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NCT02595424 · REGISTRY CONDITION SEARCH

Cisplatin and Etoposide Versus Temozolomide and Capecitabine in Patients With Advanced Poorly Differentiated (G3) Non-Small Cell Gastrointestinal Neuroendocrine Carcinomas

Found through the registry condition index, not selected as a treatment recommendation. This discovery collection was restricted to studies with posted results.

Phase
PHASE2
Status at capture
ACTIVE NOT RECRUITING
Registry last update
2026-07-27

This randomized phase II trial studies how well temozolomide and capecitabine work compared to standard treatment with cisplatin or carboplatin and etoposide in treating patients with neuroendocrine carcinoma of the gastrointestinal tract or pancreas that has spread to other parts of the body (metastatic) or cannot be removed by surgery. Drugs used in chemotherapy, such as temozolomide, capecitabine, cisplatin, carboplatin and etoposide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Certain types of neuroendocrine carcinomas may respond better to treatments other than the current standard treatment of cisplatin and etoposide. It is not yet known whether temozolomide and capecitabine may work better than cisplatin or carboplatin and etoposide in treating patients with this type of neuroendocrine carcinoma, called non-small cell neuroendocrine carcinoma.

Open the original ClinicalTrials.gov record → · Download preserved record

What did the study report?

Outcomes, safety and baseline populations are separate source sections. Quality-of-life measures appear under their original outcome titles.

flow

Participant flow

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baseline

Baseline characteristics

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outcome · POSTED

Progression-free Survival (PFS)

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outcome · POSTED

Overall Survival (OS)

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outcome · POSTED

Objective Response Rate (ORR)

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outcome · POSTED

To Assess the Objective Response Rate Based on Marker of Proliferation Ki-67 Index

