IRB Study Number 25-493
Status Recruiting
Phase Phase 1
Location Cleveland Clinic Main Campus
Institute Taussig Cancer Institute
Description
- Evaluate the safety and tolerability of tarlatamab in combination with YL201 with or without anti-PD-L1
- Evaluate preliminary anti-tumor activity of tarlatamab in combination with YL201 with or without anti-PD-L1
- Characterize the pharmacokinetics (PK) of tarlatamab when combined with YL201 with or without anti-PD-L1
- Evaluate the immunogenicity of tarlatamab when combined with YL201 with or without anti-PD-L1
- Evaluate the immunogenicity of YL201 when combined with tarlatamab with or without anti-PD-L1
- Investigate tumor target expression and the tumor microenvironment
- Characterize the immune cell profile and pharmacodynamics of tarlatamab when combined with YL201 with or without anti-PD-L1
- Explore circulating tumor DNA (ctDNA) and association with response
- Characterize the PK of YL201 ADC, YL201 total antibody (YL201 TAb), and YL0010014 when combined with tarlatamab with or without anti-PD-L1
- Characterize the PK of anti-PD-L1 when combined with tarlatamab and YL201
Inclusion Criteria
Subject has provided informed consent before initiation of any study-specific activities/procedures.
Age ≥ 18 years (or legal age within the country if it is older than 18 years) at the time of signing informed consent.
Histologically or cytologically confirmed ES-SCLC (American Joint Committee on Cancer 8th edition, (Goldstraw, et al 2016) stage IV SCLC [T any, N any, M1 a/b/c], or T3 to T4 due to multiple lung nodules that are too extensive or have tumor/nodal volume that is too large to be encompassed in a tolerable radiation plan). For Parts 1 and 2, subjects must have ES-SCLC that has progressed or recurred following at least 1 line of platinum-based anti-cancer therapy. For Part 3, subjects must have ES-SCLC and no prior systemic treatment for ES-SCLC other than 1 cycle of platinum-based chemotherapy, etoposide, and PD-(L)1 inhibitor in the first-line setting. Subjects with prior treatment for limited stage SCLC (LS-SCLC) before diagnosis of ES-SCLC are permitted if the interval is > 6 months since the end of previous LS-SCLC therapy and progression.
Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
Minimum life expectancy of 12 weeks.
Subjects must have at least 1 measurable lesion as defined per RECIST 1.1 within 21-day screening period, not previously irradiated.
For Parts 1 and 2, subjects must submit a fresh tumor biopsy at screening unless a new biopsy cannot be performed safely or is infeasible. Subjects who cannot provide fresh tissue may provide archival tissue taken after the last cancer therapy. For Part 3, subjects must submit either a fresh tumor biopsy at screening or archival tissue obtained at time of diagnosis of ES-SCLC.
Adequate organ function, defined as follows:
Hematological function:
Absolute neutrophil count (ANC) ≥ 1.5 X 109/L.
Platelet count ≥ 100 X 109/L.
Hemoglobin ≥ 9 g/dL (90 g/L).
Coagulation function:
- Prothrombin time/international normalized ratio and partial thromboplastin time or activated partial thromboplastin time ≤ 1.5 x institutional upper limit of normal (ULN).
Renal function:
- Estimated glomerular filtration rate based on Modification of Diet in Renal Disease calculation > 60 mL/min/1.73 m2.
Hepatic function:
Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) ≤ 3 X ULN (or ≤ 5 X ULN for subjects with liver involvement).
Total bilirubin ≤ 1.5 X ULN (or ≤ 2 X ULN for subjects with liver metastases)
with the exception of subjects with Gilbert's disease.
Pulmonary function:
No clinically significant pleural effusion after appropriate treatment.
Baseline oxygen saturation > 90% on room air.
No oxygen supplementation.
Cardiac function:
Baseline electrocardiogram (ECG) QTc < 470 msec for both male and female subjects (based on average of screening triplicate).
No clinically significant ECG findings.
Left ventricular ejection fraction (LVEF) ≥ 50% and no clinically significant pericardial effusion as determined by echocardiogram (ECHO) or multi-gated acquisition (MUGA).
Exclusion Criteria
Disease Related
- Symptomatic CNS metastases. Subjects with brain metastases are eligible provided the following criteria are met:
Subject is asymptomatic from brain metastases.
Whole brain radiation or surgery was completed at least 2 weeks prior to first dose of study treatment (stereotactic radiosurgery completed at least 7 days prior to first dose of study treatment). Note: Subjects with asymptomatic brain metastases are eligible provided the subject has received definitive treatment or brain metastasis does not require local therapy per investigator’s judgement.
Any CNS disease is clinically stable, subject is off steroids for CNS disease for at least 5 days (unless steroids are indicated for a reason unrelated to CNS disease), and subject is off or on stable doses of anti-epileptic drugs at least 14 days prior to first dose of study treatment. - Diagnosis or evidence of leptomeningeal disease.
- Prior history of immune checkpoint inhibitors resulting in:
Any severe or life-threatening immune-mediated adverse event.
