Gemcitabine Hydrochloride and Tanespimycin in Treating Patients With Stage IV Pancreatic Cancer

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT00577889
• Collaborator: (none)
• Enrollment: 21
• Location: 1
• Arms: 3
• Duration (Months): 62
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

This randomized phase II trial is studying three different schedules of gemcitabine hydrochloride and tanespimycin to see how well they work in treating patients with stage IV pancreatic cancer. Drugs used in chemotherapy, such as gemcitabine hydrochloride and tanespimycin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more tumor cells

Condition or Disease	Intervention/Treatment	Phase
Adenocarcinoma of the Pancreas; Recurrent Pancreatic Cancer; Stage IV Pancreatic Cancer	Drug: gemcitabine hydrochloride; Drug: tanespimycin	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. To assess the effect of gemcitabine hydrochloride and tanespimycin (17-AAG) on 6-month survival rate in patients with stage IV pancreatic adenocarcinoma.

SECONDARY OBJECTIVES:

1. To determine the overall survival of these patients. II. To determine the time to disease progression (TTP) in these patients. III. To determine the confirmed response rate and duration of response in these patients.

2. To determine the time to treatment failure in these patients. V. To determine the adverse events in these patients.

TERTIARY OBJECTIVES:

1. To determine the effects of treatment on molecular targets, such as CDK4, akt, phospho-akt, Hsp90, Hsp70, and CHK1, and correlate these with clinical endpoints, including survival at 6 months, TTP, response rate, and overall survival.

2. To determine the effect of gemcitabine hydrochloride metabolizing enzyme genotype on toxicity, and clinical outcome.

OUTLINE: This is a multicenter study. Patients are stratified according to Eastern Cooperative Oncology Group (ECOG) performance status (0, 1, or 2). Patients are randomized to 1 of 3 treatment arms.

ARM I: Patients receive gemcitabine hydrochloride intravenously (IV) over 30 minutes on days 1 and 8 and tanespimycin IV over 1 hour on day 9 of course one.

ARM II: Patients receive gemcitabine hydrochloride IV over 30 minutes on days 1 and 8 and tanespimycin IV over 1 hour on days 2 and 9 of course one.

ARM III: Patients receive gemcitabine hydrochloride IV over 30 minutes on day 8 and tanespimycin IV over 1 hour on days 1 and 9 of course one. Beginning with course two (and for all subsequent courses), all patients receive gemcitabine hydrochloride IV over 30 minutes on days 1 and 8 and tanespimycin IV over 1 hour on days 2 and 9.

Treatment repeats every 3 weeks in the absence of disease progression or unacceptable toxicity. Blood samples are collected at baseline and periodically during treatment for pharmacogenetic studies. Tumor tissue samples that are available are also collected for laboratory studies. Samples are analyzed for number of circulating tumor cells, levels of intracellular targets (e.g., CDK4, akt, phospho-akt, Hsp90, Hsp70, and CHK1), single nucleotide DNA polymorphisms, and Vav1 expression. Samples are analyzed by reverse transcriptase-polymerase chain reaction, immunofluorescence, and immunohistochemistry.

After completion of study treatment, patients are followed periodically for up to 2 years.

