Irinotecan Hydrochloride With or Without Alvocidib in Treating Patients With Advanced Stomach or Gastroesophageal Junction Cancer That Cannot Be Removed By Surgery

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT00991952
• Collaborator: (none)
• Enrollment: 19
• Locations: 5
• Arms: 2
• Duration (Months): 55
• Patients Per Site: 3.8
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This randomized phase II trial studies how well giving irinotecan hydrochloride with or without alvocidib works in treating patients with advanced stomach or gastroesophageal junction cancer that cannot be removed by surgery. Drugs used in chemotherapy, such as irinotecan hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Alvocidib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether irinotecan hydrochloride is more effective with or without alvocidib.

Condition or Disease	Intervention/Treatment	Phase
Adenocarcinoma of the Gastroesophageal Junction; Diffuse Adenocarcinoma of the Stomach; Intestinal Adenocarcinoma of the Stomach; Mixed Adenocarcinoma of the Stomach; Recurrent Gastric Cancer; Stage IIIA Gastric Cancer; Stage IIIB Gastric Cancer; Stage IIIC Gastric Cancer; Stage IV Gastric Cancer	Drug: alvocidib; Drug: irinotecan hydrochloride; Other: laboratory biomarker analysis	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. To examine the antitumor efficacy of irinotecan (irinotecan hydrochloride) followed by flavopiridol (alvocidib) (Arm A) and of irinotecan alone (Arm B) in patients with advanced gastric/ gastroesophageal junction (GEJ) adenocarcinoma wild type for p53.

SECONDARY OBJECTIVES:

1. To evaluate the safety and toxicity of both study arms in patients with advanced gastric/GEJ adenocarcinoma.

2. To examine other measures of antitumor activity in both study arms, including response rate (in patients with measurable disease) and overall survival.

TERTIARY OBJECTIVES:

1. To evaluate pre- and post-treatment tumor biopsies for p21 and RAD51 homolog (S. cerevisiae) (Rad51) expression in patients who agree to tumor biopsies (Memorial Sloan-Kettering Cancer Center [MSKCC] and Weill-Cornell only).

2. To explore the response to irinotecan and flavopiridol and to irinotecan alone by deoxyribonucleic acid (DNA) microarray technology on pre- and post-treatment tumor biopsies (MSKCC and Weill-Cornell only).

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM A: Patients receive irinotecan hydrochloride intravenously (IV) over 30 minutes and alvocidib IV over 1 hour on days 1 and 8. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

ARM B: Patients receive irinotecan hydrochloride as in Arm A. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 1 year.

Study Design

• Study Type: Interventional
• Actual Enrollment: 19 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Multicenter Random Assignment Phase II Study of Irinotecan and Alvocidib (Flavopiridol) Versus Irinotecan Alone for Patients With p53 Wild Type Gastric Adenocarcinoma
• Study Start Date: Sep 1, 2009
• Actual Primary Completion Date: Feb 1, 2012
• Actual Study Completion Date: Apr 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm A (irinotecan hydrochloride, alvocidib) Patients receive irinotecan hydrochloride IV over 30 minutes and alvocidib IV over 1 hour on days 1 and 8. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.	Drug: alvocidib; Given IV; Other Names: FLAVO flavopiridol HMR 1275 L-868275 ; Drug: irinotecan hydrochloride; Given IV; Other Names: Campto Camptosar CPT-11 irinotecan U-101440E ; Other: laboratory biomarker analysis; Correlative studies
Active Comparator: Arm B (irinotecan hydrochloride) Patients receive irinotecan hydrochloride as in Arm A. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.	Drug: irinotecan hydrochloride; Given IV; Other Names: Campto Camptosar CPT-11 irinotecan U-101440E ; Other: laboratory biomarker analysis; Correlative studies

Outcome Measures

Primary Outcome Measures

1. Overall Response Rate [From the start of treatment for up to 3 months]

   Response was determined as indicated in the protocol.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• The patient must have pathologically confirmed carcinoma of the stomach or GEJ (Siewert's type I, II, or III); confirmation will be performed locally at each participating institution

• The patient must have advanced disease not amenable to surgical resection

• Patients must have disease that can be evaluated radiographically; this may be measurable disease or non-measurable disease; measurable disease is defined as that which can be measured in at least one dimension as > 20 mm with conventional techniques, or > 10 mm by high resolution imaging; disease that is identified on radiology studies, but does not meet the criteria for measurable disease, is considered non-measurable

