E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Metastatic Castration-resistant Prostate Cancer |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10076506 |
E.1.2 | Term | Castration-resistant prostate cancer |
E.1.2 | System Organ Class | 100000004864 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
All subprotocols
To evaluate the safety, tolerability, and maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of investigational therapies in subjects with metastatic castration-resistant prostate cancer (mCRPC)
Subprotocol C Part 3 only
•To evaluate preliminary anti-tumor activity of AMG 404 monotherapy |
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E.2.2 | Secondary objectives of the trial |
All subprotocols
•To evaluate preliminary anti-tumor activity of investigational therapies in subjects with mCRPC
•To characterize the pharmacokinetics (PK) of investigational therapies in subjects with mCRPC
Subprotocol C part 3 only
• Safety: To evaluate the safety and tolerability of AMG 404 monotherapy
• Efficacy: To evaluate anti-tumor activity of AMG 404 monotherapy with additional measures |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
All Subprotocols
- Subjects with mCRPC with histologically or cytologically confirmed adenocarcinoma of the prostate without pure neuroendocrine differentiation or small cell features
- Subjects should have undergone bilateral orchiectomy or should be on continuous androgen deprivation therapy with a gonadotropin releasing hormone agonist or antagonist.
- Total serum testosterone should be ≤ 50 ng/dL (or 1.7 nmol/L)
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 – 1
- Life expectancy of > 3 months
- Adequate organ function, defined as follows:
• absolute neutrophil count ≥ 1.5 x 10^9/L (without growth factor support within 7 days from screening assessment)
• platelet count ≥ 100 x 10^9/L (without platelet transfusion within 7 days from screening assessment)
• hemoglobin > 9 g/dL (90 g/L) (subprotocol A & C) / > 10 g/dL (100g/L) (subprotocol B) (without blood transfusion within 7 days from screening assessment)
• estimated glomerular filtration rate based on Modification of Diet in Renal Disease (MDRD) calculation ≥ 30 mL/min/1.73 m2
• AST and ALT < 3 x upper limit of normal (ULN) (or < 5 x ULN for subjects with liver involvement)
• total bilirubin (TBL) < 1.5 x ULN (or < 2 x ULN for subjects with liver metastases)
• left ventricular ejection fraction (LVEF)> 50% (2-D transthoracic echocardiogram [ECHO] is the preferred method of evaluation; multi-gated acquisition scan is acceptable if ECHO is not available)
- Baseline electrocardiogram (ECG) QTc ≤ 470 msec
Subprotocol A & B only
- Subjects planning to receive enzalutamide (subprotocol A) / abiraterone (subprotocol B) for the first time for mCRPC (subjects who received prior enzalutamide (subprotocol A) / abiraterone (subprotocol B) are not eligible).
Subprotocol C only
- Subjects who are refractory to a novel antiandrogen therapy (abiraterone, apalutamide, and/or enzalutamide) given for metastatic or non-metastatic prostate cancer. Subjects must be ineligible for or refuse taxane therapy.
- Evidence of progressive disease, defined as 1 or more PCWG3 criteria:
• PSA level of at least 1 ng/mL that has risen 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 |
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E.4 | Principal exclusion criteria |
All Subprotocols
- Pathological finding consistent with pure small cell, neuroendocrine carcinoma of the prostate or any other histology different from adenocarcinoma
- CNS metastases/leptomeningeal disease
- Symptomatic peripheral sensory/motor neuropathy ≥grade3
- History/presence of clinically relevant CNS pathology
- Confirmed history/current autoimmune disease or other diseases resulting in permanent immunosuppression/requiring permanent immunosuppressive therapy
- Presence of fungal, bacterial, viral, or other infection requiring IV antimicrobials (Subprotocol A&B) /active fungal, bacterial, viral, or other infection requiring systemic therapy (Subprotocol C) within 7days of dosing
- History/evidence of inflammatory bowel disease or any other GI disorder causing chronic nausea, vomiting, or diarrhea
- History of arterial/venous thrombosis within 12months of 1st dose
- Myocardial infarction, uncontrolled hypertension (Subprotocol A&C), unstable angina, cardiac arrhythmia requiring medication, &/or symptomatic congestive heart failure (New York Heart Association > class II) within 12 months (Subprotocol A&B) /within 6months (Subprotocol C) of 1st dose of AMG 160
- Unresolved toxicities from prior anti-tumor therapy not having resolved to CTCAE version 5.0 grade 1, except for alopecia or toxicities that are stable and well-controlled & there is agreement to allow by both the investigator & sponsor
- Known HIV infection, hepatitis C or hepatitis B infection
- History of other malignancy within the past 2years, with the following exceptions:
• Malignancy treated with curative intent & with no known active disease present for ≥3 years before enrollment and felt to be at low risk for recurrence by treating physician
• Adequately treated non-melanoma skin cancer/lentigo maligna without evidence of disease
• Adequately treated urothelial papillary noninvasive carcinoma/carcinoma in situ
- Prior treatment with a taxane for mCRPC
- Radiation therapy within 4weeks of 1st dose (or local or focal radiotherapy within 2 weeks)
- Any anticancer therapy/immunotherapy within 4 weeks (2 weeks Subprotocol C) of start of 1st dose, not including LHRH/GnRH analogue. Subjects on a stable bisphosphonate/denosumab regimen for ≥30 days prior to enrollment are eligible
- Prior PSMAxCD3 bispecific therapy (not subprotocol C part 3)
- Requiring chronic systemic corticosteroid therapy/any other immunosuppressive therapies. Low dose corticosteroids permitted
- Prior major surgery within 4 weeks of 1st dose
