Study of AMG 509 in Participants With Metastatic Castration-Resistant Prostate Cancer

JRCT ID: jRCT2031200384

Registered date:01/03/2021

Basic Information

• Recruitment status: Recruiting
• Health condition(s) or Problem(s) studied: Prostate Cancer
• Date of first enrollment: 04/03/2020
• Target sample size: 461
• Countries of recruitment: United States,Japan,Australia,Japan,Korea,Japan,Taiwan,Japan,Germany,Japan,Portugal,Japan,Spain,Japan,Switzerland,Japan,China,Japan
• Study type: Interventional

Intervention(s)

- Experimental: Part 1: AMG 509 Intravenous (IV) Monotherapy
Part 1 will evaluate AMG 509 in participants with metastatic castration-resistant prostate cancer (mCRPC) who have been previously treated with novel hormonal therapy (NHT) and 1 to 2 prior taxanes.
The dose exploration phase of the study will estimate the MTD of AMG 509 using a Bayesian logistic regression model (BLRM; Neuenschwander et al, 2008).
RP2D may be identified based on emerging safety, efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) data, as well as patient experience prior to reaching an MTD. Alternative dosing schedule(s) (including a third step dose) may be explored based on emerging efficacy, safety, PK data and patient experience.
During the dose expansion phase, individual cohorts of participants from China will been rolled with a safety lead-in at 1 dose level below the MTD or RP2D followed by evaluation at the MTD or RP2D to confirm the safety, tolerability, MTD and/or RP2D of AMG 509 in Chinese participants.
Intervention: Drug: AMG 509

- Experimental: Part 2: AMG 509 Subcutaneous (SC) Monotherapy
Part 2 will explore the safety, tolerability, and PK of AMG 509 SC dosing in participants with mCRPC who have been previously treated with NHT and 1 to 2 prior taxanes.
Recommended phase 2 dose for SC monotherapy may be identified based on emerging safety, efficacy, PK, and PD data, as well as patient experience prior to reaching an MTD.
Intervention: Drug: AMG 509

- Experimental: Part 3: AMG 509 IV Monotherapy in Earlier Lines of Treatment
Part 3 will explore AMG 509 in participants with mCRPC who have received 1 prior NHT (may have been given for HSPC) and no prior taxanes (may have been given for HSPC). This dose expansion will be conducted to confirm safety, PK, and PD of AMG509 at the MTD or RP2D determined in Part 1 dose exploration, and to obtain further safety and efficacy data and correlative biomarker analysis.
Intervention: Drug: AMG 509

- Experimental: Part 4: AMG 509 IV Combination Therapy
Part 4 will explore the safety, tolerability, and PK of AMG 509 for participants with mCRPC who have received no or 0/2 prior NHT (for hormone sensitive or castration-resistant disease) at dose regimens previously determined to be safe and tolerable in Part 1, in combination with abiraterone (Part 4A), orenzalutamide (Part 4B) and no or 1 prior taxane for hormone sensitive disease in Parts 4A and 4B. Part 4 consists of a dose exploration phase and a dose expansion phase.

This dose exploration study will estimate the MTD and/or RP2D of AMG 509 in combination with abiraterone or enzalutamide using a modified toxicity probability interval design. The dose-expansion phase will confirm safety, PK, and PD at the MTD or RP2D and to obtain further safety and efficacy data and correlative biomarker analysis.
Interventions:
Drug: AMG 509
Drug: Abiraterone
Drug: Enzalutamide

- Experimental: Part 5: AMG 509 IV Monotherapy in Outpatient Setting
Part 5 will evaluate the safety and tolerability of AMG 509 IV dosing in participants with mCRPC who have been previously treated with NHT and 1 to 2 prior taxanes, when administered in outpatient infusion centers.
The Part 5 dosing regimen and schedule was selected based on emerging data and DLRT recommendations and will utilize the doses explored in Part 1 dose-expansion phase.
Intervention: Drug: AMG 509

Outcome(s)

Primary Outcome

1. Incidence of treatment-emergent adverse events [Time Frame: 3 years]
2. Incidence of treatment-related adverse events [Time Frame: 3 years]
3. Dose limiting toxicities (DLTs) [Time Frame: 3 years]
4. Number of participants with changes in vital signs [Time Frame: 3 years]
5. Number of participants with changes in the electrocardiogram (ECG) records. [Time Frame: 3 years]
6. Number of participants with changes in the clinical laboratory tests results. [Time Frame: 3 years]

