Pazopanib as Single Agent in Advanced NETs

NCT01280201 | Completed Phase 2 Results

• 2 other identifiers: GETNE-10022010-020749-28
• Study Type: interventional
• Target: 44
• Locations: 1 country
• Sites: 10

Brief Summary

The incidence of new diagnosed patients with NET of the digestive tract including carcinoid and pancreatic islet cells tumors ranges from 2 to 10 per 100,000 in the western Countries (Kulke M, Mayer R. N Engl J Med 340:858-868, 1999). Despite of the low incidence, the prevalence of these tumors is high because of their relatively long survival estimated in 35% at 5 years for those patients with well or moderate differentiated tumors (Yao JC, et al. J Clin Oncol. 2008;26:3063-3072). In fact, digestive NETs are the second most prevalent tumors derived from the digestive tract after colorectal carcinoma. NETs are characterized by abundant vasculature, moreover VEGFR and VEGFR are overexpressed in 60-84% of the carcinoids and pancreatic islet cells NETs (Zhang et al. Cancer 2007;109:1478-1486). Other pro-angiogenic factors like the platelet derived growth factor (PDGFR) have been also involved in NET progression and development (Chaudhry A, et al.Cancer Res 1992;52:1006-12). Pazopanib is an oral tyrosine kinase inhibitor of the VEGFR, PDGFR and KIT with a dual activity both as an antiangiogenic and also and anti-tumoral agent (Kumar et al. Mol Cancer Ther2007;6:2012-2021, Hurwitz et al. Clin Cancer Res 2009;15:4220-4227). Pazopanib seems to have a better toxicity profile versus the other antiangiogenic tyrosine kinase inhibitors and has already shown activity in several tumor types like renal cell carcinoma (Sternberg et al. J Clin Oncol 2009;27:abst. 5021), soft tissue sarcomas (Sleijfer et al. J Clin Oncol 2009;27:3126-32), hepatocellular carcinoma (Yau et al. J Clin Oncol 2009;27:abst. 3561), colorectal cancer (Brady et al. J Clin Oncol 2009;27:abst.4133), and thyroid cancers (Bible et al. J Clin Oncol 2009;27:abst. 3521). The Spanish Group for Research in Neuroendocrine Tumors (GETNE) group is an active Member inside of the GENET group and has a large tradition in clinical trials in NETs. The investigators hypothesize that pazopanib may have at least as good activity and better safety profile than other VEGFR inhibitors in progressive advanced or metastatic NET tumors derived from the digestive tract.

Conditions

Advanced/Metastatic Neuroendocrine Tumors

Keywords

Neuroendocrine Tumors; Pazopanib; GETNE; Biomarkers

Outcome Measures

Primary Outcomes (1)

• Clinical Benefit Rate

  Per Response Evaluation Criteria In Solid Tumor Criteria (RECIST v1.0) for target lesions and assessed by MRI: complete response (CR) considered as dissapereance of all target lesions: partial response (PR), considered as \>=30% decrease in the sum of the longest diameter of target lesions, or stable disease (SD) considered as a decrease \<30%, after pazopanib was started. Clinical benefit rate (CBR) was defined as the percentage of patients achieving CR, PR or SD.

  6 months

Secondary Outcomes (5)

• Number of Patients Who Had an Event (Disease Progression or Death)

  3 years

• Radiological Objective Complete Response Rate

  3 years

• Duration of Response (DoR)

  3 years

• Safety Assessment Criteria

  3 years

• Predictive Value of Baseline CTC (Count of 0) for Response to Treatma

  3 years

Study Arms (1)

Pazopanib

EXPERIMENTAL

Drug: Pazopanib

Interventions

Pazopanib DRUG

Single arm of pazopanib 800 mg (2x400mg) given once daily as a single agent.

Pazopanib

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 signed informed consent form prior to performance of study-specific procedures or assessments, and must be willing to comply with treatment and follow-up.
• Procedures conducted as part of the subject's clinical routine (e.g., blood count, imaging study) and obtained prior to signing the consent form might be used for screening or baseline purposes provided these procedures have been conducted as specified in the protocol.
• Age ≥ 18 years.
• Diagnosis of pancreatic islet cell tumors, well differentiated gastrointestinal NETs, pulmonary carcinoids and well differentiated thymic carcinoids. Locally-advanced or metastatic disease documented as progressive by CT scan, MRI, or Octreoscan at baseline and within 12 months prior to baseline. The previous scans will be used to classify the patient as having progressive disease at baseline according to RECIST criteria. Octreoscan results may be used to document progressive disease at baseline, but not for RECIST determination during the study.
• ECOG performance status 0-1.
• Disease not amenable to surgery, radiation or combined modality therapy with curative intent.
• Presence of at least one dimensionally measurable target lesion for further evaluation according to RECIST 1.0 criteria (contrast enhancing lesion with the largest diameter \> 1cm, based on CT or MRI scan done within 4 weeks before the start of treatment).
• Patients could have received treatment with somatostatin analogs, chemotherapy, anti-VEGF, and anti-mTOR agents previously to the entrance into this study if the final toxicity was grade ≤ 1.
• From patients who sign an informed consent form to donate biological samples: Tumor tissue must be provided for all available subjects at baseline and serum samples will be collected at baseline and at week 12 of treatment for biomarker analysis as defined at the biomarker section of this protocol.
• Adequate organ system function as follows:
• Hematologic system:
• Absolute neutrophil count (ANC) ≥ 1.5 X 10\^9/L
• Hemoglobin (1) ≥ 9 g/dL (5.6 mmol/L)
• Platelets ≥ 100 X 10\^9/L
• Prothrombin time (PT) or international normalized ratio (INR) ≤ 1.2 X upper limit of normal (ULN)

