Neuroendocrine Prostate Cancer
Conditions
Keywords
De novo or treatment emergent neuroendocrine prostate cancer, Non-canonical Notch ligand
Brief summary
To evaluate the safety and tolerability of Tarlatamab and will determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D).
Interventions
DRUGTarlatamab
Tarlatamab will be administered as an intravenous (IV) infusion.
Sponsors
Amgen
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
(Part 1: Dose Exploration and Part 2: Dose Expansion): * Participant has provided informed consent prior to initiation of any study specific activities/procedures. * Men aged ≥ 18 years at time of signing the informed consent. * Metastatic de novo or treatment-emergent neuroendocrine prostate cancer (NEPC) defined by histology, immunohistochemistry, or genomic analyses of baseline tumor tissue (by local assessment) or circulating tumor DNA (ctDNA) (by local assessment) as per protocol * At least 1 line of prior systemic treatment per protocol. * Participants with treatment-emergent NEPC or de novo NEPC with histologic evidence of prostate cancer with neuroendocrine differentiation without a history of bilateral orchiectomy are required to remain on luteinizing hormone-releasing hormone (LHRH) analogue therapy during the course of protocol therapy * Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 per Prostate Cancer Working Group 3 (PCWG3) modifications * Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤ 2 * Participants with treated brain metastases are eligible provided they meet defined criteria * Adequate organ function as defined in protocol
Exclusion criteria
(Part 1: Dose Exploration and Part 2: Dose Expansion): * History of other malignancy within the past 2 years, with exceptions: * Malignancy treated with curative intent and with no known active disease present for ≥ 2 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 non-muscle invasive urothelial carcinoma * History or presence of hematological malignancies unless curatively treated with no evidence of disease ≥ 2 years * Untreated or symptomatic brain metastases and leptomeningeal disease * Anti-tumor therapy within 28 days of study day 1; concurrent use of hormone deprivation therapy for hormone refractory prostate cancer is permitted; participants on a stable bisphosphonate or denosumab prior to study day 1 are eligible Exceptions: * Participants who received conventional chemotherapy are eligible if at least 14 days have elapsed and if all treatment-related toxicities have resolved to Grade ≤ 1 * Prior palliative radiotherapy must have been completed at least 7 days before the first dose of tarlatamab * Participants who received androgen signaling inhibitor are eligible if at least 14 days have elapsed and if all treatment-related toxicity has been resolved to Grade ≤ 1 * Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior study day 1 * Active autoimmune disease requiring systemic treatment within the past 2 years * Known positive test for human immunodeficiency virus (HIV) or hepatitis * Unresolved toxicities from prior anti-tumor therapy, defined as not having resolved to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 grade 0 or 1 (with the exception of alopecia or toxicities that are stable and well-controlled) * History of hypophysitis or pituitary dysfunction * Has evidence of interstitial lung disease or active, non-infectious pneumonitis. * Participants on prior delta-like ligand 3 (DLL3)-targeted therapy may be eligible if discussed with Amgen Medical Monitor prior to enrollment * Evidence of severe acute respiratory syndrome coronavirus 2 (SARS-COV2) infection unless agreed upon with Medical Monitor and with no acute symptoms of coronavirus disease 2019 (COVID19) disease within 14 days prior to first dose of investigational product (counted from day of positive test for asymptomatic participants).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Experienced One or More Treatment-emergent Adverse Events (TEAEs) | Up to approximately 3 years | An adverse event (AE) was defined as any untoward medical occurrence in a clinical study participant irrespective of a causal relationship with the study treatment. A TEAE was defined as an AE starting on or after the first dose of tarlatamab, and up to and including 47 days after the last dose of tarlatamab excluding the events reported after End of Study date. Clinically significant changes from baseline in vital signs, 12-lead electrocardiograms (ECGs) and clinical laboratory tests were also reported as TEAEs. |
| Number of Participants Who Experienced One or More Treatment-related Adverse Events (TRAE) | Up to approximately 3 years | A TRAE was defined as a TEAE that per investigator review had a reasonable possibility of being caused by tarlatamab. Clinically significant changes from baseline in vital signs, 12-lead ECGs and clinical laboratory tests were also reported as TEAEs. |
