Clinical trial NCT04676477: HER3-DXd (Patritumab Deruxtecan; U3-1402) in Combination With Osimertinib in Subjects With Locally Advanced or Metastatic EGFR-mutated Non-Small Cell Lung Cancer
Official title: A Phase 1 Open-Label Study of HER3-DXd (Patritumab Deruxtecan; U3-1402) in Combination With Osimertinib in Subjects With Locally Advanced or Metastatic EGFR-mutated Non-Small Cell Lung Cancer (NSCLC)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
Conditions: Non-Small Cell Lung Cancer (NSCLC)
Keywords: Advanced Non-small Cell Lung Cancer
Inoperable Non-small Cell Lung Cancer
HER3-DXd (Patritumab Deruxtecan; U3-1402)
Unresectable
Epidermal growth factor receptor
Metastatic
EGFR
Osimertinib
HER3
Lead sponsor: Daiichi Sankyo
Sponsor class: INDUSTRY
Collaborators: name: AstraZeneca
name: Merck Sharp & Dohme LLC
First posted: 2020-12-21
Enrollment: 280
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: This study includes a Dose Escalation Part to identify the recommended combination dose (RCD) and a Dose Expansion Part to further evaluate efficacy and safety.

The primary objectives:

Dose Escalation: To assess the safety and tolerability of HER3-DXd (patritumab deruxtecan; U3-1402) and osimertinib in subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) with an EGFR exon 19 deletion or L858R mutation with tumor progression after treatment with osimertinib, and to determine the recommended combination dose (RCD).

Second-Line Dose Expansion Arm 1 and Arm 1b: To assess the preliminary antitumor activity of HER3-DXd and osimertinib in subjects with locally advanced or metastatic NSCLC with an EGFR exon 19 deletion or L858R mutation with tumor progression after treatment with osimertinib. Note: One or both of the study arms may open with one or two distinct dosing schedules.

Second-Line Dose Expansion Arm 2: To assess the preliminary antitumor activity of HER3-DXd monotherapy in subjects with locally advanced or metastatic NSCLC with an EGFR exon 19 deletion or L858R mutation with tumor progression after treatment with osimertinib.

First-Line Dose Expansion Cohorts 3, 4a, and 4b: To assess the preliminary antitumor activity of HER3-DXd and osimertinib in subjects with locally advanced or metastatic NSCLC with an EGFR exon 19 deletion or L858R mutation without prior systemic treatment for locally advanced or metastatic disease.

Detailed description: Dose Escalation:

Population includes subjects with locally advanced or metastatic NSCLC with an EGFR exon 19 deletion or L858R mutation with tumor progression after treatment with osimertinib. The starting combination dose regimen is HER3-DXd 3.2 mg/kg IV every 21 days (Q3W) and osimertinib 80 mg orally (PO) once daily. At least 3 to 6 subjects will be enrolled in each cohort.

Dose Expansion: Two subject populations will be evaluated in the Dose Expansion Part:

* Second-Line: Subjects with locally advanced or metastatic NSCLC with an EGFR exon 19 deletion or L858R mutation with tumor progression after treatment with osimertinib
* First-Line: Subjects with locally advanced or metastatic NSCLC with an EGFR exon 19 deletion or L858R mutation, and without prior systemic therapy for advanced or metastatic disease. Note: The first line expansion will only be initiated if the RCD includes osimertinib 80 mg PO once daily.

Eligibility criteria: Inclusion Criteria:

Inclusion Criteria Specific to Dose Escalation and Second-line Dose Expansion:

* Documentation of EGFR exon 19 deletion or L858R mutation detected from tumor tissue
* Must have received osimertinib for locally advanced or metastatic disease at a dose of 80 mg once daily (QD) for at least 6 weeks and must not miss more than two doses during the 2 weeks prior to the first day of study treatment (Cycle 1, Day 1)
* Must not have received any other prior systemic cancer therapies in the locally advanced/metastatic setting
* Has documentation of radiological disease progression following first-line treatment with osimertinib in the locally advanced or metastatic setting

Inclusion Criteria Specific to First-line Dose Expansion:

* The tumor tissue harbors one of the 2 common EGFR mutations occurring in NSCLC known to be associated with EGFR-TKI sensitivity (exon 19 deletion or L858R) as assessed by Clinical Laboratory Improvement Amendments (CLIA)-certified (United States \[US\] sites), accredited (outside of the US), local laboratory or central laboratory. Only tissue-based testing will be accepted.
* Participants must have previously untreated locally advanced or metastatic NSCLC and must be eligible to receive first-line treatment with osimertinib, according to the judgment of the investigator. Prior adjuvant or neo-adjuvant therapy (chemotherapy, radiotherapy, investigational agents; except with osimertinib) is permitted.

