Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outcomes
Outline
Published Results
Trial Contact Information
Registry Information

Alternate Title

Gemcitabine and Irinotecan in Treating Patients With Cancer of Unknown Primary

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase II	Treatment	Completed	18 and over	NCI	NCCTG-N004E N004E, NCT00066781

Objectives

Primary

1. Determine the response rate in patients with carcinoma of unknown primary when treated with gemcitabine and irinotecan.
2. 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)
3. Determine the adverse event profile and tolerability of this regimen. (Cohort II)

Secondary

1. Determine the time to progression and overall survival of patients treated with this regimen.
2. Correlate patterns of immunohistochemical staining with response in patients treated with this regimen.
3. 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.
4. Determine primary origin of cancer of unknown primary samples by completing a 92-gene RT-PCR cancer classification assay.
5. Determine whether the 92-gene assay results are correlated with clinical response to gemcitabine and irinotecan.

Entry Criteria

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

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

Patient Characteristics:

Age

• 18 and over

Performance status

• ECOG 0-2

Life expectancy

• At least 12 weeks

Hematopoietic

• Granulocyte count at least 1,500/mm³
• Platelet count at least 100,000/mm³

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

Expected Enrollment

A total of 42 patients will be accrued for this study.

Outcomes

Confirmed response rate (partial or complete response for 2 consecutive evaluations at least 4 weeks apart) as measured by RECIST criteria

Overall survival periodically for up to 2 years from registration
Time to disease progression periodically for up to 2 years from registration
Adverse event rates assessed by NCI common toxicity criteria for adverse events (CTCAE v3.0) at all courses
Relationship between genetic variations and the clinical outcomes of response, adverse events, survival, and time to progression at baseline

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.

Holtan SG, Foster NR, Erlichman CE, et al.: Gemcitabine (G) and irinotecan (CPT-11) as first-line therapy for carcinoma (ca) of unknown primary (CUP): An NCCTG phase II trial. [Abstract] J Clin Oncol 26 (Suppl 15): A-13525, 2008.

Trial Contact Information

Trial Lead Organizations

North Central Cancer Treatment Group

Matthew Goetz, MD, Protocol chair		Ph: 507-538-7623 Email: cancerclinicaltrials@mayo.edu
Preston Steen, MD, Protocol co-chair		Ph: 701-234-2397 Email: preston.steen@meritcare.com
Charles Erlichman, MD, Protocol co-chair		Ph: 507-538-7623 Email: cancerclinicaltrials@mayo.edu

Registry Information
Official Title		A Phase II Study Of Gemcitabine (GEMZAR) And Irinotecan (CPT-11) In Previously Untreated Patients With Measurable Disease With Unknown Primary Carcinoma
Trial Start Date		2004-02-20
Trial Completion Date		2009-03-06
Registered in ClinicalTrials.gov		NCT00066781
Date Submitted to PDQ		2003-07-02
Information Last Verified		2009-03-06
NCI Grant/Contract Number		CA25224

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