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

Amgen

Status and phase: Enrolling; Phase 1

Conditions: Prostate Cancer

Treatments: Drug: Abiraterone; Drug: Enzalutamide; Drug: AMG 509

Study type: Interventional

Funder types: Industry

Identifiers

NCT04221542

20180146

2023-504361-23 (Other Identifier)

2021-005052-11 (EudraCT Number)

Details and patient eligibility

About

Evaluate the safety and tolerability of AMG 509 in adult participants and determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D).

Enrollment: 461 estimated patients

Sex: Male

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion 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 0-2 prior 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.
  3. 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 to 2 NHTs with a similar mechanism of action (apalutamide, enzalutamide or darolutamide) in the non-mCRPC and mCRPC setting.
  4. 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) agonist or 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 as defined in I106 within 12 months of final dose in their initial treatment with 6 cycles (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.

Exclusion 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.
• 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.
• Any anti-cancer 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 < 2 cycles (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.

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Sequential Assignment

Masking: None (Open label)

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461 participants in 5 patient groups

Part 1: AMG 509 Intravenous (IV) Monotherapy

Experimental group

Description:

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 be enrolled 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.

Treatment:

Drug: AMG 509

Part 2: AMG 509 Subcutaneous (SC) Monotherapy

Experimental group

Description:

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.

Treatment:

Drug: AMG 509

Part 3: AMG 509 IV Monotherapy in Earlier Lines of Treatment

Experimental group

Description:

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 AMG 509 at the MTD or RP2D determined in Part 1 dose exploration, and to obtain further safety and efficacy data and correlative biomarker analysis.

Treatment:

Drug: AMG 509

Part 4: AMG 509 IV Combination Therapy

Experimental group

Description:

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), or enzalutamide (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.

Treatment:

Drug: AMG 509

Drug: Enzalutamide

Drug: Abiraterone

Part 5: AMG 509 IV Monotherapy in Outpatient Setting

Experimental group

Description:

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

Treatment:

Drug: AMG 509