Secondary Outcome

1. Maximum serum concentration (Cmax) for AMG 509 [Time Frame: 3 years]
To characterize the pharmacokinetics (PK) of AMG 509
2. Time to maximum serum concentration (Tmax) for AMG 509 [Time Frame: 3 years]
To characterize the pharmacokinetics (PK) of AMG 509
3. Minimum serum concentration (Cmin) for AMG 509 [Time Frame: 3 years]
To characterize the pharmacokinetics (PK) of AMG 509
4. Area under the concentration-time curve (AUC) over the dosing interval for AMG 509 [Time Frame: 3 years]
To characterize the pharmacokinetics (PK) of AMG 509
5. Accumulation following multiple dosing for AMG 509 [Time Frame: 3 years]
To characterize the pharmacokinetics (PK) of AMG 509
6. Objective response (OR) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 with Prostate Cancer Working Group 3 (PCWG3) modifications [Time Frame: 3 years]
To evaluate preliminary anti-tumor activity of AMG 509
7. Prostate specific antigen (PSA) response [Time Frame: 3 years]
To evaluate preliminary anti-tumor activity of AMG 509
8. PSA decline of at least 50% from baseline at 12 weeks [Time Frame: Week 12]
To evaluate preliminary anti-tumor activity of AMG 509
9. Duration of response (DOR) (radiographic and PSA) [Time Frame: 3 years]
To evaluate preliminary anti-tumor activity of AMG 509
10. Time to progression (radiographic and PSA) [Time Frame: 3 years]
To evaluate preliminary anti-tumor activity of AMG 509
11. Progression-free survival (PFS) (radiographic and PSA) [Time Frame: 3 years]
To evaluate preliminary anti-tumor activity of AMG 509
12. 6 month radiographic PFS [Time Frame: 6 months]
To evaluate preliminary anti-tumor activity of AMG 509
13. 1, 2, and 3-year radiographic PFS [Time Frame: Year 1, 2, and 3]
To evaluate preliminary anti-tumor activity of AMG 509
14. 1, 2, and 3-year overall survival (OS) [Time Frame: Year 1, 2, and 3]
To evaluate preliminary anti-tumor activity of AMG 509
15. Circulating tumor cells response (CTC0) [Time Frame: 3 years]
To evaluate preliminary anti-tumor activity of AMG 509
16. Rate of circulating tumor cells (CTC) conversion [Time Frame: 3 years]
To evaluate preliminary anti-tumor activity of AMG 509
17. time to symptomatic skeletal events. [Time Frame: 3 years]
To evaluate preliminary anti-tumor activity of AMG 509. Measure of disease burden based on PCWG3-recommended endpoints.
18. alkaline phosphatase (total, bone) [Time Frame: 3 years]
To evaluate preliminary anti-tumor activity of AMG 509. Measure of disease burden based on PCWG3-recommended endpoints.
19. lactate dehydrogenase (LDH) [Time Frame: 3 years]
To evaluate preliminary anti-tumor activity of AMG 509. Measure of disease burden based on PCWG3-recommended endpoints.
20. hemoglobin [Time Frame: 3 years]
To evaluate preliminary anti-tumor activity of AMG 509. Measure of disease burden based on PCWG3-recommended endpoints.
21. urine N-telopeptide [Time Frame: 3 years]
To evaluate preliminary anti-tumor activity of AMG 509. Measure of disease burden based on PCWG3-recommended endpoints.
22. neutrophil-to-lymphocyte ratio [Time Frame: 3 years]
To evaluate preliminary anti-tumor activity of AMG 509. Measure of disease burden based on PCWG3-recommended endpoints.

