IRB Study Number 25-531
Status Recruiting
Phase Phase 1
Location Cleveland Clinic Main Campus
Institute Taussig Cancer Institute
Description
Primary Objectives:
• To assess the safety and tolerability of YL217 in patients with advanced solid tumors
• To determine the maximum tolerated dose (MTD) of YL217 in patients with advanced solid tumors
• To further evaluate the safety and tolerability of YL217 in patients with advanced solid tumors
• To determine the recommended dose(s) for expansion (RDE(s)) of YL217 in patients with advanced solid tumors
• To further evaluate the efficacy of YL217 at the RDE(s) in patients with the selected advanced solid tumors such as colorectal adenocarcinoma, gastric, esophageal or gastroesophageal junction adenocarcinoma, and pancreatic adenocarcinoma
• To determine the recommended phase 2 dose (RP2D) of YL217
Secondary Objectives:
• To characterize the pharmacokinetics (PK) of YL217 antibody-drug conjugate (YL217-ADC), YL217 total antibody (YL217-TAb), and unconjugated payload YL0010014, metabolite YL0010034 and, if applicable, other potential metabolite(s)
• To evaluate immunogenicity as measured by the presence of anti-drug antibodies (ADAs) in patients treated with YL217
• To document any preliminary efficacy of YL217 in patients with advanced solid tumors
• To further evaluate the efficacy of YL217 in patients with advanced solid tumors
• To characterize the PK of YL217-ADC, YL217-TAb, unconjugated payload YL0010014, metabolite YL0010034 and, if applicable, other potential metabolite(s)
• To evaluate immunogenicity as measured by the presence of ADAs in patients treated with YL217
• To further evaluate the safety and tolerability of YL217 at the RDE(s) in patients with the selected advanced solid tumors
• To characterize the PK of YL217-ADC, YL217-TAb, unconjugated payload YL0010014, metabolite YL0010034 and, if applicable, other potential metabolite(s)
• To evaluate immunogenicity as measured by the presence of ADAs in patients treated with YL217
Inclusion Criteria
1) Informed of the study before the start of the study and voluntarily sign their name and date in the informed consent form (ICF)
2) Able and willing to comply with protocol visits and procedures
3) Aged ≥ 18 years
4) Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1
5) Tumor types as below:
For Part 1 and Part 2
Pathologically confirmed diagnosis of an advanced solid tumor, including adenocarcinoma and neuroendocrine neoplasm in GI, esophagus, gastroesophageal junction, pancreas or ampulla, and other solid tumors agreed upon after discussion with the sponsor, for which prior standard treatment had proven to be ineffective or intolerable or no standard treatment is available
For Part 3
For patients with colorectal adenocarcinoma (Cohort A):
Histologically or cytologically confirmed diagnosis of colorectal adenocarcinoma
Have locally advanced unresectable or metastatic disease at study entry
Have clear documentation of RAS, BRAF, and microsatellite instability/mismatch repair status
Have documentation of disease progression on or after, or are intolerant to the most recent treatment regimen. Participants must have received at least one line of prior cytotoxic chemotherapeutic regimen for locally advanced or metastatic disease. The following therapies must be also included in prior lines of therapy if applicable:
‒ anti-EGFR antibody (including, but not limited to cetuximab or panitumumab) in patients with RAS wild type
‒ anti-vascular endothelial growth factor (VEGF) monoclonal antibody (including but not limited to bevacizumab, ramucirumab, or aflibercept)
‒ targeted therapy and immune checkpoint inhibitor
For patients with HER2-negative gastric, esophageal or gastroesophageal junction adenocarcinoma (Cohort B):
Histologically or cytologically confirmed diagnosis of HER2-negative gastric, esophageal or gastroesophageal junction adenocarcinoma
Have locally advanced recurrent or metastatic disease at study entry
Have documentation of disease progression on or after, or are intolerant to the most recent treatment regimen. Participants must have received at least one line of prior cytotoxic chemotherapeutic regimen for locally advanced or metastatic disease. The following therapies must be also included in prior lines of therapy if applicable:
‒ an immune checkpoint inhibitor
For patients with pancreatic adenocarcinoma (Cohort C):
Histologically or cytologically confirmed diagnosis of pancreatic adenocarcinoma (including pancreatic acinar cell adenocarcinoma and pancreatic ductal cell adenocarcinoma)
Have locally advanced or metastatic disease at study entry
Have documentation of disease progression on or after, or are intolerant to the most recent treatment regimen. Participants must have received at least one line of prior cytotoxic chemotherapeutic regimen for locally advanced or metastatic disease. The following therapies must be also included in prior lines of therapy if applicable:
‒ an immune checkpoint inhibitor
‒ a poly (ADP-ribose) polymerase (PARP) inhibitor
For patients with other advanced solid tumors (Cohort D):
Histologically or cytologically confirmed diagnosis of advanced solid tumors agreed upon after discussion with the sponsor, for which prior standard treatment had proven to be ineffective or intolerable or no standard treatment is available
Note: For all cohorts, if participants received a cytotoxic chemotherapeutic regimen as neoadjuvant or adjuvant therapy for early-stage disease and have relapsed or progressed while on the treatment or within 6 months of the last dose, this regimen could be considered as one line of therapy for locally advanced or metastatic disease.