All Participants:

Participants must meet all criteria to be eligible for inclusion in this study:

* Histologically or cytologically documented locally advanced or metastatic NSCLC not amenable to curative surgery or radiation.
* At least 1 measurable lesion as assessed by Investigator as per Response Evaluation Criteria in Solid Tumors (RECIST v1.1)
* Tissue requirements

  * For Dose Escalation (all cohorts): provide an optional pre-treatment tumor tissue of sufficient quantity, as defined in the laboratory manual. The optional pre-treatment tumor tissue can be provided as either:

    * Pre-treatment tumor biopsy from at least 1 lesion not previously irradiated and amenable to core biopsy OR
    * Archival tissue collected from a biopsy performed prior to signing of the tissue consent, and since progression while on treatment with the most recent cancer therapy
  * For First-line Dose Expansion (Cohorts 3, 4a, and 4b): provide an optional pre-treatment and optional on-treatment tumor tissues of sufficient quantity, as defined in the laboratory manual. The optional pre-treatment tumor tissue can be provided as either:

    * Pre-treatment tumor biopsy from at least 1 lesion not previously irradiated and amenable to core biopsy OR
    * Archival tissue collected from a biopsy performed at the time of initial diagnosis or later
  * For Second-line Dose Expansion (Arm 1, Arm 2, and Arm 1b): provide a required pre-treatment and required on-treatment tumor tissues of sufficient quantity, as defined in the laboratory manual. The required pre-treatment tumor tissue can be provided as either:

    * Pre-treatment tumor biopsy from at least 1 lesion not previously irradiated and amenable to core biopsy OR
    * Archival tissue collected from a biopsy performed prior to signing of the tissue consent, and since progression while on treatment with the most recent cancer therapy regimen

      * Note: For all participants who consent to a pre-treatment biopsy, in order to ensure an adequate amount of tissue is available, a core needle biopsy is required.
* Has adequate bone marrow reserve and organ function based on local laboratory data within 14 days prior to Cycle 1, Day 1 (Dose Escalation and First-line Dose Expansion) or within 14 days prior to randomization (Second-line Dose Expansion):

  * Platelet count: ≥100 000/mm\^3 or ≥100 × 10\^9/L (platelet transfusions are not allowed within 14 days prior to the assessment of platelets during the screening period in order to meet the study inclusion criterion)
  * Hemoglobin: ≥9.0 g/dL (transfusion of red blood cells and/or growth factor support is not allowed within 14 days prior to the assessment of hemoglobin during the screening period in order to meet the study inclusion criterion)
  * Absolute neutrophil count (ANC): 1500/mm\^3 or ≥1.5 × 10\^9/L (granulocyte colony stimulating factor support is not allowed within 14 days prior to the assessment of ANC during the screening period in order to meet the study inclusion criterion)
  * Creatinine clearance (CrCl): CrCl ≥30 mL/min as calculated using the Cockcroft-Gault equation or measured CrCl
  * Aspartate aminotransferase/ alanine aminotransferase: ≤3 × ULN (if liver metastases are present, ≤5 × ULN)
  * Total bilirubin: ≤1.5 × ULN if no liver metastases (\<3 × ULN in the presence of documented Gilbert's syndrome \[unconjugated hyperbilirubinemia\] or liver metastases)
  * Serum albumin: ≥2.5 g/dL
  * Alkaline phosphatase (ALP) and Gamma-glutamyl transferase (GGT): ≤2.5 × ULN of both ALP and GGT
  * Prothrombin time (PT) or PT-international normalized ratio (INR) and Activated partial thromboplastin time (aPTT) / Partial thromboplastin time (PTT): ≤1.5 × ULN, except for subjects on coumarin-derivative anticoagulants or other similar anticoagulant therapy, who must have PT-INR within therapeutic range as deemed appropriate by the Investigator.

