Clinical trial NCT00367679: Pazopanib As Pre-Surgical Therapy In Treatment-Naive Subjects With Non-Small Cell Lung Cancer
Official title: A Phase II Open-Label Multicenter Study to Evaluate the Safety and Efficacy of Pazopanib (GW786034) as Neoadjuvant Therapy in Treatment-Naïve Subjects With Stage IA, IB, IIA or IIB (to T2) Resectable Non-Small Cell Lung Cancer (NSCLC)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Non-Small Cell Lung Cancer
Lung Cancer, Non-Small Cell
Keywords: pazopanib
I-ELCAP
non-small cell lung cancer
antiangiogenesis
NSCLC
GW786034
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2006-08-23
Enrollment: 35
Sex: ALL
Minimum age (years): 21
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This is a phase 2 open-label, multicenter, non-randomized study to evaluate the safety and efficacy of oral pazopanib as neoadjuvant treatment for patients with stage 1A, 1B, IIA or IIB (to T2) resectable Non-Small Cell Lung Cancer (NSCLC).


Eligibility criteria: Inclusion criteria:

* Signed, written informed consent provided prior to performing any study-specific procedures or assessments. Subject must be willing to comply with treatment and follow-up.
* Subjects ≥21 years of age with a life expectancy of ≥12 weeks
* The time between initial diagnosis and the scheduled surgery date allows for the subject to receive a minimum of 2 weeks or a maximum of 6 weeks treatment with pazopanib. Note: At least 4 weeks must be available between the diagnostic biopsy and surgery to allow for 1) one-week delay following the diagnostic biopsy prior to first dose of study drug, 2) minimum of 2 weeks on study drug, and 3) minimum of 1 week wash out prior to surgery.
* Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1.
* Histologically- or cytologically-confirmed Stage IA, IB, IIA, or IIB (to T2) NSCLC according to the International Staging System \[Mountain, 1997\] and must be scheduled for surgical resection.
* Disease must consist of only a single lesion and must be measurable according to high-resolution CT scan-assisted volumetric measurement \[Yankelevitz, 2000, Armato, 2004\]. In addition to the measurable single lesion, other small indeterminate nodules may also be present
* No approved or investigational anti-cancer therapy concurrently or in the 6 months prior to start of study drug, including surgery, tumor embolization, chemotherapy, radiation therapy, immunotherapy, hormone therapy, biologic therapy, or anti-angiogegneic therapy (e.g., inhibitors of VEGF or VEGFR).
* Fresh tumor biopsy for apoptosis and relevant biomarker analyses must be obtained within 30 to 8 days of first dose of study drug and must be available for all subjects prior to start of pazopanib treatment.
* System (Laboratory Values)
* Hematologic:Absolute neutrophil count (ANC)(≥ 1.5 X 109/L), Hemoglobin (≥9 g/dL), Platelets(≥100 X 109/L)
* Hepatic:Albumin (≥ 2.5 g/dL), Serum bilirubin(≤1.5 X upper limit of normal (ULN) unless due to Gilbert's syndrome), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) (≤2.0 X ULN) Renal:Serum creatinine(≤1.5 mg/dL) OR Calculated creatinine clearance (≥30 mL/min), Urine Protein (Trace or +1 by dipstick urinalysis or \<1.0 gram determined by 24-hour urine protein analysis.)
* Ability to swallow and retain oral medication
* A female is eligible to enter and participate in this study if she is of:
* Non-childbearing potential (i.e., physiologically incapable of becoming pregnant), including any female who has had:
* A hysterectomy
* A bilateral oophorectomy (ovariectomy)
* A bilateral tubal ligation
* Is post-menopausal:
* Subjects not using hormone replacement therapy (HRT) must have experienced total cessation of menses for ≥1 year and be greater than 45 years in age, OR, in questionable cases, have a follicle stimulating hormone (FSH) value \>40mIU/mL and an estradiol value \<40pg/mL (\<140pmol/L).
* Subjects must discontinue HRT prior to study enrollment due to the potential for inhibition of cytochrome P450 enzymes that metabolize estrogens and progestins. For most forms of HRT, at least 2-4 weeks must elapse between the cessation of HRT and determination of menopausal status; length of this interval depends on the type and dosage of HRT. If a female subject is determined not to be post-menopausal, they must use adequate contraception, as defined immediately below.
* Childbearing potential, including any female who has had a negative serum pregnancy test within 2 weeks prior to the first dose of study treatment, preferably as close to the first dose as possible, and agrees to use adequate contraception. GlaxoSmithKline (GSK)-acceptable contraceptive methods, when used consistently and in accordance with both the product label and the instructions of the physician, are as follow:
* An intrauterine device with a documented failure rate of less than 1% per year
* Vasectomized partner who is sterile prior to the female subject's entry and is the sole sexual partner for that female
* Complete abstinence from sexual intercourse for 14 days before exposure to investigational product, through the dosing period, and for at least 21 days after the last dose of investigational product
* Double-barrier contraception (condom with spermicidal jelly, foam suppository, or film; diaphragm with spermicide; or male condom and diaphragm with spermicide) Note: Oral contraceptives are not reliable due to potential drug-drug interactions.
* Female subjects who are lactating should discontinue nursing prior to the first dose of study drug and should refrain from nursing throughout the treatment period and for 15 days following the last dose of study drug.
* A male with a female partner of childbearing potential is eligible to enter and participate in the study if he uses a barrier method of contraception or abstinence during the study.
* Subjects must complete all screening assessments as outlined in the protocol

