Temozolomide for Second-Line Treatment of Neuroendocrine Carcinomas

Study Overview
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Brief Summary
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To assess the efficacy and safety of Temozolomide for second-line treatment of Neuroendocrine Carcinomas progressing after first-line Platinum-based therapy.

Official Title
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A Phase II Single Arm Trial Evaluating the Efficacy and Safety of Temozolomide for Second-Line Treatment of Neuroendocrine Carcinomas Progressing After First-Line Platinum- Based Therapy

Conditions
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Neuroendocrine Carcinomas

Intervention / Treatment
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* Drug: Temozolomide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed informed consent prior to initiation of any study-specific procedures or treatment, as confirmation of the patient's awareness and willingness to comply with the study requirements. Patients ≥18 years of age. Histologically confirmed Metastatic Neuroendocrine Carcinoma (Ki67>20% Ki67 must be quantified in percentage) with documented progression of disease per investigator assessment following or during first-line platinum-based treatment. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-2. At least 28 days since prior radiation therapy or surgery and recovery from treatment. Patients must have measurable disease which must be evaluable per RECIST v1.1. Estimated life expectancy of ≥12 weeks. Exclusion Criteria: - Patients < 18 years of age Diagnosis of well differentiated G1/G2 NEN Psychiatric or addictive disorders or other conditions that, in the opinion of the investigator, would prevent the patient from meeting the study requirements. Serious active infection requiring i.v. antibiotics and/or hospitalization at study entry. Patients who are treated with any medicinal product that contraindicates the use of the study drug, may interfere with the planned treatment, affects patient compliance or puts the patient at high risk for treatment-related complications. Pregnant or lactating females. Serum pregnancy test to be assessed within 7 days prior to study treatment start, or within 14 days with a confirmatory urine pregnancy test within 7 days prior to study treatment start. Women of childbearing potential (defined as <2 years after last menstruation and not surgically sterile) not using effective, non-hormonal means of contraception (intrauterine contraceptive device, barrier method of contraception in conjunction with spermicidal jelly). Perimenopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential Patients with meningeal carcinomatosis Patients with organ allografts requiring immunosuppression Patients with known positive HIV status Patients with a hypersensitivity to Temozolomide or Dacarbazine Any laboratory values at baseline as follows: Hematology: Absolute Neutrophil Count (ANC) <1.5x109/L or 1500/mm3 Platelet count <100x109/L Hemoglobin <8 g/dL (Note: hemoglobin levels may be supported by transfusion or erythropoietin or other approved hematopoietic growth factors). Coagulation: International Normalized Ratio (INR) >1.5 except for patients on stable anticoagulant therapy Activated Partial Thromboplastin Time (aPTT) ≥1.5 times upper limit of normal (ULN) or greater than the lower limit of the therapeutic range Note: The use of full-dose oral or parenteral anticoagulants is permitted as long as the INR or aPTT is within therapeutic limits (according to the medical standard in the institution) and the patient has been on a stable dose of anticoagulants for at least two weeks at the time of Day 1, Cycle 1. Serum chemistry: Total bilirubin >1.5 times ULN Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) >2 times ULN (>5 times ULN for patients with known liver involvement) Alkaline Phosphatase (ALP) >2 times ULN (>5 times ULN for patients with known liver involvement and >7 times ULN for patients with known bone involvement).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Temozolomide<br>Temozolomide 75mg/m2 metronomic schedule: one week on/one week off in a cycle of 28 days | Drug: Temozolomide<br>* pharmacological<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall response rate (ORR) | Overall response rate (ORR) | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Second Line Progression Free Survival (PFS) | Second Line Progression Free Survival (PFS) | 12 months | 
| Overall survival (OS) | Overall survival (OS) | 12 months | 
| Clinical Benefit Rate (CBR) | Clinical benefit rate (CBR) was defined as the proportion of patients with a complete or partial response or with stable disease (Complete Response + Partial Response + Stable Disease [CR+PR+SD]) at Week 24. | 12 month | 
| Safety and tolerability - Incidence of treatment-related adverse events (AE). | The NCI-CTCAE version 4.0 will be used to evaluate the clinical safety of the treatment in this study. Intensity of all adverse events (AEs) will be graded according to the NCI-CTCAE v 4.0 on a five-point scale (Grade 1 to 5). AEs not listed on the NCI-CTCAE should be graded according below. Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe; Grade 4: Life threatening/disabling; Grade 5: Death. | 1 month | 
| Safety and tolerability - Incidence of abnormal laboratory test results | The following assessments will be conducted in order to monitor patient safety: Hematology tests as per institutional standards. Biochemistry tests as per institutional standards. Coagulation tests as per institutional standards. Pregnancy test for women of child-bearing potential. | 1 month | 
| Safety and tolerability - Incidence of abnormal vital signs | Blood pressure (mm/Hg) Temperature (°C) | 1 month | 
| Safety and tolerability - Incidence of abnormal ECG readings | This examination is essential to highlight the presence of: arrhythmias, discontinuous heart rhythm changes, ischemia, i.e. reduced blood supply to the heart, presence of ailments such as heartbeat, chest pain, loss of consciousness or dizziness. | 1 month | 
| Quality of Life (QoL) - QoL will be assessed using the European Organization for Research and Trial in Cancer QOL core (EORTC QLQ-C30) questionnaire (version 3) [Quality of life questionnaire - QLQ] | The EORTC QLQ-C30 is a questionaire of 30-item and it incorporates 9 multi-item scales:5 functional scales (Physical,Role,Cognitive,Emotional and Social Functioning);3 symptom scales (Fatigue,Pain and Nausea/Vomiting) and a Global Health Status/QoL scale.6 single item scales are also included (Dyspnoea,Insomnia,Appetite Loss,Constipation,Diarrhoea and Financial Difficulties).Version 3.0 has 4-point scales for the first 5 items comprising the Physical Functioning scale.These are coded with the same response categories as items 6 to 28,namely 1 Not at all (minimum value),2 A little,3 Quite a bit and 4 Very much (maximum value).The last 2 question foresee a 7-point response scale:minimum value is 1 Very poor,maximum value is 7 Excellent. | 1 month | 
| Quality of Life (QoL) - QoL will be assessed using disease specific modules for Neuroendocrine Tumors (NET), the EORTC QLQ GINET21 (EORTC QLQ Gastrointestinal Neuroendocrine Tumors 21). | The QLQ-GINET21 contains 21 items:4 single-item assessments relating to muscle and/or bone pain (MBP),body image (BI),information (INF) and sexual functioning (SX),together with 17 items organised into 5 proposed scales:endocrine symptoms (ED 3 items),GI symptoms (GI 5 items),treatment-related symptoms (TR 3 items),social functioning (SF) of the new module (SF21, 3 items) and disease-related worries (DRW 3 items).The response format of the questionnaire is a 4-point Likert scale:1 Not at all (minimum value),2 A little,3 Quite a bit and 4 Very much (maximum value). | 1 month | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Temozolomide, second-line chemotherapy