• The patient must have received one prior chemotherapy regimen for his or her unresectable or metastatic disease; this does not include therapy administered in the adjuvant or neoadjuvant setting

• At least 2 weeks must have elapsed since the patient received prior chemotherapy, anti-angiogenic therapy, or other targeted therapy; 2 weeks since prior radiation therapy; or, 4 weeks if the last regimen included carmustine (BCNU) or mitomycin C

• The patient must have a Karnofsky performance status of >= 60

• Serum creatinine =< 2 mg/dl

• Total serum bilirubin =< 2 mg/dl

• If the patient has Gilbert's disease and has a serum bilirubin greater than 2.0 mg/dl, the case must be discussed with the principal investigator; such a patient may be considered eligible on a case-by-case basis

• Serum aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/ alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 times the upper limit of normal, or

• Serum AST (SGOT)/ ALT (SGPT) =< 5 times the upper limit of normal in case of liver metastases

• White blood cell (WBC) >= 3000/mm^3

• Absolute neutrophil count (ANC) >= 1000/mm^3

• Platelets >= 75,000/mm^3

• The patient must have available tumor tissue for assessment of p53 status by immunohistochemistry (IHC) (=< 20% cutoff for positivity)

• Tumor must be p53 wild type as defined as =< %20 nuclear staining on immunohistochemistry

• Women of child-bearing potential and sexually active males must be counseled to use an accepted and effective method of contraception (including intrauterine device [IUD], oral contraceptives, or barrier devices) while on treatment and for at least two months after their last treatment on this study; woman also must agree to refrain from nursing during the duration of this study and for at least two months after their last treatment on this study; women of child-bearing potential must have a negative serum pregnancy test to be eligible for this study

• The patient must have the mental capacity to understand the nature of this study and provide informed consent to participate

Exclusion Criteria:

• The patient may not have previously received irinotecan or flavopiridol

• The patient may not be receiving any other investigational agents

• The patient may not have any ongoing grade 2 or greater toxicity from a prior treatment

• The patient may not have an ongoing uncontrolled illness including, but not limited to active infection, symptomatic congestive heart failure, myocardial infarction in the past 6 months, or new cardiac arrhythmia in the past 6 months

• Patients with a diagnosis of active human immunodeficiency virus (HIV) infection, on anti-retroviral therapy, or with a cluster of differentiation 4 (CD4) count less than 200 are ineligible due to potential interactions between irinotecan, flavopiridol, and anti-retroviral medications as well as possible immunosuppressive activity of the study treatment

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	City of Hope	Duarte	California	United States	91010
2	UC Davis Comprehensive Cancer Center	Sacramento	California	United States	95817
3	University of Chicago Comprehensive Cancer Center	Chicago	Illinois	United States	60637-1470
4	University of Michigan	Ann Arbor	Michigan	United States	48109
5	Memorial Sloan-Kettering Cancer Center	New York	New York	United States	10065

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Yelena Janjigian, Memorial Sloan Kettering Cancer Center

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT00991952
• Other Study ID Numbers: NCI-2011-03825; NCI-2011-03825; CDR0000655636; MSKCC-8060; 8060; 09-074; 8060; N01CM00038
• First Posted: Oct 8, 2009
• Last Update Posted: May 26, 2014
• Last Verified: Dec 1, 2013

• Additional relevant MeSH terms: Adenocarcinoma; Stomach Neoplasms; Irinotecan; Alvocidib

Study Results

Participant Flow

Recruitment Details	Protocol Open to Accrual 09/09/2009 Protocol Closed to Accrual 02/28/2012 Recruitment Location is the medical clinic

Arm/Group Title	Irinotecan Hydrochloride and Alvocidib	Irinotecan Hydrochloride
Arm/Group Description	Patients receive irinotecan hydrochloride IV over 30 minutes and alvocidib IV over 1 hour on days 1 and 8. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Irinotecan: 100 mg/m2 IV over 30 min on days 1 and 8 followed 7 hours later by Flavopiridol 60 mg/m2 IV over 1 hr on days 1 and 8	Patients receive irinotecan hydrochloride as in Arm A. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Irinotecan: 100 mg/m2 IV over 30 min on days 1 and 8
Period Title: Overall Study
STARTED	13	6
COMPLETED	13	5
NOT COMPLETED	0	1

