Safety, Tolerability, Pharmacokinetics, and Efficacy of Acapatamab in Subjects With mCRPC

Sponsor

Amgen (Industry)

Overall Status

Active, not recruiting

CT.gov ID

NCT03792841

Collaborator

(none)

212

Enrollment

Locations

Arms

75.3

Anticipated Duration (Months)

7.1

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

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).

Condition or Disease	Intervention/Treatment	Phase
Metastatic Castration-resistant Prostate Cancer Prostate Cancer	Drug: acapatamab Drug: Pembrolizumab Drug: Etanercept Drug: Cytochrome P450 (CYP) Cocktail	Phase 1

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

212 participants

Allocation:

Non-Randomized

Intervention Model:

Sequential Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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

Actual Study Start Date :

Feb 5, 2019

Anticipated Primary Completion Date :

May 16, 2025

Anticipated Study Completion Date :

May 16, 2025

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Part 1 Dose-exploration: acapatamab treatment Part 1 dose-exploration: acapatamab is administered intravenously. The dose-exploration phase of the study will estimate the MTD of acapatamab. RP2D may be identified based on emerging safety, efficacy, and pharmacodynamic data prior to reaching an MTD.	Drug: acapatamab Investigational immunotherapy for the treatment of metastatic castration-resistant prostate cancer Other Names: PSMA Targeted Therapy
Experimental: Part 1 Dose-expansion: acapatamab treatment Part 1 dose-expansion: acapatamab is administered intravenously at the MTD/RP2D.	Drug: acapatamab Investigational immunotherapy for the treatment of metastatic castration-resistant prostate cancer Other Names: PSMA Targeted Therapy
Experimental: Part 2: acapatamab + Pembrolizumab Part 2: acapatamab is administered intravenously at the MTD/RP2D. Pembrolizumab will be administered intravenously.	Drug: acapatamab Investigational immunotherapy for the treatment of metastatic castration-resistant prostate cancer Other Names: PSMA Targeted Therapy Drug: Pembrolizumab Combined with acapatamab for investigational treatment of mCRPC Other Names: PD-1 inhibitor
Experimental: Part 3: acapatamab + Etanercept Prophylaxis Part 3: acapatamab is administered intravenously at RP2D/MTD levels. Etanercept will be administered subcutaneously in cycle 1 only.	Drug: acapatamab Investigational immunotherapy for the treatment of metastatic castration-resistant prostate cancer Other Names: PSMA Targeted Therapy Drug: Etanercept Prophylaxis for acapatamab-related cytokine release syndrome. Other Names: TNF-alpha inhibitor
Experimental: Part 4: acapatamab 24 Hour Monitoring Part 4: acapatamab is administered intravenously at RP2D/MTD with 24-hour monitoring.	Drug: acapatamab Investigational immunotherapy for the treatment of metastatic castration-resistant prostate cancer Other Names: PSMA Targeted Therapy
Experimental: Part 5: acapatamab Outpatient Cohort Part 5: acapatamab is administered intravenously at RP2D/MTD in an outpatient setting with 8-hour monitoring.	Drug: acapatamab Investigational immunotherapy for the treatment of metastatic castration-resistant prostate cancer Other Names: PSMA Targeted Therapy
Experimental: Part 6: acapatamab + Cytochrome P450 (CYP) Cocktail Drug Interaction Part 6: acapatamab is administered intravenously at RP2D/MTD. A CYP phenotyping cocktail will be administered orally.	Drug: acapatamab Investigational immunotherapy for the treatment of metastatic castration-resistant prostate cancer Other Names: PSMA Targeted Therapy Drug: Cytochrome P450 (CYP) Cocktail Evaluate the effect of co-administration of multiple dosing of acapatamab on plasma Other Names: Cooperstown 5+1 CYP phenotyping cocktail

Outcome Measures

Primary Outcome Measures

Number of participants with dose-limiting toxicity [Up to 3 years]
Parts 1, 2, 3, 4, 5, and 6 of the study
Number of participants with treatment-emergent adverse events [Up to 3 years]
Parts 1, 2, 3, 4, 5, and 6 of the study
Number of participants with treatment-related adverse events [Up to 3 years]
Parts 1, 2, 3, 4, 5, and 6 of the study
Number of participants with clinically significant changes in vital signs [Up to 3 years]
Parts 1, 2, 3, 4, 5, and 6 of the study
Number of participants with clinically significant changes in electrocardiogram (ECG) [Up to 3 years]
Parts 1, 2, 3, 4, 5, and 6 of the study
Number of participants with clinically significant changes in clinical laboratory tests [Up to 3 years]
Parts 1, 2, 3, 4, 5, and 6 of the study