| Number of Participants Who Experienced Dose Limiting Toxicities (DLTs) | Up to 28 days | A DLT was defined as any qualifying toxicity that was at least possibly related to tarlatamab with an onset within the first 28 days following first dose with either of the following criteria: 1. Grade 3 adverse event lasting more than 3 days (with the exception of fatigue and Grade 3 non-febrile neutropenia that improved to ≤ Grade 1 within 3 weeks including the use of growth factor support per neutropenia management guidelines); 2. ≥ Grade 4 adverse event regardless of duration (with the exception of grade 4 non-febrile neutropenia lasting less than or equal to 7 days including the use of growth factor support per neutropenia management guidelines). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | Up to approximately 3 years | OS was defined as the time from the start of treatment until event of death due to any cause. The distribution of OS was summarized using the KM method with CI calculated using the Brookmeyer and Crowley (Brookmeyer and Crowley, 1982) method. |
| Disease Control Rate (DCR) | Up to approximately 3 years | DCR was defined as the percentage of participants with a best overall response of confirmed response (CR/PR) or stable disease (SD) as per RECIST 1.1. The DCR was assessed per RECIST 1.1. The percentage of participants with disease control with corresponding exact 95% CI was calculated using the Clopper-Pearson (Clopper and Pearson, 1934) method. The result reported was evaluated by central reviewer assessment. |
| Maximum Serum Concentration (Cmax) of Tarlatamab | Cycle 2 Day 1 and Day 15: Predose, end of infusion (EOI), 2, 6, 24, 48, 96 and 168 hours after EOI | Pharmacokinetic (PK) parameters of tarlatamab were determined from the time concentration profile using standard non-compartmental approaches and considering the profile over the complete sampling interval. |
| Objective Response Rate (ORR) | Up to approximately 3 years | OR was assessed per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 with Prostate Cancer Working Group 3 (PCWG3) modifications. OR was defined as best overall response of partial response (PR) or complete response (CR) per RECIST 1.1, confirmed by an assessment at least 4 weeks later. Participants who did not experience a PR/CR or did not have any follow-up tumor assessments were regarded as non-responders. ORR was defined as the percentage of participants with a best overall response of confirmed CR or PR per RECIST 1.1. The percentage of participants with an OR was summarized along with the Clopper-Pearson (Clopper and Pearson, 1934) exact 95% confidence interval (CI). The result reported was evaluated by central reviewer assessment. |
| Area Under the Concentration-time Curve Over the Dosing Interval From Time 0 to 336 Hours (AUC336) of Tarlatamab | Cycle 2 Day 1 and Day 15: Predose, EOI, 2, 6, 24, 48, 96, 168, and 336 hours after EOI | PK parameters of tarlatamab were determined from the time concentration profile using standard non-compartmental approaches and considering the profile over the complete sampling interval. The result for this endpoint is given for cycle 2 only. |
| Terminal Phase Elimination Half-life (t1/2,z) of Tarlatamab | Cycle 2 Day 15: Predose, EOI, 2, 6, 24, 48, 96 and 168 hours after EOI | PK parameters of tarlatamab were determined from the time concentration profile using standard non-compartmental approaches and considering the profile over the complete sampling interval. The result for this endpoint is given for cycle 2 only. |
| Tarlatamab Concentration at the End of a Dosing Interval or Before Planned Next Dose (Ctrough) | Cycle 2 Day 15: Predose | PK parameters of tarlatamab were determined from the time concentration profile using standard non-compartmental approaches and considering the profile over the complete sampling interval. The result for this endpoint is given for cycle 2 only. |
| Duration of Response (DOR) | Up to approximately 3 years | DOR was defined as the time from the date of an initial objective response to the earlier of progressive disease or death for participants with an objective response per RECIST 1.1. DOR was assessed per RECIST 1.1 with PCWG3 modifications. The distribution of DOR was summarized using the Kaplan-Meier (KM) method with CI calculated using the Brookmeyer and Crowley (Brookmeyer and Crowley, 1982) method. The result reported was evaluated by central reviewer assessment. |
| Radiographic Progression-free Survival (PFS) | Up to approximately 3 years | Radiographic PFS was defined as the interval from the first dose of tarlatamab to the earlier of a radiographic progression or death from any cause. Radiographic PFS was assessed per RECIST 1.1 with PCWG3 modifications. The distribution of radiographic PFS was summarized using the KM method with CI calculated using the Brookmeyer and Crowley (Brookmeyer and Crowley, 1982) method. The result reported was evaluated by central reviewer assessment. |
Countries
Australia, Austria, Belgium, France, Japan, Netherlands, Spain, United Kingdom, United States
Participant flow
Recruitment details
A total of 41 participants were enrolled into this study in the United States, Australia, Austria, Belgium, France, Japan, Netherlands, and Spain between June 2021 and July 2024.
