Advanced Cancer, Neuroendocrine Tumors
Conditions
Keywords
Advanced neuroendocrine tumours of non-pancreatic origin, axitinib
Brief summary
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%).
Interventions
DRUGAxitinib
Orally, 5mg, twice daily, until progression or until unacceptable toxicity, with or without food intake.
DRUGSandostatin LAR
Intramuscular, 30mg, single injection every 28 days, until disease progression or unacceptable toxicity
DRUGPlacebo
orally, twice daily, until disease progression or unacceptable toxicity, with or without food intake.
Sponsors
Grupo Espanol de Tumores Neuroendocrinos
Pfizer
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Efficacy of Axitinib in Terms of PFS (Investigator Assessment) | From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to approximately 25 months | Calculated from the date of random assignment until the date of first progressive disease or death, whichever occurs first. Progression of the disease was assessed by investigators using tumor imaging computed tomography scans and Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 PFS was analysed by Kaplan-Meier method and compared with log-rank tests. Patients alive with no event at data cut off were censored on their last tumor assessment |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) (Investigator Assessment) | From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to approximately 25 months | Measured changes in the sum of longest diameter of target lesions measured in mm according to RECIST 1.1 criteria. Assessed by investigators. Patients are categorized depending on the percentage of tumor redution: Complete response (CR): dissapearance of all lesions Partial response (PR): reduction \> 30% in the sum of longest diameter of target lesions Stable disease (SD): Tumor size betwee 30% reduction and 20% increase in the sum of longest diameter of target lesions Progressive disease (PD): increase \> 20% in the sum of longest diameter of target lesions ORR comprise all patients who achieved at least a CR or PR at any timepoint during follow-up. |
| Biochemical Response (5-OH-indoleacetic Acid and Chromogranin A) | From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to approximately 25 months | measurable in mL/ 24h and ng/ml respectively, through blood and urine test in patients with baseline elevation of CgA or 5-HIAA levels. This endpoint measures the negativization of these two tumor biomarkers. |
| Safety and Tolerability of Axitinib (National Cancer Institute Common Terminology Criteria for Adverse Events [NCI-CTCAE], Version 4.0) | From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to approximately 25 months | 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) |
| Efficacy of Axitinib in Terms of PFS (Central Blinded Assessment) | From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to approximately 25 months | Calculated from the date of random assignment until the date of first progressive disease or death, whichever occurs first. Progression of the disease was assessed by central blinded reviewers using tumor imaging by computed tomography scans and Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 PFS was analysed by Kaplan-Meier method and compared with log-rank tests. Patients alive with no event at data cut off were censored on their last tumor assessment |
| Objective Response Rate (ORR) (Central Blinded Assessment) | From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to approximately 25 months | Measured changes in the sum of longest diameter of target lesions measured in mm according to RECIST 1.1 criteria. Assessed by central blinded reviewers. Patients are categorized depending on the percentage of tumor redution: Complete response (CR): dissapearance of all lesions Partial response (PR): reduction \> 30% in the sum of longest diameter of target lesions Stable disease (SD): Tumor size betwee 30% reduction and 20% increase in the sum of longest diameter of target lesions Progressive disease (PD): increase \> 20% in the sum of longest diameter of target lesions ORR comprise all patients who achieved at least a CR or PR at any timepoint during follow-up. |