Study Design

• Study Type: Interventional
• Actual Enrollment: 21 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Trial of 17-N-Allylamino-17-Demethoxygeldanamycin (17-AAG) in Combination With Gemcitabine in Patients With Metastatic Pancreatic Adenocarcinoma
• Study Start Date: Mar 1, 2008
• Actual Primary Completion Date: Jan 1, 2011
• Actual Study Completion Date: May 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm I (combination chemotherapy) Patients receive 750 mg/m2 gemcitabine hydrochloride IV over 30 minutes on days 1 and 8 and 154 mg/m2 tanespimycin IV over 1 hour on day 9 of course one. Beginning with course two (and for all subsequent courses), all patients receive gemcitabine hydrochloride IV over 30 minutes on days 1 and 8 and tanespimycin IV over 1 hour on days 2 and 9.	Drug: gemcitabine hydrochloride; 750 mg/m2 Given IV; Other Names: dFdC difluorodeoxycytidine hydrochloride gemcitabine Gemzar ; Drug: tanespimycin; 154 mg/m2 Given IV; Other Names: 17-AAG 17-N-Allylamino-17-Demethoxygeldanamycin
Experimental: Arm II (combination chemotherapy) Patients receive 750 mg/m2 gemcitabine hydrochloride IV over 30 minutes on days 1 and 8 and 154 mg/m2 tanespimycin IV over 1 hour on days 2 and 9 of course one. Beginning with course two (and for all subsequent courses), all patients receive gemcitabine hydrochloride IV over 30 minutes on days 1 and 8 and tanespimycin IV over 1 hour on days 2 and 9.	Drug: gemcitabine hydrochloride; 750 mg/m2 Given IV; Other Names: dFdC difluorodeoxycytidine hydrochloride gemcitabine Gemzar ; Drug: tanespimycin; 154 mg/m2 Given IV; Other Names: 17-AAG 17-N-Allylamino-17-Demethoxygeldanamycin
Experimental: Arm III (combination chemotherapy) Patients receive 750 mg/m2 gemcitabine hydrochloride IV over 30 minutes on day 8 and 154 mg/m2 tanespimycin IV over 1 hour on days 1 and 9 of course one. Beginning with course two (and for all subsequent courses), all patients receive gemcitabine hydrochloride IV over 30 minutes on days 1 and 8 and tanespimycin IV over 1 hour on days 2 and 9.	Drug: gemcitabine hydrochloride; 750 mg/m2 Given IV; Other Names: dFdC difluorodeoxycytidine hydrochloride gemcitabine Gemzar ; Drug: tanespimycin; 154 mg/m2 Given IV; Other Names: 17-AAG 17-N-Allylamino-17-Demethoxygeldanamycin

Outcome Measures

Primary Outcome Measures

1. Six Month Survival Rate [6 months]

   A patient that is alive at 6 months is considered a treatment "success". Estimated by the number of successes divided by the total number of evaluable patients. Ninety-five percent confidence intervals for the true success proportion will be calculated according to the approach of Duffy and Santner.

Secondary Outcome Measures

1. Overall Survival Time [Assessed up to 2 years from registration]

   Overall Survival time is defined as the time from registration to death due to any cause. Estimated using the method of Kaplan-Meier.

2. Time to Disease Progression [Time from registration to documentation of disease progression, assessed up to 2 years]

   The time to disease progression is defined as the time from registration to the time of confirmed disease progression using the Response Evaluation Criteria In Solid Tumors (RECIST). Estimated using the method of Kaplan-Meier. Complete Response (CR): Disappearance of all target lesions and normalization of tumor biomarkers (CA 19-9 or CEA). Partial Response (PR): At least a 30% decrease in the sum of largest dimension(LD) of target lesions taking as reference the baseline sum LD.

3. Confirmed Response Rate [2 consecutive evaluations at least 4 weeks, up to 6 courses of treatment]

   A confirmed response is defined as a complete response (CR) or partial response (PR) observed in two consecutive evaluations at least 4 weeks apart using the Response Evaluation Criteria In Solid Tumors (RECIST). Estimated using the method of Kaplan-Meier. Complete Response (CR): Disappearance of all target lesions and normalization of tumor biomarkers (CA 19-9 or CEA). Partial Response (PR): At least a 30% decrease in the sum of largest dimension(LD) of target lesions taking as reference the baseline sum LD.Evaluated using RECIST criteria.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Histologically or cytologically confirmed pancreatic adenocarcinoma

• Clinical stage IV disease

• No known brain metastases

• ECOG performance status 0-2

• Life expectancy ≥ 12 weeks

• Absolute Neutrophil Count (ANC) ≥ 1,500/mm³

• Platelet count ≥ 100,000/mm³

• Total bilirubin normal

• Aspartate aminotransferase (AST) ≤ 2.5 times upper limit of normal (ULN)