Pre-assignment details
The planned Part 1 did not enrol participants. It was eliminated as pre-specified in the protocol due to sufficient data from Study 20160323 (NCT03319940) at the time of study initiation allowing the recommended phase 2 dose (RP2D) of tarlatamab to be determined for Part 2. Therefore no dose escalation occurred during the study.
Participants by arm
| Arm | Count |
|---|---|
| Tarlatamab Dose Expansion Participants received tarlatamab as a short term IV infusion Q2W in a 28 day cycle until disease progression. All participants received the same target dose of tarlatamab which was reached using a step-dosing approach including a run-in dose on day 1 of the first cycle. | 40 |
| Total | 40 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 35 |
| Overall Study | Decision by Sponsor | 1 |
| Overall Study | Lost to Follow-up | 1 |
| Overall Study | Withdrawal of Consent from Study | 3 |
Baseline characteristics
| Characteristic | Tarlatamab Dose Expansion |
|---|---|
| Age, Continuous | 64 years STANDARD_DEVIATION 9.1 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 27 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 11 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 8 Participants |
| Race (NIH/OMB) White | 29 Participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 40 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 35 / 41 |
| other Total, other adverse events | 40 / 40 |
| serious Total, serious adverse events | 27 / 40 |
Outcome results
Primary
Number of Participants Who Experienced Dose Limiting Toxicities (DLTs)
A DLT was defined as any qualifying toxicity that was at least possibly related to tarlatamab with an onset within the first 28 days following first dose with either of the following criteria: 1. Grade 3 adverse event lasting more than 3 days (with the exception of fatigue and Grade 3 non-febrile neutropenia that improved to ≤ Grade 1 within 3 weeks including the use of growth factor support per neutropenia management guidelines); 2. ≥ Grade 4 adverse event regardless of duration (with the exception of grade 4 non-febrile neutropenia lasting less than or equal to 7 days including the use of growth factor support per neutropenia management guidelines).
Time frame: Up to 28 days
Population: DLT Analysis Set: all participants who were enrolled and received at least 1 dose of tarlatamab with an evaluable DLT endpoint.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Tarlatamab Dose Expansion | Number of Participants Who Experienced Dose Limiting Toxicities (DLTs) | 1 Participants |
Primary
Number of Participants Who Experienced One or More Treatment-emergent Adverse Events (TEAEs)
An adverse event (AE) was defined as any untoward medical occurrence in a clinical study participant irrespective of a causal relationship with the study treatment. A TEAE was defined as an AE starting on or after the first dose of tarlatamab, and up to and including 47 days after the last dose of tarlatamab excluding the events reported after End of Study date. Clinically significant changes from baseline in vital signs, 12-lead electrocardiograms (ECGs) and clinical laboratory tests were also reported as TEAEs.
Time frame: Up to approximately 3 years
Population: Safety Analysis Set: all participants who were enrolled and received at least 1 dose of tarlatamab.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Tarlatamab Dose Expansion | Number of Participants Who Experienced One or More Treatment-emergent Adverse Events (TEAEs) | 40 Participants |
Primary
Number of Participants Who Experienced One or More Treatment-related Adverse Events (TRAE)
A TRAE was defined as a TEAE that per investigator review had a reasonable possibility of being caused by tarlatamab. Clinically significant changes from baseline in vital signs, 12-lead ECGs and clinical laboratory tests were also reported as TEAEs.
