Study of Erlotinib With or Without Investigational Drug (U3-1287) in Subjects With Advanced Non-small Cell Lung Cancer

Randomized, Placebo-controlled, Double-blind Phase 1b/2 Study of U3-1287 (AMG 888) in Combination With Erlotinib in EGFR Treatment Naïve Subjects With Advanced Non-Small Cell Lung Cancer (NSCLC) Who Have Progressed on at Least One Prior Chemotherapy

This is a Phase 1b/2 study. In Phase 1b, subjects will know the treatment they are receiving. Subjects will receive Erlotinib + U3-1287. The Phase 1b portion will determine if adding U3-1287 to Erlotinib will be safe in subjects with advanced non-small cell lung cancer who fail prior treatment. In the Phase 2 portion, subjects will be blinded to the treatments they are receiving. Subjects will receive either Erlotinib alone or Erlotinib + U3-1287.

The Phase 2 portion will determine if adding U3-1287 to Erlotinib will be safe and improve survival in subjects with advanced non-small cell lung cancer who failed the first treatment.

Study Overview

• Status: Completed
• Conditions: NSCLC (Advanced Non-small Cell Lung Cancer)
• Intervention / Treatment: Drug: U3-1287; Drug: Erlotinib; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 222
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Austria
  • Graz, Austria
  • Innsbruck, Austria
• Belgium
  • Gent, Belgium
  • Liege, Belgium
• Bulgaria
  • Plovdiv, Bulgaria
  • Sofia, Bulgaria
• Germany
  • Essen, Germany
  • Frankfurt am Main, Germany
  • Freiburg, Germany
  • Gauting, Germany
  • Halle, Germany
  • Hamburg, Germany
  • Herne, Germany
  • Lowenstein, Germany
  • Mainz, Germany
  • Tubingen, Germany
• Hungary
  • Budapest, Hungary
  • Pecs, Hungary
• Israel
  • Petah Tikva, Israel
  • Tel Aviv, Israel
  • Tel HaShomer, Israel
• Italy
  • Lido di Camaiore, Italy
  • Piacenza, Italy
  • Pisa, Italy
  • Reggio Emilia, Italy
• Lithuania
  • Kaunas, Lithuania
  • Vilnius, Lithuania
• Romania
  • Suceava, Romania
  • Târgu-Mureş, Romania
• Slovenia
  • Golnik, Slovenia
• Ukraine
  • Dnipropetrovsk, Ukraine
  • Donetsk, Ukraine
  • Ivano-Frankivsk, Ukraine
  • Kharkiv, Ukraine
  • Sumy, Ukraine
  • Uzhgorod, Ukraine
• United Kingdom
  • London, United Kingdom
  • Wirral, United Kingdom
• United States
  • Arizona
    • Glendale, Arizona, United States
    • Scottsdale, Arizona, United States, 85258
      • TRM - Oncology Research Associates, PLLC, d/b/a Pinnacle Oncology Hematology
  • California
    • Anaheim, California, United States
    • Encinitas, California, United States
    • La Verne, California, United States
    • Los Angeles, California, United States
  • Florida
    • Orlando, Florida, United States
  • Georgia
    • Atlanta, Georgia, United States
  • Illinois
    • Joliet, Illinois, United States
  • Indiana
    • Evansville, Indiana, United States
  • Louisiana
    • Baton Rouge, Louisiana, United States
  • Michigan
    • Detroit, Michigan, United States
  • New York
    • Bronx, New York, United States
  • Pennsylvania
    • York, Pennsylvania, United States

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• ≥ 18 years of age.
• Histologically or cytologically confirmed stage IIIB not amenable to surgery or curative intent or stage IV NSCLC.
• Disease progression or recurrence following treatment after last chemotherapy or chemoradiation regimen (completed within the previous 12 months) documented by radiographic assessment.
• Measurable disease by Response Evaluation Criteria for Solid Tumors v1.1 (RECIST v1.1).
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• Adequate bone marrow, renal, and hepatic function.
• Prothrombin time and partial thromboplastin time ≤1.5 x upper limit of normal (ULN).
• Availability of recent (before treatment start) or archival tumor specimens (Phase 2 participants only).
• For female participants, must be postmenopausal, surgically sterile, or must use maximally effective birth control during the period of therapy, and must be willing to use effective contraception up to 6 months after the last dose of study drug and had a negative urine or serum pregnancy test before entry into the study if female participants were of childbearing potential.
• For male participants, must be surgically sterile or willing to use a double barrier contraception method upon enrollment, during the course of the study, and for 6 months following the last investigational drug dose
• Written informed consent.

