IRB Study Number 25-772
Status Recruiting
Phase Phase 1
Location Cleveland Clinic Main Campus
Institute Taussig Cancer Institute
Description
Aim 1:
Dose Escalation Part (Part 1)
•To assess the safety and tolerability of YL201 in patients with advanced solid tumors
• To determine the maximum tolerated dose (MTD) and select the recommended dose(s) for expansion
(RDE(s)) of YL201 in patients with advanced solid tumors
Dose-Expansion Part (Part 2)
• To further evaluate the safety and tolerability of YL201 at the RDE(s) in patients with SCLC, Nsq-NSCLC, mCRPC, HNSCC, PDAC, and other solid tumors
• To evaluate the efficacy of YL201 at the RDE(s) in patients with SCLC, Nsq-NSCLC, mCRPC, HNSCC, PDAC, and other solid tumors
• To determine the recommended phase 2 dose (RP2D) of YL201 in patients with SCLC, Nsq-NSCLC, mCRPC, HNSCC, PDAC, and other solid tumors
Dose Expansion with Safety Run-in in 1L ES-SCLC maintenance therapy part (Part 3)
• To evaluate the safety and tolerability of YL201 in combination with atezolizumab or other anti-cancer agents as maintenance therapy in ESSCLC patients whose disease has not progressed after first-line induction therapy with a PD-L1 inhibitor and platinum containing therapy.
• To determine the recommended dose for YL201 in combination with atezolizumab or other anti-cancer agents as maintenance therapy after first line induction therapy with PD-L1 inhibitor and platinum containing therapy.
Aim 2:
Dose Escalation Part (Part 1)
• To characterize the pharmacokinetics (PK) of YL201 antibody-drug conjugate (YL201-ADC), YL201 total antibody (YL201-TAb), and unconjugated payload YL0010014
• To evaluate immunogenicity as measured by the presence of anti-drug antibodies (ADAs) in patients treated with YL201
• To document any preliminary evidence of YL201 efficacy in patients with advanced solid tumors
Dose-Expansion Part (Part 2)
• To characterize the PK of YL201-ADC, YL201-TAb, unconjugated payload YL0010014, metabolite YL0010034 and if applicable, other potential metabolite(s)
• To characterize the metabolite profile of YL201
• To evaluate immunogenicity as measured by the presence of ADAs in patients treated with YL201
Dose Expansion with Safety Run-in in 1L ES-SCLC maintenance therapy part (Part 3)
• To characterize the PK profile of YL201-ADC, YL201-TAb, unconjugated payload YL0010014, metabolite YL0010034, and if applicable, other potential metabolite(s) in combination with atezolizumab as maintenance therapy after first line induction therapy with a PD-L1 inhibitor and platinum containing therapy.
• To characterize the PK profile of atezolizumab administered in combination with Y201 as maintenance therapy after first line induction therapy with a PD-L1 inhibitor and platinum containing therapy.
• To evaluate the immunogenicity of YL201 and atezolizumab in combination as maintenance therapy after first line induction therapy with a PD-L1 inhibitor and platinum containing therapy.
• To evaluate the anti-cancer activity of YL201 in combination with atezolizumab as maintenance therapy after first line induction therapy with a PD-L1 inhibitor and platinum containing therapy.
Inclusion Criteria
Patients must satisfy all of the following criteria to be included in the study:
Common Inclusion Criteria (Part 1, Part 2, and Part 3) (Criteria 1 to 8)
1) Informed of the trial before the start of the trial and voluntarily sign their name and date on the ICF
2) Aged ≥18 years
3) ECOG PS of 0 or 1
4) For Parts 1 and 2, 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)
• 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)
• Platelet count ≥100 × 109/L (have not received platelet transfusion, thrombopoietin, or interleukin-11 treatment within 14 days before the first dose)
• 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
5) For Part 3, adequate hematologic and end-organ function, defined by the following laboratory test results, obtained within 7 days prior to start of study treatment into the maintenance phase:
• ANC ≥1.5 × 109/L (1500/uL) for participants of non-African descent or ≥1.3 × 109/L (1300/uL) for participants of African descent without G-CSF support
• Lymphocyte count ≥0.5 × 109/L (500/uL)
• Platelet count ≥ 100× 109 / L (have not received platelet transfusion, thrombopoietin, or interleukin-11 treatment within 14 days before the first dose)
• Hemoglobin ≥ 90 g/L (have not received blood transfusion or erythropoietin treatment within 14 days before the first dose)
Note that the washout period between last transfusion and collection of blood for screening assessments should be ≥ 14 days.
