Clinical trial NCT03792841: Safety, Tolerability, Pharmacokinetics, and Efficacy of Acapatamab in Subjects With mCRPC
Official title: A Phase 1 Study Evaluating the Safety, Tolerability, Pharmacokinetics, and Efficacy of Prostate Specific Membrane Antigen Half-life Extended Bispecific T-cell Engager Acapatamab in Subjects With Metastatic Castration-resistant Prostate Cancer
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Metastatic Castration-resistant Prostate Cancer
Prostate Cancer
Keywords: acapatamab
HLE-BiTE®
mCRPC
Metastatic Castration-resistant Prostate Cancer
Prostate cancer
PSMA
BiTE®
Bispecific T-Cell engager
Immunotherapy
Immuno-oncology
Immunooncology
Solid tumor
PSMA Targeted Therapy
Lead sponsor: Amgen
Sponsor class: INDUSTRY
First posted: 2019-01-03
Enrollment: 212
Sex: MALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: A phase 1 study evaluating the safety, tolerability, pharmacokinetics, and efficacy of prostate specific membrane antigen half-life extended bispecific T-cell engager acapatamab in subjects with metastatic castration-resistant prostate cancer, and to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D).

Detailed description: This is a phase I, first-in-human study to evaluate the safety and tolerability of acapatamab; a half-life extended (HLE) bispecific T-cell engager (BiTE®) construct, alone and in combination with pembrolizumab, etanercept prophylaxis and cytochrome P450 (CYP) phenotyping cocktail in subjects with metastatic castration-resistant prostate cancer.

Eligibility criteria: All Parts

Inclusion Criteria:

* Subject has provided informed consent prior to initiation of any study specific activities/procedures
* Subjects with histologically or cytologically confirmed mCRPC who are refractory to a novel antiandrogen therapy (abiraterone, enzalutamide, and/or apalutamide) and have failed at least 1 (but not more than 2) taxane regimens (or who are deemed medically unsuitable to be treated with a taxane regimen or have actively refused treatment with a taxane regimen). Progression on novel antiandrogen therapy may have occurred in the non-metastatic CRPC setting
* Subjects must have undergone bilateral orchiectomy or must be on continuous ADT with a gonadotropin releasing hormone (GnRH) agonist or antagonist
* Total serum testosterone \</= 50 ng/dL or 1.7 nmol/L
* Evidence of progressive disease, defined as 1 or more PCWG3 criteria:
* PSA level \>/= 1 ng/mL that has increased on at least 2 successive occasions at least 1 week apart
* nodal or visceral progression as defined by RECIST 1.1 with PCGW3 modifications
* appearance of 2 or more new lesions in bone scan
* Eastern Cooperative Oncology Group (ECOG) performance status of 0 - 1
* Life expectancy \>/= 6months

Exclusion Criteria:

* Any anticancer therapy or immunotherapy within 4 weeks of start of first dose, not including luteinizing hormone-releasing hormone agonist (LHRH)/GnRH analogue (agonist/antagonist). Subjects on a stable bisophosphonate or denosumab regimen for \>/= 30 days prior to randomization are eligible
* Prior PSMA-targeted therapy (subjects on prior therapy may be eligible if discussed with Amgen medical monitor prior to enrollment)
* Central nervous system (CNS) metastases, leptomeningeal disease, or spinal cord compression
* Active autoimmune disease or any other diseases requiring immunosuppressive therapy while on study
* Needing chronic systemic corticosteroid therapy (prednisone \> 10 mg per day or equivalent) or any other immunosuppressive therapies (including anti-tumor necrosis factor alpha \[TNF alpha\] therapies) unless stopped 7 days prior to start of first dose
* Myocardial infarction, unstable angina, cardiac arrhythmia requiring medication, and/or symptomatic congestive heart failure (New York Heart Association \> class II) within 12 months of first dose of acapatamab

Part 2 only:

* Subjects on a prior PD-1 or PD-L1 inhibitor who experienced a Grade 3 or higher immune-related adverse event prior to first day of dosing
* History or evidence of interstitial lung disease or active, non-infectious pneumonitis

Part 3 only:

- Evidence of active tuberculosis on chest radiograph within 3 months prior to the first dose of investigational product

Part 6 only:

Subjects are excluded from this cohort if any of the following additional criteria apply:

* Subjects taking strong OAT3 inhibitors (eg, probenecid) or adjust the dosing to 1 mg PO QD.
* Subjects with latent or active tuberculosis at screening

