A Phase 1/2 Open-label, Multicenter, Dose Escalation and Dose Expansion Study of the Safety, Tolerability, and Pharmacokinetics of HPN328 Monotherapy and HPN328 With Atezolizumab or Ifinatamab Deruxtecan (I-DXd) in Patients With Advanced Cancers Associated With Expression of Delta-like Canonical Notch Ligand 3 (DLL3).
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 发起方
- 入组人数
- 232
- 试验地点
- 11
- 主要终点
- Percentage of participants who experience an adverse event
研究概览
简要总结
This study will investigate the maximum tolerated dose, the recommended dose for expansion (RDE), safety, efficacy, and pharmacokinetics of gocatamig alone, gocatamig with Atezolizumab and gocatamig with I-DXd in participants with advanced cancers associated with expression of Delta-like Canonical Notch Ligand 3 (DLL3).
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None (Participant)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •The main inclusion criteria include but are not limited to the following:
- •Has a histologically or cytologically confirmed malignancy associated with expression of Delta-like Canonical Notch Ligand 3 (DLL3)
- •Has small cell lung cancer (SCLC) which is relapsed/refractory following at least 1 prior line of systemic therapy that included platinum-based chemotherapy
- •Has Neuroendocrine Prostate Cancer (NEPC; de novo or treatment-emergent) which is relapsed/refractory to standard systemic therapy
- •Has high-grade neuroendocrine tumor types other than SCLC and NEPC, with at least one of the following:
- •Disease that is relapsed/refractory to standard systemic therapy
- •Disease for which standard therapy does not exist
- •Disease for which standard therapy is not considered appropriate by the Investigator
- •Must be able to provide archival tissue sample or fresh biopsy tissue sample
排除标准
- •The main exclusion criteria include but are not limited to the following:
- •Has untreated central nervous system (CNS) metastases
- •Has a glioma or other primary CNS malignancy
- •Has spinal cord compression or symptomatic/uncontrolled epidural disease
- •Has a history of intracranial hemorrhage or spinal cord hemorrhage
- •Has active neurologic paraneoplastic syndrome
- •Has uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (e.g., biweekly or more frequently)
- •Has active or history of autoimmune disease or immune deficiency, including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, psoriatic arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome, or multiple sclerosis
- •Is ongoing treatment with immunosuppressive medications (including, but not limited to, systemic corticosteroids [prednisone dose >10mg per day or equivalent], cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor [TNF] alpha agents) within 2 weeks prior to initiation of treatment, or anticipation of need for systemic immunosuppressive medication during study treatment (except protocol-required pre-medications)
- •Has a history of clinically significant cardiovascular disease such as myocardial infarction, symptomatic congestive heart failure (New York Heart Association > class II), and/or uncontrolled cardiac arrhythmia within 6 months of the first dose of study drug
- •Has a history of arterial thrombosis (e.g., stroke or transient ischemic attack) within 6 months
- •Has active viral hepatitis, defined as hepatitis A (hepatitis A virus immunoglobulin M [IgM] positive), hepatitis B (hepatitis B virus surface antigen [HbsAg] positive), or hepatitis C (hepatitis C virus [HCV] antibody positive, confirmed by HCV ribonucleic acid). HCV with undetectable virus after treatment are eligible. Hepatitis B virus (HBV) with undetectable viral load by quantitative polymerase chain reaction (PCR) are eligible.
- •Has uncontrolled infection with Human Immunodeficiency Virus (HIV)-1 or HIV-
- •Well-controlled HIV are eligible.
- •Has a history of allogeneic stem cell transplant or solid-organ transplant
- •Has had 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
- •Has a history of severe anaphylactic reactions to chimeric or humanized antibodies or fusion proteins
- •Has a history of interstitial lung disease, 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). History of radiation pneumonitis in the radiation field is permitted
- •Has had treatment with other investigational drug within 3 weeks of scheduled dosing (or 5 half-lives of drug, whichever is shorter)
研究组 & 干预措施
Gocatamig monotherapy dose escalation with 1 week dosing interval
Participants will receive gocatamig once weekly (Q1W) via intravenous (IV) infusion during each 21-day cycle. Dose escalation may continue until one or more RDEs are identified, participant discontinuation or the Sponsor decides to stop enrollment.