• Alkaline phosphatase ≤ 2 times ULN (5 times ULN if liver metastases are present)

• Creatinine normal

• Not pregnant or nursing

• Negative pregnancy test

• Fertile patients must use effective contraception

• Ejection fraction > 40% by echocardiogram

• Patients who received prior anthracyclines must have a normal ejection fraction by echocardiogram

• Corrected QT interval (QTc) < 500 msec

• Pulse oximetry > 88% on room air at rest and after gentle exercise (according to Group Medicare Guidelines)

• No history of allergic reactions attributed to compounds of similar chemical or biologic composition to tanespimycin (17-AAG) or gemcitabine hydrochloride

• No known allergy to eggs

• No concurrent uncontrolled illness including, but not limited to, any of the following:

• Ongoing or active infection

• Symptomatic congestive heart failure

• Unstable angina pectoris

• Cardiac arrhythmia

• Psychiatric illness/social situations that would limit compliance with study requirements

• No active ischemic heart disease within the past 12 months

• No history of uncontrolled dysrhythmias

• No congenital long QT syndrome

• No left bundle branch block

• No other significant cardiac disease, including any of the following:

• New York Heart Association class III or IV heart failure

• Myocardial infarction within the past year

• Poorly controlled angina

• Uncontrolled dysrhythmias

• History of serious ventricular arrhythmia (ventricular tachycardia or ventricular fibrillation ≥ 3 beats in a row)

• No clinically significant interstitial lung disease

• No symptomatic pulmonary disease requiring medication, including any of the following:

• Dyspnea

• Dyspnea on exertion

• Paroxysmal nocturnal dyspnea

• Significant pulmonary disease requiring oxygen*, including chronic obstructive/restrictive pulmonary disease

• No pulmonary or cardiac symptoms ≥ grade 2

• No history of cardiac or pulmonary toxicity after receiving anthracyclines (e.g., doxorubicin hydrochloride, daunorubicin hydrochloride, mitoxantrone hydrochloride, bleomycin, or vincristine)

• No prior chemotherapy for metastatic disease

• No prior radiotherapy to the chest

• No prior radiotherapy that potentially included the heart in the field (e.g.,mantle radiotherapy)

• More than 3 months since prior adjuvant chemotherapy or chemotherapy for locally advanced disease

• More than 3 weeks since prior radiotherapy

• No concurrent medications that prolong or may prolong QTc

• No concurrent antiarrhythmic drugs

• No concurrent prophylactic colony-stimulating factors

• No other concurrent investigational agents

• No other concurrent anticancer therapy

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic	Rochester	Minnesota	United States	55905

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Robert McWilliams, Mayo Clinic

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT00577889
• Other Study ID Numbers: NCI-2009-00156; MC0542; CDR0000445454; N01CM17104; NCT01647022
• First Posted: Dec 20, 2007
• Last Update Posted: Jul 25, 2014
• Last Verified: Sep 1, 2013

• Additional relevant MeSH terms: Adenocarcinoma; Pancreatic Neoplasms; Gemcitabine

Study Results

Participant Flow

Recruitment Details	A total of 21 patients were accrued from May 30, 2008 to September 2, 2010.
Pre-assignment Detail	A total of 21 patients were accrued and randomized onto one of 3 parallel arms (Arm I: 9 patients; Arm II: 6 patients; Arm III: 6 patients). One patient from Arm I canceled and was not used in baseline analysis nor endpoint analysis.