Key inclusion & exclusion criteria

• Age minimum: >= 18age old
• Age maximum: Not applicable
• Gender: Male

Include criteria

- Parts 1, 2, and 5: Participants with histologically or cytologically confirmed metastatic castration-resistant prostate cancer (mCRPC) who are refractory to a novel antiandrogen therapy (abiraterone acetate and/or enzalutamide, apalutamide, or darolutamide) and have failed at least 1 (but not more than 2) taxane regimens including for metastatic hormone-sensitive prostate cancer (mHSPC) (or who are deemed medically unsuitable to be treated with a taxane regimen or have actively refused treatment with a taxane regimen).
Note: A taxane regimen is defined as a minimum exposure of 2 cycles of a taxane. Any NHT that has been administered and has been stopped for reasons other than progression will not be counted as an additional line of treatment.
1. Dose exploration phase: Novel antiandrogen therapy must have been given for treatment of metastatic disease.
2. Dose expansion phase: participants must not have had more than 2 NHTs and 2 taxane regimens in any setting, and an additional up to 2 other systemic anti-cancer treatments are allowed (eg, anti-PD1, PARP inhibitors, radioligand therapies, sipuleucel-T, experimental agents) Note: Combinations are considered one systemic anti-cancer treatment.
- Part 3: Participants with histologically or cytologically confirmed mCRPC who are refractory to a NHT (abiraterone acetate, enzalutamide, apalutamide, or darolutamide) given in any disease setting and who are deemed medically unsuitable to be treated with a taxane regimen or have actively refused treatment with a taxane regimen (no prior taxanes). 0-1 prior PARP inhibitors or sipuleucel-T treatments are acceptable. Participants who received prior investigational therapy for the treatment of metastatic disease are not eligible.
- Parts 4A and 4B:
1. Participants with histologically or cytologically confirmed mCRPC who are refractory to 0-2prior NHT (given in any disease setting depending on the part), and no or 1 taxane (given for hormone sensitive prostate cancer).
2. Dose-expansion phase: at least 1 prior NHT must have been given; 0-1 prior PARP inhibitors are acceptable.
2. 4A: Participants planning to receive abiraterone acetate for the first time (participants who received prior abiraterone acetate are not eligible). Participants may have had exposure to up to2 NHTs with a similar mechanism of action (apalutamide, enzalutamide or darolutamide) in the non-mCRPC and mCRPC setting.
3. 4B: Participants planning to receive enzalutamide for the first time (participants who received prior enzalutamide/apalutamide or daralutamide are not eligible).
- All parts:
- Participants must have undergone bilateral orchiectomy or be on continuous androgen-deprivation therapy with a gonadotropin releasing hormone (GnRH) agonis tor antagonist.
- Total serum testosterone <= 50 ng/dL or 1.7 nmol/L.
- Evidence of progressive disease, defined as 1 or more Prostate Cancer Working Group 3 (PCWG3) criteria:
1. PSA level >= 1 ng/mL that has increased on at least 2 successive occasions at least 1 week apart.
2. nodal or visceral progression as defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 with PCGW3 modifications.
3. appearance of 2 or more new lesions in bone scan.
- Eastern Cooperative Oncology Group performance status of 0-1.
- Adequate organ function, defined as follows:
1. Hematological function:
1. absolute neutrophil count >= 1 x 10^9/L (without growth factor support within 7 days from screening assessment).
2. platelet count >= 75 x 10^9/L (without platelet transfusion within 7 days from screening assessment).
3. hemoglobin >= 9 g/dL (90 g/L) (without blood transfusion within 7 days from screening assessment).
2. Renal function:
1. estimated glomerular filtration rate based on Modification of Diet in Renal Disease calculation >= 30 ml/min/1.73 m^2.
3. Hepatic function:
1. aspartate aminotransferase (AST) and alanine aminotransferase (ALT) <3 x upper limit of normal (ULN) (or < 5 x ULN for participants with liver involvement).
2. total bilirubin (TBL) < 1.5 x ULN (or < 2 x ULN for participants with liver metastases).
4. Cardiac function:
1. left ventricular ejection fraction > 50% (2-D transthoracic echocardiogram [ECHO] is the preferred method of evaluation; multi-gated acquisition scan is acceptable if ECHO is not available).
2. Baseline electrocardiogram (ECG) QTcF <= 470 msec. (average of triplicate values).
Part 3-Retreatment group:
- Deriving benefit from initial treatment with AMG 509 as evidenced by one of the following:
1. confirmed PSA50 response.
2. radiographic stable disease/partial response/complete response during 6 cycles of initial treatment with AMG 509 and without progression during the first 6 cycles.
- No discontinuation for toxicity during the initial treatment with 6 cycles of AMG 509.
- Progressive disease within 12 months of final dose in their initial treatment with 6cycles (EOT_1).
- Willingness to have a fresh tumor biopsy prior to initiating the additional course of treatment, depending on safety and feasibility as assessed by investigator.

