Gemcitabine and Irinotecan in Treating Patients With Cancer of Unknown Primary

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy such as gemcitabine and irinotecan use different ways to stop tumor cells from dividing so they stop growing or die. Combining more than one drug may kill more tumor cells. PURPOSE: This phase II trial is studying how well giving gemcitabine together with irinotecan works in treating patients with cancer of unknown primary origin.

Detailed Description
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OBJECTIVES: Primary Determine the response rate in patients with carcinoma of unknown primary when treated with gemcitabine and irinotecan. Determine the adverse event profile and tolerability of this regimen, based on the presence or absence of the UGT1A1*28 polymorphism, in these patients. (Cohort I closed to accrual 11/17/05) Determine the adverse event profile and tolerability of this regimen. (Cohort II) Secondary Determine the time to progression and overall survival of patients treated with this regimen. Correlate patterns of immunohistochemical staining with response in patients treated with this regimen. Correlate variation in multiple different genes, whose protein products are involved in the uptake, metabolism, and distribution of these drugs, with clinical outcomes, in terms of response and toxicity, in these patients. Determine primary origin of cancer of unknown primary samples by completing a 92-gene RT-PCR cancer classification assay. Determine whether the 92-gene assay results are correlated with clinical response to gemcitabine and irinotecan. OUTLINE: Cohort I (closed to accrual 11/17/05): Patients receive gemcitabine IV over 30 minutes and irinotecan IV over 90 minutes on days 1, 8, 15, and 22. Irinotecan dose may be escalated or de-escalated after course 1 depending on toxicity. Courses repeat every 6 weeks in the absence of disease progression or unacceptable toxicity. Cohort II: Patients receive gemcitabine IV over 30 minutes and irinotecan IV over 90 minutes on days 1, 8, and 15. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. Patients are followed every 3 months for 2 years.

Official Title
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A Phase II Study Of Gemcitabine (GEMZAR) And Irinotecan (CPT-11) In Previously Untreated Patients With Measurable Disease With Unknown Primary Carcinoma

Conditions
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Carcinoma of Unknown Primary

Intervention / Treatment
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* Drug: gemcitabine hydrochloride
* Drug: irinotecan hydrochloride


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed carcinoma of undetermined origin, with any of the following light microscopic diagnoses: Adenocarcinoma Poorly differentiated non-small cell carcinoma Poorly differentiated squamous cell carcinoma Primary site not revealed by the following diagnostic tests: Complete history and physical Complete blood count and chemistries Chest x-ray and/or CT scan Abdominal CT scan Directed evaluation of symptomatic areas Mammogram in women Colonoscopy in patients with liver metastases to exclude a colon primary Hematoxylin and eosin (H&E) staining OR immunostaining if H&E results are unclear, including all of the following: Keratin or epithelial membrane antigen S-100 or HMB45 LCA (CD45) Chromogranin or synaptophysin Thyroid transcription factor 1 Measurable disease Patients with any of the following conditions are not eligible: Neuroendocrine tumors Women with axillary node involvement only Women with adenocarcinoma of the peritoneum Carcinoma involving only 1 site, with resectable tumor at that site Squamous cell carcinoma limited to cervical, supraclavicular, or inguinal lymph nodes Men with poorly differentiated mediastinal or retroperitoneal tumor with stains suggestive of germ cell origin or serum tumor markers (AFP/HCG) Men with prominent blastic bony metastases or markedly elevated prostate-specific antigen, suggesting prostate origin Must be willing to provide blood and tissue samples No brain or meningeal involvement PATIENT CHARACTERISTICS: Age 18 and over Performance status ECOG 0-2 Life expectancy At least 12 weeks Hematopoietic Granulocyte count at least 1,500/mm^3 Platelet count at least 100,000/mm^3 Hepatic Bilirubin must meet 1 of the following criteria: Less than or equal to upper limit of normal (ULN) and no UGT1A1 genotyping is required Greater than ULN but less than 2 times ULN and UGT1A1 for 6/7 genotype or 7/7 genotype patients Alkaline phosphatase no greater than 3 times ULN AST no greater than 3 times ULN (5 times ULN if liver metastases are present) Renal Creatinine no greater than 2.0 times ULN Other Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception No other invasive malignancy within the past 5 years No other severe concurrent disease that would make the patient inappropriate for the study in the judgment of the investigator No uncontrolled infection PRIOR CONCURRENT THERAPY: Biologic therapy No concurrent biologic agents No concurrent filgrastim (G-CSF) Chemotherapy No prior chemotherapy No other concurrent chemotherapy Endocrine therapy Not specified Radiotherapy No prior radiotherapy to more than 25% of the bone marrow No concurrent radiotherapy Surgery More than 4 weeks since prior major surgery

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
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort I (closed to accrual 11/17/05)<br>Patients receive gemcitabine IV over 30 minutes and irinotecan IV over 90 minutes on days 1, 8, 15, and 22. Irinotecan dose may be escalated or de-escalated after course 1 depending on toxicity. Courses repeat every 6 weeks in the absence of disease progression or unacceptable toxicity. | Drug: gemcitabine hydrochloride<br>* Given IV<br>Drug: irinotecan hydrochloride<br>* Given IV<br>|
| Experimental: Cohort II<br>Patients receive gemcitabine IV over 30 minutes and irinotecan IV over 90 minutes on days 1, 8, and 15. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. | Drug: gemcitabine hydrochloride<br>* Given IV<br>Drug: irinotecan hydrochloride<br>* Given IV<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Confirmed Response Rate (Partial or Complete Response for 2 Consecutive Evaluations at Least 4 Weeks Apart) as Measured by RECIST Criteria | The primary endpoint is confirmed response rate. If measurable disease is present, a confirmed tumor response is defined to be either a CR or PR noted as the objective status on 2 consecutive evaluations at least 4 weeks apart. All registered patients meeting the eligibility criteria that have signed a consent form and have begun treatment will be evaluable for response. | Up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Overall survival time is defined as the time from registration to death due> to any cause. The distribution of survival time will be estimated using> the method of Kaplan-Meier . Overall survival will be calculated for> all evaluable patients combined and by group (ie. for patients with or> without the UGT1A1*28 polymorphism). | Up to 2 years | 
| Time to Disease Progression | Time to disease progression is defined as the time from registration to documentation of disease progression. If a patient dies without a documentation of disease progression, the patient will be considered to have had tumor progression at the time of their death unless there is sufficient documented evidence to conclude no progression occurred prior to death. If the patient is declared to be a major treatment violation, the patient will be censored on the date the treatment violation was declared to have occurred. In the case of a patient starting treatment and then never returning for any evaluations, the patient will be censored for progression on day 1 post-registration. The distribution of time to progression will be estimated using the method of Kaplan-Meier. Time to disease progression will be calculated for all evaluable patients combined and by group (ie. for patients with or without the UGT1A1*28 polymorphism). | Up to 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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adenocarcinoma of unknown primary, newly diagnosed carcinoma of unknown primary, squamous cell carcinoma of unknown primary, undifferentiated carcinoma of unknown primary