Exclusion Criteria:

* Any previously documented histologic or cytologic evidence of small cell OR combined small cell/non-small cell disease
* Has a history of (non-infectious) interstitial lung disease (ILD)/pneumonitis that required corticosteroid therapy, has current ILD, or is suspected to have such disease by imaging during screening.
* Clinically severe pulmonary compromise (based on Investigator's assessment) resulting from intercurrent pulmonary illnesses including, but not limited to:

  * Any underlying pulmonary disorder (eg, pulmonary emboli within three months of the study enrollment or randomization, severe asthma, severe chronic obstructive pulmonary disease, restrictive lung disease, pleural effusion);
  * Any autoimmune, connective tissue or inflammatory disorders with pulmonary involvement (eg, rheumatoid arthritis, Sjogren's syndrome, sarcoidosis); OR prior complete pneumonectomy.
* Is receiving chronic systemic corticosteroids dosed at \>10 mg prednisone or equivalent anti-inflammatory activity or any form of immunosuppressive therapy prior to Cycle 1, Day 1. Participants who require use of bronchodilators, inhaled or topical steroids, or local steroid injections may be included in the study.
* Evidence of any leptomeningeal disease.
* Has spinal cord compression or clinically active central nervous system metastases, defined as symptomatic, or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms. Participants with clinically inactive brain metastases may be included in the study. Participants with treated brain metastases who are no longer symptomatic and who require no treatment with corticosteroids or anticonvulsants may be included in the study, but must have a stable neurologic status for at least 4 weeks prior to Cycle 1, Day 1. Participants with asymptomatic brain metastases and treated with anticonvulsants as prophylaxis are able to enroll following a 14-day washout period. Note: A CT or MRI scan of the brain at baseline is required for all participants.
* Inadequate washout period prior to Cycle 1, Day 1 defined as:

  * Whole brain radiation therapy \<28 days or stereotactic brain radiation therapy \<7 days;
  * Any systemic anticancer therapy (excluding osimertinib in all Dose Escalation Cohorts and in Second-line Dose Expansion \[Arm 1, Arm 2, and Arm 1b\]), including investigational agents, \<14 days or 5 half-lives, whichever is longer
  * Immune checkpoint inhibitor therapy ≤21 days
  * Major surgery (excluding placement of vascular access) \<4 weeks
  * Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation \< 28 days or palliative radiation therapy \<7 days
  * Chloroquine or hydroxychloroquine ≤14 days
  * Medications or herbal supplemented known to be strong inducers of cytochrome P450 (CYP) 3A4 \<21 days.
* Has unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0, Grade ≤1 or baseline. Subjects with chronic Grade 2 toxicities may be eligible per the discretion of the Investigator after consultation with the Sponsor Medical Monitor or designee.
* Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow osimertinib, or previous significant bowel resection that would preclude adequate absorption of osimertinib.
* Has any primary malignancy other than locally advanced or metastatic NSCLC within 3 years prior to Cycle 1, Day 1 (Dose Escalation and First-line Dose Expansion) or within 3 years prior to randomization (Second-Line Dose Expansion), except adequately resected non-melanoma skin cancer, curatively treated in situ disease, or other solid tumors curatively treated.
* Uncontrolled or significant cardiovascular disease prior to Cycle 1, Day 1 including:

  * Mean corrected QT interval using Fridericia's formula (QTcF) interval of \>450 ms in 3 successive central screening measurements
  * Left ventricular ejection fraction (LVEF) ≤45% by either echocardiogram (ECHO) or multigated acquisition (MUGA) scan
  * Resting systolic blood pressure \>180 mmHg or diastolic blood pressure \>110 mmHg
  * Myocardial infarction within 6 months
  * New York Heart Association (NYHA) Classes 3 or 4 congestive heart failure within 28 days
  * Uncontrolled angina pectoris within 6 months
  * Has cardiac arrhythmia requiring antiarrhythmic treatment
  * Complete left or right bundle branch block within 6 months
  * History of second- or third-degree heart block or PR interval \>250 ms within 6 months
  * History of clinically relevant ventricular arrhythmias, such as ventricular tachycardia, ventricular fibrillation, or Torsade de Pointes
  * Has any factors that increase the risk of corrected QT (QTc) prolongation or risk of arrhythmic events, such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome, or unexplained sudden death under 40 years of age in first-degree relatives, or any concomitant medication known to prolong the QT interval
* Has clinically significant corneal disease
* Any evidence of severe or uncontrolled diseases including active bleeding diatheses, active infection, psychiatric illness/social situations, geographical factors, substance abuse, or other factors which in the Investigator's opinion makes it undesirable for the subject to participate in the study or which would jeopardize compliance with the protocol. Screening for chronic conditions is not required.
* Has a known human immunodeficiency virus (HIV) infection that is not well controlled.