Countries
Germany, Italy, Spain, United Kingdom
Contacts
STUDY_CHAIRRocio Garcia Carbonero, MD
Hospital 12 de Octubre
Participant flow
Recruitment details
Patients enrolled and randomized
Baseline characteristics
| Characteristic | — |
|---|---|
| 5-HIAA levels > 1 x ULN | 10 Participants |
| 5-HIAA levels > 2 x ULN | 51 Participants |
| 5-HIAA levels Not determined | 40 Participants |
| 5-HIAA levels ≤ ULN | 20 Participants |
| Age, Continuous | 60 years |
| Carcinoid syndrome Absent | 101 Participants |
| Carcinoid syndrome Present | 35 Participants |
| Chromogranin A (CGA) levels > 1 x ULN | 30 Participants |
| Chromogranin A (CGA) levels > 2 x ULN | 78 Participants |
| Chromogranin A (CGA) levels Not determined | 23 Participants |
| Chromogranin A (CGA) levels ≤ upper limit normal (ULN) | 37 Participants |
| Eastern Cooperative Oncology Group performance status (ECOG-PS) Score 0 | 163 Participants |
| Eastern Cooperative Oncology Group performance status (ECOG-PS) Score 1 | 49 Participants |
| Eastern Cooperative Oncology Group performance status (ECOG-PS) Score 2 | 1 Participants |
| Eastern Cooperative Oncology Group performance status (ECOG-PS) Unknown | 1 Participants |
| Ki-67 ki-67 0-2 | 43 Participants |
| Ki-67 ki-67 >10 - 20 | 19 Participants |
| Ki-67 ki-67 >2-5 | 45 Participants |
| Ki-67 ki-67 >5 - 10 | 27 Participants |
| Ki-67 Not specified | 3 Participants |
| Lactate dehydrogenase (LDH) levels > 1 x ULN | 24 Participants |
| Lactate dehydrogenase (LDH) levels Not determined | 12 Participants |
| Lactate dehydrogenase (LDH) levels ≤ ULN | 180 Participants |
| Metastatic sites Bone Affected | 33 Participants |
| Metastatic sites Bone Not Affected | 97 Participants |
| Metastatic sites Liver Affected | 225 Participants |
| Metastatic sites Liver Not Affected | 15 Participants |
| Metastatic sites Lung Affected | 17 Participants |
| Metastatic sites Lung Not Affected | 109 Participants |
| Metastatic sites Lymph nodes Affected | 66 Participants |
| Metastatic sites Lymph nodes Not Affected | 61 Participants |
| Number of Organs Affected 1 location | 41 Participants |
| Number of Organs Affected 2 locations | 48 Participants |
| Number of Organs Affected ≥3 locations | 42 Participants |
| Number of prior lines of systemic treatment 0 line | 61 Participants |
| Number of prior lines of systemic treatment 1 line | 84 Participants |
| Number of prior lines of systemic treatment ≥2 | 29 Participants |
| Primary tumour location Colorectal | 24 Participants |
| Primary tumour location Gastric | 3 Participants |
| Primary tumour location Lung | 38 Participants |
| Primary tumour location Other locations | 10 Participants |
| Primary tumour location Small intestine | 60 Participants |
| Primary tumour location Unknown primary | 16 Participants |
| Prior systemic treatments Chemotherapy Administered | 33 Participants |
| Prior systemic treatments Chemotherapy NOT administered | 223 Participants |
| Prior systemic treatments Everolimus Administered | 14 Participants |
| Prior systemic treatments Everolimus NOT administered | 225 Participants |
| Prior systemic treatments Radioligand therapy (RLT) Administered | 12 Participants |
| Prior systemic treatments Radioligand therapy (RLT) NOT administered | 126 Participants |
| Prior systemic treatments Somatostatin analogs (SSA) Administered | 58 Participants |
| Prior systemic treatments Somatostatin analogs (SSA) NOT administered | 73 Participants |
| Race and Ethnicity Not Collected | 0 Participants |
| Sex: Female, Male Female | 63 Participants |
| Sex: Female, Male Male | 67 Participants |
| Time from initial cancer diagnosis to study entry ≤ 12 months | 105 Participants |
| Time from initial cancer diagnosis to study entry > 12 months | 79 Participants |
| Tumor grade (WHO) Grade 1 | 78 Participants |
| Tumor grade (WHO) Grade 2 | 94 Participants |
| Tumor grade (WHO) Unknown | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 68 / 125 | 48 / 130 |
| other Total, other adverse events | 121 / 125 | 124 / 130 |
| serious Total, serious adverse events | 48 / 125 | 30 / 130 |
Outcome results
None listed