6) Adequate organ and bone marrow function, defined as:
Hemoglobin ≥ 90 g/L (have not received blood transfusion or erythropoietin treatment within 14 days before the first dose of study drug)
Absolute neutrophil count ≥ 1.5 × 109/L (have not received granulocyte colony-stimulating factor or granulocyte-macrophage colony-stimulating factor treatment within 14 days before the first dose of study drug)
Platelet count ≥ 100 × 109/L (have not received platelet transfusion, thrombopoietin, or
For patients with HER2-negative gastric, esophageal or gastroesophageal junction adenocarcinoma (Cohort B):
Histologically or cytologically confirmed diagnosis of HER2-negative gastric, esophageal or gastroesophageal junction adenocarcinoma
Have locally advanced recurrent or metastatic disease at study entry
Have documentation of disease progression on or after, or are intolerant to the most recent treatment regimen. Participants must have received at least one line of prior cytotoxic chemotherapeutic regimen for locally advanced or metastatic disease. The following therapies must be also included in prior lines of therapy if applicable:
‒ an immune checkpoint inhibitor
For patients with pancreatic adenocarcinoma (Cohort C):
Histologically or cytologically confirmed diagnosis of pancreatic adenocarcinoma (including pancreatic acinar cell adenocarcinoma and pancreatic ductal cell adenocarcinoma)
Have locally advanced or metastatic disease at study entry
Have documentation of disease progression on or after, or are intolerant to the most recent treatment regimen. Participants must have received at least one line of prior cytotoxic chemotherapeutic regimen for locally advanced or metastatic disease. The following therapies must be also included in prior lines of therapy if applicable:
‒ an immune checkpoint inhibitor
‒ a poly (ADP-ribose) polymerase (PARP) inhibitor
For patients with other advanced solid tumors (Cohort D):
Histologically or cytologically confirmed diagnosis of advanced solid tumors agreed upon after discussion with the sponsor, for which prior standard treatment had proven to be ineffective or intolerable or no standard treatment is available
Note: For all cohorts, if participants received a cytotoxic chemotherapeutic regimen as neoadjuvant or adjuvant therapy for early-stage disease and have relapsed or progressed while on the treatment or within 6 months of the last dose, this regimen could be considered as one line of therapy for locally advanced or metastatic disease.
