Gemcitabine and Irinotecan in Treating Patients With Cancer of Unknown Primary

• Sponsor: Alliance for Clinical Trials in Oncology (Other)
• Overall Status: Completed
• CT.gov ID: NCT00066781
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 31
• Locations: 4
• Arms: 2
• Duration (Months): 60.9
• Patients Per Site: 7.8
• Patients Per Site Per Month: 0.1

Study Details

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
• 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: Feb 1, 2004
• Actual Primary Completion Date: Apr 1, 2008
• Actual Study Completion Date: Mar 1, 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 [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 [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 [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

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

	Site	City	State	Country	Postal Code
1	Mercy Cancer Center at Mercy Medical Center - North Iowa	Mason City	Iowa	United States	50401
2	Mayo Clinic Cancer Center	Rochester	Minnesota	United States	55905
3	Cancer Resource Center - Lincoln	Lincoln	Nebraska	United States	68510
4	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

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Alliance for Clinical Trials in Oncology
• ClinicalTrials.gov Identifier: NCT00066781
• Other Study ID Numbers: NCCTG-N004E; NCI-2011-01592; CDR0000318830
• First Posted: Aug 7, 2003
• Last Update Posted: Apr 4, 2017
• Last Verified: Feb 1, 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; Gemcitabine; Irinotecan

Study Results

Participant Flow

Arm/Group Title	Cohort I	Cohort II
Arm/Group Description	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.	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.
Period Title: Overall Study
STARTED	14	17
COMPLETED	14	17
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Cohort I	Cohort II	Total
Arm/Group Description	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.	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.	Total of all reporting groups
Overall Participants	14	17	31
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	62 (9)	61 (15)	62 (12)
Sex: Female, Male (Count of Participants)
Female	6 42.9%	8 47.1%	14 45.2%
Male	8 57.1%	9 52.9%	17 54.8%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	1 5.9%	1 3.2%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	1 5.9%	1 3.2%
White	13 92.9%	15 88.2%	28 90.3%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	1 7.1%	0 0%	1 3.2%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

All evaluable patients

Arm/Group Title	Cohort I	Cohort II
Arm/Group Description	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.	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.
Measure Participants	11	15
Number (95% Confidence Interval) [percentage of patients with response]	9	13

2. Secondary Outcome

Title	Overall Survival
Description	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).
Time Frame	Up to 2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Cohort I	Cohort II
Arm/Group Description	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.	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.
Measure Participants	11	15
Median (95% Confidence Interval) [Months]	4	9.3

3. Secondary Outcome

Title	Time to Disease Progression
Description	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).
Time Frame	Up to 2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Cohort I	Cohort II
Arm/Group Description	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.	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.
Measure Participants	11	15
Median (95% Confidence Interval) [Months]	3.7	3.4