Exclusion Criteria:

• Left ventricular ejection fraction (LVEF) < 45%.
• Prior epidermal growth factor receptor (EGFR)-targeted regimen, anti-HER2, anti-HER3, or anti-HER4 therapy.
• More than 2 prior chemotherapy regimens for NSCLC (Phase 2 participants only).
• History of other malignancies, except adequately treated nonmelanoma skin cancer, curatively treated in-situ disease, or other solid tumors curatively treated with no evidence of disease for ≥ 5 years.
• History of corneal disease.
• History of interstitial lung disease.
• Clinically active brain metastases, defined as untreated symptomatic, or requiring therapy with steroids or anticonvulsants to control associated symptoms. Participants with treated brain metastases that were no longer symptomatic and required no treatment with steroids could be included in the study if they had recovered from the acute toxic effect of radiotherapy.
• Uncontrolled hypertension (diastolic > 100 mmHg or systolic > 140 mmHg).
• Clinically significant electrocardiogram changes that obscured the ability to assess the respiratory rate, pulse rate, QT, QTc, and QRS intervals.
• Ascites or pleural effusion requiring chronic medical intervention.
• Myocardial infarction within 1 year before enrollment, symptomatic congestive heart failure (New York Heart Association > Class II), unstable angina, or unstable cardiac arrhythmia requiring medication.
• Treatment with anticancer therapy, antibody based therapy, retinoid therapy, or hormonal therapy within 4 weeks before study treatment or treatment with nitrosoureas or mitomycin C within 6 weeks before study drug treatment or treatment with small molecule tyrosine kinase inhibitors (TKIs) within 2 weeks before study drug treatment. Prior and concurrent use of hormone replacement therapy was permitted.
• Therapeutic radiation or major surgery within 4 weeks before study treatment or palliative radiation therapy within 2 weeks before study drug treatment.
• Participated in clinical drug trials within 4 weeks (2 weeks for small molecule TKIs) before study drug treatment. Current participation in other investigational procedures.
• Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals, known human immunodeficiency virus (HIV) infection, or active hepatitis B or C infection.
• History of hypersensitivity to any of the study drugs or to any excipients.
• Concurrent use of CYP3A4 inducers or inhibitors.
• Any known pre-existing condition including substance abuse that could interfere with participant's participation in and completion of the protocol.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Part A: U3-1287 (high dose) + Erlotinib; U3-1287 (high dose) intravenously (IV) every three weeks (Q3W) + Erlotinib 150 mg/day orally (PO) until cancer gets worse, side effects become unacceptable or participant withdraws consent	Drug: U3-1287; Liquid 70 mg/mL for IV infusion at high dose or low dose; Other Names: Patritumab; Drug: Erlotinib; Tablet 150 mg for oral administration
EXPERIMENTAL: Part B: U3-1287 (low dose) + Erlotinib; U3-1287 (low dose) IV Q3W + Erlotinib 150 mg/day PO until cancer gets worse, side effects become unacceptable or participant withdraws consent	Drug: U3-1287; Liquid 70 mg/mL for IV infusion at high dose or low dose; Other Names: Patritumab; Drug: Erlotinib; Tablet 150 mg for oral administration
PLACEBO_COMPARATOR: Part B: Placebo + Erlotinib; Placebo matching U3-1287 IV Q3W + Erlotinib150 mg/day PO until cancer gets worse, side effects become unacceptable or participant withdraws consent	Drug: Erlotinib; Tablet 150 mg for oral administration; Drug: Placebo; Placebo liquid matching U3-1287 for IV infusion

