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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)

HER3-DXd (Patritumab Deruxtecan ; U3-1402) in Combination With Osimertinib in Subjects With Locally Advanced or Metastatic EGFR-mutated Non-Small Cell Lung Cancer

Inoguchi Akihiro

DAIICHI SANKYO Co.,Ltd.

1-2-58, Hiromachi, Shinagawa-ku, Tokyo

dsclinicaltrial@daiichisankyo.co.jp

Contact for Clinical Trial Information

DAIICHI SANKYO Co.,Ltd.

1-2-58, Hiromachi, Shinagawa-ku, Tokyo

+81-3-6225-1111

dsclinicaltrial@daiichisankyo.co.jp

Not Recruiting

Dec. 11, 2020

Interventional

randomized controlled trial

open(masking not used)

uncontrolled control

parallel assignment

treatment purpose

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 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 (US sites), accredited (outside of the US), local laboratory or central laboratory. Only tissue-basedtesting will be accepted.
-Subjects 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.

Common Inclusion Criteria For All Subjects:
-Male or female subjects aged >=18 years (follow local regulatory requirements if the legal age of consent for study participation is >18 years old).
-Has locally advanced or metastatic NSCLC, not amenable to curative surgery or radiation
-At least 1 measurable lesion as assessed by investigator assessment according to RECIST v1.1
-Tissue requirements
a. 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 regimen.
b. 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 the initial diagnosis or later
c. Second-line Dose Expansion (Arm 1, Arm 1b, and Arm 2): 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
-Has adequate bone marrow reserve and organ function, based on local laboratory data within 14 days prior to Cycle 1, Day 1 defined as:
Platelet count: >=100 000/mm^3 or >=100 x 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 x 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 x ULN (if liver metastases are present, <=5 x ULN)
Total bilirubin: <=1.5 x ULN if no liver metastases (<3 x 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 x ULN of both ALP and GGT
Prothrombin time or prothrombin time-international normalized ratio and activated partial thromboplastin time/ partial thromboplastin time: <=1.5 x ULN, except for subjects on coumarin-derivative anticoagulants or other similar anticoagulant therapy, who must have prothrombin time-international normalized ratio within therapeutic range as deemed appropriate by the Investigator

-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:
a. any underlying pulmonary disorder (eg, pulmonary emboli within three months of the study enrollment or randamization, severe asthma, severe chronic obstructive pulmonary disease, restrictive lung disease, or pleural effusion)
b. any autoimmune, connective tissue or inflammatory disorder with pulmonary
involvement (eg, rheumatoid arthritis, Sjogren's syndrome, or 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. Subjects 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. Subjects with clinically inactive brain metastases may be included in the study. Subjects 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. Subjects 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 subjects.
-Inadequate washout period prior to Cycle 1, Day 1 (Dose Escalation and First-Line Dose Expansion) or prior to randomization (Second-Line Dose Expansion) defined as:
a. Whole brain radiation therapy <28 days or stereotactic brain radiation therapy <7 days
b. Any systemic anticancer (excluding osimertinib in all Dose Escalation cohorts and in Second-Line Dose Expansion [Arms 1, 2, and 1b]), including investigational agents, <14 days or 5 half-lives, whichever is longer
c. Immune checkpoint inhibitor therapy <=21 days
d. Major surgery (excluding placement of vascular access) <4 weeks
e. 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
f. Chloroquine or hydroxychloroquine <=14 days
g. Medications or herbal supplements 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, 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:
a. Mean corrected QT interval using Fridericia's formula (QTcF) interval of >450 ms in 3 successive central screening measurements
b. Left ventricular ejection fraction (LVEF) <=45% by either echocardiogram (ECHO) or multigated acquisition (MUGA) scan
c. Resting systolic blood pressure >180 mmHg or diastolic blood pressure >110 mmHg)
d. Myocardial infarction within 6 months
e. New York Heart Association (NYHA) Classes 3 or 4 congestive heart failure within 28 days
f. Uncontrolled angina pectoris within 6 months
g. Has cardiac arrhythmia requiring antiarrhythmic treatment
h. Complete left or right bundle branch block within 6 months
i. History of second- or third-degree heart block or PR interval >250 ms within 6 months
j. History of clinically relevant ventricular arrhythmias, such as ventricular tachycardia, ventricular fibrillation, or Torsade de Pointes
k. Has any factors that increase the risk of 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.

Both

Metastatic or Locally Advanced Non-Small Cell Lung Cancer

Dose Escalation Part:
Administer HER3-DXd in combination with osimertinib in the following dosages (Maximun 8 patterns).
Administer HER3-DXd 3.2 mg/kg, 4.8 mg/kg, or 5.6 mg/kg intravenous every 21 days, and osimertinib 40 mg or 80 mg orally once daily.

Second Line Dose Expansion Part:
In arm 1, administer HER3-DXd and osimertinib in the recommended comnination dose (RCD), which is selected in the dose escalation part. (Arm 1and Arm 1b).
In arm 2, administer HER3-DXd 5.6 mg/kg intravenous every 21 days.

First Line Dose Expansion Part:
In cohor3, If the RCD includes osimertinib 80 mg, this arm occurs, Administer HER3-DXd and osimertinib in the RCD. (if two RCDs are selected, one of the RCD).
In cohor 4a, administer HER3-DXd 5.6 mg/kg intravenous every 21 days and osimertinib 80 mg orally once daily.
In cohort 4b, administer HER3-DXd 4.8 mg/kg intravenous every 21 days and osimertinib 80 mg orally once daily.

Dose Escalation Part:
safety parameters

Second Line and First Line in Dose Expansion Part::
Objective Response Rate (ORR) as Assessed by Blinded Independent Central Review(BICR) Based on RECIST v1.1

Dose Escalation Part:
ORR, duration of response (DoR), disease control rate (DCR), time to response (TTR), progression-free survival (PFS), overall survival (OS), immunogenicity of HER3-DXd, PK parameters of HER3-DXd and osimertinib

Second Line Dose Expansion Part:
ORR as Assessed by Investigator Review Based on RECIST v1.1, DoR, clinical benefit rate (CBR), DCR, TTR, PFS, OS, safety parameters, immunogenicity of HER3-DXd, PK parameters of HER3-DXd and osimertinib, correlation between HER3 protein expression and efficacy

First Line Dose Expansion Part:
ORR as Assessed by Investigator Review Based on RECIST v1.1, safety parameters, DoR, DCR, TTR, PFS, OS, immunogenicity of HER3-DXd, PK parameters of HER3-DXd and osimertinib, correlation between HER3 protein expression and efficacy

+81-3-3542-2511

Nov. 11, 2020

Yes

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