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A Study to Assess the Safety and the Efficacy of the Combination of TH-302 and Sunitinib in Neuroendocrine Pancreatic Tumours

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT02402062
Recruitment Status : Active, not recruiting
First Posted : March 30, 2015
Last Update Posted : June 12, 2019
Threshold Pharmaceuticals
Information provided by (Responsible Party):
Grupo Espanol de Tumores Neuroendocrinos

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.

Condition or disease Intervention/treatment Phase
Neuroendocrine Tumors Pancreatic Neoplasms Drug: TH-302 + Sunitinib Phase 2

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).

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 16 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II Study to Assess the Activity and Safety of TH-302 in Combination With Sunitinib in Treatment-naïve Patients With Well- and Moderately-differentiated Metastatic Pancreatic Neuroendocrine Tumours (pNET)
Actual Study Start Date : May 11, 2015
Estimated Primary Completion Date : June 2019
Estimated Study Completion Date : June 2019

Arm Intervention/treatment
Experimental: TH-302 + Sunitinib
TH-302 + Sunitinib. Single arm Study.
Drug: 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.

Other Name: TH-302 + Sutent

Primary Outcome Measures :
  1. Objective response rate [ Time Frame: 48 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 analysed population.

Secondary Outcome Measures :
  1. Progression Free Survival (PFS) [ Time Frame: 48 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.

  2. Time to Tumour Progression (TTP) [ Time Frame: 48 months ]
    It is defined as the time between the start of study treatment to date of the first objective evidence of radiological progression.

  3. Duration of Response (DR) [ Time Frame: 48 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).

  4. Overall Survival (OR) [ Time Frame: 48 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.

  5. Safety (adverse events) [ Time Frame: time between the date of signing the informed consent until 28 days after the last dose of study drug ]
    Safety will be assessed according to the reports of adverse events, the frequency of treatment discontinuations due to adverse events, laboratory evaluations or ECG

  6. Biomarkers in serum and tumor tissue [ Time Frame: 48 months ]
    Assess the predictive/prognostic value of the analysed biomarkers in plasm and tumour.

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT02402062

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Institut Catalá d'Oncologia L'Hospitalet
L'Hospitalet de Llobregat, Barcelona, Spain, 08907
Hospital Universitario Marqués de Valdecilla
Santander, Cantabria, Spain, 39008
Hospital Provincial de Castellón
Castelló, Valencia, Spain
Hospital Universitari Vall d'Hebron
Barcelona, Spain, 08035
Hospital Universitario Virgen de las Nieves
Granada, Spain, 18014
Hospital Universitario Ramón y Cajal
Madrid, Spain, 28034
Hospital Universitario 12 de Octubre
Madrid, Spain, 28041
Hospital Universitario La Paz
Madrid, Spain, 28046
Hospital Universitario Virgen de la Victoria
Málaga, Spain, 29010
Hospital Universitario Virgen del Rocío
Sevilla, Spain, 41013
Sponsors and Collaborators
Grupo Espanol de Tumores Neuroendocrinos
Threshold Pharmaceuticals
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Study Chair: Enrique Grande, MD Grupo Espanol de Tumores Neuroendocrinos

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Responsible Party: Grupo Espanol de Tumores Neuroendocrinos Identifier: NCT02402062     History of Changes
Other Study ID Numbers: GETNE-1408
2014-004072-30 ( EudraCT Number )
First Posted: March 30, 2015    Key Record Dates
Last Update Posted: June 12, 2019
Last Verified: June 2019
Keywords provided by Grupo Espanol de Tumores Neuroendocrinos:
Additional relevant MeSH terms:
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Neuroendocrine Tumors
Pancreatic Neoplasms
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms, Nerve Tissue
Digestive System Neoplasms
Neoplasms by Site
Endocrine Gland Neoplasms
Digestive System Diseases
Pancreatic Diseases
Endocrine System Diseases
Phosphoramide Mustards
Antineoplastic Agents
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Growth Inhibitors
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents, Alkylating
Alkylating Agents