Arm/Group Title	Arm I (Combination Chemotherapy)	Arm II (Combination Chemotherapy)	Arm III (Combination Chemotherapy)
Arm/Group Description	Patients receive 750 mg/m2 gemcitabine hydrochloride IV over 30 minutes on days 1 and 8 and 154 mg/m2 tanespimycin IV over 1 hour on day 9 of course one. Beginning with course two (and for all subsequent courses), all patients receive gemcitabine hydrochloride IV over 30 minutes on days 1 and 8 and tanespimycin IV over 1 hour on days 2 and 9.	Patients receive 750 mg/m2 gemcitabine hydrochloride IV over 30 minutes on days 1 and 8 and 154 mg/m2 tanespimycin IV over 1 hour on days 2 and 9 of course one. Beginning with course two (and for all subsequent courses), all patients receive gemcitabine hydrochloride IV over 30 minutes on days 1 and 8 and tanespimycin IV over 1 hour on days 2 and 9.	Patients receive 750 mg/m2 gemcitabine hydrochloride IV over 30 minutes on day 8 and 154 mg/m2 tanespimycin IV over 1 hour on days 1 and 9 of course one. Beginning with course two (and for all subsequent courses), all patients receive gemcitabine hydrochloride IV over 30 minutes on days 1 and 8 and tanespimycin IV over 1 hour on days 2 and 9.
Period Title: Overall Study
STARTED	9	6	6
COMPLETED	8	6	6
NOT COMPLETED	1	0	0

Baseline Characteristics

Arm/Group Title	Arm I (Combination Chemotherapy)	Arm II (Combination Chemotherapy)	Arm III (Combination Chemotherapy)	Total
Arm/Group Description	Patients receive 750 mg/m2 gemcitabine hydrochloride IV over 30 minutes on days 1 and 8 and 154 mg/m2 tanespimycin IV over 1 hour on day 9 of course one. Beginning with course two (and for all subsequent courses), all patients receive gemcitabine hydrochloride IV over 30 minutes on days 1 and 8 and tanespimycin IV over 1 hour on days 2 and 9.	Patients receive 750 mg/m2 gemcitabine hydrochloride IV over 30 minutes on days 1 and 8 and 154 mg/m2 tanespimycin IV over 1 hour on days 2 and 9 of course one. Beginning with course two (and for all subsequent courses), all patients receive gemcitabine hydrochloride IV over 30 minutes on days 1 and 8 and tanespimycin IV over 1 hour on days 2 and 9.	Patients receive 750 mg/m2 gemcitabine hydrochloride IV over 30 minutes on day 8 and 154 mg/m2 tanespimycin IV over 1 hour on days 1 and 9 of course one. Beginning with course two (and for all subsequent courses), all patients receive gemcitabine hydrochloride IV over 30 minutes on days 1 and 8 and tanespimycin IV over 1 hour on days 2 and 9.	Total of all reporting groups
Overall Participants	8	6	6	20
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	59	71	67	61.5
Sex: Female, Male (Count of Participants)
Female	3 37.5%	2 33.3%	4 66.7%	9 45%
Male	5 62.5%	4 66.7%	2 33.3%	11 55%
Region of Enrollment (participants) [Number]
United States	8 100%	6 100%	6 100%	20 100%

Outcome Measures

1. Primary Outcome

Title	Six Month Survival Rate
Description	A patient that is alive at 6 months is considered a treatment "success". Estimated by the number of successes divided by the total number of evaluable patients. Ninety-five percent confidence intervals for the true success proportion will be calculated according to the approach of Duffy and Santner.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm I (Combination Chemotherapy)	Arm II (Combination Chemotherapy)	Arm III (Combination Chemotherapy)
Arm/Group Description	Patients receive 750 mg/m2 gemcitabine hydrochloride IV over 30 minutes on days 1 and 8 and 154 mg/m2 tanespimycin IV over 1 hour on day 9 of course one. Beginning with course two (and for all subsequent courses), all patients receive gemcitabine hydrochloride IV over 30 minutes on days 1 and 8 and tanespimycin IV over 1 hour on days 2 and 9.	Patients receive 750 mg/m2 gemcitabine hydrochloride IV over 30 minutes on days 1 and 8 and 154 mg/m2 tanespimycin IV over 1 hour on days 2 and 9 of course one. Beginning with course two (and for all subsequent courses), all patients receive gemcitabine hydrochloride IV over 30 minutes on days 1 and 8 and tanespimycin IV over 1 hour on days 2 and 9.	Patients receive 750 mg/m2 gemcitabine hydrochloride IV over 30 minutes on day 8 and 154 mg/m2 tanespimycin IV over 1 hour on days 1 and 9 of course one. Beginning with course two (and for all subsequent courses), all patients receive gemcitabine hydrochloride IV over 30 minutes on days 1 and 8 and tanespimycin IV over 1 hour on days 2 and 9.
Measure Participants	8	6	6
Number (95% Confidence Interval) [percentage of patients]	25	67	33