Primary outcomes:
measure: Dose Escalation: Incidence of Dose-limiting Toxicities (DLT), Treatment-emergent Adverse Events (TEAE), Serious Adverse Events (SAE), Adverse Events of Special Interest (AESI)
timeFrame: From signing of informed consent form up to 40 days (+7 days) after the last dose of study drugs, up to approximately 9 months
measure: Second-line Dose Expansion and First-line Dose Expansion: Objective Response Rate (ORR)
timeFrame: From start of study treatment until date of documented disease progression or other protocol-defined reason for discontinuation from the study (e.g, withdrawal of consent, lost to follow-up), whichever occurs first, up to approximately 18 months
Secondary outcomes:
measure: Dose Escalation: Objective Response Rate (ORR)
timeFrame: From start of treatment until date of disease progression or other reason for discontinuation (e.g, withdrawal of consent, lost to follow-up), whichever occurs first, up to approximately 9 months (Dose Escalation) and 18 months (Dose Expansion)
measure: Second-line Dose Expansion and First-line Dose Expansion: Objective Response Rate (ORR)
timeFrame: From start of study treatment until the date of documented disease progression or other protocol-defined reason for discontinuation from the study (e.g, withdrawal of consent, lost to follow-up), whichever occurs first, up to approximately 18 months
measure: Dose Escalation, Second-line Dose Expansion, and First-Line Dose Expansion: Duration of Response (DoR)
timeFrame: From start of treatment until date of disease progression or other reason for discontinuation (e.g, withdrawal of consent, lost to follow-up), whichever occurs first, up to approximately 9 months (Dose Escalation) and 18 months (Dose Expansion)
measure: Second-line Dose Expansion: Clinical Benefit Rate (CBR)
timeFrame: From start of treatment until date of disease progression or other reason for discontinuation (e.g, withdrawal of consent, lost to follow-up), whichever occurs first, up to approximately 9 months (Dose Escalation) and 18 months (Dose Expansion)
measure: Dose Escalation, Second-line Dose Expansion, and First-line Dose Expansion: Disease Control Rate (DCR)
timeFrame: From start of treatment until date of disease progression or other reason for discontinuation (e.g, withdrawal of consent, lost to follow-up), whichever occurs first, up to approximately 9 months (Dose Escalation) and 18 months (Dose Expansion)
measure: Dose Escalation, Second-line Dose Expansion, and First-line Dose Expansion: Time to Response (TTR)
timeFrame: From start of treatment until date of disease progression or other reason for discontinuation (e.g, withdrawal of consent, lost to follow-up), whichever occurs first, up to approximately 9 months (Dose Escalation) and 18 months (Dose Expansion)
measure: Dose Escalation, Second-line Dose Expansion, and First-line Dose Expansion: Progression-free Survival (PFS)
timeFrame: From start of treatment until date of disease progression or other reason for discontinuation (e.g, withdrawal of consent, lost to follow-up), whichever occurs first, up to approximately 9 months (Dose Escalation) and 18 months (Dose Expansion)
measure: Dose Escalation, Second-line Dose Expansion, and First-line Dose Expansion: Overall Survival (OS)
timeFrame: From start of treatment until date of disease progression or other reason for discontinuation (e.g, withdrawal of consent, lost to follow-up), whichever occurs first, up to approximately 9 months (Dose Escalation) and 18 months (Dose Expansion)
measure: Second-line Dose Expansion and First-line Dose Expansion: Incidence of Treatment-emergent Adverse Events (TEAE), Serious Adverse Events (SAE), Adverse Events of Special Interest (AESI)
timeFrame: From signing of informed consent form up to 40 (+7 days) days after the last dose of study drugs, up to approximately 18 months
measure: Dose Escalation, Second-line Dose Expansion, and First-line Dose Expansion: Proportion of Participants Who Are Anti-Drug Antibody (ADA)-Positive (Baseline and Post-Baseline) and Proportion of Participants Who Have Treatment-emergent ADA
