Sandostatin LAR and Axitinib vs Pbo in Pnts With Advanced Well-differentiated Non-pancreatic Neuroendocrine Carcinomas

This study is currently recruiting participants.
Verified October 2013 by Grupo Espanol de Tumores Neuroendocrinos
Sponsor:
Information provided by (Responsible Party):
Grupo Espanol de Tumores Neuroendocrinos
ClinicalTrials.gov Identifier:
NCT01744249
First received: September 25, 2012
Last updated: October 7, 2013
Last verified: October 2013
  Purpose

The purpose of this study is to determine if Axitinib prolongs progression-free survival of patients with advanced well differentiated neuroendocrine carcinomas of non-pancreatic origin compared to placebo.


Condition Intervention Phase
Well-differentiated Non-pancreatic Neuroendocrine Carcinoma
Drug: Axitinib
Drug: Sandostatin LAR
Drug: Placebo
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Phase II Randomized Double-blind Study of Sandostatin LAR in Combination With Axitinib Versus Placebo in Patients With Progressive Advanced Well-differentiated Neuroendocrine Carcinomas of Non-pancreatic Origin

Resource links provided by NLM:


Further study details as provided by Grupo Espanol de Tumores Neuroendocrinos:

Primary Outcome Measures:
  • Progression Free Survival [ Time Frame: until disease progression, end of treatment or minimum 6 months ] [ Designated as safety issue: No ]
    calculated from the date of random assignment until the date of first progressive disease or tumor-related death


Secondary Outcome Measures:
  • Objective response rate (RECIST criteria) and duration of response [ Time Frame: Until disease progression, end of treatment or minimum 6 months ] [ Designated as safety issue: No ]
  • Biochemical response (5-OH-Indolacetic acid and chromogranin A) [ Time Frame: Until disease progression, end of treatment or minimum 6 months ] [ Designated as safety issue: No ]
  • Overall survival [ Time Frame: Until death, last follow-up, or minimum 6 months ] [ Designated as safety issue: No ]
  • Safety profile [ Time Frame: Until disease progression, end of treatment or minimum 6 months ] [ Designated as safety issue: Yes ]
    All adverse events and serious adverse events will be monitored with regular monitoring of hematology and blood chemistry parameters and regular physical examinations. Adverse events will be evaluated continuously throughout the study. Safety and tolerability will be assessed according to the National Institute of Health/National Cancer Institute (NIH/NCI) Common Terminology Criteria for Adverse Events version 4 (CTCAE v4)

  • Biomarkers [ Time Frame: Until disease progression or after 6 months of treatment ] [ Designated as safety issue: No ]

    The following parameters will be measured: Circulating tumor cells, circulating endothelial cells, hypertension and other biomarkers of angiogenesis(in tumor and serum).

    Peripheral blood samples (9ml) will be obtained before treatment, after 1 month since the start of treatment and after disease progression. If progression is not achieved, an additional sample will be collected after 6 months of treatment. The blood samples will be processed for mRNA extraction. Hypoxia dependant genes and marker genes which transcription depends on the activation of VEGF, will be analyzed using qPCR. The dynamic profile of those genes will then be analyzed in relation to the response to axitinib, evaluating their predictive value of response.

    Paraffin-embedded tumor tissue will also be collected from all patients to investigate the prognostic value and predictive potential of the different intracellular pathways related to VEGFR, PDGFR and other signaling pathways.



