Japanease

Dec. 15, 2020

Mar. 25, 2021

jRCT2031200247

A PHASE 1 OPEN-LABEL STUDY OF PATRITUMAB DERUXTECAN (U3-1402) IN COMBINATION WITH OSIMERTINIB IN SUBJECTS WITH LOCALLY ADVANCED OR METASTATIC EGFR-MUTATED NONSMALL CELL LUNG CANCER (NSCLC)

A PHASE 1 STUDY OF PATRITUMAB DERUXTECAN IN COMBINATION WITH OSIMERTINIB IN SUBJECTS WITH NONSMALL CELL LUNG CANCER (NSCLC)

Nagao Kiminori

DAIICHI SANKYO Co.,Ltd.

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

+81-3-6225-1111

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

Dec. 21, 2020

260

Interventional

single arm study

open(masking not used)

uncontrolled control

single assignment

treatment purpose

The United States of America

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
-Willing to provide required tumor tissue of sufficient quantity (as defined in the laboratory manual) and contain adequate tumor tissue content (as confirmed by hematoxylin and eosin (H&E) staining at central laboratory). Required tumor tissue can be provided as either:
a. Pre-treatment tumor biopsy from at least 1 lesion not previously irradiated and amenable to core biopsy.
OR
b. Archival tissue collected from a biopsy performed within 3 months prior to signing of the tissue consent and since progression while on treatment with the most recent cancer therapy regimen.
c. On-study tumor biopsy is mandatory in Dose Escalation. When at least 15 on-study tumor biopsies per arm/cohort in Dose Expansion have been collected, the Sponsor will provide written notification of a change to the requirement.
-Eastern Cooperative Oncology Group performance status (ECOG PS) 0 or 1 at the time of screening
-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/mm3 or >=100 x 109/L (platelet transfusions are not allowed up to 14 days prior to Cycle 1, Day 1 to meet eligibility)
Hemoglobin: >=9.0 g/dL (transfusion and/or growth factor support is allowed)
Absolute neutrophil count: >=1500/mm3 or >=1.5 x 109/L
Serum creatinine (SCr) OR creatinine clearance (CrCl): SCr <=1.5 x Upper limit of normal (ULN), OR CrCl >=30 mL/min as calculated using the Cockcroft-Gault equation or measured CrCl; confirmation of CrCl is only required when creatinine is >1.5 x ULN
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
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 previous histologic or cytologic evidence of small cell OR combined small cell/non-small cell disease in the archival or pretreatment tumor biopsy
-Any history of interstitial lung disease (including pulmonary fibrosis or radiation pneumonitis), 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, 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 pneumonectomy
-Is receiving chronic systemic corticosteroids dosed at >10 mg prednisone or equivalent or any form of immunosuppressive therapy prior to Cycle 1, Day 1. Subjects who require use of bronchodilators, inhaled steroids, or local steroid injections may be included in the study.
-Evidence of any leptomeningeal disease
-Evidence of clinically active spinal cord compression or brain metastases, defined as untreated and symptomatic, or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms. Subjects with clinically inactive or treated brain metastases who are asymptomatic (ie, without neurologic signs or symptoms and do not require treatment with corticosteroids or anticonvulsants) may be included in the study.
Subjects with treated brain metastases that are no longer symptomatic and who require no treatment with corticosteroids or anticonvulsants may be included in the study.
-Inadequate washout period prior to Cycle 1, Day 1, defined as:
a. Whole brain radiation therapy <14 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 <5 half-lives
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 <14 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) prolongation interval of >470 ms for females and >450 ms for males in 3 successive screening measurements
b. Left ventricular ejection fraction (LVEF) <50% by either echocardiogram (ECHO) or multigated acquisition (MUGA) scan
c. Uncontrolled hypertension (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 2 to 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
-Active hepatitis B and/or hepatitis C infection, such as those with serologic evidence of viral infection within 28 days of Cycle 1, Day 1.
a. Subjects with past or resolved hepatitis B virus (HBV) infection are eligible if:
a.1. Hepatitis B surface antigen (HBsAg) negative and hepatitis B core antibody [anti-HBc] positive; OR
a.2. HBsAg positive and HBV deoxyribonucleic acid (DNA) viral load is documented to be <= 2000 IU/mL in the absence of anti-viral therapy and during the previous 12 weeks prior to the viral load evaluation with normal transaminases; OR
a.3. HBsAg positive and HBV DNA viral load is documented to be <= 2000 IU/mL in the absence of anti-viral therapy and during the previous 12 weeks prior to the viral load evaluation with liver metastasis and abnormal transaminases, alanine aminotransferase (ALT)/ aspartate aminotransferase (AST)<3 upper limit of normal (ULN)
b. Subjects with a history of hepatitis C infection will be eligible for enrollment only if the viral load according to local standards of detection is documented to be below the level of detection in the absence of anti-viral therapy during the previous 12 weeks (ie, sustained viral response according to the local product label but no less than 12 weeks, whichever is longer) prior to the viral load evaluation.
-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.
-Subjects with human immunodeficiency virus (HIV) infection