2. Secondary Outcome

Title	Overall Survival Time
Description	Overall Survival time is defined as the time from registration to death due to any cause. Estimated using the method of Kaplan-Meier.
Time Frame	Assessed up to 2 years from registration

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm I (Combination Chemotherapy)	Arm II (Combination Chemotherapy)	Arm III (Combination Chemotherapy)
Arm/Group Description	Patients receive 750 mg/m2 gemcitabine hydrochloride IV over 30 minutes on days 1 and 8 and 154 mg/m2 tanespimycin IV over 1 hour on day 9 of course one. Beginning with course two (and for all subsequent courses), all patients receive gemcitabine hydrochloride IV over 30 minutes on days 1 and 8 and tanespimycin IV over 1 hour on days 2 and 9.	Patients receive 750 mg/m2 gemcitabine hydrochloride IV over 30 minutes on days 1 and 8 and 154 mg/m2 tanespimycin IV over 1 hour on days 2 and 9 of course one. Beginning with course two (and for all subsequent courses), all patients receive gemcitabine hydrochloride IV over 30 minutes on days 1 and 8 and tanespimycin IV over 1 hour on days 2 and 9.	Patients receive 750 mg/m2 gemcitabine hydrochloride IV over 30 minutes on day 8 and 154 mg/m2 tanespimycin IV over 1 hour on days 1 and 9 of course one. Beginning with course two (and for all subsequent courses), all patients receive gemcitabine hydrochloride IV over 30 minutes on days 1 and 8 and tanespimycin IV over 1 hour on days 2 and 9.
Measure Participants	8	6	6
Median (95% Confidence Interval) [months]	4.8	6.9	4.3

3. Secondary Outcome

Title	Time to Disease Progression
Description	The time to disease progression is defined as the time from registration to the time of confirmed disease progression using the Response Evaluation Criteria In Solid Tumors (RECIST). Estimated using the method of Kaplan-Meier. Complete Response (CR): Disappearance of all target lesions and normalization of tumor biomarkers (CA 19-9 or CEA). Partial Response (PR): At least a 30% decrease in the sum of largest dimension(LD) of target lesions taking as reference the baseline sum LD.
Time Frame	Time from registration to documentation of disease progression, assessed up to 2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm I (Combination Chemotherapy)	Arm II (Combination Chemotherapy)	Arm III (Combination Chemotherapy)
Arm/Group Description	Patients receive 750 mg/m2 gemcitabine hydrochloride IV over 30 minutes on days 1 and 8 and 154 mg/m2 tanespimycin IV over 1 hour on day 9 of course one. Beginning with course two (and for all subsequent courses), all patients receive gemcitabine hydrochloride IV over 30 minutes on days 1 and 8 and tanespimycin IV over 1 hour on days 2 and 9.	Patients receive 750 mg/m2 gemcitabine hydrochloride IV over 30 minutes on days 1 and 8 and 154 mg/m2 tanespimycin IV over 1 hour on days 2 and 9 of course one. Beginning with course two (and for all subsequent courses), all patients receive gemcitabine hydrochloride IV over 30 minutes on days 1 and 8 and tanespimycin IV over 1 hour on days 2 and 9.	Patients receive 750 mg/m2 gemcitabine hydrochloride IV over 30 minutes on day 8 and 154 mg/m2 tanespimycin IV over 1 hour on days 1 and 9 of course one. Beginning with course two (and for all subsequent courses), all patients receive gemcitabine hydrochloride IV over 30 minutes on days 1 and 8 and tanespimycin IV over 1 hour on days 2 and 9.
Measure Participants	8	6	6
Median (95% Confidence Interval) [months]	2.2	4.1	2.3

