, the potential for drug-drug interactions will be considered
  • Participants with known or suspected viral hepatitis with positive test at screening for active hepatitis B (hepatitis B surface antigen-positive and/or hepatitis B core antibody (HbcAb) positive with hepatitis B virus-DNA higher than the ULN of the study site; if the study site does not have the ULN, quantitative hepatitis B virus-DNA must be less than 1000 copies/mL or 500 IU/mL) or active hepatitis C (anti-hepatitis C virus positive and hepatitis C virus-RNA higher than the lower limit of detection of the analytical method). Participants with negative hepatitis B surface antigen and positive HbcAb or positive hepatitis B surface antibody and HbcAb who are immune due to natural infection or vaccination will be permitted to enroll
  • Have history of active tuberculosis within 1 year before enrollment per medical history or on imaging examination or history of active tuberculosis over 1 year without appropriate treatment
  • Had adverse reactions to previous anti-tumor treatment that have not recovered to CTCAE Grade ≤ 1 (except for alopecia and other conditions meeting the requirements in the inclusion criteria or not affecting the study treatment as judged by the Investigator)
  • For participants enrolling to receive the combination with durvalumab, must not have had any prior Grade 2 or higher myocarditis or any other Grade 3 or higher immune-related AE. If the participant has had a prior immune-related AE, must have recovered to < Grade 1
  • For participants enrolling to receive the combination with IDE161, must not have had prior gastrectomy or upper bowel removal or any other gastrointestinal disorder or defect eg, malabsorption disorder such as Crohn’s disease or ulcerative colitis, that would interfere with absorption of IDE161
  • Have received chemotherapy within 3 weeks of first dose of IMP; immunotherapy or biologic targeted anti-tumor treatments within 2 weeks before the first dose of IMP; for small molecule treatments within 2 weeks before the first dose of the IMP or within 5 half-lives of the drug (whichever is longer); other investigational products within 4 weeks or within 5 half-lives of the drug (whichever is longer). Participants who received an immunotherapy agent (eg, PD-1/PD-L1 inhibitor) immediately prior to study enrollment must have documented radiologic disease progression as per the Investigator prior to first dose of IMP
  • Administration of any of the following within 2 weeks before the first dose of IDE849 or within 5 half-lives of the drug (whichever is longer), unless, in the opinion of the Investigator and Sponsor, the medication will not interfere with the study • Strong inhibitors or inducers of CYP3A4 • Strong inhibitors of CYP2D6 • Strong inhibitors of P-gp and BCRP • Use of drugs with a known risk of QT prolongation within 5 half-lives of their administration
  • For participants enrolling to receive the combination with IDE161: • Use of drugs of narrow therapeutic index that are sensitive substrates of MATE2-K, BCRP, and P-gp within 2 weeks or within 5 half-lives of the drug (whichever is longer) prior to the first dose of the IDE161 • Use of known moderate and strong CYP3A4/5 inducers and inhibitors is not permitted within 2 weeks or 5 half-lives of the CYP3A4/5 inducers(whichever is longer) prior to the first dose of IDE161 • Administration of PPIs (eg, omeprazole, esomeprazole, lansoprazole, pantoprazole, rabeprazole, or dexlansoprazole) within 7 days prior to and during IDE161 dosing • Use of an H2 blocking agent within 10 to 12 hours before the first dose of IDE161 • Use of a local antacid within 2 hours of the first dose of IDE161 • Use of drugs with a known risk of QT prolongation within 5 half-lives of their administration
  • Have prior treatment with DLL3 ADC with topoisomerase I inhibitor payload or prior treatment with a topoisomerase I inhibitor 20. For participants enrolling to receive the combination with durvalumab, have history of prior intolerance to PD-1/PD-L1 inhibitors
  • For participants enrolling to receive the combination with durvalumab, have history of prior intolerance to PD-1/PD-L1 inhibitors
  • Have received > 30 Gy of chest radiotherapy within 12 weeks prior to the first dose of the IMP, > 30 Gy of non-chest radiotherapy within 4 weeks prior to the first dose (participants who have completed radiotherapy for brain metastases within 14 days prior to the first dose can be enrolled and palliative radiotherapy for other sites of ≤ 30 Gy is allowed if completed more than 14 days prior to the first dose)
  • Have undergone major surgery or experienced significant trauma within 4 weeks prior to the first dose or need to undergo elective surgery during the study. Aspirations and core biopsies are allowed
  • Have received live attenuated vaccine within 28 days prior to the first dose or are expected to receive live attenuated vaccine during the study treatment
  • Female participants who are pregnant, lactating, or planning to become pregnant
  • Are known to be allergic to any component or excipient of the IMP or have a history of severe allergic reactions to other monoclonal antibody/fusion protein drugs
  • Participants with other factors, as determined by the Investigator which may affect the study results or result in study termination, such as alcohol abuse, drug abuse, other serious medical conditions (including mental illnesses) requiring concomitant treatment, serious laboratory abnormalities, family or social factors, and other conditions that may affect participants’ safety or collection of study data

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Study Locations

Location
Investigator
Status
Condition(s) Treated at Site
Location
START Midwest
Grand Rapids, MI, United States, 49546
Investigator
Sreenivasa Chandana
Status
Recruiting
Condition(s) Treated at Site
Melanoma
Small Cell Lung
Neuroendocrine