Primary outcomes:
measure: Number of participants with dose-limiting toxicity
timeFrame: Up to 3 years
measure: Number of participants with treatment-emergent adverse events
timeFrame: Up to 3 years
measure: Number of participants with treatment-related adverse events
timeFrame: Up to 3 years
measure: Number of participants with clinically significant changes in vital signs
timeFrame: Up to 3 years
measure: Number of participants with clinically significant changes in electrocardiogram (ECG)
timeFrame: Up to 3 years
measure: Number of participants with clinically significant changes in clinical laboratory tests
timeFrame: Up to 3 years
Secondary outcomes:
measure: Maximum serum concentration (Cmax) of acapatamab
timeFrame: Up to 3 years
measure: Minimum serum concentration (Cmin) of acapatamab
timeFrame: Up to 3 years
measure: Area under the concentration-time curve (AUC) over the dosing interval of acapatamab
timeFrame: Up to 3 years
measure: Accumulation ratio of acapatamab
timeFrame: Up to 3 years
measure: Half-life of acapatamab
timeFrame: Up to 3 years
measure: Objective response (OR)
timeFrame: Up to 3 years
measure: Prostate-specific antigen (PSA) response
timeFrame: Up to 3 years
measure: Duration of response (DOR) (radiographic and PSA)
timeFrame: Up to 3 years
measure: Percentage of participants experiencing a response based on 68Gallium (68Ga)-prostate-specific membrane antigen (PSMA)-11 positron emission tomography (PET)/computed tomography (CT) response evaluations
timeFrame: Up to 3 years
measure: Percentage of participants experiencing a response based on 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) response evaluations
timeFrame: Up to 3 years
measure: Change in time to progression (radiographic and PSA)
timeFrame: Up to 3 years
measure: Progression-free survival (PFS) (radiographic and PSA)
timeFrame: Up to 3 years
measure: 1, 2 and 3-year overall survival (OS)
timeFrame: Up to 3 years
measure: Percentage of participants experiencing circulating tumor cells (CTC) response
timeFrame: Up to 3 years
measure: Other PCWG3-recommended endpoints - time to symptomatic skeletal events
timeFrame: Up to 3 years
measure: Other PCWG3-recommended endpoints - lactate dehydrogenase [LDH] levels
timeFrame: Up to 3 years
measure: Other PCWG3-recommended endpoints - hemoglobin levels
timeFrame: Up to 3 years
measure: Other PCWG3-recommended endpoints - neutrophil-to-lymphocyte ratio
timeFrame: Up to 3 years
measure: Other PCWG3-recommended endpoints - urine N-telopeptide levels
timeFrame: Up to 3 years
measure: Other PCWG3-recommended endpoints - alkaline phosphatase [total, bone] levels
timeFrame: Up to 3 years
measure: Maximum serum concentration (Cmax) of acapatamab when administered with CYP enzymes
timeFrame: Up to 3 years
measure: Area under the concentration-time curve over a 24-hour period (AUC24) of acapatamab when administered with CYP enzymes
timeFrame: Up to 3 years
measure: Half-life of acapatamab when administered with CYP enzymes
timeFrame: Up to 3 years
Other outcomes:
Locations:
city: Campbell
country: United States
facility: El Camino Hospital
state: California
city: Duarte
country: United States
facility: City of Hope National Medical Center
state: California
city: Long Beach
country: United States
facility: City of Hope at Long Beach Elm
state: California
city: Los Angeles
country: United States
facility: University of California Los Angeles
state: California
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Indianapolis
country: United States
facility: Indiana University
state: Indiana
city: Iowa City
country: United States
facility: University of Iowa Hospitals and Clinics
state: Iowa
city: New Orleans
country: United States
facility: Tulane Medical Center
state: Louisiana
city: Saint Louis
country: United States
facility: Washington University
state: Missouri
city: Las Vegas
country: United States
facility: Comprehensive Cancer Centers of Nevada
state: Nevada
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: New York
country: United States
facility: Weill Cornell Medical College
state: New York
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center
state: Texas
city: Camperdown
country: Australia
facility: Chris OBrien Lifehouse
state: New South Wales
city: Randwick
country: Australia
facility: Scientia Clinical Research Ltd
state: New South Wales
city: Parkville
country: Australia
facility: Peter MacCallum Cancer Centre
state: Victoria
city: Linz
country: Austria
facility: Ordensklinikum Linz Elisabethinen
city: Salzburg
country: Austria
facility: Landeskrankenhaus Salzburg
city: Wien
country: Austria
facility: Krankenhaus der Barmherzigen Brueder Wien
city: Wien
country: Austria
facility: Universitaetsklinikum Allgemeines Krankenhaus Wien
city: Bruxelles
country: Belgium
facility: Universite Catholique de Louvain Cliniques Universitaires Saint Luc
city: Gent
country: Belgium
facility: Universitair Ziekenhuis Gent
city: Vancouver
country: Canada
facility: BC Cancer Vancouver
state: British Columbia
city: Villejuif Cedex
country: France
facility: Institut Gustave Roussy
city: Kashiwa-shi
country: Japan
facility: National Cancer Center Hospital East
state: Chiba
city: Yokohama-shi
country: Japan
facility: Yokohama City University Medical Center
state: Kanagawa
city: Rotterdam
country: Netherlands
facility: Erasmus Medisch Centrum
city: Singapore
country: Singapore
facility: National University Hospital
city: Singapore
country: Singapore
facility: National Cancer Centre Singapore
city: Taoyuan
country: Taiwan
facility: Linkou Chang Gung Memorial Hospital of Chang Gung Medical Foundation
Study officials:
affiliation: Amgen
name: MD
role: STUDY_DIRECTOR
References:
citation: Dorff T, Horvath LG, Autio K, Bernard-Tessier A, Rettig MB, Machiels JP, Bilen MA, Lolkema MP, Adra N, Rottey S, Greil R, Matsubara N, Tan DSW, Wong A, Uemura H, Lemech C, Meran J, Yu Y, Minocha M, McComb M, Penny HL, Gupta V, Hu X, Jurida G, Kouros-Mehr H, Janat-Amsbury MM, Eggert T, Tran B. A Phase I Study of Acapatamab, a Half-life Extended, PSMA-Targeting Bispecific T-cell Engager for Metastatic Castration-Resistant Prostate Cancer. Clin Cancer Res. 2024 Apr 15;30(8):1488-1500. doi: 10.1158/1078-0432.CCR-23-2978.