Irinotecan, Cisplatin, Bevacizumab, Radiation Therapy, and Surgery in Treating Patients With Locally Advanced Esophageal Cancer

• Sponsor: Memorial Sloan Kettering Cancer Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT00354679
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 34
• Location: 1
• Arm: 1
• Duration (Months): 110
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

RATIONALE: Drugs used in chemotherapy, such as irinotecan and cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some find tumor cells and kill them or carry tumor-killing substances to them. Others interfere with the ability of tumor cells to grow and spread. Bevacizumab may also stop the growth of esophageal cancer by blocking blood flow to the tumor. Radiation therapy uses high-energy x-rays to kill tumor cells. Giving chemotherapy and monoclonal antibody therapy together with radiation therapy before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. Giving bevacizumab after surgery may kill any tumor cells that remain after surgery.

PURPOSE: This phase II trial is studying how well giving irinotecan, cisplatin, and bevacizumab together with radiation therapy followed by surgery and bevacizumab works in treating patients with locally advanced esophageal cancer.

Condition or Disease	Intervention/Treatment	Phase
Esophageal Cancer	Biological: bevacizumab; Drug: cisplatin; Drug: irinotecan hydrochloride; Genetic: proteomic profiling; Other: diagnostic laboratory biomarker analysis; Other: mass spectrometry; Procedure: adjuvant therapy; Procedure: neoadjuvant therapy; Procedure: therapeutic conventional surgery; Radiation: radiation therapy	Phase 2

Detailed Description

OBJECTIVES:

Primary

• Evaluate the toxicity and safety of bevacizumab when given together with cisplatin, irinotecan hydrochloride, and radiotherapy followed by surgery and adjuvant bevacizumab in patients with locally advanced esophageal adenocarcinoma.

Secondary

• Observe the rate of pathologic complete response in patients treated with this regimen.

• Observe overall survival, disease-free survival, and patterns of failure in these patients.

• Clarify toxicity and tolerability of this regimen.

• Evaluate pre-treatment levels of vascular endothelial growth factor in patient serum as a corollary of response to this regimen.

• Correlate serum proteomics data with complete pathologic response.

OUTLINE: This is a nonrandomized, open-label study.

• Induction therapy: Patients receive cisplatin IV over 30 minutes and irinotecan hydrochloride IV over 30 minutes on days 1, 8, 22, and 29. Patients also receive bevacizumab IV over 30-90 minutes on days 1 and 22.

• Combination therapy and radiotherapy: Patients receive cisplatin and irinotecan hydrochloride as in induction chemotherapy on days 43, 50, 64, and 71. Patients also receive bevacizumab IV over 30-90 minutes on days 43 and 64. Patients undergo external beam radiotherapy 5 days a week for 6 weeks beginning on day 43.

• Surgery: Patients undergo surgery 6-8 weeks after finishing combination therapy and radiotherapy.

• Maintenance therapy: Approximately 6 weeks after surgery, patients receive bevacizumab IV over 30-90 minutes every 3 weeks for 6 months.

Blood samples are obtained at baseline, after finishing chemoradiotherapy, and prior to maintenance therapy and are examined by the matrix-assisted laser-desorption ionization time of flight (MALDI-TOF) mass spectometry for proteomic profiling.

After completion of study treatment, patients are followed every 3 months for 1 year, every 4 months for 1 year, every 6 months for 3 years, and then annually thereafter.

Study Design

• Study Type: Interventional
• Actual Enrollment: 34 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Trial of Irinotecan, Cisplatin, Bevacizumab and Concurrent Radiotherapy in Locally Advanced Esophageal Adenocarcinoma
• Study Start Date: Apr 1, 2006
• Actual Primary Completion Date: Jun 1, 2015
• Actual Study Completion Date: Jun 1, 2015

