Clinical Trial 23419

• Overview

  Study Title:

  A Phase I/II Study Evaluating the Safety, Tolerability, and Efficacy of Sotorasib Plus Trastuzumab Deruxtecan in Patients with Advanced Non-Small Cell Lung Cancer with a KRASG12C Mutation

  Summary:

  This phase I/II trial tests the safety, side effects and best dose of sotorasib with trastuzumab deruxtecan and how well the combination works in treating patients with KRAS G12C mutated non-small cell lung cancer that has spread to nearby tissues or lymph nodes (locally advanced) or that has spread from where it first started (primary site) to other places in the body (metastatic). Sotorasib blocks a protein made by the mutated KRAS gene (KRAS p.G12C), which may help keep tumor cells from growing and may kill them. It is a type of targeted therapy. Trastuzumab deruxtecan is in a class of medications called antibody-drug conjugates. It is composed of a monoclonal antibody, called trastuzumab, linked to a chemotherapy drug, called deruxtecan. Trastuzumab attaches to HER2 positive tumor cells in a targeted way and delivers deruxtecan to kill them. Giving sotorasib in combination with trastuzumab deruxtecan may be safe, tolerable, and/or effective in treating patients with locally advanced or metastatic non-small cell lung cancer with a KRAS G12C mutation.

  Objective:

  Primary Objective Phase 1 *To determine the safety and tolerability of sotorasib (AMG-510) combined with trastuzumab deruxtecan (DS-8201a) in patients with advanced/metastatic non-small cell lung cancer (NSCLC) harboring a KRASG12C mutation who progress on a KRASG12C inhibitor and platinum-based chemotherapy with or without programmed cell death protein 1 (PD1)/programmed death-ligand 1 (PD-L1) inhibitors or PD1/L1 inhibitors alone. Phase 2 *To determine ORR defined as the proportion of patients with a confirmed response as per investigator assessment according to RECIST version 1.1. Secondary Objectives Phase 1 *To observe and record anti-tumor activity. Although the clinical benefit of this drug combination has not yet been established, the intent of offering this treatment is to provide a possible therapeutic benefit, and thus the patient will be carefully monitored for tumor response and symptom relief in addition to safety and tolerability. *To determine the maximum tolerated dose (MTD) and the recommended phase II dose (RP2D) of trastuzumab deruxtecan (DS-8201a)and sotorasib (AMG-510) when combined. *To estimate overall response rate (ORR) defined as the proportion of patients with a confirmed response as per investigator assessment according to RECIST version 1.1. Phase 2 *To estimate progression free survival (PFS) *To estimate duration of response (DOR) *To estimate overall survival (OS). *To estimate adverse events (AEs) associated with the combination treatment.

• Treatments

  Therapies:

  (HER2)-targeted antibody and topoisomerase I inhibitor conjugate; KRAS G12C inhibitor

  Medications:

  AMG 510 (Sotorasib); DS-8201a (Trastuzumab Deruxtecan); Sotorasib (); Trastuzumab Deruxtecan ()