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outcome · NOT POSTED

To Assess the Treatment Effect Based on Marker of Proliferation Ki-67 Index

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outcome · NOT POSTED

Association Between Tumor Differentiation and Treatment Effect

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adverse events

Adverse events

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more info

Limitations, agreements, and source contact

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Who could take part
eligibility Criteria
Inclusion Criteria: * Patients must have a locally advanced and unresectable or metastatic gastroenteropancreatic neuroendocrine carcinoma that is either known or suspected to be of gastrointestinal (GI) origin; primary tumors arising from the lung, gynecologic organs or prostate are not permitted * Patients must have pathologically/histologically confirmed tumor of non-small cell histology * Patients must have a Ki-67 proliferative index of 20-100% OR at least 10 mitotic figures per 10 high powered fields * Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria; baseline measurements and evaluations of all sites of disease must be obtained within 4 weeks prior to randomization and must be acquired by multiphasic computed tomography (CT) or contrast magnetic resonance imaging (MRI) * NOTE: positron emission tomography (PET)-CT scans are allowed provided the CT portion of the exam is equivalent to a diagnostic CT scan and includes both oral and IV contrast * Any prior surgeries must have been completed at least 4 weeks prior to randomization * Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 * Patients may not be receiving any other investigational agents while on study treatment * Patients may not be receiving Coumadin while on treatment; other anticoagulants are allowed * Leukocytes \>= 3,000/mm\^3 * Absolute neutrophil count \>= 1,500/mm\^3 * Hemoglobin \>= 9 g/dL * Platelets \>= 100,000/mm\^3 * Total bilirubin =\< institutional upper limit of normal (ULN) or =\< 1.5 X institutional ULN (if the patient has liver metastases) * Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase \[SGPT\]) =\< 2.5 X institutional ULN or (=\< 5 X institutional ULN if the patient has liver metastases) * Serum creatinine =\< 1.5 X institutional ULN and creatinine clearance \>= 60 ml/min * NOTE: creatinine clearance must be calculated using the Cockcroft-Gault equation * Patients must have a life expectancy of \>= 12 weeks as determined clinically by the treating physician * Patients with impaired decision-making capacity may participate in the study if a legal authorized representative is available to consent * Women of childbearing potential and sexually active males must be strongly advised to use an accepted and effective method of contraception or to abstain from sexual intercourse for the duration of their participation in the study * Patients must be able to swallow pills * Patients must be able to tolerate CT or magnetic resonance (MR) imaging including contrast agents as required for the treatment and the protocol Exclusion Criteria: * Patients may not have had any prior systemic treatment for this malignancy (for example chemotherapy or somatostatin analogues); prior palliative radiation is permitted but radiated lesions may not be used for measurement * Patients may not have received any of the protocol agents within 5 years prior to randomization * Patients with brain metastases (either remote or current) or presence of carcinomatous meningitis are not eligible * Patients with known dihydropyrimidine dehydrogenase (DPD) deficiency will be excluded * Patients must NOT have active or uncontrolled infection, symptomatic heart failure, unstable angina pectoris, cardiac arrhythmia or a serious psychiatric illness/social situation that would limit compliance with study requirements * Patients must NOT have a history of allergic reactions attributed to compounds of similar chemical or biochemical composition to cisplatin, carboplatin, etoposide, temozolomide or capecitabine * Patients must NOT have absorption issues that would limit the ability to absorb study agents * Patients with a history of the following within =\< 12 months of study entry are not eligible: * Arterial thromboembolic events * Unstable angina * Myocardial Infarction * Patients with symptomatic peripheral vascular disease are not eligible * Patients must NOT have previous or concurrent malignancy; exceptions are made for patients who meet any of the following conditions: * Non-melanoma skin cancer, in situ cervical cancer, superficial bladder cancer, or breast cancer in situ OR * Prior malignancy completely excised or removed and patient has been continuously disease free for \> 5 years OR * Prior malignancy cured by non-surgical modalities and patient has been continuously disease free for \> 5 years * Women must not be pregnant or breast-feeding * All females of childbearing potential must have a blood test or urine study within 2 weeks prior to randomization to rule out pregnancy * A female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months) * Patients who are known to have human immunodeficiency virus (HIV) or are on combination antiretroviral therapy are ineligible
healthy Volunteers
false
minimum Age
18 Years
sex
ALL
std Ages
  1. ADULT
  2. OLDER_ADULT
Treatment arms and interventions
arm Groups
  1. description
    Patients receive capecitabine PO BID on days 1-14 and temozolomide PO QD on days 10-14. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
    intervention Names
    1. Drug: Capecitabine
    2. Other: Laboratory Biomarker Analysis
    3. Drug: Temozolomide
    label
    Arm A (capecitabine, temozolomide)
    type
    EXPERIMENTAL
  2. description
    Patients receive cisplatin IV on days 1-3 or carboplatin IV on day 1. Patients also receive etoposide IV on days 1-3. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
    intervention Names
    1. Drug: Carboplatin
    2. Drug: Cisplatin
    3. Drug: Etoposide
    4. Other: Laboratory Biomarker Analysis
    label
    Arm B (cisplatin, carboplatin, etoposide)
    type
    ACTIVE_COMPARATOR
interventions
  1. arm Group Labels
    1. Arm A (capecitabine, temozolomide)
    description
    Given PO
    name
    Capecitabine
    other Names
    1. Xeloda
    2. ACH-Capecitabine
    3. Mint-Capecitabine
    4. SANDOZ Capecitabine
    5. TARO-Capecitabine
    6. EVA-Capecitabine
    type
    DRUG
  2. arm Group Labels
    1. Arm B (cisplatin, carboplatin, etoposide)
    description
    Given IV
    name
    Carboplatin
    other Names
    1. Paraplatin
    type
    DRUG
  3. arm Group Labels
    1. Arm B (cisplatin, carboplatin, etoposide)
    description
    Given IV
    name
    Cisplatin
    other Names
    1. Platinol-AQ
    type
    DRUG
  4. arm Group Labels
    1. Arm B (cisplatin, carboplatin, etoposide)
    description
    Given IV
    name
    Etoposide
    other Names
    1. VP-16 or VP-16-213
    type
    DRUG
  5. arm Group Labels
    1. Arm A (capecitabine, temozolomide)
    2. Arm B (cisplatin, carboplatin, etoposide)
    description
    Correlative studies
    name
    Laboratory Biomarker Analysis
    other Names
    1. VePesid®
    type
    OTHER
  6. arm Group Labels
    1. Arm A (capecitabine, temozolomide)
    description
    Given PO
    name
    Temozolomide
    other Names
    1. Toposar®
    type
    DRUG
Study design
allocation
RANDOMIZED
intervention Model
PARALLEL
masking Info
masking
NONE
primary Purpose
TREATMENT
Enrollment
count
67
type
ACTUAL
Registered outcome plans (not posted results)
other Outcomes
