A Phase I Study Evaluating the Safety, Tolerability, Pharmacokinetics, and Efficacy of AMG 509 in Subjects With Metastatic Castration-Resistant Prostate Cancer.

Study Identifier:
20180146
CT.gov Identifier:
NCT04221542
EudraCT Identifier:
202350000000
EU Trial (CTIS) Number:
N/A
Study Contact Information:
N/A
Recruiting

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Study Summary

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

To evaluate the safety, tolerability, pharmacokinetics (PK), and efficacy of AMG 509 in patients with relapsed/refractory mCRPC.

The dose exploration phase (n=40) will estimate the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) using a Bayesian logistic regression model. The dose expansion phase (n=30) will confirm safety, PK, and pharmacodynamics at the MTD or RP2D and collect further safety, efficacy, and biomarker data.

To evaluate AMG 509 in pts with mCRPC previously treated with novel hormonal therapy (NHT) and will assess the safety, tolerability, pharmacokinetics (PK), and efficacy of AMG 509 to establish the maximum tolerated dose (MTD) and/or the recommended phase 2 dose (RP2D).

Part 2 will evaluate subcutaneous dosing of AMG 509 in the same patient population as in Part 1. Part 3 will explore AMG 509 IV dosing in chemotherapy-naivve pts who have been treated previously with one NHT and will provide additional data on the safety, PK, efficacy, pharmacodynamics, and correlative biomarkers at the MTD or RP2D determined in Part 1. Part 4 will evaluate the combination of AMG 509 with abiraterone (Part 4A) or enzalutamide (Part 4B) in pts previously treated with one NHT and up to 1 prior taxane for castration-sensitive disease.

Study objectives were to evaluate safety, tolerability, antitumor activity, PK, and determine the MTD and RP2D.

Study objectives were to evaluate safety, tolerability, antitumor activity, PK, and determine the MTD and RP2D.

To evaluate association of baseline tumor and peripheral biomarker characteristics with efficacy in the first-in-human dose exploration trial.

The study examined STEAP1 target expression by immunohistochemistry in fresh and archival tumor biopsies, peripheral immune populations by multiparameter flow cytometry, and tumor somatic mutations via circulating tumor DNA (ctDNA) in plasma

Medical Condition
The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.
  • Prostate
    • Phase
    The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
    I
    Sex
    Male
    Age
    18+ years
    Study Drug
  • Drug: Experimental: Part 1: AMG 509 Intravenous (IV) Monotherapy
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  • Drug: The dose exploration phase of the study will estimate the maximum tolerated dose (MTD) of AMG 509 using a Bayesian logistic regression model (BLRM; Neuenschwander et al, 2008).
  • Drug: Recommended phase 2 dose (RP2D) may be identified based on emerging safety, efficacy, 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.
  • Drug: 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.
  • Drug: Drug: AMG 509
  • Drug: Experimental: Part 2: AMG 509 Subcutaneous (SC) Monotherapy
  • Drug: 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.
  • Drug: Experimental: Part 3: AMG 509 IV Monotherapy in Earlier Lines of Treatment
  • Drug: Experimental: Part 4: AMG 509 IV Combination Therapy
  • Drug: Drug: Abiraterone
  • Drug: Drug: Enzalutamide
  • Drug: Experimental: Part 5: AMG 509 IV Monotherapy in Outpatient Setting
  • Drug: The Part 5 dosing regimen and schedule was selected based on emerging data and dose level review team (DLRT) recommendations and will utilize the doses explored in Part 1 dose-expansion phase.
  • Drug: Experimental: Part 6: AMG 509 IV as Monotherapy and Combination Therapy With Abiraterone Acetate
  • Drug: Part 6 dosing regimen has been previously determined as safe and tolerable and is aligned with the dosing schedule for Parts 3 and 4A expansion.
  • Drug: Experimental: Part 7 (China only): AMG 509 IV as Monotherapy or in Combination With Abiraterone Acetate
  • Drug: Part 7 dosing regime will first be enrolled to dose level-1 (1.0 mg target dose) and if tolerated and if DLRT determines it is safe to escalate to the MTD/RP2D, 1.5 mg every 2 weeks (Q2W) dosing regimen may be explored. If the RP2D is safe and tolerable and once AMG 509 monotherapy dose confirmation is complete, a cohort of participants to receive AMG 509 combination therapy with abiraterone acetate may be initiated.
  • Drug: Experimental drug
  • Drug: Patients were randomized to receive xaluritamig intravenously to reach target doses of 0.75 mg once weekly (QW), 1.5 mg QW, or 1.5 mg twice weekly (Q2W), using a 2- or 3-step dosing approach in cycle 1.
  • Drug: Xaluritamig was administered as an IV infusion with increasing doses (0.001-2.0 mg).
    • Study Status
    Indicates the current recruitment status or the expanded access status
    Recruiting

