Neuroendocrine Tumors, Pancreatic Neoplasms
Conditions
Keywords
pNET
Brief summary
The purpose of this study is to determine the safety and the efficacy of the combination of the drugs TH-302 and sunitinib in metastatic neuroendocrine tumours.
Detailed description
The purpose of this study is to determine the safety and the efficacy of the combination of the drugs TH-302 and sunitinib in Treatment-naïve patients with well- and moderately-differentiated metastatic Pancreatic Neuroendocrine Tumours (pNET).
Interventions
DRUGTH-302 + Sunitinib
Combination of the two drugs in cycles of 28 days, described as follows: Sunitinib: 37,5 mg/day Oral everyday of each 28 day cycle. TH-302: 340 mg/m2 IV on days 8, 15 and 22 of each cycle.
Sponsors
Threshold Pharmaceuticals
Pfizer
Grupo Espanol de Tumores Neuroendocrinos
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male or female, 18 years of age or older. * Eastern Cooperative Oncology Group (ECOG) performance status 0-1. * Histologically proven diagnosis of pancreatic neuroendocrine tumors (pNET) with Ki67 assessment of ≤ 20% (well and moderately differentiated) * Evidence of unresectable disease or metastatic disease. Locally advanced disease must not be amendable to resection or radiation therapy with curative intent. * Patients may be treated with somatostatin analogues prior or during the trial. Concomitant or prior interferon treatment is not permitted. * Documented progression disease by CT scan, magnetic resonance (MR) or Octreoscan in 12 months prior basal visit. * Measurable disease as per RECIST. Measurable lesions that have been previously radiated will not be considered target lesions unless increase in size has been observed following completion of radiation therapy. * Patient has to be able to swallow the medication. * Life expectancy greater than 12 weeks. * The definitions of minimum adequacy for organ function required prior to study entry are as follows: * Serum aspartate transaminase (AST) and serum alanine transaminase (ALT) ≤ 2.5 x upper limit of normal (ULN), or AST and ALT ≤ 5 x ULN if liver function abnormalities are due to underlying malignancy * Total serum bilirubin ≤ 1.5 x ULN * Serum albumin ≥ 3.0 g/dL * Absolute neutrophil count (ANC) ≥ 1500/µL * Platelets ≥ 100,000/µL * Hemoglobin ≥ 5,6 mmol/L (9.0 g/dL) * Creatinin clearance \> 40 mL/min (Cockcroft and Gault formula) * Adequate cardiac function: 12-lead ECG without pathologic findings (clinically significant alterations are allowed) and Echocardiogram / Normal multiple gated acquisition scan (MUGA) (LVEF\> 50%) * Signed and dated informed consent document indicating that the patient (or legally acceptable representative) has been informed of all the pertinent aspects of the trial prior to enrollment. * Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures.
Exclusion criteria
* Previous treatments with chemotherapy, monoclonal antibodies anti-vascular endothelial growth factor (VEGF), tyrosine kinase inhibitors, mammalian target of rapamycin (mTOR) inhibitors, or interferon are not permitted for the advanced disease. * Prior treatment on another hypoxia-activated prodrug under clinical trial. * Major surgery, radiation therapy, or systemic therapy within 3 weeks of study randomization except palliative radiotherapy to non-target metastatic lesions. * Prior high-dose chemotherapy requiring hematopoietic stem cell rescue. * Immunosuppressive drugs such as cyclosporine, tacrolimus, azathioprine, or long-term oral glucocorticoids taken concurrently or within last 3 months prior to randomization * Treatment with known inhibitors or inductors of cytochrome P450 3A4 (CYP3A4) or that prolong the QT interval in the previous 7 days. * Prior radiation therapy to \> 25% of the bone marrow. * Current treatment on another clinical trial. * Uncontrolled brain metastases, spinal cord compression, carcinomatous meningitis, or leptomeningeal disease. Patients should have completed surgery or radiation therapy for existing brain metastases, should not have documented increase in size over the previous 3 months prior to first dose of treatment on study and should be asymptomatic. * Diagnosis of any second malignancy within the last 3 years, except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of the cervix. * Any of the following within the 12 months prior to starting study treatment: * myocardial infarction, * severe/unstable angina, * coronary/peripheral artery bypass graft, * congestive heart failure class III or IV of the New York Heart Association (NYHA) or patients with clinical history of congestive heart failure class III or IV of the NYHA, unless an echocardiogram or MUGA in the previous 3 months to selection shows a LVEF ? 