A Phase I Study Of Pazopanib With Either Erlotinib Or Pemetrexed In Patients With Advanced Solid Tumors

NCT00619424 | Completed Phase 1

• 1 other identifier: VEG109607
• Study Type: interventional
• Target: 58
• Locations: 2 countries
• Sites: 4

Brief Summary

This is an open-label, two-arm, Phase I, dose escalation study to evaluate the safety and tolerability and to determine the maximum tolerated dose (MTD) of pazopanib in combination with erlotinib (Arm A) or pazopanib in combination with pemetrexed (Arm B) in patients with advanced solid tumors. Patients will be enrolled in cohorts of 3 (in each arm) to receive escalating doses of pazopanib and erlotinib or pazopanib and pemetrexed. Dose escalation schemas for each study arm are described in the protocol. For each arm, the MTD regimen will be defined as the highest dose combination of the agents where no more than one out of six patients experiences a dose-limiting toxicity. Six to twelve additional patients in each arm will be studied with the MTD regimen to evaluate toxicity and pharmacokinetics. In arm A (erlotinib), a run-in phase with each drug separately will allow an evaluation of pharmacokinetics with each drug separately and also for the two drugs in combination. This will allow an assessment of potential drug-drug interactions. Pharmacokinetic endpoints will be AUC, Cmax, tmax and t1/2 of pazopanib, erlotinib, and pemetrexed, as well as pemetrexed clearance before and after administration of pazopanib in the extension cohort of Arm B. Antitumor activity will be assessed using RECIST criteria.

Conditions

Lung Cancer, Non-Small Cell

Keywords

erlotinib; pharmacokinetics; Solid tumors; pemetrexed; anti-angiogenesis; pazopanib (GW786034); cytokine and angiogenic factors

Outcome Measures

Primary Outcomes (1)

• MTD regimen for each combination regimen in each arm of the study as determined by an evaluation of AEs and changes in laboratory values. The MTD = highest dosing regimen that results in dose limiting toxicity in <= 1 of 6 patients.

  Through a minimum of two cycles of therapy for each subject

Secondary Outcomes (4)

• Pharmacokinetic endpoints will be AUC, Cmax, tmax, and t1/2 of pazopanib, erlotinib, and pemetrexed and clearance of pemetrexed.

  Through a minimum of two cycles of therapy for each subject

• Tumor response using RECIST criteria.

  Through a minimum of two cycles of therapy for each subject

• Levels of circulating cytokine and angiogenic factors (CAF) biomarkers (such as IL-2, IL-10, VEGF, sVEGFR-2) in plasma will be determined.

• Pharmacogenetics Endpoint: Genetic variants in candidate genes in the host DNA will be evaluated.

Study Arms (2)

pazopanib + erlotinib

EXPERIMENTAL

Pazopanib and erlotinib are to be combined at different specified dose levels until an optimally tolerated dose level is identified. Pazopanib, a multi-targeted tyrosine kinase inhibitor of VEGFR-1, -2, and -3, PDGFR-alpha and beta, and c-kit and erlotinib, an epidermal growth factor (EGFR) inhibitor, are to be combined in an effort to simultaneously block two tightly woven cell signaling pathways.

Drug: pazopanib; Drug: erlotinib

pazopanib + pemetrexed

EXPERIMENTAL

Pazopanib and pemetrexed are to be combined at different specified dose levels until an optimally tolerated dose regimen is identified. Combination of an anti-VEGF therapy (such as bevacizumab) with systemic chemotherapy has demonstrated increased clinical efficacy in comparison with systemic chemotherapy alone in several malignancies. Hence, pazopanib, a multi-targeted tyrosine kinase inhibitor of VEGFR-1, -2, and -3, PDGFR-alpha and beta, and c-kit, was chosen to be combined with pemetrexed, a chemotherapeutic agent that inhibits the enzyme thymidylate synthase, in an effort to determine if an anti-angiogenesis inhibitor would enhance the activity of the approved chemotherapeutic agent pemetrexed.