Estimated Enrollment: 80
Study Start Date: November 2011
Estimated Study Completion Date: December 2014
Estimated Primary Completion Date: December 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Axitinib + Sandostatin LAR
Axitinib 5 mg BID + Sandostatin LAR 30mg/28 days
Drug: Axitinib
Orally, 5mg, twice daily, until progression or until unacceptable toxicity, with or without food intake.
Drug: Sandostatin LAR
Intramuscular, 30mg, single injection every 28 days, until disease progression or unacceptable toxicity
Placebo Comparator: Placebo + Sandostatin LAR
Placebo BID + Sandostatin LAR 30mg/28 days
Drug: Sandostatin LAR
Intramuscular, 30mg, single injection every 28 days, until disease progression or unacceptable toxicity
Drug: Placebo
orally, twice daily, until disease progression or unacceptable toxicity, with or without food intake.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Histologically confirmed well or moderately differentiated neuroendocrine carcinoma (grade I and II WHO 2010)of non-pancreatic origin
  2. Ki-67<20%
  3. Metastatic or locally advanced disease (clinically or radiologically confirmed) not amenable to treatment with curative intent
  4. Progressive disease documented in the prior 12 months (RECIST criteria)
  5. Measurable disease
  6. Prior treatment with somatostatin analogues permitted
  7. Prior interferon therapy allowed
  8. One prior systemic chemotherapy allowed
  9. No prior VEGF- or VEGFR-targeted therapy allowed
  10. Adequate organ function as defined by the following criteria:

    • absolute neutrophil count (ANC) ≥1500 cells/mm3;
    • platelets ≥75,000 cells/mm3;
    • hemoglobin ≥9.0 g/dL;
    • AST and ALT ≤2.5 x upper limit of normal (ULN), unless there are liver metastases in which case AST and ALT ≤5.0 x ULN;
    • total bilirubin ≤1.5 x ULN;
    • serum creatinine ≤1.5 x ULN or calculated creatinine clearance ≥60 mL/min;
    • urinary protein <2+ by urine dipstick. If dipstick is ≥2+ then a 24-hour urine collection can be done and the patient may enter only if urinary protein is <2 g per 24 hours.
  11. Male or female, age ≥18 years.
  12. ECOG performance status of 0-2.
  13. Life expectancy of ≥12 weeks.
  14. At least 4 weeks since the end of prior systemic treatment, radiotherapy, or surgical procedure with resolution of all treatment-related toxicity to NCI CTCAE Version 3.0 grade ≤1 or back to baseline except for alopecia or hypothyroidism.
  15. No evidence of preexisting uncontrolled hypertension as documented by 2 baseline blood pressure readings taken at least 1 hour apart. The baseline systolic blood pressure readings must be ≤150 mm Hg, and the baseline diastolic blood pressure readings must be ≤90 mm Hg. Patients whose hypertension is controlled by antihypertensive therapies are eligible.
  16. Women of childbearing potential must have a negative serum or urine pregnancy test within 3 days prior to treatment.
  17. Signed and dated informed consent document indicating that the patient (or legally acceptable representative) has been informed of all pertinent aspects of the trial prior to enrollment.
  18. Willingness and ability to comply with scheduled visits, treatment plans and study procedures.

Exclusion Criteria:

  1. The following endocrine tumor types may not be included: paraganglioma, adrenal, thyroid, parathyroid or pituitary endocrine tumors.
  2. Major surgery in <4 weeks or radiation therapy <2 weeks prior to starting the study treatment. Prior palliative radiotherapy to metastatic lesion(s) is permitted, provided there is at least one measurable lesion that has not been irradiated.
  3. Gastrointestinal abnormalities including:

    • inability to take oral medication;
    • requirement for intravenous alimentation;
    • prior surgical procedures affecting absorption including total gastric resection;
    • treatment for active peptic ulcer disease in the past 6 months;
    • active gastrointestinal bleeding, unrelated to cancer, as evidenced by hematemesis, hematochezia or melena in the past 3 months without evidence of resolution documented by endoscopy or colonoscopy;
    • malabsorption syndromes.
  4. Current use or anticipated need for treatment with drugs that are known potent CYP3A4 inhibitors (ie, grapefruit juice, verapamil, ketoconazole, miconazole, itraconazole, erythromycin, telithromycin, clarithromycin, indinavir, saquinavir, ritonavir, nelfinavir, lopinavir, atazanavir, amprenavir, fosamprenavir and delavirdine)unless they can be substituted with a different medication with minimal inhibition of CYP3A4/5. The coadministration could reduce the plasmatic concentration of axitinib.
  5. Current use or anticipated need for treatment with drugs that are known CYP3A4/5 inducers (ie, carbamazepine, dexamethasone, felbamate, phenobarbital, phenytoin, amobarbital, nevirapine, primidone, rifabutin, rifampin, and St.John's wort)unless they can be substituted with a different medication with minimal inhibition of CYP3A4. The coadministration could reduce the plasmatic concentration of axitinib.
  6. Requirement of anticoagulant therapy with oral vitamin K antagonists. Low-dose anticoagulants for maintenance of patency of central venous access devise or prevention of deep venous thrombosis is allowed. Therapeutic use of low molecular weight heparin is allowed.
  7. Active seizure disorder or evidence of brain metastases, spinal cord compression, or carcinomatous meningitis.
  8. A serious uncontrolled medical disorder or active infection that would impair their ability to receive study treatment.
  9. Any of the following within the 12 months prior to study drug administration:

    myocardial infarction, uncontrolled angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident or transient ischemic attack and 6 months for deep vein thrombosis or pulmonary embolism.

  10. Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness.
  11. History of a malignancy (other than renal cell cancer) except those treated with curative intent for skin cancer (other than melanoma), in situ breast or in situ cervical cancer, or those treated with curative intent for any other cancer with no evidence of disease for 5 years.
  12. Dementia or significantly altered mental status that would prohibit the understanding or rendering of informed consent and compliance with the requirements of this protocol.
  13. Female patients who are pregnant or lactating, or men and women of reproductive potential not willing or not able to employ an effective method of birth control/contraception to prevent pregnancy during treatment and for 6 months after discontinuing study treatment The definition of effective contraception should be in agreement with local regulation and based on the judgment of the principal investigator or a designated associate.
  14. Other severe acute or chronic medical or psychiatric condition, or laboratory abnormality that may increase the risk associated with study participation or study drug administration, or may interfere with the interpretation of study results, and in the judgment of the investigator would make the patient inappropriate for entry into this study.
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01744249

Contacts
Contact: Rocio Garcia-Carbonero, MD 0034 93 451 1724 rgcarbonero@hotmail.com