• AST, ALT, and ALP ≤ 2.5×ULN, with the following exceptions:
o Potential participants with documented liver metastases: AST and ALT ≤ 5× ULN.
o Potential participants with documented liver or bone metastases: ALP ≤ 5× ULN.
• Total bilirubin ≤ 1.5× ULN
• Creatinine clearance ≥ 60 mL/min (calculated through use of the Cockcroft-Gault formula)
• Creatine phosphokinase ≤ 2.5 ×ULN (≤ 5.0× ULN is acceptable if elevation is disease related)
• Albumin ≥ 30 g/L (3.0 g/dL)
• For potential participants not receiving therapeutic anticoagulation: INR and aPTT ≤ 1.5 ×ULN
• For potential participants receiving therapeutic anticoagulation: a stable anticoagulant regimen.
6) 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 5 months after the last dose of atezolizumab or 6 months after the last dose of YL201, whichever is later. 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 YL201.
7) Life expectancy of ≥3 months
8) Able and willing to comply with protocol visits and procedures
Additional Inclusion Criteria for Part 1 (Criteria 9 to 10)
9) Pathologically confirmed diagnosis of an advanced solid tumor (SCLC, mCRPC, ESCC and NSCLC are preferred) for which prior standard treatment had proven to be ineffective or intolerable, or no standard treatment is available
10) Have at least 1 evaluable tumor lesion according to RECIST version 1.1. Patients with prostate cancer who have bone only disease may be eligible on a case-by-case basis after discussion with the sponsor
Additional Inclusion Criteria for Part 2 (Criteria 11 to 13)
11) Criteria for selected tumor types:
For patients with SCLC (Cohort A):
• Have a histologically or cytologically confirmed diagnosis of limited-stage SCLC (LSSCLC: per AJCC 8th edition Stage I-III [any T, any N, M0], which can be treated with radiation therapy, excluding T3-4 due to multiple lung nodules or tumor/nodal volume too large to be encompassed in a tolerable radiation plan) or extensive-stage SCLC (ESSCLC: per AJCC 8th edition Stage IV [any T, any N, Mla/b/c], or T3-4 due to multiple lung nodules or tumor/nodal volume too large to be encompassed in a tolerable radiation plan)
• Have disease progression at study entry documented by imaging
o For LS-SCLC (at screening): have received at least 2 cycles of platinum-based chemotherapy. Patients with T1-2N0 who are not suitable for radical surgery will be eligible.
o For ES-SCLC (at screening): have received at least 2 cycles of platinum-based chemotherapy plus anti-PD-(L)1 therapy.
For patients with Nsq-NSCLC (Cohort B):
• Have a histologically or cytologically confirmed diagnosis of Nsq-NSCLC without any of the following actionable gene mutation: EGFR exon19 deletion, EGFR L858R S768I, L861Q, G719X mutation, EGFR exon 20 insertion, KRAS G12C mutation, ALK rearrangement, ROS1 rearrangement, BRAF V600E mutation, NTRK1/2/3 gene fusion, MET exon14 skipping mutation, RET rearrangement, ERBB2 (HER2) mutation.
Patients who have actionable gene alterations but failed standard treatment will not be eligible.
• Have disease progression at study entry documented by imaging
• Have received prior treatment with anti-PD-(L)1 therapy and platinum-based chemotherapy either given concurrently as one line or separately as two lines for Nsq- NSCLC
o Patients who received a platinum-containing chemotherapy as adjuvant therapy for early-stage disease must have relapsed or progressed while on the treatment or within 6 months of the last dose OR received at least one additional course of platinum-containing therapy (which may or may not be same as in the adjuvant setting) for recurrent or metastatic disease
For patients with mCRPC (Cohort C):
• Have a histologically or cytologically confirmed diagnosis of prostate adenocarcinoma without significant and relevant neuroendocrine differentiation or small cell features
• Clinically diagnosis of mCRPC per the following:
○ Serum testosterone level < 1.7 nmol/L (50 ng/dl) at the screening visit
○ Progressive disease at study entry defined as the one or more of the following criteria: PSA progression (defined as PSA >1 ng/ml with an interval of at least 1 week between each measurement, and by a minimum of two consecutive increases in PSA levels of >50% from baseline), or disease progression by imaging (defined by PCWG3 with two or more new lesions on bone scan; and/or soft tissue disease progressed by CT/MRI per RECIST 1.1) ○ Ongoing ADT treatment with LHRH analogue (medical castration) or have had bilateral orchiectomy (surgical castration); patients who have had surgical castration must have the surgery at least 3 months before being enrolled in the study, patient who have not had a bilateral orchiectomy, there must be a plan to have the castration therapy at least 3 months before the first administration of the study drug and maintain effective treatment for the duration of the trial.