干预措施: Gocatamig (Biological)
Gocatamig monotherapy dose escalation with 2 week dosing interval
Participants will receive gocatamig via IV infusion once every 2 weeks (Q2W) of a 28-day cycle. Dose escalation may continue until one or more RDEs are identified, participant discontinuation, or the Sponsor decides to stop enrollment.
干预措施: Gocatamig (Biological)
Gocatamig monotherapy dose escalation with 3 week dosing interval
Participants will receive gocatamig via IV infusion once every 3 weeks (Q3W) of a 21-day cycle. Dose escalation may continue until one or more RDEs are identified, participant discontinuation, or the Sponsor decides to stop enrollment.
干预措施: Gocatamig (Biological)
Gocatamig dose escalation with atezolizumab
Small cell lung cancer (SCLC) participants will receive gocatamig via IV infusion Q2W during each 28-day cycle and Atezolizumab via IV infusion every 4 weeks (Q4W) on Day 1 of each 28-day cycle. Dose escalation may continue until one or more RDEs are identified, participant discontinuation, or the Sponsor decides to stop enrollment.
干预措施: Gocatamig (Biological)
Gocatamig dose escalation with atezolizumab
Small cell lung cancer (SCLC) participants will receive gocatamig via IV infusion Q2W during each 28-day cycle and Atezolizumab via IV infusion every 4 weeks (Q4W) on Day 1 of each 28-day cycle. Dose escalation may continue until one or more RDEs are identified, participant discontinuation, or the Sponsor decides to stop enrollment.
干预措施: Atezolizumab (Biological)
Gocatamig dose escalation in combination with I-DXd
SCLC participants will receive gocatamig via IV infusion Q2W during each 42-day cycle and I-DXd via IV infusion Q3W on Day 1 and Day 22 of each 42-day cycle. Dose escalation may continue until one or more RDEs are identified, participant discontinuation, or the Sponsor decides to stop enrollment.
干预措施: Gocatamig (Biological)
Gocatamig dose escalation in combination with I-DXd
SCLC participants will receive gocatamig via IV infusion Q2W during each 42-day cycle and I-DXd via IV infusion Q3W on Day 1 and Day 22 of each 42-day cycle. Dose escalation may continue until one or more RDEs are identified, participant discontinuation, or the Sponsor decides to stop enrollment.
干预措施: Ifinatamab Deruxtecan (I-DXd) (Biological)
结局指标
主要结局
Percentage of participants who experience an adverse event
时间窗: Up to ~4 years
An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an AE. AEs will be graded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTACAE) version 5.0 (American Society for Transplant and Cellular Therapy (ASTCT) grading criteria for cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS)). The percentage of participants who experience an AE in the study will be presented.
Percentage of participants who discontinue due to an adverse event
时间窗: Up to ~4 years
An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an AE. AEs will be graded according to NCI CTACAE version 5.0 (ASTCT grading criteria for CRS and ICANS). The percentage of participants who discontinue due to an AE in the study will be presented.
Number of participants with dose limiting toxicity (DLT) following treatment with HPN328 as monotherapy or in combination with atezolizumab or I-DXd
时间窗: Up to ~4 years
A DLT is defined as an AE that represents a clinically significant shift from baseline and must be considered related or suspected to be related to study drug (gocatamig and/or atezolizumab or I-DXd) by the Investigator or Sponsor. AEs will be graded according to NCI CTACAE version 5.0 (ASTCT grading criteria for CRS and ICANS). The number of participants with a DLT will be presented.
Maximum concentration (Cmax) of Gocatamig
时间窗: At designated time points up to ~4 years
Cmax is the maximum concentration of the drug observed in serum. Blood samples collected pre dose and at multiple timepoints post dose will be used to determine Cmax of gocatamig.
Cmax of Atezolizumab
时间窗: At designated time points up to ~4 years
Cmax is the maximum concentration of the drug observed in serum. Blood samples collected pre dose and at multiple timepoints post dose will be used to determine Cmax of Atezolizumab.
Cmax of I-DXd
时间窗: At designated time points up to ~4 years
Cmax is the maximum concentration of the drug observed in plasma. Blood samples collected pre dose and at multiple timepoints post dose will be used to determine Cmax of I-DXd.