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Irinotecan, Cisplatin, Bevacizumab, Radiotherapy, & Surger Induction therapy: Patients receive cisplatin IV over 30 minutes and irinotecan hydrochloride IV over 30 minutes on days 1, 8, 22, and 29. Patients also receive bevacizumab IV over 30-90 minutes on days 1 and 22. Combination therapy and radiotherapy: Patients receive cisplatin and irinotecan hydrochloride as in induction chemotherapy on days 43, 50, 64, and 71. Patients also receive bevacizumab IV over 30-90 minutes on days 43 and 64. Patients undergo external beam radiotherapy 5 days a week for 6 weeks beginning on day 43. Surgery: Patients undergo surgery 6-8 weeks after finishing combination therapy and radiotherapy. Maintenance therapy: Approximately 6 weeks after surgery, patients receive bevacizumab IV over 30-90 minutes every 3 weeks for 6 months

Biological: bevacizumab; Drug: cisplatin; Drug: irinotecan hydrochloride; Genetic: proteomic profiling; Other: diagnostic laboratory biomarker analysis; Other: mass spectrometry; Procedure: adjuvant therapy; Procedure: neoadjuvant therapy; Procedure: therapeutic conventional surgery; Radiation: radiation therapy

Outcome Measures

Primary Outcome Measures

1. Evaluation of Safety and Toxicity [2 years]

   All toxicity will be graded according to the National Cancer Institute (NCI) Common Toxicity Criteria v3.0.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 120 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

DISEASE CHARACTERISTICS:

• Histologically confirmed adenocarcinoma of the esophagus or gastroesophageal junction

• T1, N1, M0 or T2-4, any N, M0 esophageal carcinoma that is surgically resectable

• Disease must be clinically limited to the esophagus or gastroesophageal junction

• If tumor extends below the gastroesophageal junction into the proximal stomach, 50% of the tumor must involve the distal esophagus or gastroesophageal junction

• No carcinoma in situ (Tis) or tumors determined to be T1, N0 after endoscopy, endoscopic ultrasound, or CT scan

• No gastric cancers with minor involvement of the gastroesophageal junction or distal esophagus

• No metastatic disease, including any of the following:

• M1a celiac or supraclavicular disease

• Positive malignant cytology of the pleura, pericardium, or peritoneum

• Radiographic evidence of distant organ involvement, including lung, liver, bone, or brain

• No involvement of nonregional lymph nodes including supraclavicular or celiac lymph node metastases that cannot be contained within a radiation field

• No biopsy-proven tumor invasion of the tracheobronchial tree or presence of tracheoesophageal fistula

• No recurrent laryngeal nerve or phrenic nerve paralysis

• No CNS or brain metastases

PATIENT CHARACTERISTICS:

• ECOG performance status 0-1

• WBC ≥ 3,000/mm³

• Absolute neutrophil count ≥ 1,500/mm³

• Platelet count ≥ 100,000/mm³

• Hemoglobin ≥ 9.0 g/dL

• INR ≤ 1.5 (except for patients requiring full-dose warfarin while on bevacizumab)

• Creatinine ≤ 1.5 mg/dL

• Bilirubin ≤ 1.5 mg/dL

• AST and ALT < 2.5 times normal

• Urine protein ≤ 1+ by urinalysis OR < 1 g of protein by 24-hour urine collection

• Calcium < 12 mg/dL

• Not pregnant or nursing

• Negative pregnancy test

• Fertile patients must use effective contraception

• No other prior malignancy (except for basal cell or squamous cell carcinoma of the skin, in situ cervical carcinoma, or superficial transitional cell bladder carcinoma) diagnosed and/or treated within the past 3 years

• No known Gilbert's disease

• No clinically significant hearing loss

• No known hypersensitivity to bevacizumab or other study drugs

• No severe comorbid conditions, including any of the following:

• Severe uncontrolled diabetes

• Prior stroke or cerebrovascular disease

• Uncontrolled infection

• Nonmalignant illness that precludes study treatment

• No history of serious systemic disease, including any of the following:

• Myocardial infarction within the past 6 months

• Uncontrolled hypertension (i.e., blood pressure > 160/110 mm Hg on medication)

• Unstable angina

• New York Heart Association class II-IV congestive heart failure

• Unstable symptomatic arrhythmia requiring medication

• Chronic atrial arrhythmia (i.e., atrial fibrillation or paroxysmal supraventricular tachycardia) allowed