Time frame: Up to approximately 3 years
Population: Safety Analysis Set: all participants who were enrolled and received at least 1 dose of tarlatamab.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Tarlatamab Dose Expansion | Number of Participants Who Experienced One or More Treatment-related Adverse Events (TRAE) | 40 Participants |
Secondary
Area Under the Concentration-time Curve Over the Dosing Interval From Time 0 to 336 Hours (AUC336) of Tarlatamab
PK parameters of tarlatamab were determined from the time concentration profile using standard non-compartmental approaches and considering the profile over the complete sampling interval. The result for this endpoint is given for cycle 2 only.
Time frame: Cycle 2 Day 1 and Day 15: Predose, EOI, 2, 6, 24, 48, 96, 168, and 336 hours after EOI
Population: PK Analysis Set: all participants who received at least 1 dose of tarlatamab and had at least 1 PK sample collected. The number of participants analyzed only includes participants with available data for each timepoint.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Tarlatamab Dose Expansion | Area Under the Concentration-time Curve Over the Dosing Interval From Time 0 to 336 Hours (AUC336) of Tarlatamab | Cycle 2 Day 1 | 4010 hr*μg/mL | Geometric Coefficient of Variation 28 |
| Tarlatamab Dose Expansion | Area Under the Concentration-time Curve Over the Dosing Interval From Time 0 to 336 Hours (AUC336) of Tarlatamab | Cycle 2 Day 15 | 4260 hr*μg/mL | Geometric Coefficient of Variation 26 |
Secondary
Disease Control Rate (DCR)
DCR was defined as the percentage of participants with a best overall response of confirmed response (CR/PR) or stable disease (SD) as per RECIST 1.1. The DCR was assessed per RECIST 1.1. The percentage of participants with disease control with corresponding exact 95% CI was calculated using the Clopper-Pearson (Clopper and Pearson, 1934) method. The result reported was evaluated by central reviewer assessment.
Time frame: Up to approximately 3 years
Population: Evaluable by Central Reviewer Analysis Set: all participants who were enrolled, received at least 1 dose of tarlatamab, had measurable baseline disease per RECIST 1.1 with PCWG3 modifications as assessed by a central reviewer.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tarlatamab Dose Expansion | Disease Control Rate (DCR) | 36.0 percentage of participants |
Secondary
Duration of Response (DOR)
DOR was defined as the time from the date of an initial objective response to the earlier of progressive disease or death for participants with an objective response per RECIST 1.1. DOR was assessed per RECIST 1.1 with PCWG3 modifications. The distribution of DOR was summarized using the Kaplan-Meier (KM) method with CI calculated using the Brookmeyer and Crowley (Brookmeyer and Crowley, 1982) method. The result reported was evaluated by central reviewer assessment.
Time frame: Up to approximately 3 years
Population: Evaluable by Central Reviewer Analysis Set: all participants who were enrolled, received at least 1 dose of tarlatamab, had measurable baseline disease per RECIST 1.1 with PCWG3 modifications as assessed by a central reviewer. Only participants with a confirmed response have been included here.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Tarlatamab Dose Expansion | Duration of Response (DOR) | NA months |
Secondary
Maximum Serum Concentration (Cmax) of Tarlatamab
Pharmacokinetic (PK) parameters of tarlatamab were determined from the time concentration profile using standard non-compartmental approaches and considering the profile over the complete sampling interval.