  1. description
    The impact of each treatment regimen on objective response rate (ORR, defined as above in the secondary objective) are assessed by Ki-67 index level as an exploratory analysis. Using Youden's index, which considers specificity and sensitivity equally important, the optimal cutoff point of Ki-67 index to best predict response is 50.5. Using the optimal Ki-67 cutoff value of 50.5 from the ROC analysis, patients were divided into Ki-67 low (Ki-67 \< 50.5) and high (Ki-67 ≥ 50.5) groups. The impact of each treatment regimen on ORR was explored in Ki-67 low and Ki-67 high separately.
    measure
    To Assess the Objective Response Rate Based on Marker of Proliferation Ki-67 Index
    time Frame
    assessed at baseline, every 8 weeks until treatment completion, then every 3 months within 2 years and every 6 months within 3-5 years, up to 5 years from registration; the best response among all assessments was considered as objective response
  2. description
    The impact of each treatment regimen on PFS and OS (defined as above in the primary and secondary objectives) are assessed by Ki-67 index level as an exploratory analysis. Using Youden's index, which considers specificity and sensitivity equally important, the optimal cutoff point of Ki-67 index to best predict response is 50.5. Using the optimal Ki-67 cutoff value of 50.5 from the ROC analysis, patients were divided into Ki-67 low (Ki-67 \< 50.5) and high (Ki-67 ≥ 50.5) groups. The impact of each treatment regimen on PFS and OS were explored in Ki-67 low and Ki-67 high separately.
    measure
    To Assess the Treatment Effect Based on Marker of Proliferation Ki-67 Index
    time Frame
    assessed at baseline, every 8 weeks until treatment completion, then every 3 months within 2 years and every 6 months within 3-5 years from randomization until disease progression, up to 5 years from study registration
  3. description
    The association between tumor differentiation (well differentiated versus poorly differentiated) with PFS, ORR and OS (defined as in the primary and secondary objectives) were evaluated.
    measure
    Association Between Tumor Differentiation and Treatment Effect
    time Frame
    assessed at baseline, every 8 weeks until treatment completion, then every 3 months within 2 years and every 6 months within 3-5 years from randomization until disease progression, up to 5 years from study registration
primary Outcomes
  1. description
    PFS is defined as the time from randomization to documented progression or death without progression. PFS is censored at the date of last disease evaluation. The study was closed for futility in 2021 after the 2021 Spring DSMC meeting, which found that the boundary for futility had been met (ie, temozolomide and capecitabine did not appear to be superior to platinum and etoposide chemotherapy). As the interim analysis finding led to the conclusion of the study, no PFS stratified logrank test was conducted with the data extracted on April 23rd, 2025 for the final analysis, that was presented here.
    measure
    Progression-free Survival (PFS)
    time Frame
    assessed at baseline, every 8 weeks until treatment completion, then every 3 months within 2 years and every 6 months within 3-5 years from randomization until disease progression, up to 5 years from study registration
secondary Outcomes
  1. description
    OS is defined as the time from randomization to death from any cause. OS is censored at the date of last contact. Median OS is estimated using the Kaplan-Meier method.
    measure
    Overall Survival (OS)
    time Frame
    assessed at baseline, then every 3 months within 2 years from randomization, and every 6 months if patient is 3-5 years from randomization, up to 5 years from randomization
  2. description
    ORR is defined as the proportion of patients with complete response (CR) or partial response (PR). Response is evaluated using the RECIST 1.1 criteria. CR is defined as disappearance of all lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \< 10 mm. PR is defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.
    measure
    Objective Response Rate (ORR)
    time Frame
    assessed at baseline, every 8 weeks until treatment completion, then every 3 months within 2 years and every 6 months within 3-5 years, up to 5 years from registration; the best response among all assessments was considered as objective response
Full study description
brief Summary
This randomized phase II trial studies how well temozolomide and capecitabine work compared to standard treatment with cisplatin or carboplatin and etoposide in treating patients with neuroendocrine carcinoma of the gastrointestinal tract or pancreas that has spread to other parts of the body (metastatic) or cannot be removed by surgery. Drugs used in chemotherapy, such as temozolomide, capecitabine, cisplatin, carboplatin and etoposide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Certain types of neuroendocrine carcinomas may respond better to treatments other than the current standard treatment of cisplatin and etoposide. It is not yet known whether temozolomide and capecitabine may work better than cisplatin or carboplatin and etoposide in treating patients with this type of neuroendocrine carcinoma, called non-small cell neuroendocrine carcinoma.
detailed Description
PRIMARY OBJECTIVES: I. To assess the progression free survival (PFS) of platinum (cisplatin or carboplatin) and etoposide versus the PFS of temozolomide and capecitabine in patients with advanced G3 non-small cell gastroenteropancreatic neuroendocrine carcinomas. SECONDARY OBJECTIVES: I. To assess the response rate (RR) of platinum (cisplatin or carboplatin) and etoposide versus the RR of temozolomide and capecitabine in patients with advanced G3 non-small cell gastroenteropancreatic neuroendocrine carcinomas. II. To assess the overall survival (OS) of platinum (cisplatin or carboplatin) and etoposide versus the OS of temozolomide and capecitabine in patients with advanced G3 non-small cell gastroenteropancreatic neuroendocrine carcinomas. III. To evaluate the toxicities associated with the combination of temozolomide and capecitabine and the combination of platinum (cisplatin or carboplatin) and etoposide, respectively, in patients with advanced G3 non-small cell gastroenteropancreatic neuroendocrine carcinomas. TERTIARY OBJECTIVES: I. To assess the impact of each treatment regimen on PFS, RR and OS based on marker of proliferation Ki-67 index in patients with advanced G3 non-small cell gastroenteropancreatic neuroendocrine carcinomas. (Laboratory) II. To assess the prognostic significance of well differentiated versus poorly differentiated non-small cell gastroenteropancreatic neuroendocrine tumors in relationship to survival and response to treatment. (Laboratory) III. To assess the agreement in Ki-67 status between that reported by institutional pathologist and that reported by central pathology review. (Laboratory) OUTLINE: Patients are randomized to 1 of 2 treatment arms. ARM A: Patients receive capecitabine orally (PO) twice daily (BID) on days 1-14 and temozolomide PO once daily (QD) on days 10-14. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. ARM B: Patients receive cisplatin intravenously (IV) on days 1-3 or carboplatin IV on day 1. Patients also receive etoposide IV on days 1-3. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 3 months for 2 years and then every 6 months for 3 years.
Source references
Source notices and limitations
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    Preserved source evidence · Not medical advice