A Study in Participants With Advanced Cancers Associated With Expression of DLL3 (MK-6070-001/HPN328-4001)

Phase 2Active Not RecruitingNCT04471727

Harpoon Therapeutics, Inc., a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA)232 enrolled

Overview

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).

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

232

Conditions

Small-Cell Lung Cancer Neuroendocrine Carcinoma

Interventions

GocatamigBIOLOGICAL

IV infusion

AtezolizumabBIOLOGICAL

IV infusion

Ifinatamab Deruxtecan (I-DXd)BIOLOGICAL

IV infusion

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: 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 Exclusion Criteria: 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-2. 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)

Locations (11)

Cedar-Sinai Medical Center, Samuel Oschin Comprehensive Cancer Institute

Los Angeles, California, United States

University of California San Francisco

San Francisco, California, United States

University of Colorado

Aurora, Colorado, United States

Outcomes

Primary Outcomes

Percentage of participants who experience an adverse event

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.

Time frame: Up to ~4 years

Percentage of participants who discontinue due to an adverse event

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.

Time frame: Up to ~4 years

Number of participants with dose limiting toxicity (DLT) following treatment with HPN328 as monotherapy or in combination with atezolizumab or I-DXd

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.

Time frame: Up to ~4 years

Maximum concentration (Cmax) of Gocatamig

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.

Data from ClinicalTrials.gov

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Dana Farber Cancer Institute

Boston, Massachusetts, United States

Karmanos Cancer Center

Detroit, Michigan, United States

Roswell Park Comprehensive Cancer Center

Buffalo, New York, United States

Memorial Sloan Kettering Cancer Center

New York, New York, United States

University Hospitals Cleveland Medical Center

Cleveland, Ohio, United States

Providence

Portland, Oregon, United States

Tennessee Oncology

Nashville, Tennessee, United States

...and 1 more locations

Time frame: At designated time points up to ~4 years

Cmax of Atezolizumab

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.

Time frame: At designated time points up to ~4 years

Cmax of I-DXd

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 frame: At designated time points up to ~4 years

Time to maximum concentration (Tmax) of Gocatamig

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.

Time frame: At designated time points up to ~4 years

Tmax of atezolizumab

Time frame: At designated time points up to ~4 years

Tmax of I-DXd

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.

Time frame: At designated time points up to ~4 years

Area under the concentration-time curve over the dosing interval t (AUCt) of Gocatamig

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.

Time frame: At designated time points up to ~4 years

AUCt of atezolizumab

Time frame: At designated time points up to ~4 years

AUCt of I-DXd

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.

Time frame: At designated time points up to ~4 years

Area under the concentration-time curve extrapolated to infinity (AUCinf) of Gocatamig

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.

Time frame: At designated time points up to ~4 years

AUCinf of atezolizumab

Time frame: At designated time points up to ~4 years

AUCinf of I-DXd

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.

Time frame: At designated time points up to ~4 years

Terminal half-life (t1/2) of Gocatamig

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.

Time frame: At designated time points up to ~4 years

t1/2 of atezolizumab

Time frame: At designated time points up to ~4 years

t1/2 of I-DXd

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.

Time frame: At designated time points up to ~4 years

Single dose clearance (CL) of Gocatamig

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.

Time frame: At designated time points up to ~4 years

CL of atezolizumab

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.

Time frame: At designated time points up to ~4 years

CL of I-DXd

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.

Time frame: At designated time points up to ~4 years

Steady state maximum concentration (Cmax,ss) of Gocatamig

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.

Time frame: At designated time points up to ~4 years

Cmax,ss of atezolizumab

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.

Time frame: At designated time points up to ~4 years

Cmax,ss of I-DXd

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.

Time frame: At designated time points up to ~4 years

Steady state Ctrough (Ctrough,ss) of Gocatamig

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.

Time frame: At designated time points up to ~4 years

Ctrough,ss of atezolizumab

Time frame: At designated time points up to ~4 years

Ctrough,ss of I-DXd

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.

Time frame: At designated time points up to ~4 years

Steady state time to maximum concentration (Tmax,ss) of Gocatamig

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.

Time frame: At designated time points up to ~4 years

Tmax,ss of atezolizumab

Time frame: At designated time points up to ~4 years

Tmax,ss of I-DXd

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.

Time frame: At designated time points up to ~4 years

Area under the steady state concentration-time curve over dosing interval t (AUCt,ss) of Gocatamig

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.

Time frame: At designated time points up to ~4 years

AUCt,ss of atezolizumab

Time frame: At designated time points up to ~4 years

AUCt,ss of I-DXd

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.

Time frame: At designated time points up to ~4 years

Steady state t1/2 (t1/2,ss) of Gocatamig

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.

Time frame: At designated time points up to ~4 years

t1/2,ss of Gocatamig with atezolizumab

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.

Time frame: At designated time points up to ~4 years

t1/2,ss of IDXd

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.