Time to maximum concentration (Tmax) of Gocatamig
时间窗: At designated time points up to ~4 years
Tmax is the amount of time that a drug is present at the maximum concentration observed in serum. Blood samples collected pre dose and at multiple timepoints post dose will be used to determine the Tmax of gocatamig.
Tmax of atezolizumab
时间窗: At designated time points up to ~4 years
Tmax is the amount of time that a drug is present at the maximum concentration observed in serum. Blood samples collected pre dose and at multiple timepoints post dose will be used to determine the Tmax of atezolizumab.
Tmax of I-DXd
时间窗: At designated time points up to ~4 years
Tmax is the amount of time that a drug is present at the maximum concentration observed in plasma. Blood samples collected pre dose and at multiple timepoints post dose will be used to determine the Tmax of I-DXd.
Area under the concentration-time curve over the dosing interval t (AUCt) of Gocatamig
时间窗: At designated time points up to ~4 years
AUC is a measure of serum drug concentration and time and is estimated as the area under the plot of serum concentration against time after drug administration. Blood samples collected pre dose and at multiple timepoints post dose will be used to determine t (AUCt) of gocatamig.
AUCt of atezolizumab
时间窗: At designated time points up to ~4 years
AUC is a measure of serum drug concentration and time and is estimated as the area under the plot of serum concentration against time after drug administration. Blood samples collected pre dose and at multiple timepoints post dose will be used to determine t (AUCt) of atezolizumab.
AUCt of I-DXd
时间窗: At designated time points up to ~4 years
AUC is a measure of plasma drug concentration and time and is estimated as the area under the plot of plasma concentration against time after drug administration. Blood samples collected pre dose and at multiple timepoints post dose will be used to determine t (AUCt) of I-DXd.
Area under the concentration-time curve extrapolated to infinity (AUCinf) of Gocatamig
时间窗: At designated time points up to ~4 years
AUCinf is a measure of serum drug concentration and time to infinity and is estimated as the area under the plot of serum concentration against time to infinity after drug administration. Blood samples collected at multiple timepoints post-dose will be used to determine the AUCinf of gocatamig.
AUCinf of atezolizumab
时间窗: At designated time points up to ~4 years
AUCinf is a measure of serum drug concentration and time to infinity and is estimated as the area under the plot of serum concentration against time to infinity after drug administration. Blood samples collected at multiple timepoints post-dose will be used to determine the AUCinf of atezolizumab.
AUCinf of I-DXd
时间窗: At designated time points up to ~4 years
AUCinf is a measure of plasma drug concentration and time to infinity and is estimated as the area under the plot of plasma concentration against time to infinity after drug administration. Blood samples collected at multiple timepoints post-dose will be used to determine the AUCinf of I-DXd.
Terminal half-life (t1/2) of Gocatamig
时间窗: At designated time points up to ~4 years
t1/2 is a measure of how long it takes to clear 50% of the drug from serum after reaching Cmax. Blood samples collected pre dose and at multiple timepoints post dose will be used to determine the t1/2 of gocatamig.
t1/2 of atezolizumab
时间窗: At designated time points up to ~4 years
t1/2 is a measure of how long it takes to clear 50% of the drug from serum after reaching Cmax. Blood samples collected pre dose and at multiple timepoints post dose will be used to determine the t1/2 of atezolizumab.
t1/2 of I-DXd
时间窗: At designated time points up to ~4 years
t1/2 is a measure of how long it takes to clear 50% of the drug from plasma after reaching Cmax. Blood samples collected pre dose and at multiple timepoints post dose will be used to determine the t1/2 of I-DXd.
Single dose clearance (CL) of Gocatamig
时间窗: At designated time points up to ~4 years
CL is the apparent total clearance of the drug from serum after oral administration. Blood samples collected pre dose and at multiple timepoints post dose will be used to determine CL of gocatamig.
CL of atezolizumab
时间窗: At designated time points up to ~4 years
CL is the apparent total clearance of the drug from serum after oral administration. Blood samples collected pre dose and at multiple timepoints post dose will be used to determine CL of atezolizumab.
