Evaluating BL-M14D1 in Subjects With Locally Advanced or Metastatic Small Cell Lung Cancer and Neuroendocrine Tumors
- Conditions
- Small-cell Lung CancerNeuroendocrine CancerProstate CancerGastrointestinal Neuroendocrine TumorMerkel Cell Carcinoma, Recurrent
- Interventions
- Registration Number
- NCT07080242
- Lead Sponsor
- SystImmune Inc.
- Brief Summary
The objective of this study is to evaluate the Safety, Tolerability, Pharmacokinetics, and Efficacy of BL-M14D1 in Subjects with locally Advanced or Metastatic Small Cell Lung Cancer and Other Neuroendocrine Tumors
- Detailed Description
This is a multicenter Phase 1 Open-Label Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Efficacy of BL-M14D1 in Subjects with locally advanced or metastatic small cell lung cancer (SCLC), or other neuroendocrine tumors with neuroendocrine histology (≥10%) who have failed at least 1 line of standard therapy in the advanced/metastatic setting or are unable to receive standard treatment
Recruitment & Eligibility
- Status
- NOT_YET_RECRUITING
- Sex
- All
- Target Recruitment
- 120
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Signed the informed consent form voluntarily and agreed to follow the trial requirements
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Age ≥18 years
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Subject weighs more than 40 kg
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Has a life expectancy of ≥3 months
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Has documented locally advanced or metastatic SCLC, large cell neuroendocrine cancer (LCNEC), neuroendocrine prostate cancer (NEPC), high-grade gastrointestinal neuroendocrine tumors (GI-NET), Merkel cell carcinoma (MCC), or other neuroendocrine tumors (with neuroendocrine histology ≥10%) who have failed at least 1 line of standard therapy in the advanced/metastatic setting or are unable to receive standard treatment Notes: For SCLC, the subject must have failed at least 1 line of platinum therapy in the advanced/metastatic setting. No prior topoisomerase inhibitor-based antibody-drug conjugate (ADC) therapy is permitted
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Agree to provide archival tumor samples (FFPE tissue block or slides) from primary or metastatic sites:
- In dose escalation and dose finding: archival tissue obtained within 2 years or FFPE block from fresh biopsy. If no archival tissue is available, a fresh tissue biopsy is required
- In dose expansion: an FFPE block from fresh biopsy or archival tissue (within 6 months) is required NOTE: If no archival tissue is available and, a fresh tissue biopsy is clinically contraindicated, please consult the sponsor.
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Has at least one measurable lesion based on RECIST (Response Evaluation Criteria in Solid Tumors) V1.1
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Has an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 to 1
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Toxicity of previous antitumor therapy has returned to Grade ≤1 as defined by NCI CTCAE V5.0, except for alopecia and endocrinopathies controlled by replacement therapy
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Has no serious cardiac dysfunction and left ventricular ejection fraction ≥50%
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Has adequate organ function, defined as:
- Marrow function: Absolute neutrophil count (ANC) ≥1.5×109/L, platelet count ≥100×109/L, hemoglobin (Hb) ≥9.0 g/dL (blood transfusion, platelet transfusion, erythropoietin (EPO), hematopoiesis agents (such as thrombopoietin [TPO]), and G-CSF use are not allowed 1 week prior to screening)
- Hepatic function: Total bilirubin (TBIL) ≤1.5×ULN (≤3×ULN for subjects with Gilbert's syndrome or liver metastasis at baseline), AST and ALT without liver metastasis ≤3.0×ULN, AST and ALT with liver metastasis ≤5.0×ULN
- Renal function: Creatinine (Cr) clearance ≥60 mL/minute (Cockcroft-Gault equation)
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Coagulation parameters: International normalized ratio (INR) ≤1.5×ULN, and activated partial thromboplastin time (aPTT) ≤1.5×ULN, unless receiving anticoagulation therapy with PT and aPTT levels within the intended therapeutic range
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Urine protein ≤2+ or ≤1000 mg/24 hours
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Sexually active fertile subjects and their partners must agree to use highly effective methods of contraception (defined in Appendix D) during the course of the study and for 7 months after the last dose of study treatment. An additional contraceptive method, such as a barrier method (eg, condom), is recommended.
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Women of childbearing potential (WOCBP) must have a negative serum pregnancy test at screening and must be nonlactating. Female subjects are considered WOCBP unless one of the following criteria are met: documented permanent sterilization (hysterectomy, bilateral salpingectomy, or bilateral oophorectomy) or documented postmenopausal status (defined as 12 months of amenorrhea in a woman >45 years old in the absence of other biological or physiological causes. In addition, females <55 years old must have a serum follicle stimulating hormone (FSH) level >40 mIU/mL to confirm menopause.
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Chemotherapy, biological therapy, immunotherapy, , targeted therapy (including small molecule inhibitor of tyrosine kinase), and other antitumor therapy within 4 weeks or 5 half-lives (whichever is shorter) prior to the first administration; radical radiotherapy, major surgery within 4 weeks prior to the first administration; mitomycin and nitrosoureas treatment within 6 weeks prior to the first administration; oral fluorouracil drugs such as tegafur, capecitabine, or palliative radiotherapy within 2 weeks prior to initial administration.