• Peripheral vascular disease ≥ grade 2

• No significant traumatic injury within the past 28 days

• No evidence of bleeding diathesis or coagulopathy

• No other concurrent medical or psychiatric condition or disease that would preclude study participation

PRIOR CONCURRENT THERAPY:

• No prior radiotherapy

• Recovered from prior oncologic or other major surgery

• No major surgery or open biopsy within the past 28 days

• No fine-needle aspiration or core biopsies within the past 7 days

• At least 1 week since prior and no concurrent participation in another experimental drug study (unless Genentech sponsored)

• No other concurrent major surgery

• No other concurrent chemotherapy

• No concurrent sargramostim (GM-CSF)

• No concurrent phenytoin, carbamazepine, barbiturates, rifampin, phenobarbital, Hypericum perforatum (St. John's wort), or other antiepileptic medication

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Memorial Sloan Kettering Cancer Center	New York	New York	United States	10065

Sponsors and Collaborators

• Memorial Sloan Kettering Cancer Center
• National Cancer Institute (NCI)

Investigators

• Study Chair: David H. Ilson, MD, PhD, Memorial Sloan Kettering Cancer Center

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Memorial Sloan Kettering Cancer Center

Publications

None provided.

• Responsible Party: Memorial Sloan Kettering Cancer Center
• ClinicalTrials.gov Identifier: NCT00354679
• Other Study ID Numbers: 06-013; P30CA008748; MSKCC-06013
• First Posted: Jul 20, 2006
• Last Update Posted: May 16, 2016
• Last Verified: Apr 1, 2016

• Keywords provided by Memorial Sloan Kettering Cancer Center: adenocarcinoma of the esophagus; recurrent esophageal cancer; stage III esophageal cancer; stage II esophageal cancer
• Additional relevant MeSH terms: Esophageal Neoplasms; Bevacizumab; Irinotecan

Study Results

Participant Flow

Arm/Group Title	Irinotecan, Cisplatin, Bevacizumab, Radiotherapy, & Surger
Arm/Group Description	Irinotecan, Cisplatin, Bevacizumab and Concurrent Radiotherapy in Locally Advanced Esophageal Adenocarcinoma
Period Title: Overall Study
STARTED	34
COMPLETED	33
NOT COMPLETED	1

Baseline Characteristics

Arm/Group Title	Irinotecan, Cisplatin, Bevacizumab, Radiotherapy, & Surger
Arm/Group Description	Irinotecan, Cisplatin, Bevacizumab and Concurrent Radiotherapy in Locally Advanced Esophageal Adenocarcinoma
Overall Participants	34
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	31 91.2%
>=65 years	3 8.8%
Sex: Female, Male (Count of Participants)
Female	7 20.6%
Male	27 79.4%

Outcome Measures

1. Primary Outcome

Title	Evaluation of Safety and Toxicity
Description	All toxicity will be graded according to the National Cancer Institute (NCI) Common Toxicity Criteria v3.0.
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Irinotecan, Cisplatin, Bevacizumab, Radiotherapy, & Surger
Arm/Group Description	Irinotecan, Cisplatin, Bevacizumab and Concurrent Radiotherapy in Locally Advanced Esophageal Adenocarcinoma
Measure Participants	33
Anorexia	1 2.9%
Atrial flutter	1 2.9%
CNS cerebrovascular ischemia	1 2.9%
Death not associated with CTCAE term- Death NOS	1 2.9%
Dehydration	5 14.7%
Esophagitis	7 20.6%
Febrile neutropenia	3 8.8%
Hemoglobin	1 2.9%
Hemorrhage, CNS	1 2.9%
Infection, other	2 5.9%
Leukocytes (total WBC)	2 5.9%
Nausea	2 5.9%
Neutrophils/granulocytes (ANC/AGC)	1 2.9%
Pain - Chest wall	1 2.9%
Pain - Extremity-limb	1 2.9%
Perforation, GI- Jejunum	1 2.9%
Phosphate, low (hypophosphatemia)	1 2.9%
Platelets	1 2.9%
Potassium, low (hypokalemia)	2 5.9%
Thrombosis/embolism (vascular access-related)	1 2.9%
Thrombosis/thrombus/embolism	4 11.8%
Vomiting	2 5.9%