Exclude criteria

- Pathological finding consistent with pure small cell, neuroendocrine carcinoma of the prostate or any other histology different from adenocarcinoma
- Radiation therapy within 4 weeks of first dose (or local or focal radiotherapy within 2 weeks of first dose)
- Untreated central nervous system (CNS) metastases or leptomeningeal disease. Participants with a history of treated CNS metastases are eligible if there is radiographic evidence of improvement upon the completion of CNS-directed therapy and no evidence of interim progression between the completion of CNS-directed therapy and the screening radiographic study.
- Participants with symptoms and/or clinical signs and/or radiographic signs that indicate an acute and/or uncontrolled active systemic infection within 7 days prior to the first dose of investigational product administration.
- Confirmed history or current autoimmune disease or other diseases resulting in permanent immunosuppression or requiring permanent immunosuppressive therapy
- Presence of fungal, bacterial, viral, or other infection requiring IV antimicrobials for management within 7 days of dosing
NOTE: Simple urinary tract infections and uncomplicated bacterial pharyngitis are permitted if responding to active treatment and after consultation with sponsor. Screening for chronic infectious conditions is not required.
- Positive test for human immunodeficiency virus (HIV)
- Exclusion of hepatitis infection based on the following results and/or criteria:
- Positive for hepatitis B surface antigen (HBsAg) (indicative of chronic hepatitis B or recent acute hepatitis B).
- Negative HBsAg and positive for hepatitis B core antibody: Hepatitis B virus DNA by polymerase chain reaction (PCR) is necessary. Detectable hepatitis B virus DNA suggests occult hepatitis B.
- Positive Hepatitis C virus antibody (HCVAb): hepatitis C virus RNA by PCR is necessary. Detectable hepatitis C virus RNA
suggests chronic hepatitis C.
- History of arterial or venous thrombosis (eg, stroke, transient ischemic attack, pulmonary embolism, or deep vein thrombosis); for arterial thrombosis within 12 months of AMG 509 initiation; for venous thrombosis, 6 months and stable on anti-coagulation.
- Myocardial infarction and/or symptomatic congestive heart failure (New York Heart Association > class II) within 12 months of first dose of AMG 509 with the exception of ischemia or non-ST segment elevation myocardial infarction controlled with stent placement and confirmed by a cardiologist more than 6 months prior to first dose of AMG 509.
- Unresolved toxicities from prior anti-tumor therapy not having resolved to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 grade 1, with the exception of alopecia or toxicities that are stable and well-controlled AND there is agreement to allow by both the investigator and sponsor
- History of other malignancy within the past 2 years, with the following exception(s):
- malignancy treated with curative intent and with no known active disease present for greater than or equal to 1 years before enrollment and felt to be at low risk for recurrence by the treating physician
- adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
- adequately treated urothelial papillary noninvasive carcinoma or carcinoma in situ
- History or evidence of inflammatory bowel disease (ulcerative colitis or Crohn disease) or any other gastrointestinal disorder causing chronic nausea, vomiting, or diarrhea (defined as greater than or equal to 2 CTCAE grade 2)
- Evidence of interstitial lung disease or active, non-infectious pneumonitis, or uncontrolled asthma
- Prior STEAP1-targeted therapy
- Any anticancer therapy or immunotherapy within 4 weeks of start of first dose, not including luteinizing hormone-releasing hormone (LHRH)/GnRH analogue (agonist/antagonist).
- Prior PSMA radionuclide therapy within 2 months prior to AMG 509 unless participant received < 2cycles (Note: a participant cannot have received PSMA radionuclide therapy < 35 days prior to enrollment if 1 cycle was given). Parts 3 and 4: prior PSMA radionuclide therapy is prohibited. Participants on a stable bisphosphonate or denosumab regimen for >= 30 days prior to enrollment are eligible (exception: part 3 retreatment).
- Part 3-Retreatment only: Any anticancer therapy or immunotherapy, not including luteinizing hormone-releasing hormone/gonadotropin releasing hormone (LHRH/GnRH) analogue (agonist/antagonist), and/or bisphosphonate or denosumab regimen after last dose of AMG 509 initial course of treatment.

Related Information

• Primary Sponsor: Local Contact
• Secondary ID(s): NCT04221542