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Subjects who have received prior topoisomerase inhibitor-based ADC therapy
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Concomitant use of strong inhibitors and inducers of any CYP enzyme or transporter system within 2 weeks prior to the first administration and throughout all parts of the study
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Subjects with history of severe heart disease, such as symptomatic congestive heart failure (CHF) ≥Grade 2 (CTCAE 5.0), New York Heart Association (NYHA) ≥Grade 2 heart failure at any time, history of myocardial infarction or unstable angina pectoris within 6 months before enrollment
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Subjects with prolonged QT interval (QTcF >470 msec), complete left bundle branch block, Grade 3 atrioventricular block, or a history of additional risk factors for Torsades de Pointes (TdP; eg, heart failure as defined in Exclusion Criterion 4, chronic or recurrent hypokalemia that requires medical intervention, congenital long QT syndrome, family history of long QT syndrome) or any current concomitant medication known to prolong the QT/QTc interval or cause TdP
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Active autoimmune diseases and inflammatory diseases, such as systemic lupus erythematosus, psoriasis requiring systemic treatment, rheumatoid arthritis, inflammatory bowel disease and Hashimoto's thyroiditis, etc., except for type 1 diabetes, hypothyroidism that can be controlled by standard of care treatment, and skin diseases that do not require systemic treatment (such as vitiligo, psoriasis)
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Subjects with other prior or concurrent malignancies except for basal cell carcinoma of the skin, squamous cell carcinoma of the skin and/or carcinoma in situ after adequate resection, or other malignancy treated with curative intent with a disease-free interval of at least 3 years
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Subjects with poorly controlled hypertension by 2 types of antihypertensive drugs (systolic blood pressure >150 mmHg or diastolic blood pressure >100 mmHg)
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Subjects with advanced/ clinically significant lung diseases, such as poorly controlled COPD and asthma, restrictive lung disease, pulmonary hypertension etc.
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Subjects who have a history of noninfectious interstitial lung disease (ILD)/pneumonitis that required treatment with steroids, have current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening
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Subjects with stroke or transient ischemic attack (TIA) within 6 months before screening
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Subjects with a thromboembolic event (eg, deep vein thrombosis [DVT] or pulmonary embolism [PE]) within 6 months before screening except for those who are clinically stable and receiving treatment with adequate anticoagulant therapy for at least 3 weeks before screening
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Subjects with primary tumors in the central nervous system (CNS), active or untreated CNS metastases or carcinomatous meningitis should be excluded. Patients with previously treated brain metastases may participate provided they are clinically stable for at least 4 weeks and have no evidence of new or enlarging brain metastases and no requirements for corticosteroids 14 days prior to screening.
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Subjects with pre-existing Grade ≥2 peripheral neuropathy
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Subjects who have a history of anaphylaxis or severe hypersensitivity to recombinant humanized antibodies or human-mouse chimeric antibodies or any of the components of BL-M14D1
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Previous organ transplantation or allogeneic hematopoietic stem cell transplantation
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Subjects who are receiving treatment with systemic glucocorticoids >10 mg/day equivalent of prednisone, except for the treatment of chronic obstructive pulmonary disease, antiemetic, infusion reactions; however, treatment with low dose glucocorticoids (≤10 mg/day equivalent of prednisone) is permitted. The use of topical, inhaled, and locally injected steroids is permitted
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Subjects who have received treatment with anthracyclines with a cumulative dose exceeding 360 mg/m2
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Subjects with known human immunodeficiency virus infection (HIV Ab positive). Subjects are allowed to participate if all of the following criteria are met: (1) Undetectable HIV RNA and CD4 count ≥350 cells/μL at Screening, (2) No AIDS-defining opportunistic infection within 12 months prior to screening, (3) On stable antiretroviral therapy (ART) for at least 4 weeks prior to Screening with projected continuation of ART as clinically indicated while on the study
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Subjects with active hepatitis B virus (HBV) infection (positive HBsAg test). Subjects with chronic inactive HBV infection are eligible if they meet all of the following criteria:
- Have a HBV DNA viral load ≤ 500 IU/mL
- Have normal AST and ALT, OR if liver metastasis is present, has AST and ALT < 3 × ULN which are not attributed to HBV infection
- Are on antiviral treatment, as clinically indicated.
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Subjects with active hepatitis C virus (HCV) infection (HCV antibody positive and HCV RNA > the lower limit of detection). Subjects with a positive anti-HCV antibody are eligible only if PCR is negative for HCV RNA
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Subjects with active or latent tuberculosis
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Subjects with active infections requiring IV antibiotic, antiviral, or antifungal treatment, such as severe pneumonia, bacteremia, sepsis, etc., within 1 week prior to first dose of study treatment. Subjects on stable oral antimicrobials with no clinical or laboratory evidence of active infection are eligible.