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-Free Survival Following U3-1287 (AMG 888) in Combination With Erlotinib	Progression-free survival (PFS) was defined as the time from the date of randomization to the earlier of the dates of first objective documentation of radiographic disease progression or death due to any cause (as per Response Evaluation Criteria in Solid Tumors [RECIST] Version 1.1).	Time from the randomization date up to the date of first objective documentation of disease progression or death due to any cause (whichever comes first), up to 3 years 2 months
Progression-Free Survival in Participants With High Heregulin-Expressing Tumors Following U3-1287 (AMG 888) in Combination With Erlotinib	Progression-free survival (PFS) was defined as the time from the date of randomization to the earlier of the dates of first objective documentation of radiographic disease progression or death due to any cause (as per Response Evaluation Criteria in Solid Tumors [RECIST] Version 1.1). Heregulin (HRG) high is defined as delta cycle threshold value < 3.9.	Time from the randomization date up to the date of first objective documentation of disease progression or death due to any cause (whichever comes first), up to 3 years 2 months
Progression-Free Survival in Participants With Low Heregulin-Expressing Tumors Following U3-1287 (AMG 888) in Combination With Erlotinib	Progression-free survival (PFS) was defined as the time from the date of randomization to the earlier of the dates of first objective documentation of radiographic disease progression or death due to any cause (as per Response Evaluation Criteria in Solid Tumors [RECIST] Version 1.1). Heregulin (HRG) low is defined as a delta cycle threshold value ≥ 3.9.	Time from the randomization date up to the date of first objective documentation of disease progression or death due to any cause (whichever comes first), up to 3 years 2 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival Following U3-1287 (AMG 888) in Combination With Erlotinib	Overall Survival (OS) was defined as the time from the randomization date to the date of death.	Time from the randomization date up to the date of death due to any cause, up to 3 years 2 months
Objective Response Following U3-1287 (AMG 888) in Combination With Erlotinib	Objective response was defined as the best response of either complete response (CR) or partial response (PR). As per Response Evaluation Criteria in Solid Tumors Version 1.1, CR was defined as a disappearance of all target lesions and PR was defined as at least a 30% decrease in the sum of diameters of target lesions.	Time from date of randomization up to date of first documentation of objective response of either CR or PR (whichever comes first), up to 3 years 2 months
Time to Objective Response Following U3-1287 (AMG 888) in Combination With Erlotinib	Time to objective response was defined as the time from the date of randomization to the date of the first documentation of objective response (complete response [CR] or partial response [PR]). As per Response Evaluation Criteria in Solid Tumors Version 1.1, CR was defined as a disappearance of all target lesions and PR was defined as at least a 30% decrease in the sum of diameters of target lesions.	Time from date of randomization up to date of first documentation of objective response of either CR or PR (whichever comes first), up to 3 years 2 months
Duration of Stable Disease Following U3-1287 (AMG 888) in Combination With Erlotinib	Duration of stable disease (SD) was defined for participants whose best response is SD as the time from the date of randomization to the date of the first documentation of progressive disease. SD was defined as neither sufficient shrinkage to qualify for partial response (PR; at least a 30% decrease in the sum of diameters of target lesions) nor sufficient increase to qualify for progressive disease (PD; at least a 20% increase in the sum of diameters of target lesions).	For participants whose best response is SD as the time from date of first documentation of stable disease up to the date of first documentation of progressive disease, up to 3 years 2 months
