Clinical Trials /

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

NCT01744249

Description:

Assess whether therapy with axitinib, a potent angiogenic inhibitor of the tyrosine kinase receptors of VEGF bioavailable by oral administration, is capable of improving PFS in patients with advanced G1-G2 NETs of nonpancreatic origin with progressive disease documented in the 12 months prior to entering the study.

Related Conditions:
  • Neuroendocrine Carcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 2/Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Sandostatin LAR and Axitinib vs Pbo in Pnts With Advanced Well-differentiated Non-pancreatic Neuroendocrine Carcinomas
  • Official Title: A Phase II/III Randomized Double-blind Study of Sandostatin LAR in Combination With Axitinib Versus Sandostatin LAR With Placebo in Patients With Advanced G1-G2 Neuroendocrine Tumours (WHO 2010) of Non-pancreatic Origin

Clinical Trial IDs

  • ORG STUDY ID: AXI-IIG-02
  • SECONDARY ID: 2011-001550-29
  • NCT ID: NCT01744249

Conditions

  • Neuroendocrine Tumors
  • Advanced Cancer

Interventions

DrugSynonymsArms
AxitinibAxitinib + Sandostatin LAR
Sandostatin LARAxitinib + Sandostatin LAR
PlaceboPlacebo + Sandostatin LAR

Purpose

Assess whether therapy with axitinib, a potent angiogenic inhibitor of the tyrosine kinase receptors of VEGF bioavailable by oral administration, is capable of improving PFS in patients with advanced G1-G2 NETs of nonpancreatic origin with progressive disease documented in the 12 months prior to entering the study.

Detailed Description

      Phase II/III, prospective, multicenter, randomized (1:1), double-blind study to evaluate the
      efficacy and tolerability of axitinib in patients diagnosed with advanced G1-G2
      neuroendocrine tumors (WHO 2010) of nonpancreatic origin that have presented documented
      disease progression in the 12 months prior to entering the study. In the first part of the
      study (Phase II), 105 patients were enrolled. The second part of the study is the expansion
      to Phase III, which is expected to include 148 additional patients. Patients will be
      randomized to receive Sandostatin LAR with axitinib or Sandostatin LAR with placebo until
      disease progression or unacceptable toxicity occurs. Randomization will be stratified by the
      time from diagnosis to enrollment in the study (more vs less than or equal to 12 months), the
      origin of the primary tumor (gastrointestinal tract vs non-gastrointestinal tract [lung or
      other sites]) and ki-67 (< 5% vs > 5%).
    

Trial Arms

NameTypeDescriptionInterventions
Axitinib + Sandostatin LARExperimentalAxitinib 5 mg BID + Sandostatin LAR 30mg/28 days
  • Axitinib
  • Sandostatin LAR
Placebo + Sandostatin LARPlacebo ComparatorPlacebo BID + Sandostatin LAR 30mg/28 days
  • Sandostatin LAR
  • Placebo

Eligibility Criteria

        Inclusion Criteria:

          1. G1-G2 neuroendocrine tumor (WHO 2010) of histologically confirmed non-pancreatic
             origin, functioning and nonfunctioning

          2. Metastatic or locally advanced disease not amenable to treatment with curative intent

          3. Clinical and/or radiological disease progression documented in the 12 months prior to
             study entry.

          4. Patients should have at least one measurable lesion as defined by RECIST 1.1 criteria.
             Patients should not have undergone local or regional ablative procedures
             (embolization, cryoablation, radiofrequency ablation, or others) in the 6 months prior
             to entering the study, unless there are other locations of measurable disease or clear
             radiological progression after carrying out these procedures (in these cases, local
             and regional ablation procedures shall be permitted if they have been performed at
             least 1 month prior to enrollment in the study).

          5. Ki-67 < 20%

          6. Prior treatment with somatostatin analogues is allowed

          7. Prior treatment with interferon is allowed

          8. Prior treatment is allowed with up to 2 antineoplastic systemic treatment lines
             different from SAs or IFN (systemic treatment is understood as conventional cytotoxic
             chemotherapy or new drugs for therapeutic targets as mTOR or other, as long as it is
             not directed against VEGF/VEGFR). Treatment with SAs or IFN does not count as prior
             lines of antineoplastic treatment.