45 % * significant heart valve disease * cerebrovascular accident including transient ischemic attack * pulmonary embolus. * Ongoing cardiac dysrhythmias of NCI Common Toxicity Criteria for Adverse Effects (CTCAE) grade ≥ 2, atrial fibrillation of any grade, or corrected QT interval (QTc) interval \>450 msec for males or \>470 msec for females. * Hypertension that cannot be controlled by medications (\>150/100 mmHg despite optimal medical therapy) * Chronic obstructive pulmonary disease (COPD) or any other disease concurrent with hypoxemia or oxygen saturation \< 90% after a march of two minutes. * Current treatment with therapeutic doses of Coumadin (low dose Coumadin up to 2 mg PO daily for deep vein thrombosis prophylaxis is allowed). * Known human immunodeficiency virus infection. * Pregnancy or breastfeeding. All female patients with reproductive potential must have a negative pregnancy test (serum or urine) prior to inclusion. * Previous allergic reaction to components structurally similar to TH-302 or sunitinib or any of the excipients of drugs. * Non-healing wound, fistulae, active peptic ulcer or bone fracture. * Other severe acute or chronic medical or psychiatric condition, or laboratory abnormality that would impart, in the judgment of the investigator, excess risk associated with study participation or study drug administration, or which, in the judgment of the investigator, would make the patient inappropriate for entry into this study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate | approximately 36 months | Objective response rate: percentage of patients in whom a complete response (CR) or a partial response (PR) is confirmed according Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria in relation to the total of the analyzed population. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Tumour Progression (TTP) | approximately 36 months | It is defined as the time between the start of study treatment to date of the first objective evidence of radiological progression. |
| Duration of Response (DR) | approximately 36 months | It is defined as the time between the start from the first documentation of objective response (CR or PR) which is subsequently confirmed until the first objective evidence of radiological progression or death from any cause. DR is calculated only in the subgroup of patients with an objective response (CR + PR). |
| Progression Free Survival (PFS) | approximately 36 months | Time between the start of study treatment to date of the first objective evidence of radiological progression or patient death due to any cause; which comes first. |
| Safety (Adverse Events) | time between the date of signing the informed consent until 28 days after the last dose of study drug, , an average of 2 years | Safety will be assessed according to the reports of adverse events, the frequency of treatment discontinuations due to adverse events, laboratory evaluations or ECG |
| Biomarkers in Serum and Tumor Tissue | approximately 36 months | Assess the predictive/prognostic value of the analysed biomarkers in plasm and tumour. |
| Overall Survival (OR) | approximately 36 months | It is defined as the time between the start of study treatment to date of death from any cause. If it were impossible to obtain confirmation of the death, survival will be censored with the date of the last Visit that it is satisfied that the patient was alive. |
Countries
Spain
Participant flow
Pre-assignment details
Meeting eligibility criteria: 17 patients that meet the eligibility criteria were finally included
Participants by arm
| Arm | Count |
|---|---|
| TH-302 + Sunitinib TH-302 + Sunitinib. Single arm Study.
TH-302 + Sunitinib: Combination of the two drugs in cycles of 28 days, described as follows:
Sunitinib: 37,5 mg/day Oral everyday of each 28 day cycle.