• Inclusion Criteria

  Key Inclusion Criteria:
  • Patients must have histologically or cytologically documented locally advanced or metastatic KRAS^G12C-mutant NSCLC that has previously been treated with a KRAS^G12C inhibitor AND an immune checkpoint inhibitor (ICI) AND chemotherapy, either given concurrently or sequentially, UNLESS they have any contra-indications to any drug class described above
  • Patients must have KRAS^G12C mutation identified by tumor tissue or plasma circulating tumor deoxyribonucleic acid (ctDNA) profiling using a Clinical Laboratory Improvement Act (CLIA) certified College of American Pathologists (CAP) accredited platform; local molecular testing will be allowed. Testing must have been done within the last 5 years before enrollment in this study
  • Data must be available for which prior KRAS^G12C inhibitor treatment the patient has received and the dates that they received it (type of KRAS^G12C inhibitor used and start and end dates must be collected prior to enrollment)
  • Data must be available on the date patients received the last dose of KRAS^G12C inhibitor and the date of disease progression on their last treatment prior to screening for this trial. Data must be available on the last treatment they received and if it was not or did not include a KRAS^G12C inhibitor. The time between last KRAS^G12C inhibitor and treatment on this trial will be collected prior to enrollment
  • Data must be available on historical HER2 immunohistochemistry (IHC) status (date of test, type of antibody used for the IHC test, scoring system [i.e., breast versus (vs.) gastric], and results must be collected prior to enrollment). Patients must also have ERBB2 (HER2) mutations status identified by tumor tissue or plasma ctDNA profiling; local (i.e., commercial or institutional next generation sequencing [NGS]) molecular testing will be allowed. Patients who do not have this information available for collection will not be enrolled on this study
  • Patients must have measurable disease, as defined by RECIST v1.1 using computed tomography (CT) or magnetic resonance imaging (MRI). Previously irradiated lesions cannot be counted as target lesions unless there has been demonstrated progression in the lesions since radiotherapy and no other lesions are available for selection as target lesions
  • Age ≥ 18 years at date of informed consent form signature
  • Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) (within 14 days of enrollment), (> Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT)(serum glutamic pyruvic transaminase [SGPT]) ≤ 3 x institutional ULN (within 14 days of enrollment) (> Serum albumin ≥ 2.5 g/dL (within 14 days of enrollment)
  • International normalized ratio (INR)/prothrombin time (PT) and activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN (within 14 days of enrollment)
  • Creatinine ≤ 1.5 x institutional ULN OR creatinine clearance (CrCL) ≥ 30 mL/min/ as determined by (using actual body weight) (within 14 days of enrollment)
  • Patients must have left ventricular ejection fraction (LVEF) ≥ 50% by either an echocardiogram (ECHO) or multigated acquisition (MUGA) scan within 28 days before enrollment
  • Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial.
  • Additional criteria will apply

• Exclusion Criteria

  Key Exclusion Criteria:
  • Patients with a history of (non-infectious) interstitial lung disease (ILD) that required steroids, has current ILD, or where suspected ILD cannot be ruled out by imaging at screening. These patients will be excluded because trastuzumab deruxtecan (DS-8201a) is known to increase the risk of developing ILD and pneumonitis
  • Patients with clinically severe pulmonary compromise resulting from intercurrent pulmonary illnesses including, but not limited to, any underlying pulmonary disorder (i.e., pulmonary emboli within three months of the study enrollment, severe asthma, severe chronic obstructive pulmonary disease [COPD], restrictive lung disease, prior complete pneumonectomy), and any autoimmune, connective tissue or inflammatory disorders (e.g., rheumatoid arthritis, Sjogren's, sarcoidosis, etc.) where there is documented or a suspicion of pulmonary involvement or pneumonectomy at the time of screening. These patients will be excluded because trastuzumab deruxtecan (DS-8201a) is known to increase the risk of developing ILD and pneumonitis
  • Patients who have had chest radiation therapy within 4 weeks (2 weeks for palliative stereotactic body radiation therapy). These patients will be excluded because trastuzumab deruxtecan (DS-8201a) and sotorasib (AMG-510) are known to increase the risk of developing pneumonitis
  • Patients who have had a major surgery and are not yet fully healed from surgical incisions
  • Patients who have had prior treatment with an antibody drug conjugate with a topoisomerase 1 inhibitor payload (i.e., sacituzumab govitecan, datopotomab deruxtecan, or trastuzumab deruxtecan) or with a topoisomerase inhibitor
  • Patients with a history of significant lung disease requiring systemic corticosteroids treatment (> 10 mg of prednisone daily) within the last six months of registration Based on pre-clinical data, trastuzumab deruxtecan (DS-8201a) is associated with corneal disease. Patients with clinically significant corneal disease, in the opinion of the investigator, will be excluded from this study
  • Patients with spinal cord compression, defined as untreated and symptomatic, or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms
  • Patients with an uncontrolled infection requiring IV antibiotics, antivirals, or antifungals
  • Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > grade 1) with the exception of alopecia. Subjects with chronic grade 2 toxicities (i.e., defined as no worsening to > grade 2 for at least 3 months prior to first exposure to study intervention and managed with standard of care treatment) may be eligible per the discretion of the investigator after consultation with the sponsor medical monitor or designee (e.g., grade 2 chemotherapy-induced neuropathy). Subjects should no longer be symptomatic nor require treatment with corticosteroids (prednisone > 10 mg or equivalent) or anticonvulsants and must have recovered from the acute toxic effect of radiotherapy
  • Patients who are receiving any other investigational agents
  • Patients with a history of allergic reactions attributed to compounds of similar chemical or biologic composition to sotorasib (AMG-510), such as adagrasib, or trastuzumab deruxtecan (DS-8201a)
  • Patients who have a history of severe hypersensitivity reactions to other monoclonal antibodies
  • Additional criteria will apply

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