• Have received all of the following for prostate cancer:
○ At least 1 prior line of androgen receptor axis-targeted therapy (ARAT) (eg, enzalutamide, apalutamide, abiraterone)
○ No more than 2 prior line of chemotherapy regimen
○ Patients with known BRCA or ATM mutation (germline or somatic) must have received prior treatment with a poly (ADP)-ribose polymerase (PARP) inhibitor where available, indicated and tolerated.
For patients with HNSCC (Cohort D):
• Have a histologically or cytologically confirmed diagnosis of unresectable recurrent or metastatic HNSCC (limited to oropharyngeal cancer, and hypopharyngeal cancer) but without the following conditions or history:
○ Radiographic evidence of major blood vessel invasion/infiltration or tumor
demonstrating a >90-degree abutment or encasement of a major blood vessel
○ Ulcerative or necrotic tumors in proximity to major blood vessels
○ Prior history of Grade ≥ 3 bleeding related to the primary tumor or metastatic sites 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
• Documented tumor human papillomavirus (HPV) testing by p16 immunohistochemistry (IHC)
• Have disease progression at study entry documented by imaging
• Have received prior treatment with anti-PD-(L)1 therapy and platinum-containing chemotherapy either given concurrently as one line or separately as two lines for recurrent or metastatic HNSCC
○ Patients who received a platinum-containing chemotherapy as adjuvant therapy for early-stage disease must have relapsed or progressed while on the treatment or within 6 months of the last dose OR received at least one additional course of platinum-containing therapy (which may or may not be same as in the adjuvant setting) for recurrent or metastatic disease
For patients with PDAC (Cohort E):
• Have a histologically or cytologically confirmed diagnosis of metastatic PDAC
• Have disease progression at study entry documented by imaging
• Have received at least 1 prior line of gemcitabine-based systemic therapy and no more than 2 prior lines of chemotherapy regimen for locally advanced/metastatic PDAC
○ Patients who received a gemcitabine-based systemic therapy as adjuvant therapy for early-stage disease must have relapsed or progressed while on the treatment or within 6 months of the last dose OR received at least one additional course of gemcitabine-based systemic therapy (which may or may not be same as in the adjuvant setting) for locally advanced/metastatic disease
For patients with other solid tumors (Cohort F):
• 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
12) Have at least 1 measurable tumor lesion according to RECIST version 1.1. Patients with prostate cancer who have bone only disease may be eligible on a case-by-case basis after discussion with the sponsor
13) Willing to provide archival or fresh tumor tissue samples. Patients who are not able to provide tumor samples or have inadequate samples may be eligible on a case-by-case basis after discussion with the sponsor.
Additional Inclusion Criteria for Part 3 ES-SCLC patients (Criteria 1 to 8):
- Histologically or cytologically confirmed diagnosis of ES-SCLC per AJCC 8th edition Stage IV [any T, any N, Mla/b/c], or T3-4 due to multiple lung nodules or tumor/nodal volume too large to be encompassed in a tolerable radiation plan
- No prior systemic treatment for ES-SCLC
o For potential patients who have received prior chemoradiotherapy for limited-stage SCLC: They must have had treatment with curative intent and a treatment-free interval of at least 6 months between the start of the last dose/cycle of chemotherapy, thoracic radiotherapy, or chemoradiotherapy and the diagnosis of ES-SCLC. - Patients who have received 4 cycles of first line induction treatment for ES-SCLC with either
A: carboplatin, etoposide and atezolizumab (preferred regimen), or
B: Carboplatin (preferred) or cisplatin, etoposide and durvalumab with ongoing complete response (CR), partial response (PR), or stable disease (SD) per RECIST v1.1 assessed by the investigator as compared to the last CT scan prior to initiation of maintenance therapy. The maintenance therapy must be started within 5 weeks from the last dose of induction therapy.