6) Adequate organ and bone marrow function, defined as:
Hemoglobin ≥ 90 g/L (have not received blood transfusion or erythropoietin treatment within 14 days before the first dose of study drug)
Absolute neutrophil count ≥ 1.5 × 109/L (have not received granulocyte colony-stimulating factor or granulocyte-macrophage colony-stimulating factor treatment within 14 days before the first dose of study drug)
Platelet count ≥ 100 × 109/L (have not received platelet transfusion, thrombopoietin, or interleukin
-11 treatment within 14 days before the first dose of study drug)
Total bilirubin ≤ 1.5 × ULN if no demonstrable liver lesion(s) (primary or metastases) or ≤ 3 × ULN in the presence of liver lesion(s)
ALT and AST ≤ 3 × ULN if no demonstrable liver lesion(s) (primary or metastases) or ≤ 5 × ULN in the presence of liver lesion(s)
Creatinine clearance ≥ 60 mL/min (calculated according to Cockcroft Gault formula)
Activated partial thromboplastin time and international normalized ratio ≤ 1.5 × ULN for patients not receiving therapeutic anticoagulation, or have stable anticoagulant regimen for patients receiving therapeutic anticoagulation
7) Have at least 1 extracranial measurable tumor lesion according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1
8) Adequate archival FFPE tissue from prior biopsy (collected within 2 years or after completion of the last anticancer therapy) for biomarker evaluation or willingness to undergo tissue biopsy before study treatment starts. Patients who are not able to provide tumor samples or have inadequate or expired samples may be eligible on a case-by-case basis after discussion with the sponsor
9) Female patients of childbearing potential must agree to use a highly effective form of contraception and not donate, or retrieve for their own use, ova from the time of screening and throughout the study period, and for at least 6 months after the last dose of study drug. Male patients must agree to use a highly effective form of contraception and not freeze or donate sperm from the time of screening and throughout the study period, and for at least 6 months after the last dose of study drug
Exclusion Criteria
1) Prior treatment with an agent targeting CDH17 (including but not limited to antibody, ADC, chimeric antigen receptor T/NK cell [CAR-T/CAR-NK])
2) Prior discontinuation of a topoisomerase I inhibitor due to treatment-related toxicities (e.g., severe hematological toxicities or diarrhea)
3) Have received a topoisomerase I inhibitor within 6 months before the first dose of study drug
4) Have received an ADC consisting of a topoisomerase I inhibitor
5) Concurrent enrollment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study
6) Inadequate washout period for prior anticancer treatment before the first dose of study drug, defined as follows:
Any cytotoxic chemotherapy or small molecular-targeted therapy < 2 weeks or 5 half-lives, whichever is shorter
Endocrine therapy < 3 weeks
Monoclonal antibodies or other biological therapy < 3 weeks
Herbal medicine with antitumor indications or nonspecific immunomodulators (e.g., thymosin, interferon, and interleukin) < 2 weeks
Whole brain radiation therapy < 2 weeks or stereotactic brain radiation therapy < 1 week
Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation < 4 weeks or palliative radiation therapy < 2 weeks
7) Undergone major surgery (not including diagnostic surgery) within 4 weeks before the first dose of study drug or expect major surgery during the study
8) Undergone allogeneic hematopoietic stem cell transplantation (HSCT) or solid-organ transplantation before the first dose of study drug, or autologous HSCT within 3 months before the first dose of study drug
9) Received long term systemic steroids (> 10 mg/day of prednisone or its equivalent) or other immunosuppressive therapy within 2 weeks before the first dose of study drug. The following are exceptions to this criterion:
Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra-articular injection)
Systemic steroids at physiological doses as replacement therapy (e.g., physiological corticosteroid replacement therapy for adrenal or pituitary insufficiency)
Steroids as premedication for hypersensitivity reactions (e.g., computed tomography [CT] scan premedication) or chemotherapy-induced nausea and vomiting (CINV)
10) Received any live vaccine within 4 weeks before the first dose of study drug or intend to receive a live vaccine during the study
11) Received any cytochrome P450 (CYP) 2D6 strong inhibitor and/or CYP3A strong inhibitor (Appendix 16.4) within 7 days or 5 half-lives (whichever is longer) before the first dose of study drug, or require these inhibitors during the study (for Part 1 and Part 2 only)
12) Diagnosis or evidence of spinal cord compression or leptomeningeal carcinomatosis
13) Symptomatic brain metastasis. Patients with asymptomatic brain metastasis may be eligible provided the following criteria are met:
Patients with untreated, asymptomatic brain metastasis are allowed to be enrolled, if there are no neurological symptoms, no requirements for immediate local or systemic treatment (such as mannitol or steroids, surgery, or radiotherapy), no or minimal surrounding edema, and no intracranial lesion >1.5 cm
