Gemcitabine and Irinotecan in Treating Patients With Cancer of Unknown Primary

• ClinicalTrials.gov Identifier: NCT00066781
• Recruitment Status: Completed
• First Posted: August 7, 2003
• Results First Posted: April 4, 2017
• Last Update Posted: April 4, 2017
• Sponsor: Alliance for Clinical Trials in Oncology
• Collaborator: National Cancer Institute (NCI)
• Information provided by (Responsible Party): Alliance for Clinical Trials in Oncology

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Carcinoma of Unknown Primary	Drug: gemcitabine hydrochloride; Drug: irinotecan hydrochloride	Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 31 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Study Of Gemcitabine (GEMZAR) And Irinotecan (CPT-11) In Previously Untreated Patients With Measurable Disease With Unknown Primary Carcinoma
• Study Start Date: February 2004
• Actual Primary Completion Date: April 2008
• Actual Study Completion Date: March 2009

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. Confirmed Response Rate (Partial or Complete Response for 2 Consecutive Evaluations at Least 4 Weeks Apart) as Measured by RECIST Criteria [ Time Frame: Up to 2 years ]
   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.

Secondary Outcome Measures :

1. Overall Survival [ Time Frame: Up to 2 years ]
   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).
2. Time to Disease Progression [ Time Frame: Up to 2 years ]
   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).

Eligibility Criteria

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

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

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

Contacts and Locations

Locations

United States, Iowa

Mercy Cancer Center at Mercy Medical Center - North Iowa

Mason City, Iowa, United States, 50401

United States, Minnesota

Mayo Clinic Cancer Center

Rochester, Minnesota, United States, 55905

United States, Nebraska

Cancer Resource Center - Lincoln

Lincoln, Nebraska, United States, 68510

CCOP - Missouri Valley Cancer Consortium

Omaha, Nebraska, United States, 68106

Sponsors and Collaborators

Alliance for Clinical Trials in Oncology

National Cancer Institute (NCI)

Investigators

• Study Chair: Matthew P. Goetz, MD; Mayo Clinic

More Information

Publications of Results:

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.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Alliance for Clinical Trials in Oncology
• ClinicalTrials.gov Identifier: NCT00066781
• Other Study ID Numbers: NCCTG-N004E; NCI-2011-01592 ( Registry Identifier: CTRP (Clinical Trials Reporting System) ); CDR0000318830 ( Registry Identifier: PDQ (Physician Data Query) )
• First Posted: August 7, 2003
• Results First Posted: April 4, 2017
• Last Update Posted: April 4, 2017
• Last Verified: February 2017

Keywords provided by Alliance for Clinical Trials in Oncology:

adenocarcinoma of unknown primary; newly diagnosed carcinoma of unknown primary; squamous cell carcinoma of unknown primary; undifferentiated carcinoma of unknown primary

Additional relevant MeSH terms:

Carcinoma; Neoplasms, Unknown Primary; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Neoplasm Metastasis; Neoplastic Processes; Pathologic Processes; Gemcitabine; Irinotecan; Antimetabolites, Antineoplastic; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antiviral Agents; Anti-Infective Agents; Enzyme Inhibitors; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Topoisomerase I Inhibitors; Topoisomerase Inhibitors