Baseline Characteristics

Arm/Group Title	Irinotecan Hydrochloride and Alvocidib	Irinotecan Hydrochloride	Total
Arm/Group Description	Patients receive irinotecan hydrochloride IV over 30 minutes and alvocidib IV over 1 hour on days 1 and 8. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Irinotecan: 100 mg/m2 IV over 30 min on days 1 and 8 followed 7 hours later by Flavopiridol 60 mg/m2 IV over 1 hr on days 1 and 8	Patients receive irinotecan hydrochloride as in Arm A. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Irinotecan: 100 mg/m2 IV over 30 min on days 1 and 8	Total of all reporting groups
Overall Participants	13	6	19
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	8 61.5%	4 66.7%	12 63.2%
>=65 years	5 38.5%	2 33.3%	7 36.8%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	62.5 (19.0918830)	56 (16.97056275)	60 (22.627417)
Sex: Female, Male (Count of Participants)
Female	6 46.2%	0 0%	6 31.6%
Male	7 53.8%	6 100%	13 68.4%
Region of Enrollment (participants) [Number]
United States	13 100%	6 100%	19 100%

Outcome Measures

1. Primary Outcome

Title	Overall Response Rate
Description	Response was determined as indicated in the protocol.
Time Frame	From the start of treatment for up to 3 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Irinotecan Hydrochloride and Alvocidib	Irinotecan Hydrochloride
Arm/Group Description	Patients receive irinotecan hydrochloride IV over 30 minutes and alvocidib IV over 1 hour on days 1 and 8. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Irinotecan: 100 mg/m2 IV over 30 min on days 1 and 8 followed 7 hours later by Flavopiridol 60 mg/m2 IV over 1 hr on days 1 and 8	Patients receive irinotecan hydrochloride as in Arm A. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Irinotecan: 100 mg/m2 IV over 30 min on days 1 and 8
Measure Participants	13	5
Partial Response	1 7.7%	0 0%
Stable Disease	4 30.8%	1 16.7%
Progression of Disease	8 61.5%	4 66.7%

