Clinical trial NCT01244191: Tivantinib Plus Erlotinib Versus Placebo Plus Erlotinib for the Treatment of Non-squamous, Non-small-cell Lung Cancer
Official title: A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of ARQ197 Plus Erlotinib Versus Placebo Plus Erlotinib in Previously Treated Subjects With Locally Advanced or Metastatic, Non-Squamous, Non-Small-Cell Lung Cancer (NSCLC)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Non Squamous, Non-small-cell Lung Cancer
Keywords: Non squamous, non-small-cell lung cancer
Epidermal growth factor receptor
c-Met inhibitor
Lead sponsor: Daiichi Sankyo
Sponsor class: INDUSTRY
Collaborators: name: ArQule, Inc., a subsidiary of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc. (Rahway, NJ USA)
First posted: 2010-11-19
Enrollment: 1048
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study is to determine if the combination regimen of tivantinib with erlotinib will improve overall survival relative to erlotinib alone in subjects with locally advanced or metastatic non-squamous, non-small cell lung cancer who have received 1 or 2 prior systemic anti-cancer therapies.


Eligibility criteria: Inclusion Criteria:

* Histologically or cytologically confirmed surgically unresectable locally advanced or metastatic (stage IIIB/IV) non-squamous non-small-cell lung cancer.
* Measurable disease and documented disease progression following last prior therapy according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria, Version 1.1.
* Have received one or two prior lines of systemic anti-cancer therapy therapy for advanced or metastatic disease, one of which must be a platinum-doublet therapy. Patients who received only adjuvant treatment will be eligible only if disease progression occurred \<6 months after completion of adjuvant therapy. Prior maintenance therapy is allowed and will be considered as the same line of therapy when continued without discontinuation after initiation of a treatment regimen.
* Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
* Resolution of any toxic effects of prior therapy (including radiotherapy) according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0, Grade ≤1 (with the exception of alopecia and ≤grade 2 neuropathy). Subject must have recovered from significant surgery-related complications.
* Demonstrate adequate bone marrow, liver, and renal functions, defined as:
* ALT, AST, and alkaline phosphatase ≤ 2.5 × upper limit of normal (ULN) in subjects with no liver metastasis and ≤5.0 x ULN in subjects with liver metastasis.
* Total bilirubin ≤ 1.5 × ULN (≤ 4 × ULN total and ≤1.5 × ULN direct bilirubin is acceptable for subjects with Gilbert's syndrome).
* ANC ≥1.5 × 10\^9/L.
* Platelet count ≥100 × 10\^9/L.
* Hemoglobin ≥9.0 g/dL (transfusion and/or growth factor support allowed).
* Serum creatinine ≤1.5 × ULN or creatinine clearance ≥ 60 mL/min.
* Archival and/or fresh biopsy tissue sample must be available for biomarker determination. The status of the following biomarkers will be collected in this study: EGFR and KRAS mutation status prior to randomization, and MET status post randomization
* If of child-bearing/reproductive potential (female or male), must agree to use double-barrier contraceptive measures, oral contraception, or avoidance of intercourse during the study and for 90 days after last investigational drug dose received
* If female and of childbearing potential, must have a negative result of a pregnancy test (serum or urine) within 72 hours prior to initiating study treatment.
* Must have signed and dated an approved Informed Consent Form (Including HIPAA authorization, if applicable) before performance of any study-specific procedures or tests. Subjects must be fully informed about their illness and the investigational nature of the study protocol (including forseeable risks and possible side effects)

Exclusion Criteria:

* Prior therapy with an EGFR inhibitor and/or ARQ 197 (or other known c-MET inhibitor).
* Receipt of any systemic anti-tumor treatment for NSCLC within 3 weeks prior to randomization.
* Receipt of palliative radiotherapy within 2 weeks or radiotherapy for curative intent of target lesions within 3 weeks prior to randomization. Lesions subjected to radiotherapy within 3 weeks prior to randomization may not be used as target lesions.
* Major surgical procedure within 3 weeks prior to randomization.
* History of cardiac disease:

Congestive heart failure defined as Class II to IV per New York Heart Association classification; active coronary artery disease; previously diagnosed symptomatic bradycardia (subjects with asymptomatic bradycardia and heart rate above 50 bpm are allowed) or other cardiac arrhythmia defined as ≥Grade 2 according to NCI CTCAE, version 4.0, or uncontrolled hypertension; myocardial infarction that occurred within 6 months prior to study entry (myocardial infarction that occurred \> 6 months prior to study entry is permitted).