    Requirements information
    Inclusion criteria
    • Parts 1, 2, 5 and 7: 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.
    • Dose exploration phase: Novel antiandrogen therapy must have been given for treatment of metastatic disease.
    • 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 have received no or 1-2 prior NHTs (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 (unless taxane treatment was administered in HSPC setting). 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, 4B and 7:
    • Participants with histologically or cytologically confirmed mCRPC who have received no or 1-2 prior NHTs (given in any disease setting depending on the part), and no or 1 taxane regimen (for HSPC).
    • Dose-expansion phase: at least 1 prior NHT must have been given; 0-1 prior PARP inhibitors are acceptable.
    • 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.
    • Dose-expansion phase: up to approximately 10 participants with prior exposure to abiraterone acetate may be enrolled into Part 4A expansion cohort.
    • d. 4B: Participants planning to receive enzalutamide for the first time (participants who received prior enzalutamide/apalutamide or daralutamide are not eligible).
    • Part 6:
    • Prior disease progression on 1, and only 1, NHT (either enzalutamide, apalutamide, or darolutamide) is required. NOTE: Prior progression on or intolerance to abiraterone is not allowed.
    • No prior treatment with any chemotherapy regimen in the mCRPC setting; ≤ 6 cycles of docetaxel treatment in the mHSPC setting is allowed.
    • mCRPC with ≥ 1 RECIST v1.1 measurable lesion that is present on baseline computed tomography (CT) or magnetic resonance imaging (MRI).
    • 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:
    • PSA level ≥ 1 ng/mL that has increased on at least 2 successive occasions at least 1 week apart.
    • Nodal or visceral progression as defined by RECIST v1.1 with PCGW3 modifications.
    • Appearance of 2 or more new lesions in bone scan.
    • Eastern Cooperative Oncology Group performance status of 0-1.
    • Life expectancy ≥ 3 months.
    • Adequate organ function, defined as follows:
    • Hematological function:
    • absolute neutrophil count ≥ 1 x 10^9/L (without growth factor support within 7 days from screening assessment).
    • platelet count ≥ 75 x 10^9/L (without platelet transfusion within 7 days from screening assessment).
    • hemoglobin ≥ 9 g/dL (90 g/L) (without blood transfusion within 7 days from screening assessment).
    • Renal function:
    • 1. estimated glomerular filtration rate based on Modification of Diet in Renal Disease calculation ≥ 30 ml/min/1.73 m^2.
    • Hepatic function:
    • aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3 x upper limit of normal (ULN) (or < 5 x ULN for participants with liver involvement).
    • total bilirubin (TBL) < 1.5 x ULN (or < 2 x ULN for participants with liver metastases).
    • Cardiac function:
    • 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).
    • Baseline electrocardiogram (ECG) QTcF ≤ 470 msec (average of triplicate values).
    • Pulmonary function:
    • baseline oxygen saturation > 92% on room air at rest and no oxygen supplementation.
    • Part 3-Retreatment group:
    • Deriving benefit from initial treatment with AMG 509 as evidenced by one of the following:
    • confirmed PSA50 response.
    • 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.
    • Prior major surgery within 4 weeks of first dose.
    • 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. Simple urinary tract infections and uncomplicated bacterial pharyngitis are permitted if responding to active treatment and after consultation with sponsor. Screening for chronic infectious conditions is not required.
    • 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. Participants with a recent history of venous thrombosis must be maintained on the same anti-coagulation therapy for a minimum of 28 days prior to first dose of study treatment.
    • 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 prostate specific membrane antigen (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 anti-cancer 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.

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    Study Locations

    Location
    Investigator
    Status
    Condition(s) Treated at Site
    Location
    START Lisbon
    Lisbon, Portugal, 1649-035
    Investigator
    Andre Mansinho
    Status
    Recruiting
    Condition(s) Treated at Site
    Prostate