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Participated in another clinical trial within 4 weeks prior to first dose of study treatment
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Subjects who are pregnant or breastfeeding, or planning to become pregnant during the study
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Other conditions that the Investigator or Sponsor believes are not suitable for participating in this clinical trial
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description Experimental BL-M14D1 administered Day 1 per cycle BL-M14D1 BL-M14D1 will be administered on Day 1 by intravenous (IV) infusion every 3 weeks
- Primary Outcome Measures
Name Time Method Participants with Dose-limiting toxicities 1 Year A DLT is defined as any of the following events:
Toxicity that results in a \>14-day delay in treatment
* Hematologic toxicities:
* Grade 4 neutrophil count decreased lasting \>7 days
* Grade ≥3 febrile neutropenia of any duration
* Grade ≥3 platelet count decreased with clinically significant hemorrhage
* Nonhematologic toxicities:
* Death not related to disease progression or extraneous cause
* Hy's law cases
* Grade ≥3 nonhematologic toxicities, except for:
* Grade 3 nausea/vomiting or diarrhea for less than 72 hours with adequate antiemetic and other supportive care
* Grade 3 fatigue for less than 1 week
* Grade ≥3 electrolyte abnormality that lasts up to 72 hours, is not clinically complicated, and resolves spontaneously or responds to conventional medical interventions
* Grade ≥3 amylase or lipase that is not associated with symptoms or clinical manifestations of pancreatitisParticipants with Serious Adverse Events (SAEs) and treatment-emergent adverse events (TEAEs) 1 Year Measuring the number of patients with serious adverse events (SAEs) and treatment-emergent adverse events (TEAEs)
Participants with abnormal physical examination findings 1 Year Measure the number of participants with abnormal physical examination findings.
Participants with ability to care for themselves, daily activity, and physical activity 1 Year Measure the change in participants with Eastern Clinical Oncology Group (ECOG) Scale of Performance Status. The scale is 0-4 with 0 being the fully active (best outcome) and 4 being completely disabled (worst outcome)
Participants with abnormal ECG and ECHO/MUGA reading 1 Year Patients with abnormal ECG parameters (including the change from-baseline ECG parameters: heart rate \[HR\]; PR; QTcF; and QRS intervals \[∆HR, ∆PR, ∆QTcF, and ∆QRS\]), and ECHO/MUGA findings
Participants with abnormal lab results 1 Year Measure the number of participants with abnormal clinical laboratory values
To determine the maximum tolerated dose (MTD) if reached or maximum administered dose (MAD) and two or more recommended doses for expansion (RDEs) of BL-M05D1 in metastatic or unresectable tumors 1 Year The actual number of subjects enrolled and dose levels to be explored in this study will depend on the MTD and/or RDE based on DLTs reported during the DLT observation period.
- Secondary Outcome Measures
Name Time Method Cmax of BL-M14D1 1 Year Calculate maximum (peak) observed concentration of BL-M14D1
Cmax of anti-DLL3 antibodies 1 Year Calculate maximum (peak) observed concentration of anti-BL-DLL3 antibodies
Cmax of free payload ED-04 1 Year Calculate maximum (peak) observed concentration of free payload ED-04
Tmax of BL-M14D1 1 Year Calculate time of maximum observed concentration of BL-M14D1
Tmax of anti-DLL3 antibodies 1 Year Calculate time of maximum observed concentration of anti-DLL3 antibodies
Tmax of free payload ED-04 1 Year Calculate time of maximum observed concentration of free payload ED-04
AUC(0-8) of BL-M05D1 1 Year Calculate area under the serum concentration-time curve of BL-M05D1 from time 0 to 8 hours
AUC(0-8) of anti-DLL3 antibodies 1 Year Calculate area under the serum concentration-time curve of anti-DLL3 antibodies from time 0 to 8 hours
AUC(0-8) of free payload ED-04 1 Year Calculate area under the serum concentration-time curve of free payload ED-04 from time 0 to 8 hours
AUC(last) of BL-M14D1 1 Year Calculate area under the serum concentration-time curve up of BL-M05D1 to the last quantifiable time 0 to 8 hours
AUC(last) of anti-DLL3 antibodies 1 Year Calculate area under the serum concentration-time curve up of anti-BL-M05D1 antibodies to the last quantifiable time 0 to 8 hours
AUC(last) of free payload ED-04 1 Year Calculate area under the serum concentration-time curve up of free payload ED-04 to the last quantifiable time
Overall Response Rate (ORR) 1 Year To assess the clinical efficacy of BL-M14D1 as measured by ORR using RECIST criteria v 1.1
Disease Control Rate (DCR) 1 Year To assess the clinical efficacy of BL-M14D1 as measured by DCR using RECIST criteria v 1.1
Time To Response (TTR) 1 Year To assess the clinical efficacy of BL-M05D1 as measured by TTR using RECIST criteria v 1.1
Progression-Free Survival (PFS) 1 Year To assess the clinical efficacy of BL-M14D1 as measured by PFS using RECIST criteria v 1.1
Overall Survival (OS) 1 Year To assess the clinical efficacy of BL-M14D1 as measured by OS using RECIST criteria v 1.1
Duration of response (DoR) 1 Year To assess the clinical efficacy of BL-M14D1 as measured by DoR using RECIST criteria v 1.1