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A MULTI-CENTER, OPEN-LABEL, PHASE 2 STUDY TO EVALUATE SAFETY AND EFFICACY OF U3- 1402 IN SUBJECTS WITH ADVANCED OR METASTATIC COLORECTAL CANCER (CRC)

A MULTI-CENTER, OPEN-LABEL, PHASE 2 STUDY TO EVALUATE SAFETY AND EFFICACY OF U3- 1402 IN SUBJECTS WITH ADVANCED OR METASTATIC COLORECTAL CANCER (CRC)

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

Complete

Oct. 15, 2020

Interventional

single arm study

open(masking not used)

uncontrolled control

single assignment

treatment purpose

Inclusion Criteria:

Participant has provided written informed consent prior to the start of any study specific procedures.
Participants >=18 years (follow local regulatory requirements if the legal age of consent for study participation is >18 years old).
Pathological/histological confirmation of advanced or metastatic colon or rectal adenocarcinoma.
Must be resistant, refractory, or intolerant to at least 2 prior lines of systemic therapy, that must include all of the following agents:
Fluoropyrimidine
Irinotecan
Platinum agents (e.g, oxaliplatin)
An anti-epidermal growth factor receptor (EGFR) agent, if clinically indicated
An anti-VEGF agent, unless contraindicated (eg, bevacizumab)
An immune checkpoint inhibitor (eg, microsatellite instability-high [MSI-H] status)
A BRAF inhibitor, if clinically indicated (eg, BRAF V600E positive)
Has at least 1 measurable lesion confirmed by blinded independent central review (BICR) as per Response Evaluation Criteria in Solid Tumors (RECIST) Version (v) 1.1.
Willing to provide a required pre-treatment tumor biopsy and an additional archival tissue sample for the assessment of HER3 expression levels by immunohistochemistry and exploratory biomarkers, defined as:
Pre-treatment tumor biopsy. Participants may be exempted from the requirement to provide a pre-treatment tumor biopsy if archival tumor tissue was collected within 3 months of screening during or after treatment with the last prior cancer treatment and is of sufficient quantity (2 cores or 20 slides with adequate tumor tissue content).
An additional archival tissue sample collected greater than 3 months prior to screening must be available and of sufficient quantity, as defined above, at the time of screening. If an archival tissue sample (collected greater than 3 months prior to screening) is not available, a subject may be included provided the pre-treatment tumor biopsy is obtained and after discussion and agreement from Sponsor (Medical Monitor or designee).
Consent to provide on-treatment tumor biopsy. When at least 10 treatment tumor biopsies have been collected, the Sponsor will provide written notification of a change to the requirement.
Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1.
Life expectancy >=3 months.
Has adequate bone marrow reserve and organ function at baseline based on local laboratory data defined as follows within 14 days prior to Cycle 1 Day 1:
Platelet count: >=100,000/mm^3 or >=100 x 10^9/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/mm^3 or >=1.5 x 10^9/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
Alanine aminotransferase /aspartate 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 (PT) or PT-international normalized ratio (INR) and activated partial thromboplastin time (aPTT) / partial thromboplastin time (PTT): <=1.5 x 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