timeFrame: From the start of study treatment until the end of treatment or study discontinuation (whichever occurs first), up to approximately 9 months (Dose Escalation) and 18 months (Dose Expansion)
measure: Dose Escalation, Second-line Dose Expansion, and First-line Dose Expansion: Pharmacokinetic Parameter Maximum Concentration (Cmax)
timeFrame: HER3-DXd: Cycles 1 and 3, Day 1 pre- and postdose, 4 hours (h), Days 8 and 15; Cycle 2, Day 1 pre- and postdose; Cycles 4, 6, 8, Day 1 pre- and postdose; Osimertinib: Cycles 1, 2, and 3, Day 1 pre- and postdose, 4 h (each cycle is 21 days)
measure: Dose Escalation, Second-line Dose Expansion, and First-line Dose Expansion: Pharmacokinetic Parameter Time to Maximum Concentration (Tmax)
timeFrame: HER3-DXd: Cycles 1 and 3, Day 1 pre- and postdose, 4 hours (h), Days 8 and 15; Cycle 2, Day 1 pre- and postdose; Cycles 4, 6, 8, Day 1 pre- and postdose; Osimertinib: Cycles 1, 2, and 3, Day 1 pre- and postdose, 4 h (each cycle is 21 days)
measure: Dose Escalation, Second-line Dose Expansion, and First-line Dose Expansion: Pharmacokinetic Parameter Area Under the Concentration-Time Curve (AUC)
timeFrame: HER3-DXd: Cycles 1 and 3, Day 1 pre- and postdose, 4 hours (h), Days 8 and 15; Cycle 2, Day 1 pre- and postdose; Cycles 4, 6, 8, Day 1 pre- and postdose; Osimertinib: Cycles 1, 2, and 3, Day 1 pre- and postdose, 4 h (each cycle is 21 days)
Other outcomes:
Locations:
city: Santa Monica
country: United States
facility: UCLA
state: California
city: New Haven
country: United States
facility: Yale University School of Medicine - Yale-New Haven Hospital
state: Connecticut
city: Washington
country: United States
facility: Georgetown University Medical Center
state: District of Columbia
city: Chicago
country: United States
facility: Northwestern University Feinberg School of Medicine
state: Illinois
city: Boston
country: United States
facility: Massachusetts General Hospital Cancer Center
state: Massachusetts
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: Detroit
country: United States
facility: Henry Ford Cancer Institute
state: Michigan
city: Lebanon
country: United States
facility: Dartmouth-Hitchcock Medical Center
state: New Hampshire
city: New York
country: United States
facility: Columbia University Irving Medical Center
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: Nashville
country: United States
facility: Sarah Cannon and HCA Research Institute
state: Tennessee
city: Fairfax
country: United States
facility: Virginia Cancer Specialists, PC
state: Virginia
city: Matsuyama-shi
country: Japan
facility: National Hospital Organization Shikoku Cancer Center
state: Ehime
city: Fukuoka-shi
country: Japan
facility: National Hospital Organization Kyushu Cancer Center
state: Fukuoka
city: Sapporo-shi
country: Japan
facility: National Hospital Organization Hokkaido Cancer Center
state: Hokkaido
city: Yokohama-shi
country: Japan
facility: Kanagawa Cancer Center
state: Kanagawa
city: Okayama-shi
country: Japan
facility: Okayama University Hospital
state: Okayama
city: Chuo Ku
country: Japan
facility: National Cancer Center Hospital
state: Tokyo
city: Iwakuni-shi
country: Japan
facility: National Hospital Organization Iwakuni Clinical Center
state: Yamaguchi
city: Shizuoka
country: Japan
facility: Shizuoka Cancer Center
city: Tokyo
country: Japan
facility: The Cancer Institute Hospital of JFCR
city: Ōsaka-sayama
country: Japan
facility: Kindai University Hospital
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Seoul
country: Korea, Republic of
facility: Yonsei University Health System - Severance Hospital
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Taichung
country: Taiwan
facility: Chung Shan Medical University Hospital
city: Taipei
country: Taiwan
facility: National Taiwan University Hospital
city: Taipei
country: Taiwan
facility: Taipei Medical University Hospital
city: Taipei
country: Taiwan
facility: Taipei Veterans General Hospital
Study officials:
affiliation: Daiichi Sankyo
name: Global Clinical Leader
role: STUDY_DIRECTOR
References: