Safety, Tolerability, Pharmacokinetics, and Efficacy of Acapatamab in Subjects With mCRPC

This is a phase I, first-in-human study to evaluate the safety and tolerability of acapatamab; a half-life extended (HLE) bispecific T-cell engager (BiTE®) construct, alone and in combination with pembrolizumab, etanercept prophylaxis and cytochrome P450 (CYP) phenotyping cocktail in subjects with metastatic castration-resistant prostate cancer.

Part 1 dose-exploration: acapatamab is administered intravenously. The dose-exploration phase of the study will estimate the MTD of acapatamab. RP2D may be identified based on emerging safety, efficacy, and pharmacodynamic data prior to reaching an MTD.

Drug: acapatamab

Part 1 dose-expansion: acapatamab is administered intravenously at the MTD/RP2D.

Drug: acapatamab

Part 2: acapatamab is administered intravenously at the MTD/RP2D. Pembrolizumab will be administered intravenously.

Drug: acapatamab · Drug: Pembrolizumab

Part 3: acapatamab is administered intravenously at RP2D/MTD levels. Etanercept will be administered subcutaneously in cycle 1 only.

Drug: acapatamab · Drug: Etanercept

Part 4: acapatamab is administered intravenously at RP2D/MTD with 24-hour monitoring.

Drug: acapatamab

Part 5: acapatamab is administered intravenously at RP2D/MTD in an outpatient setting with 8-hour monitoring.

Drug: acapatamab

Part 6: acapatamab is administered intravenously at RP2D/MTD. A CYP phenotyping cocktail will be administered orally.

Drug: acapatamab · Drug: Cytochrome P450 (CYP) Cocktail

Investigational immunotherapy for the treatment of metastatic castration-resistant prostate cancer

Combined with acapatamab for investigational treatment of mCRPC

Prophylaxis for acapatamab-related cytokine release syndrome.

Evaluate the effect of co-administration of multiple dosing of acapatamab on plasma

Time frame: Day 1 to 28 of Cycle 1 (length of cycle is 28 days)

DLTs are defined as any adverse event with an onset within first 28 days following first dose of AMG 160 monotherapy (Part 1) or in combination with pembrolizumab (Part 2) with any of the following criteria unless clearly attributable to causes other than AMG 160 treatment: • grade 5 toxicity (eg, death not due to disease progression)

Time frame: Up to 30 days after the last dose of study drug, or start of new anti-cancer therapy, whichever occurs first

A treatment-emergent adverse event is one that occurs on or after the first dose of study treatment and up to 30 days after the last dose. Adverse events were graded using Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Any clinically significant changes in vital signs, electrocardiograms, and clinical laboratory tests were recorded as adverse events.

Time frame: Up to 3 years

OR was defined as a partial response (PR) or complete response (CR) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, confirmed by a repeat 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.

Time frame: Up to 3 years

A PSA response (PSA 30) is defined as a ≥ 30% reduction from the baseline PSA, (PSA 50) is defined as a ≥ 50% reduction from the baseline PSA, (PSA 70) is defined as a ≥ 70% reduction from the baseline PSA, and (PSA 90) is defined as a ≥ 90% reduction from the baseline PSA. PSA response must be confirmed by a second consecutive value ≥ 3 weeks later.

Time frame: Up to 3 years

DOR is defined as the time from the date of an initial objective response per RECIST 1.1 to the earlier of progression or death. Participants who had not ended their response at the time of analysis had DOR censored at their last evaluable tumor assessment.

Time frame: Up to 3 years

PSA DOR is defined as the time from the date of an initial PSA response (PSA 50) to the earlier of PSA progression or death. Subjects who have not ended their response at the time of analysis will have PSA DOR censored on the date of their last PSA measurement. This endpoint only applies to subjects with a PSA response (PSA 50).

Time frame: Up to 3 years

A Gallium PSMA-11 response is a ≥50% reduction from baseline in the maximum standardized uptake value (SUV) using 68Gallium (68Ga)-prostate-specific membrane antigen (PSMA)-11 positron emission tomography (PET)/computed tomography (CT).

Time frame: Up to 3 years

A FDG PET response is a ≥50% reduction from baseline in the maximum SUV using 18F-FDG PET/CT.

Time frame: Up to 3 years

Time to radiographic progression is defined as the time from study Day 1 until the first documentation of radiographic disease progression in the absence of subsequent anticancer therapy. Time to radiographic progression will be censored at the last evaluable post-baseline tumor assessment prior to subsequent anti-cancer therapy; otherwise, at study Day 1.

Time frame: Up to 3 years

Time to PSA progression is defined as the interval from study Day 1 to PSA progression; otherwise, time to PSA progression is censored on the date of the last PSA measurement. If a participant has no baseline or no post-baseline PSA measurement, time to PSA progression will be censored at study Day 1.

Time frame: Up to 3 years

Radiographic progression free survival (rPFS) is defined as the interval from study day 1 to the earlier of a radiographic progression or death from any cause; otherwise, rPFS is censored at the last evaluable tumor assessment date. If a subject has no post-baseline radiographic tumor assessment and a vital status of alive or unknown, rPFS will be censored at study day 1.

Time frame: Up to 3 years

PSA PFS is defined as the interval from study day 1 to the earlier of a PSA progression or death from any cause; otherwise, PSA PFS is censored on the date of the last PSA measurement. If a subject has no baseline or no post-baseline PSA measurement and a vital status of alive or unknown, PSA PFS will be censored at study day 1.

Time frame: Up to 3 years

Overall survival (OS) is defined as the time from the date of study Day 1 until death due to any cause.

Time frame: Up to 3 years

CTC0 is defined as reduction of CTCs \> 0 to 0 at any post-baseline measurement. CTC0 response is applicable only for participants with baseline CTC \> 0.

Time frame: Up to 3 years

CTC conversion is defined as ≥ 5 CTCs/7.5 mL blood to ≤ 4 CTCs/7.5 mL blood at any post-baseline measurement. CTC conversion is applicable only for subjects with baseline CTC ≥ 5..

Time frame: Up to 3 years

Time to SSE is defined as time from study day 1 to the first SSE. Otherwise, SSE is censored at the last dose date of AMG 160 or pembrolizumab or end of safety follow up date, whichever is later.

Time frame: Cycle 1 Days 1, 8, 15, and 22; Cycle 2 Days 1 and 15 (sampling pre-dose up to 168 hours post-dose)

Serum concentrations of AMG 160 were determined using a validated assay. Noncompartmental analysis was performed for the estimation of pharmacokinetic (PK) parameters. Concentrations below the lower limit of quantification (LLOQ) (0.0500 ng/mL) were set to zero before data analysis.

PK parameters, including Cmax, Tmax, Cmin, AUClast, AUCtau, t1/2,z, were not estimated for Parts 4 and 5 because the PK sampling schedule in these parts was sparse and not designed to support parameter estimation.

Time frame: Cycle 1 Days 1, 8, 15, and 22; Cycle 2 Days 1 and 15 (sampling pre-dose up to 696 hours)

Serum concentrations of AMG 160 were determined using a validated assay. Noncompartmental analysis was performed for the estimation of PK parameters. Concentrations below the LLOQ (0.0500 ng/mL) were set to zero before data analysis.

Actual time post dose was used for calculations.

PK parameters, including Cmax, Tmax, Cmin, AUClast, AUCtau, t1/2,z, were not estimated for Parts 4 and 5 because the PK sampling schedule in these parts was sparse and not designed to support parameter estimation.

Time frame: Cycle 1 Days 1, 8, 15, and 22; Cycle 2 Days 1 and 15 (sampling pre-dose up to 168 hours post-dose))

Serum concentrations of AMG 160 were determined using a validated assay. Noncompartmental analysis was performed for the estimation of PK parameters. Concentrations below the LLOQ (0.0500 ng/mL) were set to zero before data analysis.

PK parameters, including Cmax, Tmax, Cmin, AUClast, AUCtau, t1/2,z, were not estimated for Parts 4 and 5 because the PK sampling schedule in these parts was sparse and not designed to support parameter estimation.

Time frame: Cycle 1 Days 1, 8, 15, and 22; Cycle 2 Days 1 and 15 (sampling pre-dose up to 168 hours post-dose))

Serum concentrations of AMG 160 were determined using a validated assay. Noncompartmental analysis was performed for the estimation of PK parameters. Concentrations below the LLOQ (0.0500 ng/mL) were set to zero before data analysis.

PK parameters, including Cmax, Tmax, Cmin, AUClast, AUCtau, t1/2,z, were not estimated for Parts 4 and 5 because the PK sampling schedule in these parts was sparse and not designed to support parameter estimation.

Time frame: Cycle 1 Days 1, 8, 15, and 22; Cycle 2 Days 1 and 15 (sampling pre-dose up to 168 hours post-dose)

Serum concentrations of AMG 160 were determined using a validated assay. Noncompartmental analysis was performed for the estimation of PK parameters. Concentrations below the LLOQ (0.0500 ng/mL) were set to zero before data analysis.

PK parameters, including Cmax, Tmax, Cmin, AUClast, AUCtau, t1/2,z, were not estimated for Parts 4 and 5 because the PK sampling schedule in these parts was sparse and not designed to support parameter estimation.

Time frame: Cycle 1 Days 1, 8, 15, and 22; Cycle 2 Days 1 and 15 (sampling pre-dose up to 168 hours post-dose)

Serum concentrations of AMG 160 were determined using a validated assay. Noncompartmental analysis was performed for the estimation of PK parameters. Concentrations below the LLOQ (0.0500 ng/mL) were set to zero before data analysis.

PK parameters, including Cmax, Tmax, Cmin, AUClast, AUCtau, t1/2,z, were not estimated for Parts 4 and 5 because the PK sampling schedule in these parts was sparse and not designed to support parameter estimation.

A Phase 1 Study Evaluating the Safety, Tolerability, Pharmacokinetics, and Efficacy of Prostate Specific Membrane Antigen Half-life Extended Bispecific T-cell Engager Acapatamab in Subjects With Metastatic Castration-resistant Prostate Cancer