A phase II trial to assess the activity and safety of TH-302 in combination with sunitinib in patients with well- and moderately-differentiated metastatic pancreatic neuroendocrine tumors (pNET) previously untreated

Phase 1

• Conditions: Patients with well- and moderately-differentiated metastatic pancreatic neuroendocrine tumours (pNET).; Therapeutic area: Diseases [C] - Cancer [C04]

• Registration Number: EUCTR2014-004072-30-ES
• Lead Sponsor: Grupo Español de Tumores Neuroendocrinos

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2014-12-16
• Last Update Posted: 1 February 2020

Recruitment & Eligibility

• Status: ot Recruiting
• Sex: Not specified
• Target Recruitment: 43

Inclusion Criteria

1. Male or female, 18 years of age or older.
2. ECOG performance status 0-1.
3. Histologically proven diagnosis of pancreatic neuroendocrine tumors (pNET) with Ki67 assessment of < or = 20% (well and moderately differentiated)
4. Evidence of unresectable disease or metastatic disease. Locally advanced disease must not be amendable to resection or radiation therapy with curative intent.
5. Patients may be treated with somatostatin analogues prior or during the trial. Concomitant or prior interferon treatment is not permitted.
6. Documented progression disease by CT scan, MR or Octreoscan in 12 months prior basal visit.
7. 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.
8. Patient has to be able to swallow the medication.
9. Life expectancy greater than 12 weeks.
10. 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 (Cockroft and Gault formula)
11. Adequate cardiac function: 12-lead ECG without pathologic findings (clinically significant alterations are allowed) and Echocardiogram / Normal MUGA (LVEF> 50%)
12. 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.
13. Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 43
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 43

Exclusion Criteria

1. Previous treatments with chemotherapy, monoclonal antibodies anti-VEGF, tyrosine kinase inhibitors, mTOR inhibitors, or interferon are not permitted for the advanced disease.
2. Prior treatment on another hypoxia-activated prodrug under clinical trial.
3. Major surgery, radiation therapy, or systemic therapy within 3 weeks of study randomization except palliative radiotherapy to non-target metastatic lesions.
4. Prior high-dose chemotherapy requiring hematopoietic stem cell rescue.
5. Immunosuppressive drugs such as cyclosporine, tacrolimus, azathioprine, or long-term oral glucocorticoids taken concurrently or within last 3 months prior to randomization
6. Treatment with known inhibitors or inductors of CYP3A4 or that prolong the QT interval in the previous 7 days.
7. Prior radiation therapy to >25% of the bone marrow.
8. Current treatment on another clinical trial.
9. 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.
10. 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.
11. 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 clase III or IV of the NYHA, unless an echocardiogram or MUGA in the pevious 3 months to selection shows a LVEF ? 45 %
- significant heart valve disease
- cerebrovascular accident including transient ischemic attack
- pulmonary embolus.
12. 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.
13. Hypertension that cannot be controlled by medications (>150/100 mmHg despite optimal medical therapy)
14. Chronic obstructive pulmonary disease (COPD) or any other disease concurrent with hypoxemia or oxigen saturation < 90% after a march of two minutes.
15. Current treatment with therapeutic doses of Coumadin (low dose Coumadin up to 2 mg PO daily for deep vein thrombosis prophylaxis is allowed).
16. Known human immunodeficiency virus infection.
17. Pregnancy or breastfeeding. All female patients with reproductive potential must have a negative pregnancy test (serum or urine) prior to inclusion.
18. Previous allergic reaction to components structurally similar to TH-302 or sunitinib or any of the excipients of drugs.
19. Non-healing wound, fistulae, active peptic ulcer or bone fracture.
20. Other severe acute or chronic medical or psychiatric condition, or laboratory abnormality that would impart, in the judgment of the investigator, ex

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: Objective Response Rate (OOR);<br> Secondary Objective: Progression Free Survival (PFS)<br> Time to Tumour Progression (TTP)<br> Duration of Response (DR)<br> Overall Survival (OR)<br> Safety<br> Biomarkers in serum and tumor tissue<br> ;Primary end point(s): Objective response rate: percentage of patients in whom a complete response (CR) or a partial response (PR) is confirmed according RECIST criteria in relation to the total of the analysed population.;Timepoint(s) of evaluation of this end point: the objective response rate will be assessed according to RECIST criteria which will be held every 8 weeks, regardless of delays in the secondary treatment toxicity.