o Patients who have received < 4 cycles or > 4 cycles are not eligible, except patients who have received only 3 cycles due to toxicity with ongoing CR or PR per RECIST1.1 and meet all other inclusion criteria - Radiographic tumor assessment must have occurred within 28 days from the last dose of induction chemotherapy
- Palliative radiotherapy must have been completed either prior to initiating induction or must have been completed at least 8 weeks prior to study treatment.
o Radiation to areas of progression during induction will be considered progression of disease - Treated brain metastases are allowed as long as they have been treated prior to or during the course of induction therapy and patient must be stable neurologically and off all steroids for a minimum of 4 weeks prior to the initiation of protocol maintenance treatment and there can be no CNS progression. Only a history of supratentorial and cerebellar metastasis is allowable (no history of midbrain, pons, medulla or spinal cord metastases).
o Brain metastases occurring during induction will be considered progression of disease. - Refer to Criterion 12 above underneath the section “Additional Inclusion Criteria for Part 2 (Criteria 11 to 13)”. Note that for Part 3, measurable lesions per RECIST1.1 are not required.
- Willing to provide pre-induction treatment archival tumor tissue or fresh tumor tissue samples. Patients who are not able to provide tumor samples or have inadequate samples may be eligible on a case-by-case basis after discussion with the sponsor. If archival samples are not available, screening core needle biopsies will need to be obtained.
Biopsies will only be conducted if deemed clinically safe and feasible by the Investigator.
Exclusion Criteria
Patients who meet any of the following criteria will be disqualified from entering the study:
Common Exclusion Criteria (Part 1, Part 2 and Part 3) (Criteria 1 to 24)
1) Prior treatment with an agent targeting B7H3 (including antibody, ADC, chimeric antigen receptor T cell [CAR-T], and other drugs)
2) Prior treatment with a topoisomerase I inhibitor or an ADC that consists of a topoisomerase I inhibitor, including but not limited to topotecan, irinotecan, and Dxd
3) Concurrent enrollment in another clinical study, unless it is an observational (noninterventional) clinical study or during the follow-up period of an interventional study
4) Prior systemic anticancer treatment including chemotherapy, molecular -targeted therapy, hormonal therapy, immunotherapy, or biological therapy within 3 weeks before the first dose of study drug (use of oral fluorouracil [eg, tegafur and capecitabine] or small molecular-targeted therapy within 2 weeks or 5 half-life periods [whichever is shorter] before the first dose; use of mitomycin or nitrosoureas within 6 weeks before the first dose; use of herbal medicine with antitumor indications or nonspecific immunomodulators [eg, thymosin, interferon, and interleukin] within 2 weeks before the first dose).
Note: For patients with PC, androgen deprivation therapy (ADT) with a gonadotropinreleasing hormone (GnRH) analog (GnRH agonist or GnRH antagonist) is allowed.
5) Prior radiation therapy, including palliative stereotactic radiation with abdominal, within 4 weeks before the first dose of study drug (if palliative stereotactic radiation therapy without abdominal, within 2 weeks)
6) Undergone major surgery (not including diagnostic surgery) within 4 weeks before the first dose of study drug or expect major surgery during the study
7) Undergone allogeneic hematopoietic stem cell transplantation (HSCT) before the first dose of study drug, or autologous HSCT within 3 months before the first dose of study drug
8) Received 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 (eg, intra-articular injection)
• Systemic steroids at physiological doses as replacement therapy (eg, physiological corticosteroid replacement therapy for adrenal or pituitary insufficiency)
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• Steroids as premedication for hypersensitivity reactions (eg, CT scan premedication) or chemotherapy-induced nausea and vomiting (CINV)
9) Received any live vaccine within 4 weeks before the first dose of study drug or intend to receive a live vaccine during the study
10) A history of leptomeningeal carcinomatosis
11) Has spinal cord compression or clinically active central nervous system metastases, defined as untreated or symptomatic, or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms
• Patients with treated brain metastases that are no longer symptomatic and who require no treatment with corticosteroids or anticonvulsants may be included in the study if they have recovered from acute toxic effect of radiotherapy. A minimum of 2 weeks must have elapsed between the end of whole brain radiotherapy and study enrollment.
