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A Phase 1b Study Evaluating the Safety, Tolerability, Pharmacokinetics and Efficacy of Delta-like Protein 3 Half-life Extended Bispecific T-cell Engager AMG 757 in Subjects With De Novo or Treatment Emergent Neuroendocrine Prostate Cancer

A Study of AMG 757 in Participants With Neuroendocrine Prostate Cancer (DeLLpro-300)

41

Sex: Men (40 subjects [100.0%]) Age: Mean (SD) = 64.5 (9.1) years Race: Asian (3 subjects [7.5%]); White (29 subjects [72.5%]); Unknown or Not Reported (8 subjects [20.0%]). Ethnicity: Not Hispanic/Latino (27 subjects [67.5%]); Hispanic/Latino (2 subjects [5.0%]); Unknown or Not Reported (11 subjects [27.5%])

41 subjects were enrolled in the study. Of 41 subjects, 40 (97.6%) received treatment with tarlatamab. Forty subjects (97.6%) discontinued the study; reasons for study discontinuation were death (35 subjects [85.4%]), withdrawal of consent from study (3 subjects [7.3%]), decision by sponsor and lost to follow-up (1 subject [2.4%] each).

All 40 subjects (100%) from the Safety Analysis Set developed treatment-emergent adverse events (TEAE) and treatment-related adverse events (TRAE) during the study. Serious adverse events were reported for 27 subjects (67.5%). - The adverse events reported for >= 25% of subjects by preferred term (PT) were cytokine release syndrome (CRS) (33 subjects [82.5%]), decreased appetite (20 subjects [50.0%]), constipation (18 subjects [45.0%]), dysgeusia and fatigue (17 subjects [42.5%] each), pyrexia (16 subjects [40.0%]), anemia (14 subjects [35.0%]), nausea (13 subjects [32.5%]), vomiting (11 subjects [27.5%]), and headache (10 subjects [25.0%]) - The serious adverse events reported in >= 5% subjects by PT were CRS (9 subjects [22.5%]), neuroendocrine carcinoma of prostate (5 subjects [12.5%]), fatigue and prostate cancer metastatic (4 subjects [10.0%] each), acute kidney injury (3 subjects [7.5%]), neuroendocrine cancer of the prostate metastatic, sepsis, and prostate cancer (2 subjects [5.0%] each).

Dose-limiting Toxicities (DLT) Among the 30 subjects in the DLT Analysis Set, 1 subject (3.3%) developed a DLT event. Objective Response Rate (ORR) and Disease Control Rate (DCR): - Among the 25 subjects included in the RECIST 1.1 Evaluable by Central Reviewer Analysis Set, the confirmed ORR was 12.0% (95% CI: 2.5, 31.2). The DCR was 36.0% (95% CI: 18.0, 57.5). Duration of Response (DOR): - Among the 25 subjects included in the RECIST 1.1 Evaluable by Central Reviewer Analysis Set, all 3 subjects with confirmed response were censored. The KM estimate of median DOR was NA (95% CI: NA, NA) Radiographic Progression-free Survival (PFS): - Among the 40 subjects included in the Safety Analysis Set evaluated by investigators, the KM estimate of median radiographic PFS was 2.1 months (95% CI: 1.8, 3.8). Overall Survival (OS): - Among the 40 subjects included in the Safety Analysis Set, the KM estimate of median OS was 7.9 months (95% CI: 4.4 to 13.2).

Among the DLT Analysis Set, 1 subject (3.3%) developed a DLT event. All 40 subjects (100%) developed adverse events during the study. All 40 subjects (100%) had treatment-related adverse events. Among the 25 subjects included in the RECIST 1.1 Evaluable by Central Reviewer Analysis Set, the confirmed ORR was 12.0% (95% CI: 2.5, 31.2). The median DOR was NA (95% CI: NA, NA). Among the Safety Analysis Set, 35 subjects (87.5%) died. The KM estimate of median OS was 7.9 months (95% CI: 4.4 to 13.2).