* Clinically unstable central nervous system (CNS) metastasis (to be enrolled in the study, subjects must have confirmation of stable disease by MRI or computed tomography (CT) scan within 4 weeks of randomization and have CNS metastases well controlled by steroids, anti-epileptics or other symptom-relieving medications).
* Need to breastfeed a child during or within 12 weeks of completing the study.
* Significant gastrointestinal disorder that, in the opinion of the investigator, could interfere with absorption of ARQ 197 and/or erlotinib (eg, Crohn's disease, small or large bowel resection, malabsorption syndrome).
* Inability or unwillingness to swallow the complete doses of ARQ 197 or erlotinib.
* Any known contraindication to treatment with, including hypersensitivity to, ARQ 197 or erlotinib.
* History of malignancy other than NSCLC within the 5 years prior to randomization, with the exceptions of adequately treated intraepithelial carcinoma of the cervix uteri; prostate carcinoma with a prostate-specific antigen value \<0.2 ng/mL; or basal or squamous-cell carcinoma of the skin.
* Known infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV).
* Any other significant co-morbid condition that, in opinion of the investigator, would impair study participation or cooperation.

Primary outcomes:
measure: Overall Survival Following Treatment With Tivantinib (ARQ 197) Plus Erlotinib Compared to Placebo Plus Erlotinib in Previously Treated Participants With Locally Advanced or Metastatic, Non-Squamous, Non-Small-Cell Lung Cancer
timeFrame: Date of randomization up to date of death, up to approximately 1 year 11 months postdose
Secondary outcomes:
measure: Progression-free Survival Following Treatment With Tivantinib (ARQ 197) Plus Erlotinib Compared to Placebo Plus Erlotinib in Previously Treated Participants With Locally Advanced or Metastatic, Non-Squamous, Non-Small-Cell Lung Cancer
timeFrame: Date of randomization to disease progression or death (whichever comes first), up to 1 year 11 months postdose
measure: Overall Survival in the Epidermal Growth Factor Receptor Gene Wild-Type Subpopulation Following Treatment With Tivantinib (ARQ 197) Plus Erlotinib Compared to Placebo Plus Erlotinib in Previously Treated Participants With Non-Squamous NSCLC
timeFrame: Date of randomization up to date of death, up to approximately 1 year 11 months postdose
measure: Progression-free Survival in the Epidermal Growth Factor Receptor (EGFR) Gene Wild-Type Subpopulation Following Treatment With Tivantinib (ARQ 197) Plus Erlotinib Compared to Placebo Plus Erlotinib in Previously Treated Participants Non-Squamous NSCLC
timeFrame: Date of randomization to disease progression or death (whichever comes first), up to 1 year 11 months postdose
measure: Best Overall Tumor Response Following Treatment With Tivantinib (ARQ 197) Plus Erlotinib Compared to Placebo Plus Erlotinib in Previously Treated Participants With Locally Advanced or Metastatic, Non-Squamous, Non-Small-Cell Lung Cancer
timeFrame: From baseline up to disease progression or the development of unacceptable toxicity (whichever occurs first), up to 1 year 11 months postdose
measure: Duration of Response Following Treatment With Tivantinib (ARQ 197) Plus Erlotinib Compared to Placebo Plus Erlotinib in Previously Treated Participants With Locally Advanced or Metastatic, Non-Squamous, Non-Small-Cell Lung Cancer
timeFrame: From the date of first objective response (CR or PR) or SD to date of progressive disease, up to 1 year 11 months postdose
measure: Treatment-Emergent Adverse Events Reported in ≥5% of Participants Following Treatment With Tivantinib (ARQ 197) Plus Erlotinib Compared to Placebo Plus Erlotinib in Previously Treated Participants With Non-Squamous, Non-Small-Cell Lung Cancer