4. Secondary Outcome

Title	Confirmed Response Rate
Description	A confirmed response is defined as a complete response (CR) or partial response (PR) observed in two consecutive evaluations at least 4 weeks apart using the Response Evaluation Criteria In Solid Tumors (RECIST). Estimated using the method of Kaplan-Meier. Complete Response (CR): Disappearance of all target lesions and normalization of tumor biomarkers (CA 19-9 or CEA). Partial Response (PR): At least a 30% decrease in the sum of largest dimension(LD) of target lesions taking as reference the baseline sum LD.Evaluated using RECIST criteria.
Time Frame	2 consecutive evaluations at least 4 weeks, up to 6 courses of treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm I (Combination Chemotherapy)	Arm II (Combination Chemotherapy)	Arm III (Combination Chemotherapy)
Arm/Group Description	Patients receive 750 mg/m2 gemcitabine hydrochloride IV over 30 minutes on days 1 and 8 and 154 mg/m2 tanespimycin IV over 1 hour on day 9 of course one. Beginning with course two (and for all subsequent courses), all patients receive gemcitabine hydrochloride IV over 30 minutes on days 1 and 8 and tanespimycin IV over 1 hour on days 2 and 9.	Patients receive 750 mg/m2 gemcitabine hydrochloride IV over 30 minutes on days 1 and 8 and 154 mg/m2 tanespimycin IV over 1 hour on days 2 and 9 of course one. Beginning with course two (and for all subsequent courses), all patients receive gemcitabine hydrochloride IV over 30 minutes on days 1 and 8 and tanespimycin IV over 1 hour on days 2 and 9.	Patients receive 750 mg/m2 gemcitabine hydrochloride IV over 30 minutes on day 8 and 154 mg/m2 tanespimycin IV over 1 hour on days 1 and 9 of course one. Beginning with course two (and for all subsequent courses), all patients receive gemcitabine hydrochloride IV over 30 minutes on days 1 and 8 and tanespimycin IV over 1 hour on days 2 and 9.
Measure Participants	8	6	6
Number [participants]	0 0%	0 0%	0 0%