Exclusion criteria:

* Active malignancy or any malignancy in the 6 months prior to first dose of study drug.
* Concurrent disease or condition that would make the subject inappropriate for study participation including (1) any unresolved or unstable, serious toxicity from prior administration of another investigational drug, (2) any serious medical disorder that would interfere with the subject's safety, obtaining informed consent, or compliance with all study related procedures.
* Major surgical procedure, open biopsy, or significant traumatic injury within 4 weeks prior to beginning therapy, or anticipation of the need for a major surgical procedure during the course of the study; minor surgical procedures such as fine needle aspiration or core biopsy within 1 week prior to beginning therapy are also excluded.
* History or clinical evidence of central nervous system (CNS) metastases or leptomeningeal carcinomatosis. Routine screening with CNS imaging studies (computed tomography \[CT\] or magnetic resonance imaging \[MRI\]) is required only if clinically indicated.
* History of human immunodeficiency virus (HIV) infection or chronic hepatitis B or C.
* History of hemoptysis
* Malabsorption Syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel. Subjects with ulcerative colitis are also excluded
* Active peptic ulcer disease, inflammatory bowel disease, or other gastrointestinal condition increasing the risk of perforation; history of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 4 weeks prior to beginning therapy
* Active or uncontrolled infection
* Concurrent treatment with an investigational agent or participation in another clinical trial.
* Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to pazopanib
* Has taken/received prohibited medications within specified timeframes.
* Corrected QT interval (QTc) prolongation defined as QTc interval \>480 msecs
* History of any one of the following cardiac conditions within the past 6 months: cardia angioplasty or stenting, myocardial infarction,or unstable angina
* History of cerebrovascular accident within the past 6 months
* Has Class II, III or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system.
* Poorly controlled hypertension (mean systolic blood pressure (SBP) of ≥140mmHg, or mean diastolic blood pressure (DBP) of ≥ 90mmHg. Note: Initiation or adjustment of anti-hypertensive medication(s) is permitted prior to study entry. The blood pressure (BP) must be re-assessed on two occasions that are separated by a minimum of 5 minutes. The mean SBP/DBP values from both BP assessments must be \< 140/90mmHg in order for a subject to be eligible for the study.
* History of untreated deep venous thrombosis (DVT) within the past 6 months (e.g. calf vein thrombosis).
* Presence of any non-healing wound, fracture, or ulcer, or the presence of symptomatic peripheral vascular disease.
* Receiving therapeutic warfarin or heparin as a concurrent medication. Note: prophylactic low-dose warfarin (less than or equal to 2 mg daily) is permitted.
* Evidence of bleeding diathesis or coagulopathy
* Pregnant or lactating female

