Safety of TAS-102 in Combination With Temozolomide for Metastatic Pancreatic NETs

Study Overview
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Brief Summary
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The goal of this study is to establish maximum tolerated doses/recommended phase 2 dose (RP2D) of temozolomide (TMZ) and TAS-102 when these agents are used in combination and to evaluate the safety profile of this drug combination.

Detailed Description
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The study is a two part phase 1B clinical trial consisting of three study periods: a screening period of 14 days or less, a treatment period, and a safety follow-up period 30 days after treatment discontinuation. Part 1 is a dose finding phase with the objective to assess the safety and tolerability of the proposed drug combination and to identify the maximum tolerated dose (MTD) and a recommended phase 2 dose. Part 2 is an open-label expansion study, which will enroll patients with metastatic pNETs who have not been previously treated with chemotherapy. Part 2 will obtain further safety data of the proposed drug combination.

Official Title
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Safety of TAS-102 in Combination With Temozolomide for Metastatic Pancreatic Neuroendocrine Tumors

Conditions
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Cancer, Neuroendocrine Tumors, Neoplasms, Tumors

Intervention / Treatment
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* Drug: TAS-102
* Drug: Temozolomide
* Drug: Filgrastim
* Drug: Pegfilgrastim


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Part 1: Patients with histologically or cytologically confirmed metastatic or locally advanced NETs of any origin and grade Part 1: Presence of evaluable OR measurable disease Part 2: Patients with histologically confirmed unresectable or metastatic pNETs of grade 1 or 2. Part 2: Presence of measurable disease by RECIST 1.1 criteria Concurrent somatostatin analogues are allowed provided that the dose has been stable (+/- 10mg) for at least 8 weeks Prior chemoembolization or radiation therapy (including Y90) must be performed at least 2 weeks before study enrollment ECOG performance status 0-2 Life expectancy more than 3 months Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L Hemoglobin ≥ 9 g/dL Platelets ≥ 100 x 10^9/L AST/ALT ≤ 3 x ULN (≤5 x ULN in case of liver metastases) Total serum bilirubin of ≤ x institutional ULN (except for Grade 1 hyperbilirubinemia solely due to a medical diagnosis of Gilbert's syndrome) Serum creatinine ≤ 1.5 x institutional ULN (Cockcroft and Gault formula) Ability to take oral medication (i.e. no feeding tube) Female patients of childbearing potential must have a negative pregnancy test (urine or serum) within 14 days prior to the start of the study drug treatment and must agree to use adequate birth control if conception is possible during the study and up to 6 months after discontinuation of study drug treatment Male patients must agree to use adequate birth control during the study and up to 6 months after discontinuation of study drug treatment Women who are nursing must discontinue breast feeding prior to the enrollment in the trial Patient must be able and willing to comply with study procedures as per protocol Patient able to understand and willing to sign and date the written voluntary informed consent form (ICF) at screening visit prior to any protocol-specific procedures Exclusion Criteria: Part 2: Grade 3 tumors or tumors with small cell histology will be excluded Previous treatment with TAS-102 or TMZ History of partial or total gastrectomy Symptomatic CNS metastases requiring treatment Prior radiation therapy irradiating more than 10% of total bone marrow Other active malignancy requiring treatment within the last 2 years (except for non-melanoma skin cancer, a non-invasive/in situ cancer, or indolent nonmetastatic Gleason 6 prostate cancer) Pregnancy or breast feeding Active infection requiring treatment Known chronic infection with human immunodeficiency virus, hepatitis B, or hepatitis C Major surgery within prior 4 weeks (the surgical incision should be fully healed prior to drug administration) Any anticancer therapy treatments, including other investigational agents within prior 2 weeks History of allergic reactions attributed to compounds of similar chemical or biologic composition to TAS-102 or TMZ Extended field radiation within prior 4 weeks or limited field radiation within prior 2 weeks Psychological, familial, or sociological condition potentially hampering compliance with the study protocol and follow-up schedule Ascites, pleural effusion or pericardial fluid requiring drainage in the last 4 weeks Uncontrolled diabetes mellitus Intestinal obstruction Pulmonary fibrosis Myocardial infarction within the last 12 months, severe/unstable angina, symptomatic congestive heart failure NYHA class III or IV Gastrointestinal hemorrhage

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: TAS-102 and TMZ<br>Part 1: dose-escalation phase to determine MTD of TAS-102 in combination with Temozolomide (TMZ). Treatment cycles are 28 days, with TAS-102 administered orally twice daily days 1-5 and 8-12, and TMZ administered orally days 8-12. No treatment medications administered days 13-28 of each cycle. Growth factor support is required during Part 1 and should be dosed per institutional standards. Part 2: expansion phase to evaluate preliminary efficacy of MTD. Subjects treated with the recommended phase 2 drug doses determined in part 1. Treatment will continue for up to 13 cycles (approx. 12 months). Growth factor support is allowed during Part 2 and should be dosed per institutional standards. | Drug: TAS-102<br>* Anti-metabolite agent, taken orally.<br>Drug: Temozolomide<br>* Oral chemotherapy drug.<br>* Other names: TMZ;Drug: Filgrastim<br>* Filgrastim provides growth factor support in multiple doses. It stimulates bone marrow to create neutrophils for patients undergoing chemotherapy.<br>Drug: Pegfilgrastim<br>* Pegfilgrastim provides growth factor support in a single dose. It stimulates bone marrow to create neutrophils for patients undergoing chemotherapy.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Maximum Tolerated Dose (MTD) of TAS-102 | Investigate the safety and determine the MTD of TAS-102 administered in combination with TMZ in patients with advanced NETs. Treatments will continue to disease progression according to Response Evaluation Criteria in Solid Tumors (RECIST). | Up to 2 years | 
| Part 2: Overall Response Rate | Response rate defined as the percentage of subjects with a confirmed complete response (CR) or partial response (PR), assessed as per RECIST criteria. Assessments performed using RECIST criteria. | Up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 2: Progression Free Survival (PFS) | Defined as the time from the start of treatment to the date of first documented progression or any cause of death during the study, assessed according to RECIST. Analyzed using the Kaplan-Meier method. | Up to 5 years | 
| Part 2: Overall Survival | Defined as the time from the start of treatment to the date of expiration. Analyzed using the Kaplan-Meier method. | Up to 5 years | 
| Part 2: Disease Control Rate | Defined as the percentage of patients who achieved complete response, partial response, and stable disease by investigator assessment as per RECIST. | Up to 5 years | 
| Part 2: Duration of Response | Analyzed using the Kaplan-Meier method. | Up to 5 years | 
| Part 2: Safety and Tolerability, Assessed per RECIST Criteria | Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 | Up to 5 years | 
| Part 2: Biochemical Response defined as normalization or >50% reduction in levels of Chromogranin A | A major biochemical response will be defined as normalization or >50% reduction in levels of Chromogranin A. Chromogranin A is elevated in up to 60% of functioning and nonfunctioning pancreatic endocrine tumors. | Up to 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pancreatic neuroendocrine tumors (pNETs), Pancreatic neuroendocrine tumors, pNETs, NETs