12) Uncontrolled or clinically significant cardiovascular disease, including but not limited to:
• Medical history of symptomatic congestive heart failure (New York Heart Association class II to IV) or any arterial thromboembolic event (eg, myocardial infarction, unstable angina, cerebrovascular accident, and transient ischemic attack) within 6 months before the first dose
• Uncontrolled hypertension, defined as systolic blood pressure (SBP) >160 mm Hg and/or diastolic blood pressure (DBP) >100 mm Hg after antihypertensive therapy
• Serious cardiac arrhythmia that requires treatment
• Corrected QT interval by Fridericia’s formula (QTcF) prolongation to >470 ms
13) A history of (noninfectious) ILD/pneumonitis that requires steroids, current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening
14) Clinically significant concomitant pulmonary disease, including but not limited to:
• Pulmonary emboli within 3 months of the start of study treatment
• Any autoimmune, connective tissue, or inflammatory disorder (eg, rheumatoid arthritis, Sjögren’s syndrome, sarcoidosis) where there is documented or suspicion of pulmonary involvement at the time of screening
• Prior complete pneumonectomy
15) Have a diagnosis of Gilbert’s syndrome
16) Uncontrolled third-space fluid (eg, pleural effusions, ascites, pericardial effusions) that requires repeated drainage
17) Active gastric and duodenal ulcers, ulcerative colitis, or other gastrointestinal conditions that may cause bleeding or perforation by the investigator’s discretion
18) Uncontrolled infection that requires systemic therapy within 1 week before the first dose
19) Known human immunodeficiency virus (HIV) infection
20) Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. Active HBV is defined as hepatitis B core antibody (HBcAb) or hepatitis B surface antigen (HBsAg) positive, and HBV DNA level above ULN at the study site; active HCV is defined as positive hepatitis C antibody and HCV RNA level above ULN at the study site
21) Unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia and pigmentation) not yet resolved to NCI CTCAE Grade ≤1, baseline, 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
22) A history of severe hypersensitivity reactions to the drug substances, inactive ingredients in the drug product, or other mAbs
23) Women who are breastfeeding or pregnant as confirmed by pregnancy tests performed within 7 days before the first dose
24) 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 informed consent, adversely affect the patient’s ability to cooperate and participate in the study, or compromise the interpretation of study results.
Additional Exclusion Criteria for Part 2 (Criteria 25)
25) Multiple primary malignancies within 3 years, except adequately resected non-melanoma skin cancer, curatively treated in situ disease, or other curatively treated solid tumors
Additional Exclusion Criteria for Part 3 (Criteria 26-36)
26) Consolidative chest radiation is excluded
27) Received any live vaccine within 4 weeks before the first dose of study drug or intend to receive a live vaccine during atezolizumab treatment or within 5 months after the final dose of atezolizumab
28) Active tuberculosis
29) Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including anti-CTLA-4, antiPD-1, and anti-PD-L1 therapeutic antibodies, except given for induction therapy for 1L ES-SCLC
30) Treatment with systemic immunostimulatory agents (including, but not limited to, interferon and IL-2) within 4 weeks or 5 drug-elimination half-lives (whichever is longer) prior to initiation of study treatment
31) Treatment with systemic immunosuppressive medication (including, but not limited to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti−tumor necrosis factor− [TNF-] agents) within 2 weeks prior to initiation of study treatment, or anticipation of need for systemic immunosuppressive medication during study treatment, with the following exceptions:
• Patients who received acute, low-dose systemic immunosuppressant medication or a one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of corticosteroids for a contrast allergy) are eligible for the study.
• Patients who received mineralocorticoids (e.g., fludrocortisone), inhaled or low-dose corticosteroids for COPD or asthma, or low-dose corticosteroids for orthostatic hypotension or adrenal insufficiency are eligible for the study.
32) Pregnancy or breastfeeding, or intention of becoming pregnant during study treatment or within 5 months for atezolizumab
• Women of childbearing potential must have a negative serum pregnancy test result within 14 days prior to initiation of study treatment
33) Known hypersensitivity to Chinese hamster ovary cell products or to any component of the atezolizumab formulation
34) Active or history of autoimmune disease or immune deficiency, including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, anti-phospholipid antibody syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, or multiple sclerosis (see Appendix 16.5 for a more comprehensive list of autoimmune diseases and immune deficiencies), with the following exceptions:
• Patients with a history of autoimmune-related hypothyroidism who are on thyroid replacement hormone are eligible for the study.
• Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen are eligible for the study.
• Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis are excluded) are eligible for the study provided all of following conditions are met:
– Rash must cover < 10% of body surface area.
– Disease is well controlled at baseline and requires only low-potency topical corticosteroids.
– There has been no occurrence of acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high potency or oral corticosteroids within the previous 12 months.
35) History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan
36) Current treatment with anti-viral therapy for HBV