Time frame: Cycle 2 Day 1 and Day 15: Predose, end of infusion (EOI), 2, 6, 24, 48, 96 and 168 hours after EOI
Population: PK Analysis Set: all participants who received at least 1 dose of tarlatamab and had at least 1 PK sample collected. The total number of participants analyzed includes only participants with available data at pre-specified timepoints.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Tarlatamab Dose Expansion | Maximum Serum Concentration (Cmax) of Tarlatamab | Cycle 2 Day 1 | 31.1 μg/mL | Geometric Coefficient of Variation 26 |
| Tarlatamab Dose Expansion | Maximum Serum Concentration (Cmax) of Tarlatamab | Cycle 2 Day 15 | 31.7 μg/mL | Geometric Coefficient of Variation 19 |
Secondary
Objective Response Rate (ORR)
OR was assessed per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 with Prostate Cancer Working Group 3 (PCWG3) modifications. OR was defined as best overall response of partial response (PR) or complete response (CR) per RECIST 1.1, confirmed by an assessment at least 4 weeks later. Participants who did not experience a PR/CR or did not have any follow-up tumor assessments were regarded as non-responders. ORR was defined as the percentage of participants with a best overall response of confirmed CR or PR per RECIST 1.1. The percentage of participants with an OR was summarized along with the Clopper-Pearson (Clopper and Pearson, 1934) exact 95% confidence interval (CI). The result reported was evaluated by central reviewer assessment.
Time frame: Up to approximately 3 years
Population: Evaluable by Central Reviewer Analysis Set: all participants who were enrolled, received at least 1 dose of tarlatamab, had measurable baseline disease per RECIST 1.1 with PCWG3 modifications as assessed by a central reviewer.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tarlatamab Dose Expansion | Objective Response Rate (ORR) | 12.0 percentage of participants |
Secondary
Overall Survival (OS)
OS was defined as the time from the start of treatment until event of death due to any cause. The distribution of OS was summarized using the KM method with CI calculated using the Brookmeyer and Crowley (Brookmeyer and Crowley, 1982) method.
Time frame: Up to approximately 3 years
Population: Safety Analysis Set: all participants who were enrolled and received at least 1 dose of tarlatamab. Among the 40 participants included in the Safety Analysis Set, 35 participants died because of any cause and 5 participants were censored.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Tarlatamab Dose Expansion | Overall Survival (OS) | 7.9 months |
Secondary
Radiographic Progression-free Survival (PFS)
Radiographic PFS was defined as the interval from the first dose of tarlatamab to the earlier of a radiographic progression or death from any cause. Radiographic PFS was assessed per RECIST 1.1 with PCWG3 modifications. The distribution of radiographic PFS was summarized using the KM method with CI calculated using the Brookmeyer and Crowley (Brookmeyer and Crowley, 1982) method. The result reported was evaluated by central reviewer assessment.
Time frame: Up to approximately 3 years
Population: Safety Analysis Set: all participants who were enrolled and received at least 1 dose of tarlatamab. Censoring was at the last evaluable disease assessment date (tumor assessment or bone scan).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Tarlatamab Dose Expansion | Radiographic Progression-free Survival (PFS) | 2.1 months |
Secondary
Tarlatamab Concentration at the End of a Dosing Interval or Before Planned Next Dose (Ctrough)
PK parameters of tarlatamab were determined from the time concentration profile using standard non-compartmental approaches and considering the profile over the complete sampling interval. The result for this endpoint is given for cycle 2 only.
Time frame: Cycle 2 Day 15: Predose
Population: PK Analysis Set: all participants who received at least 1 dose of tarlatamab and had at least 1 PK sample collected. The number of participants analyzed only includes participants with available data for each timepoint.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Tarlatamab Dose Expansion | Tarlatamab Concentration at the End of a Dosing Interval or Before Planned Next Dose (Ctrough) | 5.36 μg/mL | Geometric Coefficient of Variation 36 |
Secondary
Terminal Phase Elimination Half-life (t1/2,z) of Tarlatamab
PK parameters of tarlatamab were determined from the time concentration profile using standard non-compartmental approaches and considering the profile over the complete sampling interval. The result for this endpoint is given for cycle 2 only.
Time frame: Cycle 2 Day 15: Predose, EOI, 2, 6, 24, 48, 96 and 168 hours after EOI
Population: PK Analysis Set: all participants who received at least 1 dose of tarlatamab and had at least 1 PK sample collected. The number of participants analyzed only includes participants with available data for each timepoint.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Tarlatamab Dose Expansion | Terminal Phase Elimination Half-life (t1/2,z) of Tarlatamab | 7.23 days | Geometric Coefficient of Variation 33 |