| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with progressive advanced well-differentiated neuroendocrine carcinomas of non-pancreatic origin (carcinoids) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Patients with progressive advanced well-differentiated neuroendocrine carcinomas of non-pancreatic origin (carcinoids) |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10057270 |
| E.1.2 | Term | Neuroendocrine carcinoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
To evaluate the effectiveness in terms of PFS of axitinib in patients with
advanced G1-G2 neuroendocrine tumors of non-pancreatic origin and
documented disease progression within 12 months prior to study entry. |
|
| E.2.2 | Secondary objectives of the trial |
?To assess the objective response rate (ORR) (by RECIST 1.1 criteria)
and duration of response.
?To evaluate functional response by DOPA-PET (optional if available).
?To assess biochemical response (5-OH-Indolacetic acid and
chromogranin A).
?To evaluate overall survival.
?To evaluate safety and tolerability of axitinib (National Cancer Institute
Common Toxicity Criteria (NCICTC), version 4.0).
?To explore potential biomarkers (circulating tumor cells, endothelial
circulating cells, hypertension, other serum or tumoral molecular
markers related with angiogenesis). |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Histologically confirmed G1-G2 neuroendocrine tumors (per WHO
2010 classification) of non-pancreatic origin, both functioning and nonfunctioning.
2. Metastatic or locally advanced disease not amenable to treatment
with curative intent.
3. Clinical or radiological progressive disease documented within 12
months prior to study entry.
4. Patient must have at least one measurable lesion as defined by
RECIST 1.1 criteria. Patients mustn?t have previously undergone
ablative local procedures (embolization, cryoablation, radiofrequency
ablation or others) within previous 6 months unless other target lesions
are present or imaging progression disease is clear after those
treatments (in these cases at least one month interval after local
treatment is required).
5. Ki-67less than 20%.
6. Prior treatment with somatostatin analogues permitted.
7. Prior interferon therapy allowed.
8. Up to two prior lines of systemic antineoplastic medical therapy
permitted other than SSA or IFN (such as chemotherapy or targeted
agents excluding those targeting VEGF/VEGFR). Treatment with SSA or
IFN does not count as prior lines of systemic antineoplastic therapy.
9. No prior VEGF- or VEGFR-targeted therapy allowed.
10. Adequate organ function, in terms of the values of :
? Absolute neutrophil count
? Platelet count
? Hemoglobin
? Alanine aminotransferase (ALT/SGPT) and aspartate
aminotransferase (AST/SGOT)
? Total serum bilirubin
? Serum creatinine or estimated creatinine clearance
? Proteinuria
11. Male or female, age above or equal 18 years.
12. ECOG performance status of 0-2.
13. Life expectancy of above 12 weeks.
14. At least 4 weeks since the end of prior systemic treatment with
resolution of all treatment-related toxicity to NCI CTCAE Version 4.0
grade less or equal to 1 or back to baseline except for alopecia or
adequately treated hypothyroidism.
15. No evidence of preexisting uncontrolled hypertension as
documented by 2 baseline blood pressure readings taken at least 1 hour
apart. Patients whose hypertension is controlled by antihypertensive
therapies are eligible.
16. Women (or their partners) should be sterilized by surgical methods
or be postmenopausal, or should be willing to use an effective
contraceptive method while they receive the study treatment and at
least for 6 month following. Women of childbearing potential must have
a negative serum or urine pregnancy test within 7 days prior to
treatment. Men (or their partners) should be sterilized by surgical
methods or should be willing to use an effective contraceptive method
while they receive the study treatment and at least for 6 month
following. The definition of an effective contraceptive method should be
in agreement with local regulation and based on the judgement of
principal investigator or a designated associate. Lactating women will
not be allowed to participate.
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 (including the willingness to take axitinib or
placebo according to randomization), laboratory tests and other study
procedures. |
|
| E.4 | Principal 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:
a. inability to take oral medication;
b. requirement for parenteral nutrition;
c. prior surgical procedures affecting absorption including total gastric resection;
d. active peptic ulcer disease in the past 6 months;
e. 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;
f. 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 it can be replaced by other drugs with minimal inhibition potential of CYP3A4/5. Low dose oral steroid therapy is allowed (< 5 mg/day or prednisone or equivalent). Co-administration may increase plasma concentrations of axitinib.
5. Current use or anticipated need for treatment with drugs that are known CYP3A4 or CYP1A2 inducers (ie, carbamazepine, dexamethasone, felbamate, phenobarbital, phenytoin, amobarbital, nevirapine, primidone, rifabutin, rifampin, and St.John's wort), unless it can be replaced by other drugs with minimal induction potential of CYP3A4. Co-administration may decrease plasma concentrations 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. History of relevant haemorrhage within the past 6 months, including
gross hemoptysis or hematuria. Except is caused by a trated cause
8. Active seizure disorder or evidence of brain metastases, spinal cord compression, or carcinomatous meningitis.
9. A serious uncontrolled medical disorder or active infection that would impair their ability to receive study treatment.
10. 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.
11. Ongoing cardiac dysrhythmias of NCI CTCAE grade > 2, atrial
fibrillation of any grade, or QTc interval >450 msec for males or >470
msec for females.
12. Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness.
13. 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.
14. Dementia or significantly altered mental status that would prohibit the understanding or rendering of informed consent and compliance with the requirements of this protocol.
15. 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.
16. Current, recent (within 4 weeks of the study treatment administration), or planned participation in an experimental therapeutic drug study other than this protocol. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Progression-free survival (calculated from the date of random assignment until the date of first progressive disease or tumor-related death) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Date of first observed progression dissease or the date of death due to any cause (if occurring before progression) |
|
| E.5.2 | Secondary end point(s) |
? Objective response rate (measured by RECIST 1.1 criteria) and duration of response
? Biochemical response (5-OH-Indolacetic acid and chromogranin A)
? Prognostic and predictive value of F-DOPA-PET-TC
? Overall survival
? Safety and tolerability (National Cancer Institute Common Toxicity Criteria (NCICTC), version 4.0)
? Explore potential biomarkers (hypertension, and other serum, urinary
or tumoral biomarkers). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Date of first observed progression dissease or the date of death due to any cause (if occurring before progression) |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 29 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 6 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
Print