History of immune-mediated encephalitis or other immune-mediated CNS event (any grade).
Grade 2 or higher immune-mediated recurrent pneumonitis/interstitial lung disease.
Injection-related reactions leading to permanent discontinuation of immunotherapy agent. Exception: Subjects with a history of immune checkpoint inhibitor-induced endocrinopathy which is clinically stable on replacement therapy.
Other Medical Conditions - Active autoimmune disease that has required systemic treatment (except physiologic replacement therapy) within the past 2 years or any other diseases requiring immunosuppressive therapy while on study.
- History of solid organ transplantation.
- History of other malignancy within the past 2 years, with the following exceptions:
low-risk malignancy treated with curative intent and with no known active disease present for 1 year prior to first dose of study treatment and believed to be at low risk for recurrence per investigator discretion.
adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease.
adequately treated cervical carcinoma in situ without evidence of disease.
adequately treated breast ductal carcinoma in situ without evidence of disease.
prostatic intraepithelial neoplasia without evidence of prostate cancer.
low-risk prostate cancer treated only with active surveillance.
adequately treated urothelial papillary noninvasive carcinoma or carcinoma in situ. - Myocardial infarction and/or symptomatic congestive heart failure (New York Heart Association > class II) within 12 months of first dose of study treatment.
- History of arterial thrombosis (eg, stroke or transient ischemic attack) within 12 months of first dose of study treatment.
- Clinically significant corneal disease.
- History of gastrointestinal perforation and/or fistula within 6 months prior to first dose of study treatment.
- Presence/history of viral infection:
Human immunodeficiency virus (HIV) infection.
-Subjects with HIV infection on antiviral therapy and undetectable viral load are permitted with a requirement for regular monitoring for reactivation for the duration of treatment on study per local or institutional guidelines.
Active hepatitis C infection (subjects with detectable hepatitis C virus antibody [HCV Ab] and hepatitis C virus (HCV) RNA viral load above the limit of quantification).
-Subjects with presence of HCV Ab and HCV RNA viral load below the limit of quantification (HCV RNA negative) with or without prior treatment are allowed.
Active hepatitis B infection (presence of hepatitis B surface antigen [HBsAg] and hepatitis B virus [HBV] DNA viral load above the limit of quantification [HBV DNA positive]).
-Subjects with resolved HBV infection defined as absence of HBsAg and presence of HBV core antibody followed by an HBV DNA viral load below the limit of quantification (HBV DNA negative) are allowed, with a requirement for regular monitoring for reactivation for the duration of treatment on the study and assessing the need for HBV prophylaxis therapy per local or institutional guidelines.
-Subjects with chronic HBV infection inactive carrier state defined as presence of HBsAg and HBV DNA viral load below the limit of quantification (HBV DNA negative) are allowed, with a requirement for regular monitoring for reactivation for the duration of treatment on the study and assessing the need for HBV prophylaxis therapy per local or institutional guidelines. - Receiving systemic corticosteroid therapy or any other form of immunosuppressive therapy within 7 days prior to first dose of study treatment:
Prophylactic dexamethasone required by the protocol and any anti-emetic therapies are allowed.
Low-dose corticosteroids (prednisone 10 mg per day or equivalent) are permitted. - Subject with symptoms and/or clinical signs and/or radiographic signs that indicate an acute and/or uncontrolled active systemic infection within 7 days prior to the first dose of study treatment. Note: Simple urinary tract infection and uncomplicated bacterial pharyngitis are permitted if responding to active treatment. Subjects requiring oral antibiotics who have been afebrile for > 24 hours, have no leukocytosis, nor clinical signs of infection are eligible. Subjects requiring parenteral antibiotic treatment who have completed parenteral antibiotics and have resolution of symptoms may be considered eligible for the study from an infection standpoint. Screening for chronic infectious conditions is not required unless otherwise noted as exclusion criteria.
- History of (non-infectious) ILD/pneumonitis that required corticosteroids, current ILD/pneumonitis, or suspected ILD/pneumonitis that cannot be ruled out by imaging at screening.
Prior/Concomitant Therapy - Prior therapy with tarlatamab.
- Prior therapy with any DLL3-directed therapy.
- Prior therapy with any B7-H3 targeted agents.
- Prior exposure to topoisomerase I inhibitors or ADC with topoisomerase I inhibitor payload.
- Prior systemic anti-cancer therapy within 28 days prior to first dose of study treatment for subjects in Part 1 and 2 only (not applicable to Part 3). Exceptions:
Subjects who received conventional chemotherapy are eligible if at least 14 days have elapsed and if all treatment-related toxicity has resolved to grade ≤ 1 (or to levels dictated in the eligibility criteria) before first dose of study treatment, with the exception of alopecia or toxicities considered irreversible (defined as having been present and stable for > 30 days) which are not otherwise described in the exclusion criteria. - Prior palliative radiotherapy must have been completed at least 7 days before the first dose of study treatment.