timeFrame: Baseline up to 30 days after last dose, up to 1 year 11 months postdose
measure: Treatment-Emergent Adverse Events Related to Tivantinib/Placebo Experienced by ≥5% of Participants Following Treatment With Tivantinib (ARQ 197) Plus Erlotinib Compared to Placebo Plus Erlotinib in Previously Treated Participants With Non-Squamous NSCLC
timeFrame: Baseline up to 30 days after last dose, up to 1 year 11 months postdose
Other outcomes:
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city: Arequipa
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city: Cluj-Napoca
country: Romania
city: Craiova
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city: Chelyabinsk
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city: Kursk
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city: Moscow
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city: Moscow
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city: Novgorod
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city: Novosibirsk
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city: Pyatigorsk
country: Russian Federation
city: St Petersburg
country: Russian Federation
city: St Petersburg
country: Russian Federation
city: St. Petersburg
country: Russian Federation
city: Tula
country: Russian Federation
city: Tyumen
country: Russian Federation
city: Barakaldo
country: Spain
state: Bilbao
city: Vigo
country: Spain
state: Pontevedra
city: Alicante
country: Spain
city: Barcelona
country: Spain
city: Barcelona
country: Spain
city: Coruna
country: Spain
city: Coruna
country: Spain
city: La Laguna
country: Spain
city: Madrid
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city: Madrid
country: Spain
city: Madrid
country: Spain
city: Malaga
country: Spain
city: Manresa
country: Spain
city: Oviedo
country: Spain
city: Palma de Mallorca
country: Spain
city: Sabadell
country: Spain
city: Santiago de Compostela
country: Spain
city: Sevilla
country: Spain
city: Sevilla
country: Spain
city: Valencia
country: Spain
city: Zaragoza
country: Spain
city: Linkoping
country: Sweden
city: Lund
country: Sweden
city: Guildford
country: United Kingdom
state: Surrey
city: Aberdeen
country: United Kingdom
city: Glasgow
country: United Kingdom
city: London
country: United Kingdom
city: London
country: United Kingdom
city: Manchester
country: United Kingdom
city: Nottingham
country: United Kingdom
city: Sheffield
country: United Kingdom
Study officials:
affiliation: Daiichi Sankyo
name: Global Clinical Leader
role: STUDY_DIRECTOR
References:
citation: Scagliotti G, von Pawel J, Novello S, Ramlau R, Favaretto A, Barlesi F, Akerley W, Orlov S, Santoro A, Spigel D, Hirsh V, Shepherd FA, Sequist LV, Sandler A, Ross JS, Wang Q, von Roemeling R, Shuster D, Schwartz B. Phase III Multinational, Randomized, Double-Blind, Placebo-Controlled Study of Tivantinib (ARQ 197) Plus Erlotinib Versus Erlotinib Alone in Previously Treated Patients With Locally Advanced or Metastatic Nonsquamous Non-Small-Cell Lung Cancer. J Clin Oncol. 2015 Aug 20;33(24):2667-74. doi: 10.1200/JCO.2014.60.7317. Epub 2015 Jul 13.
citation: Scagliotti GV, Novello S, Schiller JH, Hirsh V, Sequist LV, Soria JC, von Pawel J, Schwartz B, Von Roemeling R, Sandler AB. Rationale and design of MARQUEE: a phase III, randomized, double-blind study of tivantinib plus erlotinib versus placebo plus erlotinib in previously treated patients with locally advanced or metastatic, nonsquamous, non-small-cell lung cancer. Clin Lung Cancer. 2012 Sep;13(5):391-5. doi: 10.1016/j.cllc.2012.01.003. Epub 2012 Mar 21.