CL of I-DXd
时间窗: At designated time points up to ~4 years
CL is the apparent total clearance of the drug from plasma after oral administration. Blood samples collected pre dose and at multiple timepoints post dose will be used to determine CL of I-DXd.
Steady state maximum concentration (Cmax,ss) of Gocatamig
时间窗: At designated time points up to ~4 years
Cmax,ss is the maximum concentration of the drug in serum observed in serum under steady state conditions. Blood samples collected pre dose and at multiple timepoints post dose will be used to determine Cmax,ss of gocatamig.
Cmax,ss of atezolizumab
时间窗: At designated time points up to ~4 years
Cmax,ss is the maximum concentration of the drug observed in serum under steady state conditions. Blood samples collected pre dose and at multiple timepoints post dose will be used to determine Css,max of atezolizumab.
Cmax,ss of I-DXd
时间窗: At designated time points up to ~4 years
Cmax,ss is the maximum concentration of the drug observed in plasma under steady state conditions. Blood samples collected pre dose and at multiple timepoints post dose will be used to determine Cmax,ss of I-DXd.
Steady state Ctrough (Ctrough,ss) of Gocatamig
时间窗: At designated time points up to ~4 years
Ctrough,ss is the lowest concentration reached by a drug in serum under steady state conditions before the next dose is administered. Blood samples collected pre dose and at multiple timepoints post dose will be used to determine Ctrough,ss of gocatamig.
Ctrough,ss of atezolizumab
时间窗: At designated time points up to ~4 years
Ctrough,ss is the lowest concentration reached by a drug in serum under steady state conditions before the next dose is administered. Blood samples collected pre dose and at multiple timepoints post dose will be used to determine Ctrough,ss of atezolizumab.
Ctrough,ss of I-DXd
时间窗: At designated time points up to ~4 years
Ctrough,ss is the lowest concentration reached by a drug in plasma under steady state conditions before the next dose is administered. Blood samples collected pre dose and at multiple timepoints post dose will be used to determine Ctrough,ss of I-DXd.
Steady state time to maximum concentration (Tmax,ss) of Gocatamig
时间窗: At designated time points up to ~4 years
Tmax,ss is the amount of time that a drug is present at the maximum concentration observed in serum under steady state conditions. Blood samples collected pre dose and at multiple timepoints post dose will be used to determine the Tmax,ss of gocatamig.
Tmax,ss of atezolizumab
时间窗: At designated time points up to ~4 years
Tmax,ss is the amount of time that a drug is present at the maximum concentration observed in serum under steady state conditions. Blood samples collected pre dose and at multiple timepoints post dose will be used to determine the Tmax,ss of atezolizumab.
Tmax,ss of I-DXd
时间窗: At designated time points up to ~4 years
Tmax,ss is the amount of time that a drug is present at the maximum concentration observed in plasma under steady state conditions. Blood samples collected pre dose and at multiple timepoints post dose will be used to determine the Tmax,ss of I-DXd.
Area under the steady state concentration-time curve over dosing interval t (AUCt,ss) of Gocatamig
时间窗: At designated time points up to ~4 years
AUCt,ss is a measure of serum drug concentration and time and is estimated as the area under the plot of serum concentration against time after drug administration under steady state conditions. Blood samples collected pre dose and at multiple timepoints post dose will be used to determine AUCt,ss of gocatamig.
AUCt,ss of atezolizumab
时间窗: At designated time points up to ~4 years
AUCt,ss is a measure of serum drug concentration and time and is estimated as the area under the plot of serum concentration against time after drug administration under steady state conditions. Blood samples collected pre dose and at multiple timepoints post dose will be used to determine AUCt,ss of atezolizumab.
AUCt,ss of I-DXd
时间窗: At designated time points up to ~4 years
AUCt,ss is a measure of plasma drug concentration and time and is estimated as the area under the plot of plasma concentration against time after drug administration under steady state conditions. Blood samples collected pre dose and at multiple timepoints post dose will be used to determine AUCt,ss of I-DXd.