Yes

De-identified individual patient data for variables necessary to address the specific research question in an approved data sharing request.

https://jrct.mhlw.go.jp/latest-detail/jRCT2031210415

Tagashira Shuzo

Amgen K.K.

Midtown Tower 9-7-1 Akasaka, Minato-ku, Tokyo

clinicaltrials_japan@amgen.com

Local Contact

Amgen K.K.

Midtown Tower 9-7-1 Akasaka, Minato-ku, Tokyo

+81-80-7217-8592

clinicaltrials_japan@amgen.com

Complete

June. 10, 2021

Interventional

non-randomized controlled trial

open(masking not used)

dose comparison control

parallel assignment

treatment purpose

Part 1: Dose Exploration and Part 2: Dose Expansion:
1. Participant has provided informed consent prior to initiation of any study specific activities/procedures.
2. Men aged >= 18 years at time of signing the informed consent.
3. 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
4. At least 1 line of prior systemic treatment per protocol.
5. 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
6. Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 per Prostate Cancer Working Group 3 (PCWG3) modifications
7. Eastern Cooperative Oncology Group (ECOG) Performance Status of <= 2
8. Participants with treated brain metastases are eligible provided they meet defined criteria
9. Adequate organ function as defined in protocol

Part 1: Dose Exploration and Part 2: Dose Expansion :
1. 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
2. History or presence of hematological malignancies unless curatively treated with no evidence of disease >= 2 years
3. Untreated or symptomatic brain metastases and leptomeningeal disease
4. 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
5. 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
6. Active autoimmune disease requiring systemic treatment within the past 2 years
7. Known positive test for human immunodeficiency virus (HIV) or hepatitis
8. 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)
9. History of hypophysitis or pituitary dysfunction
10. Has evidence of interstitial lung disease or active, non-infectious pneumonitis.
11. Participants on prior delta-like ligand 3 (DLL3)-targeted therapy may be eligible if discussed with Amgen Medical Monitor prior to enrollment
12. 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).

Male

Neuroendocrine Prostate Cancer

Experimental: Part 1: Dose Exploration
The maximum tolerated dose (MTD) will be estimated using isotonic regression (Ji et al, 2010). The recommended phase 2 dose (RP2D) may be identified based on emerging safety data prior to reaching an MTD.
Drug: Tarlatamab
Tarlatamab will be administered as an intravenous (IV) infusion.

Experimental: Part 2: Dose Expansion
Participants will receive the RP2D/MTD identified in Part 1 (dose exploration) of the study.
Drug: Tarlatamab
Tarlatamab will be administered as an intravenous (IV) infusion.

1. Number of Participants Who Experienced One or More Treatment-emergent Adverse Events (TEAEs) [Time Frame: 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.
2. Number of Participants Who Experienced One or More Treatment-related Adverse Events (TRAE) [Time Frame: 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 TRAEs.
3. Number of Participants Who Experienced Dose Limiting Toxicities (DLTs) [Time Frame: Up to28 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).

1. Objective Response Rate (ORR) [Time Frame: 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.
2. Duration of Response (DOR) [Time Frame: 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.
3. Radiographic Progression-free Survival (PFS) [Time Frame: 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.
4. Overall Survival (OS) [Time Frame: 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.
5. Disease Control Rate (DCR) [Time Frame: 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.
6. Maximum Serum Concentration (Cmax) of Tarlatamab [Time Frame: Cycle 2 Day 1 and Day15: 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.
7. Tarlatamab Concentration at the End of a Dosing Interval or Before Planned Next Dose (Ctrough) [Time Frame: 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.
8. Area Under the Concentration-time Curve Over the Dosing Interval From Time 0 to 336 Hours (AUC336) of Tarlatamab [Time Frame: 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.
9. Terminal Phase Elimination Half-life (t1/2,z) of Tarlatamab [Time Frame: 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.

Sept. 14, 2021

United States/Australia/Austria/Belgium/France/Spain/United Kingdom/Netherlands