Secondary Outcome Measures

Maximum serum concentration (Cmax) of acapatamab [Up to 3 years]
Parts 1, 2, 3, 4, 5, and 6 of the study
Minimum serum concentration (Cmin) of acapatamab [Up to 3 years]
Parts 1, 2, 3, 4, 5, and 6 of the study
Area under the concentration-time curve (AUC) over the dosing interval of acapatamab [Up to 3 years]
Parts 1, 2, 3, 4, 5, and 6 of the study
Accumulation ratio of acapatamab [Up to 3 years]
Parts 1, 2, 3, 4, 5, and 6 of the study
Half-life of acapatamab [Up to 3 years]
Parts 1, 2, 3, 4, 5, and 6 of the study
Objective response (OR) [Up to 3 years]
Parts 1, 2, 3, 4, 5, and 6 of the study
Prostate-specific antigen (PSA) response [Up to 3 years]
Parts 1, 2, 3, 4, 5, and 6 of the study
Duration of response (DOR) (radiographic and PSA) [Up to 3 years]
Parts 1, 2, 3, 4, 5, and 6 of the study
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 [Up to 3 years]
Parts 1, 2 and 3 only.
Percentage of participants experiencing a response based on 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) response evaluations [Up to 3 years]
Parts 1, 2 and 3 only.
Change in time to progression (radiographic and PSA) [Up to 3 years]
Parts 1, 2, 3, 4, 5, and 6 of the study
Progression-free survival (PFS) (radiographic and PSA) [Up to 3 years]
Parts 1, 2, 3, 4, 5, and 6 of the study.
1, 2 and 3-year overall survival (OS) [Up to 3 years]
Parts 1, 2, 3, 4, 5, and 6 of the study
Percentage of participants experiencing circulating tumor cells (CTC) response [Up to 3 years]
Parts 1, 2, 3, 4, 5, and 6 of the study. CTC response defined as CTC0 (reduction of CTCs > 0 to 0) or CTC conversion (≥ 5 CTCs/7.5 mL blood to ≤ 4 CTCs/7.5 mL blood)
Other PCWG3-recommended endpoints - time to symptomatic skeletal events [Up to 3 years]
Parts 1, 2, 3, 4, 5, and 6 of the study
Other PCWG3-recommended endpoints - lactate dehydrogenase [LDH] levels [Up to 3 years]
Parts 1, 2, 3, 4, 5, and 6 of the study
Other PCWG3-recommended endpoints - hemoglobin levels [Up to 3 years]
Parts 1, 2, 3, 4, 5, and 6 of the study
Other PCWG3-recommended endpoints - neutrophil-to-lymphocyte ratio [Up to 3 years]
Parts 1, 2, 3, 4, 5, and 6 of the study
Other PCWG3-recommended endpoints - urine N-telopeptide levels [Up to 3 years]
Parts 1, 2, 3, 4, 5, and 6 of the study
Other PCWG3-recommended endpoints - alkaline phosphatase [total, bone] levels [Up to 3 years]
Parts 1, 2, 3, 4, 5, and 6 of the study
Maximum serum concentration (Cmax) of acapatamab when administered with CYP enzymes [Up to 3 years]
Part 6 only.
Area under the concentration-time curve over a 24-hour period (AUC24) of acapatamab when administered with CYP enzymes [Up to 3 years]
Part 6 only.
Half-life of acapatamab when administered with CYP enzymes [Up to 3 years]
Part 6 only.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

Male

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	El Camino Hospital	Campbell	California	United States	95008
2	City of Hope National Medical Center	Duarte	California	United States	91010
3	City of Hope at Long Beach Elm	Long Beach	California	United States	90813
4	University of California Los Angeles	Los Angeles	California	United States	90095
5	Emory University	Atlanta	Georgia	United States	30322
6	Indiana University	Indianapolis	Indiana	United States	46202
7	University of Iowa Hospitals and Clinics	Iowa City	Iowa	United States	52242
8	Tulane Medical Center	New Orleans	Louisiana	United States	70112
9	Washington University	Saint Louis	Missouri	United States	63110
10	Comprehensive Cancer Centers of Nevada	Las Vegas	Nevada	United States	89169
11	Memorial Sloan Kettering Cancer Center	New York	New York	United States	10065
12	Weill Cornell Medical College	New York	New York	United States	10065
13	University of Texas Southwestern Medical Center	Dallas	Texas	United States	75390
14	Chris OBrien Lifehouse	Camperdown	New South Wales	Australia	2050
15	Scientia Clinical Research Ltd	Randwick	New South Wales	Australia	2031
16	Peter MacCallum Cancer Centre	Parkville	Victoria	Australia	3050
17	Ordensklinikum Linz Elisabethinen	Linz		Austria	4020
18	Landeskrankenhaus Salzburg	Salzburg		Austria	5020
19	Krankenhaus der Barmherzigen Brueder Wien	Wien		Austria	1020
20	Universitaetsklinikum Allgemeines Krankenhaus Wien	Wien		Austria	1090
21	Universite Catholique de Louvain Cliniques Universitaires Saint Luc	Bruxelles		Belgium	1200
22	Universitair Ziekenhuis Gent	Gent		Belgium	9000
23	BC Cancer Vancouver	Vancouver	British Columbia	Canada	V5Z 4E6
24	Institut Gustave Roussy	Villejuif Cedex		France	94805
25	National Cancer Center Hospital East	Kashiwa-shi	Chiba	Japan	277-8577
26	Yokohama City University Medical Center	Yokohama-shi	Kanagawa	Japan	232-0024
27	Erasmus Medisch Centrum	Rotterdam		Netherlands	3015 GD
28	National University Hospital	Singapore		Singapore	119074
29	National Cancer Centre Singapore	Singapore		Singapore	169610
30	Linkou Chang Gung Memorial Hospital of Chang Gung Medical Foundation	Taoyuan		Taiwan	33305