AMG 410 Alone and in Combination With Other Agents in Participants With KRAS Altered Advanced or Metastatic Solid Tumors

Official title

A Phase 1/1b Study Evaluating the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Efficacy of AMG 410 Alone and in Combination With Other Agents in Participants With KRAS Altered Advanced or Metastatic Solid Tumors

Overview

The purpose of this first-in-human study is to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of AMG 410 when administered alone or in combination with other agents in participants with advanced or metastatic solid tumors harboring KRAS alterations. This is a dose-escalation study in which participants will be assigned to multiple dose levels (DLs) of AMG 410, either as monotherapy or in combination with other agents, followed by expansion cohorts. The goal is to determine the Maximum Tolerated Dose (MTD)-the highest dose with acceptable safety and manageable side effects-or the Recommended Phase 2 Dose (RP2D) of AMG 410 in adult participants with KRAS-altered advanced or metastatic solid tumors.

Detailed description

This is a multicenter, multinational, open-label Phase 1/1b study designed to evaluate the safety, tolerability, PK, PD, and preliminary antitumor activity of AMG 410 in adult participants with advanced or metastatic solid tumors characterized by KRAS alterations.

The study will begin with a dose-escalation phase, during which AMG 410 will be administered orally, either as monotherapy or in combination with other agents. Dose escalation will follow a model-based approach to identify the MTD or RP2D.

Following dose escalation, additional expansion cohorts may be enrolled at selected dose levels to further characterize the safety profile, PK/PD relationships, and preliminary efficacy in specific tumor types or molecular subgroups.

Participants will continue treatment until disease progression, unacceptable toxicity, withdrawal of consent, or other protocol-defined discontinuation criteria. The maximum duration of AMG 410 administration in this study is 3 years.

Interventions

• Drug AMG 410
  Administered as an oral tablet.
• Drug Pembrolizumab
  Administered as an intravenous (IV) infusion.
• Drug Panitumumab
  Administered as an IV infusion.

Primary outcome measures

• Number of Participants with Dose Limiting Toxicities (DLTs) [Time frame: Up to 28 days]
• Number of Participants with Treatment Emergent Adverse Events (TEAEs) [Time frame: Up to approximately 3 years]
• Number of Participants with Serious Adverse Events (SAEs) [Time frame: Up to approximately 3 years]

Secondary outcome measures (12)

• Maximum Concentration (Cmax) of AMG 410 [Time frame: Up to 85 days]
• Time to Reach Cmax (Tmax) of AMG 410 [Time frame: Up to 85 days]
• Area Under the Concentration-time Curve (AUC) Over the Dosing Interval of AMG 410 [Time frame: Up to 85 days]
• Confirmed Objective Response (OR) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 [Time frame: Up to approximately 3 years]
• Clinical Benefit per RECIST v1.1 [Time frame: Up to approximately 3 years]
• Duration of Response (DoR) per RECIST v1.1 [Time frame: Up to approximately 3 years]
• Time to Response (TTR) per RECIST v1.1 [Time frame: Up to approximately 3 years]
• Progression-free Survival (PFS) per RECIST v1.1 [Time frame: Up to approximately 3 years]
• Overall Survival (OS) [Time frame: Up to approximately 3 years]
• Food Effect Substudy Cohort: Cmax of AMG 410 in the Fed and/or Fasted State [Time frame: Up to 24 days]
• Food Effect Substudy Cohort: Tmax of AMG 410 in the Fed and/or Fasted State [Time frame: Up to 24 days]
• Food Effect Substudy Cohort: AUC Over the Dosing Interval of AMG 410 in the Fed and/or Fasted State [Time frame: Up to 24 days]

Eligibility criteria

Inclusion criteria

• Age ≥ 18 years (or > legal age within the country if it is older than 18 years).
• Pathologically documented, locally-advanced or metastatic malignancy with any missense mutation in the KRAS gene or evidence of KRAS amplification using an analytically validated KRASWT amplification assay.
• Participants must have no standard of care treatment options or have actively refused such therapy.
• Able to swallow and retain per oral administered study treatment.
• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.
• Disease measurable as defined by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1), as determined by the site investigator.
• Adequate organ function.
• Archival (formalin-fixed, paraffin-embedded \[FFPE\]) tumor tissue or block collected within 5 years before screening must be available. Participants without archived tumor tissue may undergo tumor biopsy before AMG 410 dosing (Day1).