TH-302: 340 mg/m2 IV on days 8, 15 and 22 of each cycle. | 17 |
| Total | 17 |
Baseline characteristics
| Characteristic | TH-302 + Sunitinib |
|---|---|
| Abbreviated Charlson comorbidity index index 2 | 11 Participants |
| Abbreviated Charlson comorbidity index index 3 | 4 Participants |
| Abbreviated Charlson comorbidity index index 4 | 2 Participants |
| Absolute Lymphocytes count | 1.69 x10^9 cells/L STANDARD_DEVIATION 0.41 |
| Absolute neutrophil count | 4.52 x10^9 cells/L STANDARD_DEVIATION 1.84 |
| Age, Continuous | 60.78 Years STANDARD_DEVIATION 10.78 |
| Alanine transaminase ALT (SGPT) | 69.63 u/L STANDARD_DEVIATION 61.12 |
| Albumin | 4.28 mg/dL STANDARD_DEVIATION 0.43 |
| Alkaline phosphatase (AP) | 201.64 u/L STANDARD_DEVIATION 183.95 |
| Aspartate AST (SGOT) | 48.95 u/L STANDARD_DEVIATION 40.18 |
| AST (SGOT)/ ALT (SGPT) (baseline) | 0.83 Ratio (arbitrary units) STANDARD_DEVIATION 0.3 |
| Baseline concomitant medication No | 1 Participants |
| Baseline concomitant medication Yes | 16 Participants |
| Blood pressure diastolic (BPd) | 79.12 mm Hg STANDARD_DEVIATION 7.42 |
| Blood pressure systolic (BPs) | 134.82 mm Hg STANDARD_DEVIATION 10.95 |
| Body mass index (BMI) | 25.46 kg/m^2 STANDARD_DEVIATION 4.75 |
| Body surface area (BSA) | 1.79 m^2 STANDARD_DEVIATION 0.2 |
| Calcium blood levels | 9.18 mmol/L STANDARD_DEVIATION 1.83 |
| CG a tumor marker | 474.41 ng/L STANDARD_DEVIATION 626.35 |
| Creatinine | 0.76 mg/dL STANDARD_DEVIATION 0.17 |
| Diabetes No | 12 Participants |
| Diabetes Yes | 5 Participants |
| ECOG PS grade 0 | 11 Participants |
| ECOG PS grade 1 | 6 Participants |
| Electrocardiogram (ECG) | 17 Participants |
| Enolase 1 | 31.92 ng/mL STANDARD_DEVIATION 31.08 |
| Gamma-glutamyltransferase (GGT) | 351.25 u/L STANDARD_DEVIATION 488.76 |
| Glucose | 133.44 mmol/L STANDARD_DEVIATION 59.92 |
| Haemoglobin | 13.82 g/dL STANDARD_DEVIATION 1.21 |
| Height | 166.71 cm STANDARD_DEVIATION 7.74 |
| Ki-67 index >10% | 8 Participants |
| Ki-67 index >2%-5% | 5 Participants |
| Ki-67 index >5%-10% | 4 Participants |
| Lactate dehydrogenase (LDH) | 216.88 u/L STANDARD_DEVIATION 83.41 |
| Left ventricular ejection fraction (LVEF) | 17 Participants |
| Magnesium blood levels | 1.9 mmol/L STANDARD_DEVIATION 0.38 |
| Mitosis 10 HPF <2 | 6 Participants |
| Mitosis 10 HPF 2-20 | 5 Participants |
| Mitosis 10 HPF Unknown | 6 Participants |
| Peripheral arterial disease No | 16 Participants |
| Peripheral arterial disease Yes | 1 Participants |
| Platelet count | 202.94 x10^9 cells/L STANDARD_DEVIATION 77.34 |
| Potassium blood levels | 4.35 mmol/L STANDARD_DEVIATION 0.35 |
| Primary tumor surgery No | 11 Participants |
| Primary tumor surgery Yes | 6 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 17 Participants |
| Region of Enrollment Spain | 17 Participants |
| Sex: Female, Male Female | 6 Participants |
| Sex: Female, Male Male | 11 Participants |
| Sodium blood levels | 139.22 mmol/L STANDARD_DEVIATION 3.06 |
| Somatostanine analogues prior the trial No | 10 Participants |
| Somatostanine analogues prior the trial Yes | 7 Participants |
| Time between diagnosis (anatomical pathology) and CT relapse in months | 8.9 months STANDARD_DEVIATION 13.77 |
| Time between diagnosis (anatomical pathology) and surgery in months | 1.1 months STANDARD_DEVIATION 2.94 |
| Time between diagnosis (anatomical pathology) and treatment initiation in months | 14.12 months STANDARD_DEVIATION 22.72 |
| Total bilirubin | 0.86 mg/dL STANDARD_DEVIATION 0.58 |
| Tumor histological grade Grade I | 2 Participants |
| Tumor histological grade Grade II | 15 Participants |
| Tumor relapse location Extra-hepatic | 1 Participants |
| Tumor relapse location Hepatic | 12 Participants |
| Tumor relapse location Unknown | 4 Participants |
| Tumor stage at diagnosis II | 3 Participants |