You may not qualify if:

• Diagnosis of any second malignancy within the last 5 years, except for adequately treated basal cell or squamous cell skin cancer, or in situ carcinoma of the cervix uteri.
• 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 6 months prior to first dose of study drug. Screening with CNS imaging studies (computed tomography \[CT\] or magnetic resonance imaging \[MRI\]) is required only if clinically indicated or if the subject has a history of CNS metastases.
• Clinically significant gastrointestinal abnormalities that may increase the risk for gastrointestinal bleeding including, but not limited to:
• Active peptic ulcer disease 3.2.Known intraluminal metastatic lesion/s with risk of bleeding 3.3.Inflammatory bowel disease (e.g. ulcerative colitis, Chrohn's disease), or other gastrointestinal conditions with increased risk of perforation 3.4.History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 28 days prior to beginning study treatment.
• Clinically significant gastrointestinal abnormalities that may affect absorption of investigational product including, but not limited to:
• Malabsorption syndrome 4.2.Major resection of the stomach or small bowel. 4.3.Active peptic ulcer disease 4.4.Known intraluminal metastatic lesion/s with risk of bleeding 4.5.Inflammatory bowel disease (e.g. ulcerative colitis, Chrohn's disease), or other gastrointestinal conditions with increased risk of perforation 4.6.History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 28 days prior to beginning study treatment.
• Presence of uncontrolled infection.
• Corrected QT interval (QTc) \> 480 msecs using Bazett's formula.
• History of any one or more of the following cardiovascular conditions within the past 6 months:
• Cardiac angioplasty or stenting 7.2.Myocardial infarction 7.3.Unstable angina 7.4.Coronary artery bypass graft surgery 7.5.Symptomatic peripheral vascular disease 7.6.Class III or IV congestive heart failure, as defined by the New York Heart Association (NYHA)
• Poorly controlled hypertension \[defined as systolic blood pressure (SBP) of ≥140 mmHg or diastolic blood pressure (DBP) of ≥ 90mmHg\].
• History of cerebrovascular accident including transient ischemic attack (TIA), pulmonary embolism or untreated deep venous thrombosis (DVT) within the past 6 months.
• Note: Subjects with recent DVT who have been treated with therapeutic anti-coagulating agents for at least 6 weeks are eligible.
• Prior major surgery or trauma within 28 days prior to first dose of study drug and/or presence of any non-healing wound, fracture, or ulcer (procedures such as catheter placement not considered to be major).
• Evidence of active bleeding or bleeding diathesis.

Sponsors & Collaborators

• Grupo Espanol de Tumores Neuroendocrinos: lead

Study Sites (10)

Institut Català d'Oncologia L'Hospitalet

L'Hospitalet de Llobregat, Barcelona, Spain

Location

Hospital Universitari Vall d'Hebron

Barcelona, Spain

Location

Centro Integral Oncológico Clara Campal

Madrid, Spain

Location

Hospital Clínico San Carlos

Madrid, Spain

Location

Hospital Universitario 12 de Octubre

Madrid, Spain

Location

Hospital Universitario Ramón y Cajal

Madrid, Spain

Location

Hospital Universitario Virgen de la Victoria

Málaga, Spain

Location

Hospital Universitari Son Espases

Palma de Mallorca, Spain

Location

Hospital Universitario Virgen del Rocío

Seville, Spain

Location

Hospital Clínico Universitario Lozano Blesa

Zaragoza, Spain

Location

Related Publications (1)

• Grande E, Capdevila J, Castellano D, Teule A, Duran I, Fuster J, Sevilla I, Escudero P, Sastre J, Garcia-Donas J, Casanovas O, Earl J, Ortega L, Apellaniz-Ruiz M, Rodriguez-Antona C, Alonso-Gordoa T, Diez JJ, Carrato A, Garcia-Carbonero R. Pazopanib in pretreated advanced neuroendocrine tumors: a phase II, open-label trial of the Spanish Task Force Group for Neuroendocrine Tumors (GETNE). Ann Oncol. 2015 Sep;26(9):1987-1993. doi: 10.1093/annonc/mdv252. Epub 2015 Jun 10.

  PMID: 26063633 DERIVED

MeSH Terms

Conditions

Neuroendocrine Tumors

Interventions

pazopanib

Condition Hierarchy (Ancestors)

Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue

Limitations and Caveats

Small sample size, heterogeneous location and degree of differentiation of primary tumors, and lack of an appropriate control group. Additionally,response was evaluated by the investigator and not by an independent committee.

Results Point of Contact

• Title: Dr. Enrique Grande (Hospital Universitario Ramón y Cajal)
• Organization: Group for Neuroendocrine Tumors (GETNE)

getne@getne.org

931780742

Study Officials

• Enrique Grande Pulido, MD

  Grupo Espanol de Tumores Neuroendocrinos

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 19, 2011
• First Posted: January 20, 2011
• Study Start: January 26, 2011
• Primary Completion: April 1, 2013
• Study Completion: March 15, 2015
• Last Updated: May 29, 2019
• Results First Posted: March 4, 2019

Record last verified: 2019-05

Locations

ES (10)