Adverse Events

Arm/Group Title	Cohort I		Cohort II
Arm/Group Description	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.		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.
All Cause Mortality
	Cohort I		Cohort II
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Cohort I		Cohort II
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/14 (0%)		0/17 (0%)
Other (Not Including Serious) Adverse Events
	Cohort I		Cohort II
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	14/14 (100%)		16/17 (94.1%)
Blood and lymphatic system disorders
Febrile neutropenia	1/14 (7.1%)	1	2/17 (11.8%)	2
Hemoglobin decreased	4/14 (28.6%)	5	3/17 (17.6%)	3
Hemolysis	1/14 (7.1%)	1	0/17 (0%)	0
Cardiac disorders
Myocardial ischemia	1/14 (7.1%)	1	0/17 (0%)	0
Gastrointestinal disorders
Abdominal pain	1/14 (7.1%)	1	5/17 (29.4%)	5
Colitis	2/14 (14.3%)	2	0/17 (0%)	0
Constipation	1/14 (7.1%)	2	0/17 (0%)	0
Diarrhea	9/14 (64.3%)	13	12/17 (70.6%)	14
Dyspepsia	0/14 (0%)	0	1/17 (5.9%)	1
Gastrointestinal pain	1/14 (7.1%)	1	0/17 (0%)	0
Ileus	0/14 (0%)	0	1/17 (5.9%)	1
Mucositis oral	1/14 (7.1%)	1	0/17 (0%)	0
Nausea	7/14 (50%)	9	7/17 (41.2%)	8
Small intestinal obstruction	1/14 (7.1%)	1	0/17 (0%)	0
Vomiting	6/14 (42.9%)	7	8/17 (47.1%)	9
General disorders
Edema limbs	0/14 (0%)	0	3/17 (17.6%)	6
Fatigue	6/14 (42.9%)	10	7/17 (41.2%)	14
Multi-organ failure	1/14 (7.1%)	1	0/17 (0%)	0
Sudden death	1/14 (7.1%)	1	0/17 (0%)	0
Hepatobiliary disorders
Bile duct stenosis	0/14 (0%)	0	1/17 (5.9%)	1
Immune system disorders
Hypersensitivity	1/14 (7.1%)	1	0/17 (0%)	0
Infections and infestations
Bronchitis	1/14 (7.1%)	1	0/17 (0%)	0
Pneumonia	0/14 (0%)	0	2/17 (11.8%)	2
Skin infection	0/14 (0%)	0	1/17 (5.9%)	1
Investigations
Alanine aminotransferase increased	0/14 (0%)	0	2/17 (11.8%)	2
Alkaline phosphatase increased	0/14 (0%)	0	1/17 (5.9%)	1
Aspartate aminotransferase increased	0/14 (0%)	0	2/17 (11.8%)	2
Blood bilirubin increased	1/14 (7.1%)	1	2/17 (11.8%)	2
Creatinine increased	0/14 (0%)	0	1/17 (5.9%)	1
Leukocyte count decreased	4/14 (28.6%)	8	3/17 (17.6%)	3
Lymphocyte count decreased	0/14 (0%)	0	2/17 (11.8%)	5
Neutrophil count decreased	4/14 (28.6%)	7	2/17 (11.8%)	2
Platelet count decreased	3/14 (21.4%)	4	3/17 (17.6%)	4
Weight gain	2/14 (14.3%)	3	2/17 (11.8%)	3
Weight loss	3/14 (21.4%)	4	5/17 (29.4%)	6
Metabolism and nutrition disorders
Anorexia	10/14 (71.4%)	14	12/17 (70.6%)	19
Blood glucose increased	1/14 (7.1%)	1	2/17 (11.8%)	3
Dehydration	2/14 (14.3%)	2	2/17 (11.8%)	2
Serum calcium decreased	0/14 (0%)	0	1/17 (5.9%)	1
Serum potassium decreased	0/14 (0%)	0	1/17 (5.9%)	1
Serum sodium decreased	1/14 (7.1%)	1	2/17 (11.8%)	2
Musculoskeletal and connective tissue disorders
Back pain	1/14 (7.1%)	1	0/17 (0%)	0
Nervous system disorders
Dysgeusia	0/14 (0%)	0	1/17 (5.9%)	2
Headache	1/14 (7.1%)	1	0/17 (0%)	0
Peripheral sensory neuropathy	1/14 (7.1%)	1	0/17 (0%)	0
Syncope vasovagal	0/14 (0%)	0	1/17 (5.9%)	1
Renal and urinary disorders
Renal failure	0/14 (0%)	0	1/17 (5.9%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnea	3/14 (21.4%)	3	2/17 (11.8%)	2
Hypoxia	1/14 (7.1%)	1	0/17 (0%)	0
Pleuritic pain	1/14 (7.1%)	1	0/17 (0%)	0
Skin and subcutaneous tissue disorders
Alopecia	1/14 (7.1%)	1	0/17 (0%)	0
Dry skin	1/14 (7.1%)	1	0/17 (0%)	0
Rash desquamating	6/14 (42.9%)	10	2/17 (11.8%)	4
Vascular disorders
Peripheral ischemia	1/14 (7.1%)	1	0/17 (0%)	0
Thrombosis	0/14 (0%)	0	1/17 (5.9%)	3

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.