Time to Disease Progression Following U3-1287 (AMG 888) in Combination With Erlotinib	Time to disease progression was defined as the time from the randomization date to the date of first objective documentation of disease progression. As per Response Evaluation Criteria in Solid Tumors Version 1.1, progressive disease (PD) was defined as at least a 20% increase in the sum of diameters of target lesions.	Time from date of randomization up to the date of first objective documentation of disease progression, up to 3 years 2 months
Pharmacokinetic Parameter of Cycle 3 Patritumab Area Under the Concentration-time Curve Over the Dosing Interval 0 to τ (AUC) Following U3-1287 (AMG 888) in Combination With Erlotinib	AUC was calculated from the concentration-time data at Cycle 3 using a noncompartmental analysis (NCA) method.	Cycle 1: predose, end of infusion (EOI), 3 hour (h) postdose; Cycle 2: predose; Cycle 3: predose, EOI, 3 h, 6h, 24 h, 72 h, 168 h, 336 h; Cycle 4, Cycle 5, Cycle 7, and Cycle 9: predose (each cycle is 21 days)
Pharmacokinetic Parameter of Cycle 3 Patritumab Concentration End of Infusion (CEOI) and Minimum (Trough) Concentration (Cmin) Following U3-1287 (AMG 888) in Combination With Erlotinib	Concentration end of infusion (CEOI) was defined as the concentration within ± 5 minutes of the end of infusion. Cmin was defined as minimum (trough) observed concentration within ± 15% of the prescribed dosing interval. Preinfusion patritumab concentrations observed within 15% of nominal time after the start of the previous infusion (ie, 21 days ± 3.15 days) were considered trough concentrations	Cycle 1: predose, end of infusion (EOI), 3 hour (h) postdose; Cycle 2: predose; Cycle 3: predose, EOI, 3 h, 6h, 24 h, 72 h, 168 h, 336 h; Cycle 4, Cycle 5, Cycle 7, and Cycle 9: predose (each cycle is 21 days)
Erlotinib Concentrations at Cycle 3 Day 1 Following U3-1287 (AMG 888) in Combination With Erlotinib		Cycle 3, Day 1: predose, 1 h, 2 h, 3 h, 6h, 24 h postdose (each cycle is 21 days)
Pharmacokinetic Parameter of Erlotinib Trough (Cmin) Concentrations From Participants Receiving 150 mg Erlotinib Following U3-1287 (AMG 888) in Combination With Erlotinib	Trough concentrations (Cmin) was defined as minimum (trough) observed concentration within ± 15% of the prescribed dosing interval. Erlotinib Cmin was predose (or for participants with at least 2 prior doses, within 15% of nominal time after postdose) plasma erlotinib concentration.	Cycle 1: predose, end of infusion (EOI), 3 hour (h) postdose; Cycle 2: predose; Cycle 3: predose, EOI, 3 h, 6h, 24 h, 72 h, 168 h, 336 h; Cycle 5, Cycle 7, and Cycle 9: predose (each cycle is 21 days)
Treatment-Emergent Adverse Events Occurring in ≥10% of Participants Following U3-1287 (AMG 888) in Combination With Erlotinib	A treatment-emergent adverse event (TEAE) was defined as an adverse event (AE) that: emerged during treatment, having been absent at pretreatment; or reemerged during treatment, having been present at baseline but stopped prior to treatment; or worsened in severity since treatment relative to the pretreatment state, when the AE was continuous.	From the date of signing the informed consent form up to 53 days after the last dose of patritumab/placebo or up to 30 days after the last dose of erlotinib if patritumab/placebo was discontinued earlier, up to 3 years 2 months

Collaborators and Investigators

• Sponsor: Daiichi Sankyo, Inc.

Study record dates

Study Major Dates

• Study Start (ACTUAL): September 1, 2010
• Primary Completion (ACTUAL): October 1, 2013
• Study Completion (ACTUAL): November 23, 2013

Study Registration Dates

• First Submitted: September 28, 2010
• First Submitted That Met QC Criteria: September 28, 2010
• First Posted (ESTIMATE): September 29, 2010

Study Record Updates

• Last Update Posted (ACTUAL): June 16, 2021
• Last Update Submitted That Met QC Criteria: May 21, 2021
• Last Verified: May 1, 2021

More Information

Terms related to this study

• Keywords: Lung cancer
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Erlotinib Hydrochloride
• Other Study ID Numbers: U31287-A-U201

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD 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/
• IPD Sharing 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.
• IPD Sharing 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.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; CSR