Locations
Spain
Hospital Central de Asturias Recruiting
Oviedo, Asturias, Spain
Principal Investigator: Paula Jiménez Fonseca, MD         
Institut Català d'Oncologia L'Hospitalet Recruiting
L'Hospitalet de Llobregat, Barcelona, Spain
Principal Investigator: Alexandre Teulé, MD         
Complejo Hospitalario Univ A Coruña Recruiting
A Coruña, Spain
Principal Investigator: Luis antón Aparicio, MD         
Sub-Investigator: María Quindós, MD         
Hospital Universitari Vall d'Hebron Recruiting
Barcelona, Spain
Principal Investigator: Jaume Capdevila, MD         
Hospital Universitario de Burgos Recruiting
Burgos, Spain
Contact: Guillermo Crespo Herrero, MD         
Principal Investigator: Guillermo Crespo Herrero, MD         
Hospital Virgen de las Nieves Recruiting
Granada, Spain
Principal Investigator: Encarnación González Flores, MD         
Hospital universitario de Leon Recruiting
Leon, Spain
Contact: Beatriz Nieto Mangudo, MD         
Principal Investigator: Beatriz Nieto Mangudo, MD         
Hospital Universitario Ramón y Cajal Recruiting
Madrid, Spain
Principal Investigator: Enrique Grande Pulido, MD         
Hospital Universitario 12 de Octubre Recruiting
Madrid, Spain
Principal Investigator: Daniel Castellano, MD         
Hospital Clínico San Carlos Recruiting
Madrid, Spain
Principal Investigator: Javier Sastre         
Hospital Clara Campal Recruiting
Madrid, Spain
Contact: Jesus Rodríguez Pascual, MD         
Principal Investigator: Jesus Rodríguez Pascual, MD         
Hospital Univ La Paz Recruiting
Madrid, Spain
Principal Investigator: Jorge Barriuso, MD         
Hospital Gregorio Marañón Recruiting
Madrid, Spain
Principal Investigator: Pilar García Alfonso, MD         
Hospital Univ de Salamanca Recruiting
Salamanca, Spain
Principal Investigator: Miguel Navarro, MD         
Hospital de Donostia Recruiting
San Sebastian, Spain
Principal Investigator: Adelaida La Casta, MD         
Sub-Investigator: Sara Arévalo, MD         
Hospital Marqués de Valdecilla Recruiting
Santander, Spain
Principal Investigator: Carlos López, MD         
Hospital Universitario Virgen del Rocío Recruiting
Sevilla, Spain
Principal Investigator: Rocío García, MD         
Hospital La Fe Recruiting
Valencia, Spain
Contact: Ángel Segura, MD         
Principal Investigator: Ángel Segura, MD         
Hospital Miguel Servet Recruiting
Zaragoza, Spain
Principal Investigator: Vicente Alonso, MD         
Sponsors and Collaborators
Grupo Espanol de Tumores Neuroendocrinos
Investigators
Principal Investigator: Luis Antón Aparicio, MD Complejo Hospitalario Universitario A Coruña
Principal Investigator: Paula Jiménez Fonseca, MD Hospital Central de Asturias
Principal Investigator: Carlos López, MD Hospital Marques de Valdecilla
Principal Investigator: Vicente Alonso Orduña, MD Hospital Miguel Servet
Principal Investigator: Adelaida La Casta, MD Hospital de Donostia
Principal Investigator: Miguel Navarro, MD Hospital Universitario de Salamanca
Principal Investigator: Pilar Garcia Alfonso, MD Hospital Gregorio Marañón
Principal Investigator: Jorge Barriuso, MD Hospital Universitario La Paz
Principal Investigator: Encarnación González Flores, MD University Hospital Virgen de las Nieves
Study Director: Rocio Garcia Carbonero, MD Hospital Universitario Virgen del Rocio
Principal Investigator: Javier Sastre, MD Hospital Clínico San Carlos
Principal Investigator: Enrique Grande, MD Hospital Universitario Ramón y Cajal
Principal Investigator: Daniel Castellano, MD Hospital U 12 de Octubre
Principal Investigator: Jaume Capdevila, MD Hospital Vall d'Hebron
Principal Investigator: Alexandre Teulé Vega, MD ICO Hospitalet
Principal Investigator: Jesus Rodríguez Pascual, MD Hospital Clara Campal
Principal Investigator: Beatriz Nieto Mangudo, MD Hospital Universitario de León
Principal Investigator: Guillermo Crespo Herrero, MD Hospital Universitario de Burgos
Principal Investigator: Ángel Segura, MD Hospital La Fe
  More Information

No publications provided

Responsible Party: Grupo Espanol de Tumores Neuroendocrinos
ClinicalTrials.gov Identifier: NCT01744249     History of Changes
Other Study ID Numbers: AXI-IIG-02, 2011-001550-29
Study First Received: September 25, 2012
Last Updated: October 7, 2013
Health Authority: Spain: Agencia Española de Medicamentos y Productos Sanitarios

Keywords provided by Grupo Espanol de Tumores Neuroendocrinos:
carcinoid tumor
axitinib

Additional relevant MeSH terms:
Carcinoma
Carcinoma, Neuroendocrine
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Adenocarcinoma
Neoplasms, Nerve Tissue
Octreotide
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Gastrointestinal Agents

ClinicalTrials.gov processed this record on April 23, 2014