20age old over
No limit

Both

Metastatic or Locally Advanced Non-Small Cell Lung Cancer

Dose Escalation Part:
Administer patritumab deruxtecan in combination with osimertinib in the following dosages (Maximun 8 patterns).
Administer patritumab deruxtecan 1.6 mg/kg, 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 patritumab deruxtecan and osimertinib in the recommended comnination dose (RCD), which is selected in the dose escalation part. If two RCDs are selected, administer patritumab deruxtecan and osimertinib in the two RCDs (Arm 1 and Arm 1b).
In arm 2, administer patritumab deruxtecan 5.6 mg/kg intravenous every 21 days.

First Line Dose Expansion Part:
If the RCD includes osimertinib 80 mg, this arm occurs, Administer patritumab deruxtecan and osimertinib in the RCD (if two RCDs are selected, one of the RCD).

Dose Escalation Part:
safety parameters

Second Line Dose Expansion Part:
objective response rate (ORR)

First Line Dose Expansion Part:
safety parameters

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 patritumab deruxtecan, PK parameters of patritumab deruxtecan and osimertinib

Second Line Dose Expansion Part:
DoR, DCR, TTR, PFS, OS, safety parameters, immunogenicity of patritumab deruxtecan, PK parameters of patritumab deruxtecan and osimertinib, correlation between HER3 protein expression and efficacy

First Line Dose Expansion Part:
ORR, DoR, DCR, TTR, PFS, OS, immunogenicity of patritumab deruxtecan, PK parameters of patritumab deruxtecan and osimertinib, correlation between HER3 protein expression and efficacy

Recruiting

Daiichi Sankyo Co., Ltd.
National Cancer Ctr IRB#2-j
Tsukiji 5-1-1, Chuo-ku, Tokyo

+81-3-3542-2511

Chiken_CT@ml.res.ncc.go.jp
Approval

Nov. 11, 2020

Yes

Plan Description: De-identified individual participant data (IPD) and applicable supporting clinical trial documents may be available upon request at https://vivli.org/. In cases where clinical trial data and supporting documents are provided pursuant to our company policies and procedures, Daiichi Sankyo will continue to protect the privacy of our clinical trial participants. Details on data sharing criteria and the procedure for requesting access can be found at this web address: https://vivli.org/ourmember/daiichi-sankyo/ Supporting Documents: - Study Protocol - Statistical Analysis Plan - Clinical Study Report Time Frame: Studies for which the medicine and indication have received European Union (EU) and United States (US), and/or Japan (JP) marketing approval on or after 01 January 2014 or by the US or EU or JP Health Authorities when regulatory submissions in all regions are not planned and after the primary study results have been accepted for publication. Access Criteria: Formal request from qualified scientific and medical researchers on IPD and clinical study documents from clinical trials supporting products submitted and licensed in the United States, the European Union and/or Japan from 01 January 2014 and beyond for the purpose of conducting legitimate research. This must be consistent with the principle of safeguarding study participants' privacy and consistent with provision of informed consent. URL: https://vivli.org/ourmember/daiichi-sankyo/

NCT04676477
ClinicalTrials.gov