          9. Prior treatment with targeted therapy against VEGF or VEGFR is not allowed.

         10. Adequate organ function as defined by the following criteria:

               -  Absolute neutrophil count ≥ 1500 cells/mm3,

               -  Platelet count ≥ 75,000 cells/mm3,

               -  Hemoglobin ≥ 9.0 g/dL,

               -  AST y ALT ≤ 2.5 x upper limit of normal (ULN), except if liver metastases exist,
                  in which case AST and ALT 5.0 ≤ x ULN is allowed,

               -  Total bilirubin ≤ 1.5 x ULN,

               -  Serum creatinine ≤ 1.5 x ULN or calculated creatinine clearance ≥ 60 mL/min,

               -  Proteinuria < 2+ by reactive strip. If the reactive strip is ≥ 2+, a 24-hour
                  urine sample should be collected and the patient may be eligible if urinary
                  protein excretion is < 2 g every 24 hours.

         11. Men or women aged ≥ 18 years.

         12. ECOG performance status 0-2

         13. Life expectancy ≥ 12 weeks

         14. At least 4 weeks should pass from the end of the previous systemic treatment with
             resolution of all treatment-related toxicities to grade ≤ 1 according to NCI CTCAE
             Version 4.0 or to baseline, except for alopecia or properly treated hypothyroidism.

         15. No prior evidence of uncontrolled hypertension should exist, as documented by 2
             baseline blood pressure readings taken at least 1 hour apart. Baseline readings of
             systolic blood pressure should be ≤ 150 mm Hg and baseline readings of diastolic
             pressure should be ≤ 90 mm Hg. Patients whose hypertension is being controlled with
             antihypertensive therapy are eligible.

         16. Women (or their partners) should be surgically sterilized or postmenopausal, or must
             agree to use an effective contraceptive method during and for at least 6 months after
             receiving study treatment. All women of childbearing age should have a negative
             pregnancy test (serum/urine) within 7 days prior to starting treatment. Men (or their
             partners) should be surgically sterilized or must agree to use an effective
             contraceptive method during and for at least 6 months after receiving study treatment.
             The definition of an effective contraceptive method must comply with local regulations
             and will be based on the criterion of the principal investigator or a designated
             associate. Lactating women may not participate in this study.

         17. Signed and dated informed consent document stating that the patient has been informed
             of all the pertinent aspects of the trial prior to recruitment.

         18. Willingness and ability to comply with scheduled visits, treatment plans (including
             willingness to take axitinib or placebo according to randomization), laboratory tests,
             and other study procedures.

        Exclusion Criteria:

        1. Subjects must be evaluated with regard to the following exclusion criteria:

          1. The following types of endocrine tumors will not be included: paraganglioma, adrenal
             endocrine tumor, thyroid, parathyroid, or pituitary.

          2. Major surgery within previous 4 weeks, or radiation therapy within 2 weeks prior to
             the start of treatment. Prior palliative radiotherapy for metastatic lesions is
             permitted if there is at least one measurable lesion that has not been irradiated
             (i.e., if there are other non-irradiated target lesions).

          3. Gastrointestinal abnormalities, including:

               -  Inability to swallow oral medication;

               -  Need for intravenous feeding;

               -  Prior surgical procedures that affect absorption, including total gastric
                  resection;

               -  Treatment for active peptic ulcer in the last 6 months;

               -  Uncontrolled active gastrointestinal bleeding unrelated to cancer, as evidenced
                  by hematemesis, hematochezia or clinically significant melena in the last 3
                  months without evidence of resolution documented by endoscopy or colonoscopy;

               -  Malabsorption syndromes;

          4. Current or anticipated need for treatment with drugs that are potent inhibitors of
             CYP3A4 (grapefruit juice, verapamil, ketoconazole, miconazole, itraconazole,
             erythromycin, telithromycin, clarithromycin, indinavir, saquinavir, ritonavir,
             nelfinavir, lopinavir, atazanavir, amprenavir, fosamprenavir, and delavirdine) unless
             they can be replaced by another medication with minimal potential for CYP3A4/5
             inhibition. The use of low-dose oral steroids (< 5 mg/day prednisone or equivalent) is
             allowed. Co-administration of steroids may increase plasma concentrations of axitinib.

          5. Current use or anticipated need for treatment with drugs that are known potent
             CYP3A4/5 inducers (carbamazepine, dexamethasone, felbamate, phenobarbital, phenytoin,
             amobarbital, nevirapine, primidone, rifabutin, rifampicin, and St. John's wort) unless
             they can be replaced by another medication with minimal potential for CYP3A4
             induction. Co-administration of CYP3A4/5 inducers may decrease plasma concentrations
             of axitinib.

