Study to Evaluate the Safety, Tolerability,Pharmacokinetics, and Antitumor Activity of a Thorium-227 Labeled Antibody-chelator Conjugate Alone and in Combination With Darolutamide, in Patients With Metastatic Castration Resistant Prostate Cancer

NCT03724747 | Completed Phase 1 FDA Drug

• 2 other identifiers: 194452018-001490-25
• Study Type: interventional
• Target: 63
• Locations: 3 countries
• Sites: 5

Brief Summary

The study medication (BAY 2315497 Injection) is a thorium-227 labeled immuno-conjugate, specific for the prostate-specific membrane antigen (PSMA), which will be evaluated in patients with metastatic castration resistant prostate cancer. In this study, this investigational medication will be administered to patients for the first time. The primary objective of the study is to define the safety and tolerability profile and Maximal Tolerated Dose (MTD) of BAY2315497 Injection alone, or in combination with darolutamide. The secondary objectives are to determine the recommended dose for further clinical development of BAY2315497 Injection alone, or in combination with darolutamide and to investigate how the study drug is distributed and cleared from the body.

Conditions

Metastatic Castration Resistant Prostate Cancer (mCRPC)

Keywords

Metastatic castration resistant prostate cancer, thorium-227, targeted alpha therapy,PSMA

Outcome Measures

Primary Outcomes (2)

• Maximum tolerated dose (MTD) of BAY2315497 injection

  The maximum dose at which the incidence of DLTs occurring during Cycle 1 is below 30%.

  Cycle 1 (42 days)

• Maximum tolerated dose (MTD) of BAY2315497 injection in combination with darolutamide

  The maximum dose at which the incidence of DLTs occurring during Cycle 1 is below 30%.

  Cycle 1 (42 days)

Secondary Outcomes (14)

• Recommended dose for further clinical development of BAY2315497 injection

  Up to 6 cycles (each cycle is 42 days, a maximum of 3 additional treatment cycles may be administered in case a favorable benefit risk profile is documented)

• Maximum observed concentration (Cmax) of thorium of BAY2315497 Injection

  Cycle 1 (From day 1 to 43)

• Area under the curve from time of dosing to 42 days after dosing [AUC(0-42)] days of thorium of BAY2315497 Injection

  Cycle 1 (From day 1 to 43)

• Cmax of radium of BAY2315497 Injection

  Cycle 1 (From day 1 to 43)

• AUC(0-42) days of radium of BAY2315497 Injection

  Cycle 1 (From day 1 to 43)

Study Arms (4)

BAY2315497 dose escalation

EXPERIMENTAL

The thorium-227 dose will be escalated in a step-wise fashion to the MTD, according to a predefined dose escalation scheme. The total antibody dose of 50 mg will be evaluated first; on the basis of emerging clinical data, doses within the range of 20-100 mg may be investigated.

Drug: BAY2315497 Injection

BAY2315497 dose escalation in combination with darolutamide

EXPERIMENTAL

The thorium-227 dose will be escalated in a step-wise fashion to the MTD, according to a predefined dose escalation scheme. In addition, Darolutamide oral dosing at the approved dose of twice daily 600 mg will be initiated 14 days prior to the first BAY2315497 Injection dose on Day 1 of the first cycle. Daily darolutamide dosing will continue throughout the entire BAY2315497 Injection treatment period until withdrawal criteria from study treatment period are met.

Drug: BAY2315497 Injection; Drug: Darolutamide(BAY1841788)

BAY2315497 dose expansion:Dose regimen 1

EXPERIMENTAL

The thorium-227 and total antibody doses, as well as the treatment regimen, will be selected for expansion on the basis of the safety, PK and overall benefit risk profile of BAY2315497 Injection, observed in the course of the dose escalation.

Drug: BAY2315497 Injection

BAY2315497 dose expansion:Dose regimen 2

EXPERIMENTAL

The thorium-227 and total antibody doses, as well as the treatment regimen, will be selected for expansion on the basis of the safety, PK and overall benefit risk profile of BAY2315497 Injection, observed in the course of the dose escalation.

Drug: BAY2315497 Injection

Interventions

BAY2315497 Injection DRUG

BAY 2315497 Injection comprises 3 components: the PSMA-specific monoclonal antibody (mAb), the mAb-chelator conjugate, and the thorium-227 labeled mAb-chelator conjugate. BAY 2315497 Injection will be administered on Day 1 of each treatment cycle.

BAY2315497 dose escalation; BAY2315497 dose escalation in combination with darolutamide; BAY2315497 dose expansion:Dose regimen 1; BAY2315497 dose expansion:Dose regimen 2

Darolutamide(BAY1841788) DRUG

600 mg (2 X 300 mg tablets), twice daily with food, equivalent to a total daily dose of 1200 mg.

