Gemcitabine and Irinotecan in Treating Patients With Cancer of Unknown Primary

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

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.

Study Overview

• Status: Completed
• Conditions: Carcinoma of Unknown Primary
• Intervention / Treatment: Drug: gemcitabine hydrochloride; Drug: irinotecan hydrochloride

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 31
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Iowa
    • Mason City, Iowa, United States, 50401
      • Mercy Cancer Center at Mercy Medical Center - North Iowa
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic Cancer Center
  • Nebraska
    • Lincoln, Nebraska, United States, 68510
      • Cancer Resource Center - Lincoln
    • Omaha, Nebraska, United States, 68106
      • CCOP - Missouri Valley Cancer Consortium

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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.	Drug: gemcitabine hydrochloride; Given IV; Drug: irinotecan hydrochloride; Given IV
Experimental: 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.	Drug: gemcitabine hydrochloride; Given IV; Drug: irinotecan hydrochloride; Given IV

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Alliance for Clinical Trials in Oncology
• Collaborators: National Cancer Institute (NCI)
• Investigators: Study Chair: Matthew P. Goetz, MD, Mayo Clinic

Publications and helpful links

General Publications

• 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.
• Holtan SG, Steen PD, Foster NR, Erlichman C, Medeiros F, Ames MM, Safgren SL, Graham DL, Behrens RJ, Goetz MP. Gemcitabine and irinotecan as first-line therapy for carcinoma of unknown primary: results of a multicenter phase II trial. PLoS One. 2012;7(7):e39285. doi: 10.1371/journal.pone.0039285. Epub 2012 Jul 17.

Study record dates

Study Major Dates

• Study Start: February 1, 2004
• Primary Completion (Actual): April 1, 2008
• Study Completion (Actual): March 1, 2009

Study Registration Dates

• First Submitted: August 6, 2003
• First Submitted That Met QC Criteria: August 6, 2003
• First Posted (Estimate): August 7, 2003

Study Record Updates

• Last Update Posted (Actual): April 4, 2017
• Last Update Submitted That Met QC Criteria: February 17, 2017
• Last Verified: February 1, 2017

More Information

Terms related to this study

• Keywords: newly diagnosed carcinoma of unknown primary; undifferentiated carcinoma of unknown primary; adenocarcinoma of unknown primary; squamous cell carcinoma of unknown primary
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplastic Processes; Neoplasm Metastasis; Carcinoma; Neoplasms, Unknown Primary; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Topoisomerase Inhibitors; Topoisomerase I Inhibitors; Gemcitabine; Irinotecan
• Other Study ID Numbers: NCCTG-N004E; NCI-2011-01592 (Registry Identifier: CTRP (Clinical Trials Reporting System)); CDR0000318830 (Registry Identifier: PDQ (Physician Data Query))