Primary outcomes:
measure: Number of Participants Achieving Tumor Shrinkage Based on Change in Tumor Volume
timeFrame: Baseline to at least two weeks or at most six weeks
Secondary outcomes:
measure: Number of Participants Achieving a Clinical Response Based on RECIST
timeFrame: Baseline to at least two weeks or at most six weeks
measure: Number of Participants Achieving a >=60% Reduction in Tumor Metabolic Activity Determined as Standard Uptake Value (SUV)
timeFrame: Baseline to at least two weeks or at most six weeks
measure: Number of Participants With Shifts From Baseline to Grade 2 or Greater in Hematology Values
timeFrame: Baseline to at least three weeks and at most 8 weeks
measure: Number of Participants With Shifts From Baseline to Grade 2 or Greater in Chemistry Values
timeFrame: Baseline to at least three weeks and at most 8 weeks
measure: Number of Participants With the Indicated Change From Baseline in Systolic and Diastolic Blood Pressure
timeFrame: Baseline to at least three weeks and at most 8 weeks
measure: Number of Cells Exhibiting Apoptosis in Participant Samples
timeFrame: Baseline to at least three weeks and at most 8 weeks (surgery date)
measure: Ratio of Post- to Pretreatment Expression Levels for Each of the Indicated Pazopanib Target Genes
timeFrame: Baseline to at least three weeks and at most 8 weeks (surgery date)
measure: Gene Mutations in Pre- or Post-treatment Tumor Biopsies
timeFrame: Baseline to at least three weeks and at most 8 weeks (surgery date)
measure: Intratumoral Levels of Specific Biomarkers
timeFrame: Baseline tumor biopsy
measure: Plasma Levels of Lactate Dehydrogenase-5 (LDH5)
timeFrame: Baseline to at least three weeks and at most 8 weeks
measure: Genetic Variations in Germline DNA
timeFrame: Baseline
measure: Semiquantitative Levels of Staining in Pre-treatment Tumor Biopsies (e.g. VEGF, VEGFR-1,VEGFR-2).
timeFrame: Entire study interval
measure: Ratio of Post- to Pretreatment Expression Levels for Each of the Indicated Pazopanib Target Proteins
timeFrame: Baseline to at least two weeks and at most 6 weeks
Other outcomes:
Locations:
city: Duarte
country: United States
facility: GSK Investigational Site
state: California
city: Rancho Mirage
country: United States
facility: GSK Investigational Site
state: California
city: Aurora
country: United States
facility: GSK Investigational Site
state: Colorado
city: Newark
country: United States
facility: GSK Investigational Site
state: Delaware
city: Miami
country: United States
facility: GSK Investigational Site
state: Florida
city: Chicago
country: United States
facility: GSK Investigational Site
state: Illinois
city: Paramus
country: United States
facility: GSK Investigational Site
state: New Jersey
city: Flushing
country: United States
facility: GSK Investigational Site
state: New York
city: New York
country: United States
facility: GSK Investigational Site
state: New York
city: New York
country: United States
facility: GSK Investigational Site
state: New York
city: Jerusalem
country: Israel
facility: GSK Investigational Site
city: Barcelona
country: Spain
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Altorki N, Guarino M, Lee P, et al. Preoperative treatment with pazopanib (GW786034), a multikinase angiogenesis inhibitor in early-stage non-small cell lung cancer (NSCLC): A proof-of-concept phase II study. JCO, 2008 Vol 26, No 15S (May 20 Supplement), 2008: 7557
citation: Altorki N, Lane ME, Bauer T, Lee PC, Guarino MJ, Pass H, Felip E, Peylan-Ramu N, Gurpide A, Grannis FW, Mitchell JD, Tachdjian S, Swann RS, Huff A, Roychowdhury DF, Reeves A, Ottesen LH, Yankelevitz DF. Phase II proof-of-concept study of pazopanib monotherapy in treatment-naive patients with stage I/II resectable non-small-cell lung cancer. J Clin Oncol. 2010 Jul 1;28(19):3131-7. doi: 10.1200/JCO.2009.23.9749. Epub 2010 Jun 1.
citation: Altorki N, Heymach J, Guarino M, et al. A Phase II Study of Pazopanib (GW786034) given Preoperatively in Phase I-II Non-Small Cell Lung Cancer (NSCLC): A Proof of Concept Study. Ann Oncol. 2008;19:viii89 [suppl 8; abstr 2250]).
citation: Nikolinakos PG, Altorki N, Yankelevitz D, Tran HT, Yan S, Rajagopalan D, Bordogna W, Ottesen LH, Heymach JV. Plasma cytokine and angiogenic factor profiling identifies markers associated with tumor shrinkage in early-stage non-small cell lung cancer patients treated with pazopanib. Cancer Res. 2010 Mar 15;70(6):2171-9. doi: 10.1158/0008-5472.CAN-09-2533. Epub 2010 Mar 9.