Drug: pazopanib; Drug: pemetrexed

Interventions

pazopanib DRUG

Oral tablet administered daily in dosages of 400 - 800 mg.

pazopanib + erlotinib; pazopanib + pemetrexed

erlotinib DRUG

oral tablet taken daily in dosages of 100-150 mg.

pazopanib + erlotinib

pemetrexed DRUG

IV chemotherapeutic agent administered every 21 days in dosages of 400-500 mg/m2

pazopanib + pemetrexed

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Subjects must provide written informed consent prior to performance of study specific procedures or assessments, and must be willing to comply with treatment and follow up.
• ·Procedures conducted as a part of routine clinical management of the subject (e.g., blood count, imaging study) and obtained prior to signed informed consent may be utilized for Screening or Baseline purposes provided these tests are obtained as specified in the protocol.
• Histologically- or cytologically-confirmed diagnosis of advanced solid tumor that has failed standard therapy or for which there is no standard therapy. Subjects for whom erlotinib or pemetrexed are standard therapy may also be entered.
• Age ≥18 years.
• ECOG Performance status must be ≤1.
• Adequate organ system function as defined in Table 9. System (Laboratory Values)
• Hematologic:
• Absolute neutrophil count (ANC) ((≥1.5 X 10\^9/L)) Hemoglobin (≥10 g/dL) Platelets (≥ 100 X 10\^9/L) Prothrombin time (PT) or international normalized ration (INR) (≤ 1.2 X upper limit of normal (ULN)) Activated partial thromboplastin time (APTT) (≤ 1.2 X ULN)
• Hepatic:
• Total bilirubin (≤1.5 X ULN) AST and ALT (≤ 2.5 X ULN)
• Renal:
• Serum creatinine (≤ 1.5 mg/dL) Or, if greater than 1.5 mg/dL Calculated creatinine clearance (≤ 50 mL/min) Urine Protein to Creatinine Ratio (UPC)2 \< 1
• Subjects may not have had a transfusion within 7 days of screening assessment.
• If UPC ≥ 1, then a 24-hour urine protein must be assessed and 24-hour urine protein must be \<1 g protein to be eligible.
• Measurable disease on CT scan.

You may not qualify if:

• Prior use of pazopanib, erlotinib (for subjects in Arm A), or pemetrexed (for subjects in Arm B).
• History or clinical evidence of central nervous system (CNS) metastases or leptomeningeal carcinomatosis, except for individuals who have previously-treated CNS metastases, are asymptomatic, and have had no requirement for steroids or anti-seizure medication for one week prior to date of first dose of study drug. Screening with CNS imaging studies (computed tomography \[CT\] or magnetic resonance imaging \[MRI\]) is required for all subjects.
• Clinically significant gastrointestinal abnormalities which might interfere with oral dosing, including but not limited to:
• Malabsorption syndrome
• Major resection of the stomach or small bowel that could affect the absorption of study drug
• Active peptic ulcer disease
• Inflammatory bowel disease
• Ulcerative colitis, or other gastrointestinal conditions with increased risk of perforation
• History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 28 days prior to beginning study treatment.
• Presence of uncontrolled infection
• Prolongation of corrected QT interval (QTc) \> 480 msecs.
• History of any one of more of the following cardiovascular conditions within the past 6 months:
• Cardiac angioplasty or stenting
• Myocardial infarction
• Unstable angina

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (4)

GSK Investigational Site

Aurora, Colorado, 80045, United States

Location

GSK Investigational Site

Buffalo, New York, 14263, United States

Location

GSK Investigational Site

Nashville, Tennessee, 37203, United States

Location

GSK Investigational Site

Orbassano (TO), Piedmont, 10043, Italy

Location

Related Publications (1)

• Dy GK, Infante JR, Eckhardt SG, Novello S, Ma WW, Jones SF, Huff A, Wang Q, Suttle AB, Ottesen LH, Adjei AA, Burris HA 3rd. Phase Ib trial of the oral angiogenesis inhibitor pazopanib administered concurrently with erlotinib. Invest New Drugs. 2013 Aug;31(4):891-9. doi: 10.1007/s10637-012-9887-6. Epub 2012 Nov 8.

  PMID: 23135778 BACKGROUND

Related Links

• Results for study VEG109607 can be found on the GSK Clinical Study Register.

MeSH Terms

Conditions

Carcinoma, Non-Small-Cell Lung

Interventions

pazopanib; Erlotinib Hydrochloride; Pemetrexed

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Quinazolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Guanine; Hypoxanthines; Purinones; Purines; Glutamates; Amino Acids, Acidic; Amino Acids; Amino Acids, Peptides, and Proteins; Amino Acids, Dicarboxylic

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 8, 2008
• First Posted: February 21, 2008
• Study Start: November 15, 2007
• Primary Completion: September 4, 2009
• Study Completion: September 4, 2009
• Last Updated: November 17, 2017

Record last verified: 2017-11

Locations

IT (1); US (3)