Adverse Events

Arm/Group Title	Irinotecan Hydrochloride and Alvocidib		Irinotecan Hydrochloride
Arm/Group Description	Patients receive irinotecan hydrochloride IV over 30 minutes and alvocidib IV over 1 hour on days 1 and 8. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Irinotecan: 100 mg/m2 IV over 30 min on days 1 and 8 followed 7 hours later by Flavopiridol 60 mg/m2 IV over 1 hr on days 1 and 8		Patients receive irinotecan hydrochloride as in Arm A. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Irinotecan: 100 mg/m2 IV over 30 min on days 1 and 8
All Cause Mortality
	Irinotecan Hydrochloride and Alvocidib		Irinotecan Hydrochloride
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Irinotecan Hydrochloride and Alvocidib		Irinotecan Hydrochloride
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/13 (46.2%)		2/6 (33.3%)
Blood and lymphatic system disorders
Hemoglobin decreased	2/13 (15.4%)	2	0/6 (0%)	0
Cardiac disorders
Atrial flutter	0/13 (0%)	0	1/6 (16.7%)	1
Sinus tachycardia	0/13 (0%)	0	1/6 (16.7%)	1
Gastrointestinal disorders
Abdominal pain	1/13 (7.7%)	1	2/6 (33.3%)	2
Constipation	0/13 (0%)	0	1/6 (16.7%)	1
Nausea	2/13 (15.4%)	2	2/6 (33.3%)	2
Gastric hemorrhage	1/13 (7.7%)	1	0/6 (0%)	0
Intra-abdominal hemorrhage	1/13 (7.7%)	1	0/6 (0%)	0
Obstruction, gastric	1/13 (7.7%)	1	0/6 (0%)	0
Vomiting	2/13 (15.4%)	2	0/6 (0%)	0
General disorders
Death NOS	0/13 (0%)	0	1/6 (16.7%)	1
Edema limbs	0/13 (0%)	0	1/6 (16.7%)	1
Fatigue	1/13 (7.7%)	1	1/6 (16.7%)	1
Multi-organ failure	0/13 (0%)	0	1/6 (16.7%)	1
Death-Disease Progression NOS	1/13 (7.7%)	1	0/6 (0%)	0
Fever	1/13 (7.7%)	1	0/6 (0%)	0
Infections and infestations
Sepsis	0/13 (0%)	0	1/6 (16.7%)	1
Investigations
Alanine aminotransferase increased	0/13 (0%)	0	1/6 (16.7%)	1
Alkaline phosphatase increased	0/13 (0%)	0	1/6 (16.7%)	1
Creatinine increased	0/13 (0%)	0	1/6 (16.7%)	1
INR increased	0/13 (0%)	0	1/6 (16.7%)	1
Lymphocyte count decreased	1/13 (7.7%)	1	1/6 (16.7%)	1
Neutrophil count decrease	1/13 (7.7%)	1	0/6 (0%)	0
Metabolism and nutrition disorders
Acidosis	0/13 (0%)	0	1/6 (16.7%)	1
Anorexia	0/13 (0%)	0	1/6 (16.7%)	1
Aspartate aminotransferase increased	0/13 (0%)	0	1/6 (16.7%)	1
Dehydration	1/13 (7.7%)	1	1/6 (16.7%)	1
Hypoalbuminemia	0/13 (0%)	0	1/6 (16.7%)	1
Hyponatremia	0/13 (0%)	0	1/6 (16.7%)	1
Nervous system disorders
Dizziness	1/13 (7.7%)	1	0/6 (0%)	0
Respiratory, thoracic and mediastinal disorders
Dyspnea	0/13 (0%)	0	1/6 (16.7%)	1
Pleural effusion	0/13 (0%)	0	1/6 (16.7%)	1
Pneumothorax	1/13 (7.7%)	1	0/6 (0%)	0
Vascular disorders
Hypotension	0/13 (0%)	0	1/6 (16.7%)	1
Other (Not Including Serious) Adverse Events
	Irinotecan Hydrochloride and Alvocidib		Irinotecan Hydrochloride
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	13/13 (100%)		6/6 (100%)
Blood and lymphatic system disorders
Anemia	9/13 (69.2%)	9	2/6 (33.3%)	2
Gastrointestinal disorders
Abdominal distension	1/13 (7.7%)	1	0/6 (0%)	0
Abdominal pain	1/13 (7.7%)	1	0/6 (0%)	0
Constipation	2/13 (15.4%)	2	1/6 (16.7%)	1
Diarrhea	5/13 (38.5%)	5	0/6 (0%)	0
Nausea	6/13 (46.2%)	6	2/6 (33.3%)	2
Vomiting	3/13 (23.1%)	3	1/6 (16.7%)	1
General disorders
Edema limbs	1/13 (7.7%)	1	0/6 (0%)	0
Fatigue	9/13 (69.2%)	9	3/6 (50%)	3
Fever	1/13 (7.7%)	1	0/6 (0%)	0
Pain	1/13 (7.7%)	1	0/6 (0%)	0
Investigations
Alanine aminotransferase increased	3/13 (23.1%)	3	1/6 (16.7%)	1
Alkaline phosphatase increased	4/13 (30.8%)	4	1/6 (16.7%)	1
Aspartate aminotransferase	4/13 (30.8%)	4	0/6 (0%)	0
Blood bilirubin increased	2/13 (15.4%)	2	0/6 (0%)	0
Creatinine increased	3/13 (23.1%)	3	1/6 (16.7%)	1
INR increased	2/13 (15.4%)	2	0/6 (0%)	0
Lymphocyte count decreased	5/13 (38.5%)	5	0/6 (0%)	0
Neutrophil count decreased	6/13 (46.2%)	6	2/6 (33.3%)	2
Platelet count decreased	2/13 (15.4%)	2	1/6 (16.7%)	1
Weight loss	2/13 (15.4%)	2	1/6 (16.7%)	1
White blood cell decreased	10/13 (76.9%)	10	3/6 (50%)	3
Metabolism and nutrition disorders
Anorexia	5/13 (38.5%)	5	3/6 (50%)	3
Hyperglycemia	8/13 (61.5%)	8	2/6 (33.3%)	2
Hypernatremia	2/13 (15.4%)	2	0/6 (0%)	0
Hypoalbuminemia	7/13 (53.8%)	7	2/6 (33.3%)	2
Hypocalcemia	9/13 (69.2%)	9	2/6 (33.3%)	2
Hypoglycemia	1/13 (7.7%)	1	0/6 (0%)	0
Hypokalemia	4/13 (30.8%)	4	0/6 (0%)	0
Hypomagnesemia	3/13 (23.1%)	3	2/6 (33.3%)	2
Hyponatremia	3/13 (23.1%)	3	2/6 (33.3%)	2
Nervous system disorders
Dizziness	1/13 (7.7%)	1	0/6 (0%)	0
Peripheral sensory neuropathy	3/13 (23.1%)	3	0/6 (0%)	0
Respiratory, thoracic and mediastinal disorders
Cough	1/13 (7.7%)	1	1/6 (16.7%)	1
Dyspnea	1/13 (7.7%)	1	2/6 (33.3%)	2

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.