Time frame: At designated time points up to ~4 years

Steady state CL (CL,ss) of Gocatamig

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.

Time frame: At designated time points up to ~4 years

CL,ss of Gocatamig with atezolizumab

Time frame: At designated time points up to ~4 years

CL,ss of I-DXd

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.

Time frame: At designated time points up to ~4 years

Steady state volume of distribution (V,ss) of Gocatamig

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.

Time frame: At designated time points up to ~4 years

V,ss of atezolizumab

Time frame: At designated time points up to ~4 years

V,ss of I-DXd

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.

Time frame: At designated time points up to ~4 years

Steady state accumulation ratio (AC) of Gocatamig

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.

Time frame: At designated time points up to ~4 years

AC of atezolizumab

Time frame: At designated time points up to ~4 years

AC of I-DXd

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.

Time frame: At designated time points up to ~4 years

Secondary Outcomes

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))

ORR is defined as the percentage of participants with Complete Response (CR: disappearance of all target lesions) or Partial Response (PR: at least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1. Participants with NEPC will be evaluated using PCWG3-modified RECIST v1.1. ORR will be presented.

Time frame: Up to ~4 years

Extra-cranial objective response rate (EC-ORR) based on modified RECIST v1.1

EC-ORR is defined as the percentage of participants with Complete Response (CR: disappearance of all target lesions) or Partial Response (PR: at least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1 considering extra-cranial disease (i.e. exclusive of brain metastases). Participants with NEPC will be evaluated using PCWG3-modified RECIST v1.1 considering extra-cranial disease. EC-ORR will be presented.

Time frame: Up to ~4 years

Best Overall Response (BOR)

BOR is defined as the participants' best disease response during the study given a hierarchy of objective response results CR: disappearance of all target lesions per RECIST 1.1 \> PR: at least a 30% decrease in the sum of diameters of target lesions per RECIST 1.1 \> stable disease (SD): neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum on study \> progressive disease (PD): at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (nadir), including baseline. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. \> not all evaluated/non-PD (NE): persistence of one or more non-target lesions and/or (if applicable) maintenance of tumor marker level above the normal limits. Percentage of participants in each BOR category will be presented.

Time frame: Up to ~4 years

Progression-free survival (PFS)

PFS is defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurs first as assessed by Response Criteria in Solid Tumors Version 1.1 (RECIST 1.1). PD is defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions is also considered PD. Participants with NEPC will be evaluated using PCWG3-modified RECIST v1.1 PFS will be presented.

Time frame: Up to ~4 years

Extra-cranial progression free survival (EC-PFS)

EC-PFS is defined as the time from randomization to the first documented extra-cranial progressive disease (PD) or death due to any cause, whichever occurs first as assessed by Response Criteria in Solid Tumors Version 1.1 (RECIST 1.1). PD is defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions is also considered PD. Participants with NEPC will be evaluated using PCWG3-modified RECIST v1.1. EC-PFS will be presented.

Time frame: Up to ~4 years

Overall survival (OS)

OS is defined as the time from first dose of study drug to death due to any cause (summarized descriptively using Kaplan Meier method). OS will be presented.

Time frame: Up to ~4 years

Duration of response (DOR)

For participants who demonstrate a confirmed Complete Response (CR: disappearance of all target lesions) or Partial Response (PR: at least a 30% decrease in the sum of diameters of target lesions) per Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST 1.1), DOR is defined as the time from first documented evidence of CR or PR until progressive disease (PD) or death. Per RECIST 1.1, PD is defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered PD. Participants with NEPC will be evaluated using PCWG3-modified RECIST v1.1. DOR will be presented.

Time frame: Up to ~4 years

Duration of extra-cranial response (EC-DOR)

For participants who demonstrate a confirmed Complete Response (CR: disappearance of all target lesions) or Partial Response (PR: at least a 30% decrease in the sum of diameters of target lesions) per Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST 1.1), EC-DOR is defined as the time from first documented evidence of CR or PR until progressive disease (PD) or death. Per RECIST 1.1 considering only extra-cranial disease (i.e., exclusive of brain metastases), PD is defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered PD. Participants with NEPC will be evaluated using PCWG3-modified RECIST v1.1. EC-DOR as assessed will be presented.

Time frame: Up to ~4 years

Incidence of anti-drug antibodies (ADAs) against Gocatamig

Blood samples collected at designated timepoints will be used to determine the ADA response to gocatamig. The incidence of ADAs for gocatamig will be presented.

Time frame: At designated time points up to ~4 years

Incidence of ADAs against atezolizumab (for combination-treatment patients)

Blood samples collected at designated timepoints will be used to determine the ADA response to atezolizumab. The incidence of ADAs for atezolizumab will be presented.

Time frame: At designated time points up to ~4 years

Incidence of ADAs against I-DXd (for combination-treatment patients)

Blood samples collected at designated timepoints will be used to determine the ADA response to I-DXd. The incidence of ADAs for I-DXd will be presented.

Time frame: At designated time points up to ~4 years