Exclusion criteria

• Untreated symptomatic central nervous system or leptomeningeal metastases.
• Uncontrolled pleural effusion and/or ascites.
• History of other malignancy within the past 5 years.
• Active systemic infection or symptoms that indicate an acute and/or uncontrolled infection requiring IV antibiotics within 7days prior to the first dose of study treatment.
• History of arterial or venous thrombosis (eg, stroke, transient ischemic attack, pulmonary embolism, or deep vein thrombosis).
• Live and live-attenuated vaccines are prohibited within 28 days prior to the first dose of study treatment.
• History of solid organ transplant.
• Anti-tumor therapy (chemotherapy, antibody therapy, molecular targeted therapy, hormonal therapy, or investigational agent) within 28 days of first dose of study treatment.
• Presence or history of any of the following viral infections: HIV, Hepatitis C, Hepatitis B, and active severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
• Toxicities from prior anti-tumor therapy (including radiotherapy) not having improved to at least Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 grade 1.
• Therapeutic or palliative radiation therapy within 2 weeks of first dose of study treatment.
• Major surgery within 28 days of first dose of study treatment.
• History or evidence of any other clinically significant disorder, condition, or disease that, in the opinion of the investigator, would pose a risk to participant safety.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Sequential

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 10 centers

• City of Hope National Medical Center — Duarte
• University of California Los Angeles — Los Angeles
• Emory University — Atlanta
• Massachusetts General Hospital — Boston
• Siteman Cancer Center - Washington University — St Louis
• Duke Cancer Center — Durham
• Thomas Jefferson University — Philadelphia
• Sarah Cannon Research Institute Oncology Partners — Nashville
• … and 2 more centers

Australia · 3 centers

• Chris OBrien Lifehouse — Camperdown
• The Queen Elizabeth Hospital — Woodville South
• Peter MacCallum Cancer Centre — Melbourne

Canada · 3 centers

• Cross Cancer Institute — Edmonton
• Princess Margaret Cancer Centre — Toronto
• Sir Mortimer B Davis - Jewish General Hospital — Montreal

China · 3 centers

• Beijing Cancer Hospital — Beijing
• Chongqing University Cancer Hospital — Chongqing
• Jinan Central Hospital — Jinan

Italy · 3 centers

• Azienda Socio Sanitaria Territoriale Grande Ospedale Metropolitano Niguarda — Milan
• Azienda Ospedaliero Universitaria Pisana — Pisa
• Centro Ricerche Cliniche Di Verona Societa responsabilita limitata — Verona

Japan · 3 centers

• Aichi Cancer Center — Nagoya
• National Cancer Center Hospital East — Kashiwa-shi
• National Cancer Center Hospital — Chuo-ku

Spain · 3 centers

• Hospital Universitari Vall d Hebron — Barcelona
• Fundacion Jimenez Diaz — Madrid
• Hospital Universitario 12 de Octubre — Madrid

Belgium · 2 centers

• Universitair Ziekenhuis Antwerpen — Edegem
• Universitair Ziekenhuis Gent — Ghent

France · 2 centers

• Centre Leon Berard — Lyon
• Gustave Roussy — Villejuif

South Korea · 2 centers

• Seoul National University Hospital — Seoul
• Asan Medical Center — Seoul

United Kingdom · 2 centers

• Sarah Cannon Research Institute UK — London
• Royal Marsden Hospital — Sutton

Denmark · 1 center

• Rigshospitalet — Copenhagen

Germany · 1 center

• Universitaetsklinikum Essen — Essen

Netherlands · 1 center

• Universitair Medisch Centrum Utrecht — Utrecht

Identifiers

NCT: NCT07094113 · 20240031

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