- Receiving anti-cancer therapy such as chemotherapy, immunotherapy, or targeted therapy. Note: Patients who are receiving adjuvant hormonal therapy for resected breast cancer may be eligible (refer also to exclusion related to history of other malignancies) after discussion with and approval by Amgen medical monitor. Note: Excludes subjects in Part 3 who must have ES-SCLC and no prior systemic treatment for ES-SCLC other than 1 cycle of platinum-based chemotherapy, etoposide, and PD-(L)1 inhibitor in the first-line setting.
- Major surgical procedures within 28 days prior to first dose of study treatment.
- Live and live-attenuated vaccines are prohibited within 28 days prior to first dose of study treatment.
Prior/Concurrent Clinical Study Experience - Currently receiving treatment in another investigational device or drug study, or less than 21 days or 5 half-lives (whichever is longer) since ending treatment on another investigational device or drug study(ies). Exception: Participation in observational research while participating in this study is allowed. Other investigational procedures may be allowed after discussion with and approval by Amgen medical monitor.|
Diagnostic Assessments - Any previous diagnosis of transformed non-small cell lung cancer (NSCLC), epidermal growth factor receptor activating mutation positive NSCLC that has transformed to SCLC. Subjects with mixed histology tumors with predominant SCLC histology are allowed.
Other Exclusions - Female subjects of childbearing potential unwilling to use protocol-specified method of contraception (see Section 11.5) during treatment and for the following additional time periods (whichever is later):
6 months after the last dose of YL201 for subjects treated in Parts 1, 2, and 3.
60 days after the last dose of tarlatamab for subjects treated in Parts 1, 2, and 3.
90 days after the last dose of durvalumab for subjects treated in the durvalumab cohort of Part 3
150 days after the last dose of atezolizumab for subjects treated in the atezolizumab cohort of Part 3.
Note: contraception requirements for other protocol-required therapies including auxiliary medicinal products are based on regional/local prescribing information. - Female subjects who are breastfeeding or who plan to breastfeed while during treatment and for the following additional time periods (whichever is later):
6 months after the last dose of YL201 for subjects treated in Parts 1, 2, and 3.
60 days after the last dose of tarlatamab for subjects treated in Parts 1, 2, and 3.
90 days after the last dose of durvalumab for subjects treated in the durvalumab cohort of Part 3
150 days after the last dose of atezolizumab for subjects treated in the atezolizumab cohort of Part 3. - Female subjects planning to become pregnant or donate eggs while during treatment and for the following additional time periods (whichever is later):
6 months after the last dose of YL201 for subjects treated in Parts 1, 2, and 3.
60 days after the last dose of tarlatamab for subjects treated in Parts 1, 2, and 3.
90 days after the last dose of durvalumab for subjects treated in the durvalumab cohort of Part 3
150 days after the last dose of atezolizumab for subjects treated in the atezolizumab cohort of Part 3.
29.Female subjects of childbearing potential with a positive pregnancy test assessed at screening by a highly sensitive urine or serum pregnancy test. - Male subjects with a female partner of childbearing potential who are unwilling to practice sexual abstinence (refrain from heterosexual intercourse) or use contraception during treatment and for the following additional time periods (whichever is later):
6 months after the last dose of YL201 for subjects treated in Parts 1, 2, and 3.
60 days after the last dose of tarlatamab for subjects treated in Parts 1, 2, and 3.
90 days after the last dose of durvalumab for subjects treated in the durvalumab cohort of Part 3
150 days after the last dose of atezolizumab for subjects treated in the atezolizumab cohort of Part 3.
Refer to Section 11.5 for additional contraceptive information. - Male subjects with a pregnant partner who are unwilling to practice abstinence or use a condom during treatment and for the following additional time periods (whichever is later):
6 months after the last dose of YL201 for subjects treated in Parts 1, 2, and 3.
60 days after the last dose of tarlatamab for subjects treated in Parts 1, 2, and 3.
90 days after the last dose of durvalumab for subjects treated in the durvalumab cohort of Part 3
150 days after the last dose of atezolizumab for subjects treated in the atezolizumab cohort of Part 3. - Male subjects unwilling to abstain from donating sperm during treatment and for the following additional time periods (whichever is later):
6 months after the last dose of YL201 for subjects treated in Parts 1, 2, and 3.
60 days after the last dose of tarlatamab for subjects treated in Parts 1, 2, and 3.
90 days after the last dose of durvalumab for subjects treated in the durvalumab cohort of Part 3
150 days after the last dose of atezolizumab for subjects treated in the atezolizumab cohort of Part 3. - Subject has known sensitivity to any of the products or components to be administered during dosing.
- Subject likely to not be available to complete all protocol-required study visits or procedures, and/or to comply with all required study procedures (eg, Clinical Outcome Assessments) to the best of the subject and investigator’s knowledge.
- History or evidence of any other clinically significant disorder, condition, or disease (except for those outlined above) that, in the opinion of the investigator or Amgen medical monitor, if consulted, would pose a risk to subject safety, or interfere with the study evaluation, procedures or completion.