- Any history of interstitial lung disease (including pulmonary fibrosis or radiation pneumonitis), has current interstitial lung disease (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:
1. any underlying pulmonary disorder (e.g., pulmonary emboli, severe asthma, severe chronic obstructive pulmonary disease, restrictive lung disease, pleural effusion)
2. any autoimmune, connective tissue or inflammatory disorder 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 leptomeningeal disease.
- Evidence of clinically active spinal cord compression or brain metastases
- Inadequate washout period prior to Cycle 1 Day 1 of U3-1402:
1. Whole brain radiation therapy <14 days or stereotactic brain radiation therapy <7 days;
2. Any cytotoxic chemotherapy, investigational agent or other anticancer drug(s) from a previous cancer treatment regimen or clinical study <14 days or 5 half-lives, whichever is longer;
3. Monoclonal antibodies other than immune checkpoint inhibitors, such as bevacizumab (anti-VEGF) and cetuximab (anti-EGFRs) <28 days;
4. Immune checkpoint inhibitor therapy <21 days;
5. Major surgery (excluding placement of vascular access) <4 weeks;
6. Radiotherapy treatment to >30% of the bone marrow or with a wide field of radiation <28 days or palliative radiation therapy <14 days;
7. Chloroquine/hydroxychloroquine <=14 days
- Prior treatment with an anti-HER3 antibody and/or antibody drug conjugate (ADC) that consists of an exatecan derivative that is any topoisomerase I inhibitor (e.g, trastuzumab deruxtecan).
- 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) v5.0 Grade <=1 or baseline.
- Had primary malignancies other than CRC 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.
- Known Hepatitis B and/or Hepatitis C infection, such as those with serologic evidence of viral infection within 28 days of Cycle 1 Day 1.
1.Participants with past or resolved hepatitis B virus (HBV) infection are eligible if:
Hepatitis B surface antigen (HBsAg) negative and hepatitis B core antibody (anti-HBc) positive; OR
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 values (in the absence of liver metastasis); OR
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 for participants with liver metastasis and abnormal transaminases with a result of AST/ALT <3 x ULN.2.Participants 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).
- Participant with any human immunodeficiency virus (HIV) infection.
- Any evidence of severe or uncontrolled systemic 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 participant to participate in the study or which would jeopardize compliance with the protocol. Screening for chronic conditions is not required.

Both

Metastatic Colorectal Cancer

Drug: U3-1402
U3-1402 will be dosed at 5.6 mg/kg as an intravenous (IV) infusion administered on Day 1 of each 21-day cycle.

Objective Response Rate (ORR) As Assessed By Blinded Independent Central Review Following Administration of U3-1402 In Participants with Advanced or Metastatic Colorectal Cancer [ Time Frame: From baseline up to disease progression or other protocol-defined reasons (whichever occurs first), up to approximately 27 months ]
ORR defined as the proportion of participants with a best overall response of confirmed complete response (CR) or partial response (PR) as assessed by blinded independent central review.