Adverse Events

Arm/Group Title	Arm I (Combination Chemotherapy)		Arm II (Combination Chemotherapy)		Arm III (Combination Chemotherapy)
Arm/Group Description	Patients receive 750 mg/m2 gemcitabine hydrochloride IV over 30 minutes on days 1 and 8 and 154 mg/m2 tanespimycin IV over 1 hour on day 9 of course one. Beginning with course two (and for all subsequent courses), all patients receive gemcitabine hydrochloride IV over 30 minutes on days 1 and 8 and tanespimycin IV over 1 hour on days 2 and 9.		Patients receive 750 mg/m2 gemcitabine hydrochloride IV over 30 minutes on days 1 and 8 and 154 mg/m2 tanespimycin IV over 1 hour on days 2 and 9 of course one. Beginning with course two (and for all subsequent courses), all patients receive gemcitabine hydrochloride IV over 30 minutes on days 1 and 8 and tanespimycin IV over 1 hour on days 2 and 9.		Patients receive 750 mg/m2 gemcitabine hydrochloride IV over 30 minutes on day 8 and 154 mg/m2 tanespimycin IV over 1 hour on days 1 and 9 of course one. Beginning with course two (and for all subsequent courses), all patients receive gemcitabine hydrochloride IV over 30 minutes on days 1 and 8 and tanespimycin IV over 1 hour on days 2 and 9.
All Cause Mortality
	Arm I (Combination Chemotherapy)		Arm II (Combination Chemotherapy)		Arm III (Combination Chemotherapy)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Arm I (Combination Chemotherapy)		Arm II (Combination Chemotherapy)		Arm III (Combination Chemotherapy)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/8 (75%)		2/6 (33.3%)		2/6 (33.3%)
Gastrointestinal disorders
Abdominal distension	0/8 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0
Abdominal pain	0/8 (0%)	0	1/6 (16.7%)	1	2/6 (33.3%)	2
Constipation	2/8 (25%)	2	1/6 (16.7%)	1	0/6 (0%)	0
Diarrhea	1/8 (12.5%)	1	0/6 (0%)	0	0/6 (0%)	0
Dyspepsia	0/8 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1
Dysphagia	0/8 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1
Nausea	1/8 (12.5%)	1	1/6 (16.7%)	1	2/6 (33.3%)	2
Small intestinal obstruction	1/8 (12.5%)	1	0/6 (0%)	0	0/6 (0%)	0
Vomiting	1/8 (12.5%)	1	1/6 (16.7%)	1	2/6 (33.3%)	2
General disorders
Edema limbs	1/8 (12.5%)	1	0/6 (0%)	0	0/6 (0%)	0
Fatigue	1/8 (12.5%)	1	0/6 (0%)	0	0/6 (0%)	0
Infections and infestations
Infection	1/8 (12.5%)	1	0/6 (0%)	0	0/6 (0%)	0
Investigations
Lymphocyte count decreased	2/8 (25%)	2	0/6 (0%)	0	0/6 (0%)	0
Neutrophil count decreased	1/8 (12.5%)	2	0/6 (0%)	0	0/6 (0%)	0
Weight loss	1/8 (12.5%)	1	0/6 (0%)	0	0/6 (0%)	0
Metabolism and nutrition disorders
Anorexia	0/8 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0
Blood glucose increased	0/8 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1
Dehydration	0/8 (0%)	0	1/6 (16.7%)	1	1/6 (16.7%)	1
Serum calcium decreased	1/8 (12.5%)	1	0/6 (0%)	0	0/6 (0%)	0
Musculoskeletal and connective tissue disorders
Back pain	0/8 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1
Muscle weakness	1/8 (12.5%)	1	0/6 (0%)	0	0/6 (0%)	0
Nervous system disorders
Syncope	1/8 (12.5%)	1	0/6 (0%)	0	0/6 (0%)	0
Respiratory, thoracic and mediastinal disorders
Dyspnea	1/8 (12.5%)	1	0/6 (0%)	0	0/6 (0%)	0
Pleural effusion	1/8 (12.5%)	2	0/6 (0%)	0	0/6 (0%)	0
Pneumothorax	1/8 (12.5%)	2	0/6 (0%)	0	0/6 (0%)	0
Skin and subcutaneous tissue disorders
Rash desquamating	1/8 (12.5%)	2	0/6 (0%)	0	0/6 (0%)	0
Vascular disorders