          6. Need for anticoagulant therapy with oral vitamin K antagonists. Low doses of
             anticoagulants to maintain the patency of a central venous access device or to prevent
             deep vein thrombosis are permitted. Use with therapeutic doses of low molecular weight
             heparin is allowed.

          7. Clinically relevant history of bleeding in the last 6 months, including severe
             hemoptysis or hematuria, unless it has been due to a treated cause (e.g., completely
             resected bleeding intestinal tumor).

          8. Active epilepsy or evidence of brain metastases, spinal cord compression, or
             carcinomatous meningitis.

          9. Serious uncontrolled illness or active infections that may interfere with the
             patient's ability to receive the study treatment.

         10. Any of the following events in the 12 months prior to administration of the study
             drug: myocardial infarction, uncontrolled angina, implantation of a coronary or
             peripheral bypass, symptomatic congestive heart failure, stroke or transient ischemic
             attack. Deep vein thrombosis or pulmonary embolism in the prior 6 months.

         11. Ongoing grade ≥ 2 cardiac arrhythmias according to NCI CTCAE: atrial fibrillation of
             any grade or QTc interval > 450 ms for men or > 470 ms for women.

         12. Patients with human immunodeficiency virus (HIV) infection or acquired
             immunodeficiency syndrome-related disease.

         13. Prior history of cancer except those treated with curative intent for non-melanoma
             skin cancer in situ, breast or cervical cancer in situ, or those treated for any
             cancer with curative intent and no evidence of disease in the last 5 years prior to
             enrollment in the study.

         14. Dementia or significantly altered mental status that could prevent compression, or
             submission of informed consent and compliance with the requirements of this protocol.

         15. Any severe, acute or chronic medical or psychiatric condition, or laboratory
             abnormality that may increase the risk associated with participation in the study or
             with study drug administration, or that may interfere with the interpretation of
             results, and that could interfere with the patient's ability to take part in this
             study in the investigator's opinion.

         16. The patient's participation or intention to participate (in the 4 weeks prior to
             starting drug administration) in a study in which the patient will receive an
             investigational medicinal product.

         17. Subjects who are institutionalized by governmental or by judicial decision, or
             subjects who are dependent of the sponsor, the investigator or the trial site will be
             excluded from participation.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Effectiveness of axitinib in terms of PFS
Time Frame:until disease progression, end of treatment or minimum 6 months
Safety Issue:
Description:calculated from the date of random assignment until the date of first progressive disease or tumor-related death

Secondary Outcome Measures

Measure:Objective response rate (ORR) and the duration of response.
Time Frame:Until disease progression, end of treatment or minimum 6 months
Safety Issue:
Description:Measured according to RECIST 1.1 criteria; Sum of longest diameter of target lesions measured in mm
Measure:Functional response rate using F-DOPA-PET (optional, depending on availability)
Time Frame:Until disease progression, end of treatment or minimum 6 months
Safety Issue:
Description:measured in SUV (standardized uptake value)
Measure:Biochemical response (5-OH-indoleacetic acid and chromogranin A)
Time Frame:Until death, last follow-up, or minimum 6 months
Safety Issue:
Description:measurable in mL/ 24h and ng/ml respectively, through blood and urine test
Measure:Safety and tolerability of axitinib (National Cancer Institute Common Terminology Criteria for Adverse Events [NCI-CTCAE], version 4.0)
Time Frame:Until disease progression, end of treatment or minimum 6 months
Safety Issue:
Description: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)
Measure:Explore potential biomarkers
Time Frame:Until disease progression or or minimum 6 months
Safety Issue:
Description:The following parameters will be measured: circulating tumor cells, circulating endothelial cells, hypertension (mmHg), and other serum or tumoral biomarkers of angiogenesis). Peripheral blood samples (9ml) will be obtained before treatment, after 1 month since the start of treatment and after disease progression and or the end of study visit. 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.
Measure:Evaluate overall survival.
Time Frame:from the date of randomization to the date of death from any cause whichever came first, assessed up to 50 months.
Safety Issue:
Description:

Details

Phase:Phase 2/Phase 3
Primary Purpose:Interventional
Overall Status:Active, not recruiting
Lead Sponsor:Grupo Espanol de Tumores Neuroendocrinos

Trial Keywords

  • Advanced neuroendocrine tumours of non-pancreatic origin
  • axitinib

Last Updated

October 21, 2019