1.Duration of Response (DOR) As Assessed by Blinded Independent Central Review Following Administration of U3-1402 In Participants with Advanced or Metastatic Colorectal Cancer [ Time Frame: From baseline up to disease progression or other protocol-defined reasons (whichever occurs first), up to approximately 27 months ]
DOR defined as the time from the first documented response (CR or PR) to the date of disease progression or death due to any cause.
2.Objective Response Rate (ORR) As Assessed by Investigator Following Administration of U3-1402 In Participants with Advanced or Metastatic Colorectal Cancer [ Time Frame: From baseline up to disease progression or other protocol-defined reasons (whichever occurs first), up to approximately 27 months ]
ORR defined as the proportion of participants with a best overall response (BOR) of confirmed complete response (CR) or partial response (PR) as assessed by Investigator.
3.Duration of Response (DoR) As Assessed by Investigator Following Administration of U3-1402 In Participants with Advanced or Metastatic Colorectal Cancer [ Time Frame: From baseline up to disease progression or other protocol-defined reasons (whichever occurs first), up to approximately 27 months ]
DoR defined as the time from the first documented response (complete response [CR] or partial response [PR]) to the date of disease progression or death due to any cause.
4.Disease Control Rate (DCR) by Blinded Independent Central Review and Investigator Following Administration of U3-1402 In Participants with Advanced or Metastatic Colorectal Cancer [ Time Frame: From baseline up to disease progression or other protocol-defined reasons (whichever occurs first), up to approximately 27 months ]
DCR is defined as the proportion of participants who achieved a confirmed best overall response (BOR) of complete response (CR), partial response (PR), or stable disease (SD) as assessed by blinded independent central review or by the Investigator
5.Time to Tumor Response (TTR) As Assessed by Blinded Independent Central Review and Investigator Following Administration of U3-1402 In Participants with Advanced or Metastatic Colorectal Cancer [ Time Frame: From baseline up to disease progression or other protocol-defined reasons (whichever occurs first), up to approximately 27 months ]
TTR defined as the time from the start of study treatment to the date of the first documentation of objective response (complete response [CR] or partial response [PR]) that is subsequently confirmed by Blinded Independent Central Review or by the Investigator
6.Progression-free Survival (PFS) Assessed by Blinded Independent Central Review and Investigator Following Administration of U3-1402 In Participants with Advanced or Metastatic Colorectal Cancer [ Time Frame: From baseline until disease progression or other protocol defined reason (whichever occurs first), assessed up to 27 months ]
PFS is defined as the time from the start of study treatment to the date of the first documentation of objective PD or death due to any cause, whichever is earlier
7.Overall Survival (OS) Following Administration of U3-1402 In Participants with Advanced or Metastatic Colorectal Cancer [ Time Frame: From baseline up to the date of death due to any cause or 27 months, whichever is earlier. ]
OS defined as the time from the start of study treatment to the date of death due to any cause.
8.Summary of Reported Treatment-emergent Adverse Events (TEAEs) and other safe parameters during the study [ Time Frame: From baseline up to Day 40 post last dose, approximately 27 months ]
Incidence of TEAEs, serious adverse events, adverse events of special interests (interstitial lung disease; and elevation of aminotransferases and total bilirubin), Eastern Cooperative Oncology Group performance status, vital sign measurements, standard clinical laboratory parameters will be assessed
9.Pharmacokinetic (PK) of Maximum Serum Concentration (Cmax) of analytes of U3-1402 Following Administration In Participants with Advanced or Metastatic Colorectal Cancer [ Time Frame: At baseline (-8 hour to 0 hour), pre-infusion, and 15 minutes, 1 hour, 2 hour, 4 hour, and 8 hour post-infusion of Cycle 1 through Cycle 8 (each cycle is 21 days) ]
Plasma concentrations at each time point and PK parameters Cmax of U3-1402 (ADC, total anti-HE antibody, and MAAA-1181a) will be assessed in the full PK sampling cohort
10.Pharmacokinetic of Time to Reach Maximum Serum Concentration (Tmax) of analytes of U3-1402 Following Administration In Participants with Advanced or Metastatic Colorectal Cancer [ Time Frame: At baseline (-8 hour to 0 hour), pre-infusion, and 15 minutes, 1 hour, 2 hour, 4 hour, and 8 hour post-infusion of Cycle 1 through Cycle 8 (each cycle is 21 days) ]
Plasma concentrations at each time point and PK parameters Tmax of U3-1402 (ADC, total anti-HE antibody, and MAAA-1181a) will be assessed in the full PK sampling cohort
11.Pharmacokinetic of Trough Serum Concentration (Ctrough) of analytes of U3-1402 Following Administration In Participants with Advanced or Metastatic Colorectal Cancer [ Time Frame: At baseline (-8 hour to 0 hour), pre-infusion, and 15 minutes, 1 hour, 2 hour, 4 hour, and 8 hour post-infusion of Cycle 1 through Cycle 8 (each cycle is 21 days) ]
Plasma concentrations at each time point and PK parameters Ctrough of U3-1402 (ADC, total anti-HE antibody, and MAAA-1181a) will be assessed in the full PK sampling cohort
12.Pharmacokinetic of Area Under the Serum Concentration-Time Curve Up to Last Quantifiable Time (AUClast) and During Dosing Interval (AUCtau) of analytes of U3-1402 Following Administration In Participants with Advanced or Metastatic Colorectal Cancer [ Time Frame: At baseline (-8 hour to 0 hour), pre-infusion, and 15 minutes, 1 hour, 2 hour, 4 hour, and 8 hour post-infusion of Cycle 1 through Cycle 8 (each cycle is 21 days) ]
Plasma concentrations at each time point and PK parameters AUClast and AUCtau of U3-1402 (ADC, total anti-HE antibody, and MAAA-1181a) will be assessed in the full PK sampling cohort

+81-6-6942-1331

Aug. 18, 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/

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