- Currently receiving treatment in another investigational device/drug study, or <4 weeks since ending treatment on another investigational device or drug study
- Male subjects with a female partner of childbearing potential/pregnant partner who are unwilling to practice sexual abstinence/use contraception during treatment and for an additional 4 months (Subprotocol A&B) /8 months (Subprotocol C) after the last dose
- Male subjects unwilling to abstain from donating sperm during treatment and for an additional 4 months (Subprotocol A&B) /8 months (Subprotocol C) after the last dose
- Subject has known sensitivity to any of the products (or components) to be administered during dosing
- Subject likely to not be available to complete all protocol-required study visits/procedures, &/or to comply with all required study procedures
- History/evidence of any other clinically significant disorder, condition or disease (except for those outlined above) that, in the opinion of the investigator or Amgen physician, if consulted, would pose a risk to subject safety or interfere with the study evaluation, procedures or completion
- History of SARS-CoV-2 infection unless agreed upon with medical monitor and:
•negative test by RT-PCR within 72hours of 1st dose of AMG 160
•no acute symptoms within 10days of 1st dose of AMG 160
Subprotocol A
- Use of strong CYP2C8 inhibitors within 7 days prior to 1st dose/strong CYP3A4 inducers within 28days
- Use of narrow therapeutic index drugs that are substrates of CYP3A4, CYP2C9 or CYP2C19 within 28days
Subprotocol B
- Baseline moderate & severe hepatic impairment
- Presence of uncontrolled hypertension, hypokalemia, or fluid retention
- History/presence of adrenocortical insufficiency
- Use of concomitant medications that are sensitive substrates for CYP2D6 with a narrow therapeutic index within 7days
- Use of strong CYP3A4 inducers within 28days
Subprotocol C
- History/evidence of interstitial lung disease or active, non-infectious pneumonitis
- History of allergic reactions/acute hypersensitivity reaction to antibody therapies
- Parts 1 & 2: Subjects on a prior PD-1/PD-L1 inhibitor who experienced a grade 3/higher immune-related AE prior to 1st day of dosing
- Part 3: Subjects who have received a prior PD-1/PD-L1 inhibitor
-Live vaccine therapy within 4 weeks prior to study drug administration
- Prior allogeneic stem cell/solid organ transplantation |
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E.5 End points |
E.5.1 | Primary end point(s) |
All subprotocols
• dose-limiting toxicities (DLTs)
• treatment-emergent and treatment-related adverse events
• changes in vital signs, and clinical laboratory tests
Subprotocol C Part 3
• objective response per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 with Prostate Cancer Working Group 3 (PCWG3) modifications
• circulating tumor cell (CTC) response (CTC0 and CTC conversion)
• prostate-specific antigen (PSA) response |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The analysis of all endpoints, unless noted otherwise, will be conducted on the Safety Analysis Set defined as all subjects that are enrolled and receive at least 1 dose of AMG 160 (or AMG 404 in Parts 1 and 2 and at least 1 dose of AMG 404 in Part 3 - Subprotocol C). |
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E.5.2 | Secondary end point(s) |
All subprotocols
• objective response per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 with Prostate Cancer Working Group 3 (PCWG3) modifications
• circulating tumor cell (CTC) response (CTC0 and CTC conversion)
• prostate-specific antigen (PSA) response
• duration of response (CTC, PSA, conventional radiographic)
• overall survival (OS)
• progression-free survival (radiographic, PSA, clinical)
• time to progression (radiographic, PSA)
• time to subsequent therapy
• prostate-specific membrane antigen (PSMA) positron emission tomography (PET)/computed tomography (CT) and 18F-fluorodeoxyglucose (FDG) PET/CT based response evaluation
• other PCWG3-recommended endpoints (time to symptomatic skeletal events, alkaline phosphatase [total, bone], lactate dehydrogenase [LDH], hemoglobin, neutrophil to-lymphocyte ratio, urine N-telopeptide)
• PK parameters including, but not limited to, maximum serum concentration (Cmax), minimum serum concentration (Cmin), area under the concentration-time curve (AUC) over the dosing interval, accumulation, and half-life (t1/2)
Subprotocol C Part 3 only
• treatment-emergent adverse events
• treatment-related adverse events
• changes in vital signs, and clinical laboratory tests |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
The analysis of all endpoints, unless noted otherwise, will be conducted on the Safety Analysis Set defined as all subjects that are enrolled and receive at least 1 dose of AMG 160 (or AMG 404 in Parts 1 and 2 and at least 1 dose of AMG 404 in Part 3 - Subprotocol C). |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Yes |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
E.7.1.3.1 | Other trial type description |
Safety, tolerability, PK, PD and efficacy - dose exploration and dose expansion |
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E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 3 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 19 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
Canada |
United States |
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E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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LSLV - The end of study date is defined as the date when the last subject across all sites is assessed or receives an intervention for evaluation in the study (ie, last subject last visit), following any additional parts in the study (eg, long-term follow-up, additional antibody testing), as applicable. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 3 |