| Tumor stage at diagnosis III | 1 Participants |
| Tumor stage at diagnosis IV | 13 Participants |
| Weight | 70.97 Kg STANDARD_DEVIATION 15.01 |
| White blood cells | 6.22 x10^9 cells/L STANDARD_DEVIATION 2.17 |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 3 / 17 |
| other Total, other adverse events | 17 / 17 |
| serious Total, serious adverse events | 3 / 17 |
Outcome results
Primary
Objective Response Rate
Objective response rate: percentage of patients in whom a complete response (CR) or a partial response (PR) is confirmed according Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria in relation to the total of the analyzed population. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions
Time frame: approximately 36 months
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| TH-302 + Sunitinib | Objective Response Rate | CR or PR | 3 Participants |
| TH-302 + Sunitinib | Objective Response Rate | SD or PD | 14 Participants |
Secondary
Biomarkers in Serum and Tumor Tissue
Assess the predictive/prognostic value of the analysed biomarkers in plasm and tumour.
Time frame: approximately 36 months
Population: we obtained samples from 13 patients for Cg A and 10 patients for Enolase 1
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| TH-302 + Sunitinib | Biomarkers in Serum and Tumor Tissue | Enolase 1 | 15.06 ng/ml |
| TH-302 + Sunitinib | Biomarkers in Serum and Tumor Tissue | Cg A | 197 ng/ml |
Secondary
Duration of Response (DR)
It is defined as the time between the start from the first documentation of objective response (CR or PR) which is subsequently confirmed until the first objective evidence of radiological progression or death from any cause. DR is calculated only in the subgroup of patients with an objective response (CR + PR).
Time frame: approximately 36 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| TH-302 + Sunitinib | Duration of Response (DR) | 18.48 months |
Secondary
Overall Survival (OR)
It is defined as the time between the start of study treatment to date of death from any cause. If it were impossible to obtain confirmation of the death, survival will be censored with the date of the last Visit that it is satisfied that the patient was alive.
Time frame: approximately 36 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| TH-302 + Sunitinib | Overall Survival (OR) | 32.32 months |
Secondary
Progression Free Survival (PFS)
Time between the start of study treatment to date of the first objective evidence of radiological progression or patient death due to any cause; which comes first.
Time frame: approximately 36 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| TH-302 + Sunitinib | Progression Free Survival (PFS) | 10.38 months |
Secondary
Safety (Adverse Events)
Safety will be assessed according to the reports of adverse events, the frequency of treatment discontinuations due to adverse events, laboratory evaluations or ECG
Time frame: time between the date of signing the informed consent until 28 days after the last dose of study drug, , an average of 2 years
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| TH-302 + Sunitinib | Safety (Adverse Events) | SAE | 3 events |
| TH-302 + Sunitinib | Safety (Adverse Events) | Deaths (all causes) | 3 events |
| TH-302 + Sunitinib | Safety (Adverse Events) | Deaths (SAE related) | 1 events |
| TH-302 + Sunitinib | Safety (Adverse Events) | AE | 17 events |
| TH-302 + Sunitinib | Safety (Adverse Events) | treatment discontinuation due to toxicity | 4 events |
Secondary
Time to Tumour Progression (TTP)
It is defined as the time between the start of study treatment to date of the first objective evidence of radiological progression.
Time frame: approximately 36 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| TH-302 + Sunitinib | Time to Tumour Progression (TTP) | 5.32 months |