BAY2315497 dose escalation in combination with darolutamide

Eligibility Criteria

• Age: 18 Years+
• Sex: male
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Ability to understand and sign an approved informed consent form.
• Male adult patients (≥ 18 years of age).
• ECOG PS of 0 or 1.
• Life expectancy ≥ 6 months.
• Histological, pathological and/or cytological confirmation of adenocarcinoma of the prostate without small cell or neuroendocrine features.
• Previous treatment with at least one novel androgen axis drug (NAAD) (e.g. enzalutamide and/or abiraterone).
• Patients must have prior orchiectomy and/or ongoing androgen deprivation therapy and a castrate level of serum testosterone (\<50 ng/dL or \<1.7 nmol/L).
• Previous treatment with at least 1, but no more than 2 previous - taxane regimens. A taxane regimen is defined as a minimum exposure of 2 cycles of a taxane. If a patient has received only 1 taxane regimen, he is eligible, if refuses to receive a second taxane regimen, or is considered unsuitable to receive a second taxane regimen (e.g. intolerance).
• Documented progression of mCRPC, as defined according to the Prostate Cancer Working Group 3 (PCWG3) guidelines.
• Adequate bone marrow, liver, and renal function, as assessed by the following laboratory requirements, to be conducted within 14 days before start of study drug administration:
• Hemoglobin \> 9.0 g/dL
• Absolute neutrophil count (ANC) \> 1500/mm3
• White blood cell (WBC) count \> 3000/mL
• Platelet count \> 100,000 /mm\*3
• Total bilirubin \< 1,5 x upper limit of normal (ULN) (except if confirmed history of Gilbert's disease)

You may not qualify if:

• Diffuse bone or bone-marrow involvement (i.e. "superscan").
• Spinal cord compression or known brain metastases.
• Known incompatibility to CT/MRI, bone scan or uncontrolled pain, which results in patient's lack of compliance with the CT/MRI and bone scan required for PCWG3 tumor assessment.
• Clinically significant heart disease, as evidenced by myocardial infarction, arterial thrombotic events in the past 6 months, severe or unstable angina, or uncontrolled cardiovascular history.
• Patients known to be affected by genetic defects linked to radiation Hypersensitivity.
• Known history of myelodysplastic syndrome (MDS) / leukemia or with features suggestive of MDS/AML at any time point.
• Concurrent or active cancer within the last 2 years with a distinct primary site or histology from the cancer being evaluated in this study, with the exception of cancer types with less than 30% likelihood of recurrence.
• Known allergies, hypersensitivity, or intolerance to the study drug including excipients, or to contrast agents used in the diagnostic or exploratory imaging procedures required per protocol.
• Any infection of National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0 Grade ≥ 2.
• Known human immunodeficiency virus (HIV) infection.
• Patients who have an active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection requiring treatment.
• Serious, non-healing wound, ulcer, or bone fracture.
• Any systemic anti-neoplastic therapy (e.g. chemotherapy, immunotherapy or biological therapy \[including monoclonal antibodies\], PARP inhibitors) within at least 30 days prior to day of randomization (except for Luteinizing Hormone-releasing Hormone \[LHRH\] or Gonadotropin-releasing Hormone \[GnRH\]).
• Previous high-dose chemotherapy, needing hemopoietic stem cell rescue, is prohibited.
• Prior major surgery (excluding prostatic biopsies) must be at least 12 weeks prior to study entry.

Sponsors & Collaborators

• Bayer: lead

Study Sites (5)

Tulane Medical Center

New Orleans, Louisiana, 70112, United States

Location

GU Research Network, LLC

Omaha, Nebraska, 68130, United States

Location

Memorial Sloan-Kettering Cancer Center

New York, New York, 10065, United States

Location

HUS, Meilahden sairaala

Helsinki, FIN-00260, Finland

Location

Royal Marsden NHS Trust (Surrey)

Sutton, Surrey, SM2 5PT, United Kingdom

Location

Related Publications (1)

• Hammer S, Hagemann UB, Zitzmann-Kolbe S, Larsen A, Ellingsen C, Geraudie S, Grant D, Indrevoll B, Smeets R, von Ahsen O, Kristian A, Lejeune P, Hennekes H, Karlsson J, Bjerke RM, Ryan OB, Cuthbertson AS, Mumberg D. Preclinical Efficacy of a PSMA-Targeted Thorium-227 Conjugate (PSMA-TTC), a Targeted Alpha Therapy for Prostate Cancer. Clin Cancer Res. 2020 Apr 15;26(8):1985-1996. doi: 10.1158/1078-0432.CCR-19-2268. Epub 2019 Dec 12.

  PMID: 31831560 DERIVED

MeSH Terms

Interventions

BAY 2315497

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 23, 2018
• First Posted: October 30, 2018
• Study Start: December 18, 2018
• Primary Completion: August 25, 2022
• Study Completion: October 31, 2024
• Last Updated: November 8, 2024

Record last verified: 2024-11

Data Sharing

• IPD Sharing: Will not share

Locations

US (3); FI (1); GB (1)