Adverse Events

Arm/Group Title	Irinotecan, Cisplatin, Bevacizumab, Radiotherapy, & Surger
Arm/Group Description	Irinotecan, Cisplatin, Bevacizumab and Concurrent Radiotherapy in Locally Advanced Esophageal Adenocarcinoma
All Cause Mortality
	Irinotecan, Cisplatin, Bevacizumab, Radiotherapy, & Surger
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Irinotecan, Cisplatin, Bevacizumab, Radiotherapy, & Surger
	Affected / at Risk (%)	# Events
Total	16/33 (48.5%)
Blood and lymphatic system disorders
Hemoglobin	1/33 (3%)
Leukocytes (total WBC)	2/33 (6.1%)
Neutrophils/granulocytes	1/33 (3%)
Platelets	1/33 (3%)
Cardiac disorders
Atrial flutter	1/33 (3%)
Ischemia cerebrovascular	1/33 (3%)
Thrombosis/embolism (vascular access-related)	1/33 (3%)
Thrombosis/thrombus/embolism	4/33 (12.1%)
Gastrointestinal disorders
Dehydration	5/33 (15.2%)
Esophagitis	7/33 (21.2%)
Nausea	2/33 (6.1%)
Perforation, GI- Jejunum	1/33 (3%)
Vomiting	2/33 (6.1%)
General disorders
Anorexia	1/33 (3%)
Death not associated with CTCAE term- Death NOS	1/33 (3%)
Febrile neutropenia	3/33 (9.1%)
Pain - Chest wall	1/33 (3%)
Pain - Extremity-limb	1/33 (3%)
Infections and infestations
Infection, other	2/33 (6.1%)
Metabolism and nutrition disorders
Phosphate, low (hypophosphatemia)	1/33 (3%)
Potassium, low (hypokalemia)	1/33 (3%)
Nervous system disorders
CNS cerebrovascular ischemia	1/33 (3%)
Hemorrhage, CNS	1/33 (3%)
Other (Not Including Serious) Adverse Events
	Irinotecan, Cisplatin, Bevacizumab, Radiotherapy, & Surger
	Affected / at Risk (%)	# Events
Total	32/33 (97%)
Blood and lymphatic system disorders
ALT, SGPT	9/33 (27.3%)
AST, SGOT	7/33 (21.2%)
Hemoglobin	28/33 (84.8%)
Prothrombin time international normalized ratio	6/33 (18.2%)
Leukocytes (total WBC)	26/33 (78.8%)
Lymphopenia	31/33 (93.9%)
Neutrophils/granulocytes	22/33 (66.7%)
Platelets	8/33 (24.2%)
Partial thromboplastin time	5/33 (15.2%)
Gastrointestinal disorders
Constipation	4/33 (12.1%)
Dehydration	2/33 (6.1%)
Diarrhea	5/33 (15.2%)
Esophagitis	6/33 (18.2%)
Nausea	5/33 (15.2%)
Vomiting	5/33 (15.2%)
General disorders
Dysphagia (Difficulty swallowing)	2/33 (6.1%)
Fatigue (asthenia, lethargy, malaise)	9/33 (27.3%)
Febrile neutropenia	2/33 (6.1%)
Hair loss/alopecia (scalp or body)	7/33 (21.2%)
Metabolism and nutrition disorders
Albumin, low (hypoalbuminemia)	7/33 (21.2%)
Alkaline phosphatase	3/33 (9.1%)
Bilirubin (hyperbilirubinemia)	8/33 (24.2%)
Creatinine	2/33 (6.1%)
Glucose, high (hyperglycemia)	21/33 (63.6%)
Glucose, low (hypoglycemia)	4/33 (12.1%)
Magnesium, low (hypomagnesemia)	2/33 (6.1%)
Phosphate, low (hypophosphatemia)	23/33 (69.7%)
Potassium, high (hyperkalemia)	2/33 (6.1%)
Potassium, low (hypokalemia)	5/33 (15.2%)
Sodium, low (hyponatremia)	3/33 (9.1%)
Trglycrde, high (hypertriglyceridemia)	2/33 (6.1%)

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.