Hematoma	1/8 (12.5%)	1	0/6 (0%)	0	0/6 (0%)	0
Hypertension	0/8 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1
Hypotension	1/8 (12.5%)	1	0/6 (0%)	0	0/6 (0%)	0
Thrombosis	2/8 (25%)	2	0/6 (0%)	0	0/6 (0%)	0
Other (Not Including Serious) Adverse Events
	Arm I (Combination Chemotherapy)		Arm II (Combination Chemotherapy)		Arm III (Combination Chemotherapy)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/8 (100%)		6/6 (100%)		6/6 (100%)
Blood and lymphatic system disorders
Hemoglobin decreased	7/8 (87.5%)	22	4/6 (66.7%)	15	6/6 (100%)	16
Gastrointestinal disorders
Abdominal pain	6/8 (75%)	13	5/6 (83.3%)	9	5/6 (83.3%)	10
Constipation	0/8 (0%)	0	1/6 (16.7%)	1	1/6 (16.7%)	2
Diarrhea	3/8 (37.5%)	6	1/6 (16.7%)	1	2/6 (33.3%)	2
Gastric mucositis	1/8 (12.5%)	1	1/6 (16.7%)	1	0/6 (0%)	0
Nausea	6/8 (75%)	16	4/6 (66.7%)	8	5/6 (83.3%)	8
Vomiting	4/8 (50%)	8	3/6 (50%)	4	3/6 (50%)	5
General disorders
Edema limbs	1/8 (12.5%)	3	0/6 (0%)	0	0/6 (0%)	0
Fatigue	7/8 (87.5%)	24	5/6 (83.3%)	16	5/6 (83.3%)	15
General symptom	0/8 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0
Investigations
Activated partial thromboplastin time prolonged	1/8 (12.5%)	1	0/6 (0%)	0	0/6 (0%)	0
Alanine aminotransferase increased	4/8 (50%)	6	0/6 (0%)	0	0/6 (0%)	0
Alkaline phosphatase increased	4/8 (50%)	11	2/6 (33.3%)	9	2/6 (33.3%)	4
Aspartate aminotransferase increased	2/8 (25%)	2	2/6 (33.3%)	2	0/6 (0%)	0
Bilirubin increased	0/8 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0
Leukocyte count decreased	4/8 (50%)	12	2/6 (33.3%)	3	3/6 (50%)	6
Lymphocyte count decreased	2/8 (25%)	6	0/6 (0%)	0	2/6 (33.3%)	2
Neutrophil count decreased	4/8 (50%)	7	4/6 (66.7%)	8	2/6 (33.3%)	5
Platelet count decreased	3/8 (37.5%)	7	2/6 (33.3%)	4	1/6 (16.7%)	1
Weight loss	1/8 (12.5%)	2	0/6 (0%)	0	0/6 (0%)	0
Metabolism and nutrition disorders
Anorexia	2/8 (25%)	5	0/6 (0%)	0	2/6 (33.3%)	3
Blood glucose increased	3/8 (37.5%)	7	0/6 (0%)	0	1/6 (16.7%)	1
Dehydration	0/8 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1
Serum albumin decreased	2/8 (25%)	2	0/6 (0%)	0	0/6 (0%)	0
Serum calcium decreased	2/8 (25%)	5	0/6 (0%)	0	0/6 (0%)	0
Serum calcium increased	0/8 (0%)	0	2/6 (33.3%)	3	0/6 (0%)	0
Serum glucose decreased	1/8 (12.5%)	1	0/6 (0%)	0	0/6 (0%)	0
Serum magnesium decreased	0/8 (0%)	0	1/6 (16.7%)	3	0/6 (0%)	0
Serum potassium decreased	2/8 (25%)	4	1/6 (16.7%)	1	0/6 (0%)	0
Serum sodium decreased	2/8 (25%)	2	0/6 (0%)	0	0/6 (0%)	0
Serum sodium increased	0/8 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1
Musculoskeletal and connective tissue disorders
Back pain	1/8 (12.5%)	2	0/6 (0%)	0	1/6 (16.7%)	1
Joint pain	1/8 (12.5%)	1	0/6 (0%)	0	0/6 (0%)	0
Nervous system disorders
Dizziness	1/8 (12.5%)	1	0/6 (0%)	0	0/6 (0%)	0
Headache	1/8 (12.5%)	4	0/6 (0%)	0	0/6 (0%)	0
Psychiatric disorders
Anxiety	0/8 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1
Depression	1/8 (12.5%)	2	0/6 (0%)	0	1/6 (16.7%)	1
Renal and urinary disorders
Ureteric obstruction	0/8 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1
Respiratory, thoracic and mediastinal disorders
Cough	0/8 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1
Dyspnea	1/8 (12.5%)	1	1/6 (16.7%)	1	2/6 (33.3%)	2
Skin and subcutaneous tissue disorders
Rash desquamating	2/8 (25%)	2	0/6 (0%)	0	0/6 (0%)	0
Vascular disorders
Hypotension	1/8 (12.5%)	1	0/6 (0%)	0	0/6 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.