Patients with treated brain metastasis are allowed to be enrolled, if they are clinically stable for at least 2 weeks, have no evidence of new or enlarging brain metastases by imaging, and are off steroids for at least 5 days before the first dose of study drug
14) Uncontrolled or clinically significant cardiovascular and cerebrovascular diseases, including but not limited to:
Current dyspnea at rest due to complications of advanced malignancy, or other disease requiring continuous oxygen therapy
Medical history of symptomatic congestive heart failure (New York Heart Association class III to IV) or any arterial thromboembolic event (e.g., myocardial infarction, unstable angina, cerebrovascular accident, and transient ischemic attack) within 6 months before the first dose of study drug
Having undergone percutaneous coronary angioplasty or coronary artery bypass grafting within 6 months before the first dose of study drug
Serious arteriovenous thrombosis or emboli such as deep vein thrombosis, pulmonary arterial embolism, etc., that occurred within 3 months before the first dose of study drug
Uncontrolled hypertension, defined as adjusting antihypertensive medication treatment due to poor blood pressure control within 2 weeks before the first dose of study drug, systolic blood pressure (SBP) > 160 mmHg and/or diastolic blood pressure (DBP) > 100 mmHg after antihypertensive therapy
Clinically significant abnormalities in rhythm, conduction, or electrocardiogram (ECG) morphology determined by the investigators (such as complete left bundle branch block, 3rd degree atrioventricular block, and PR interval > 250 ms)
Corrected QT interval by Fridericia’s formula (QTcF) prolongation to > 470 ms based on average of triplicate 12-lead ECG at the time of screening
LVEF < 50 % by ECHO or MUGA scan within 28 days before the first dose of study drug
15) A history of non-infectious interstitial lung disease (ILD)/pneumonitis that requires steroids, current active ILD/pneumonitis, or evidence of active ILD/pneumonitis on screening chest CT scan
16) Have clinically severe pulmonary compromise resulting from intercurrent pulmonary illnesses, including, but not limited to, any underlying pulmonary disorder (i.e., asthma, chronic obstructive pulmonary disease [COPD], restrictive lung disease, etc.), and potential pulmonary involvement caused by any autoimmune, connective tissue, or inflammatory disorders (e.g., rheumatoid arthritis, Sjögren's syndrome, sarcoidosis, etc.), prior pneumonectomy, or requirement for supplemental oxygen
17) Uncontrolled third-space fluid (e.g., pleural effusions, ascites, pericardial effusions) that requires repeated drainage (patients who have been stable for more than 1 week after drainage can be included)
18) Have a diagnosis of Gilbert's syndrome
19) Digestive system disease that may cause bleeding, perforation, jaundice, gastrointestinal obstruction by the investigator's discretion
20) Have serious infection (NCI CTCAE Grade ≥ 3) within 4 weeks before the first dose of study drug, such as severe pneumonia requiring hospitalization, bacteremia, or complicated infections, or active infections requiring systemic antimicrobial treatment (oral or IV) for active infection (viral, bacterial, or fungal) within 2 weeks before the first dose of study drug
21) An active tuberculosis based on medical history
22) Known human immunodeficiency virus (HIV) infection
23) Active hepatitis C infection; patients who have been curatively treated for hepatitis C infection are permitted if they have documented sustained virologic response of 12 weeks
24) Patients with a positive hepatitis B surface antigen (HBsAg) and/or antihepatitic B core antibody (HBcAb); but patients with a negative polymerase chain reaction (PCR) assay are permitted with either universal prophylaxis or the use of a pre-emptive approach
25) Other malignant tumors that may alter life expectancy or interfere with disease evaluation (e.g., multiple primary malignancies within 3 years, except adequately resected non-melanoma skin cancer, curatively treated in-situ cancer, and other curatively treated solid tumors)
26) Unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia and pigmentation) not yet resolved to NCI CTCAE Grade ≤ 1 or the level specified in the inclusion/exclusion criteria. Patients with chronic Grade 2 toxicities who are asymptomatic or adequately managed with stable medication may be enrolled after discussion with the sponsor
27) A history of severe hypersensitivity reactions to the drug substances, inactive ingredients in the drug product, or other antibodies (e.g., allergic shock, or severe infusion reactions occurred before)
28) Women who are breastfeeding or pregnant as confirmed by pregnancy tests performed within 3 days before the first dose of study drug
29) Any illness, medical condition, organ system dysfunction, or social situation, including but not limited to mental illness or substance/alcohol abuse, deemed by the investigator to be likely to interfere with a patient’s ability to sign ICF, adversely affect the patient’s ability to cooperate and participate in the study, or compromise the interpretation of study results