Steady state t1/2 (t1/2,ss) of Gocatamig
时间窗: At designated time points up to ~4 years
t1/2,ss is a measure of how long it takes to clear 50% of the drug in serum after reaching Cmax under steady state conditions. Blood samples collected pre dose and at multiple timepoints post dose will be used to determine the t1/2,ss of gocatamig.
t1/2,ss of Gocatamig with atezolizumab
时间窗: At designated time points up to ~4 years
t1/2,ss is a measure of how long it takes to clear 50% of the drug after reaching Cmax under steady state conditions. Blood samples collected pre dose and at multiple timepoints post dose will be used to determine the t1/2,ss of atezolizumab.
t1/2,ss of IDXd
时间窗: At designated time points up to ~4 years
t1/2,ss is a measure of how long it takes to clear 50% of the drug in plasma after reaching Cmax under steady state conditions. Blood samples collected pre dose and at multiple timepoints post dose will be used to determine the t1/2,ss of I-DXd.
Steady state CL (CL,ss) of Gocatamig
时间窗: At designated time points up to ~4 years
CL,ss is the apparent total clearance of the drug from serum after administration under steady state conditions. Blood samples collected pre dose and at multiple timepoints post dose will be used to determine CL,ss of gocatamig.
CL,ss of Gocatamig with atezolizumab
时间窗: At designated time points up to ~4 years
CL,ss is the apparent total clearance of the drug from serum after administration under steady state conditions. Blood samples collected pre dose and at multiple timepoints post dose will be used to determine CL,ss of atezolizumab.
CL,ss of I-DXd
时间窗: At designated time points up to ~4 years
CL,ss is the apparent total clearance of the drug from plasma after administration under steady state conditions. Blood samples collected pre dose and at multiple timepoints post dose will be used to determine CL,ss of I-DXd.
Steady state volume of distribution (V,ss) of Gocatamig
时间窗: At designated time points up to ~4 years
V,ss is defined as the volume of distribution in serum under steady state conditions. Blood samples collected pre dose and at multiple timepoints post dose will be used to determine the V,ss of gocatamig.
V,ss of atezolizumab
时间窗: At designated time points up to ~4 years
V,ss is defined as the volume of distribution in serum under steady state conditions. Blood samples collected pre dose and at multiple timepoints post dose will be used to determine the V,ss of atezolizumab.
V,ss of I-DXd
时间窗: At designated time points up to ~4 years
V,ss is defined as the volume of distribution in plasma under steady state conditions. Blood samples collected pre dose and at multiple timepoints post dose will be used to determine the V,ss of I-DXd.
Steady state accumulation ratio (AC) of Gocatamig
时间窗: At designated time points up to ~4 years
AC is the ratio of accumulation of a drug in serum under steady state conditions after repeated administration as compared to a single dose. Blood samples collected pre dose and at multiple timepoints post dose will be used to determine AC of gocatamig.
AC of atezolizumab
时间窗: At designated time points up to ~4 years
AC is the ratio of accumulation of a drug in serum under steady state conditions after repeated administration as compared to a single dose. Blood samples collected pre dose and at multiple timepoints post dose will be used to determine AC of atezolizumab.
AC of I-DXd
时间窗: At designated time points up to ~4 years
AC is the ratio of accumulation of a drug in plasma under steady state conditions after repeated administration as compared to a single dose. Blood samples collected pre dose and at multiple timepoints post dose will be used to determine AC of I-DXd.
次要结局
- Objective response rate (ORR) based on Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) (Prostate cancer clinical trials working group 3 (PCWG3) for participants with neuroendocrine prostate cancer (NEPC))(Up to ~4 years)
- Extra-cranial objective response rate (EC-ORR) based on modified RECIST v1.1(Up to ~4 years)
- Best Overall Response (BOR)(Up to ~4 years)
- Progression-free survival (PFS)(Up to ~4 years)
- Extra-cranial progression free survival (EC-PFS)(Up to ~4 years)
- Overall survival (OS)(Up to ~4 years)
- Duration of response (DOR)(Up to ~4 years)
- Duration of extra-cranial response (EC-DOR)(Up to ~4 years)
- Incidence of anti-drug antibodies (ADAs) against Gocatamig(At designated time points up to ~4 years)
- Incidence of ADAs against atezolizumab (for combination-treatment patients)(At designated time points up to ~4 years)
- Incidence of ADAs against I-DXd (for combination-treatment patients)(At designated time points up to ~4 years)