Everolimus in Treating Patients With Previously Treated Unresectable or Metastatic Esophageal Cancer or Stomach Cancer

• Sponsor: Translational Oncology Research International (Other)
• Overall Status: Completed
• CT.gov ID: NCT00985192
• Collaborator: National Cancer Institute (NCI) (NIH), University of California, Los Angeles (Other)
• Enrollment: 49
• Locations: 18
• Arm: 1
• Duration (Months): 56
• Patients Per Site: 2.7
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

RATIONALE: Everolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor.

PURPOSE: This phase II trial is studying how well everolimus works in treating patients with previously treated unresectable or metastatic esophageal cancer or stomach cancer.

Condition or Disease	Intervention/Treatment	Phase
Esophageal Cancer; Gastric Cancer	Drug: everolimus; Other: laboratory biomarker analysis	Phase 2

Detailed Description

OBJECTIVES:

Primary

• To determine the overall disease-control rate (complete response, partial response, or stable disease) in patients with previously treated unresectable or metastatic adenocarcinoma of the upper gastrointestinal tract treated with everolimus.

Secondary

• To determine the safety and toxicity of everolimus in these patients.

• To determine the efficacy of everolimus, in terms of time to response, duration of response, time to tumor progression, progression-free survival, and overall survival, in these patients.

• To explore potential correlations between clinical outcome and biomarkers of interest, including S6 protein overexpression and/or other mTOR-related proteins in blood and tumor biopsy samples from these patients.

OUTLINE: This is a multicenter study.

Patients receive oral everolimus once daily on days 1-14. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.

Blood, serum, and tumor tissue samples are collected for biomarker analysis.

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 49 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Study of the mTOR Inhibitor RAD001 in Previously Treated Patients With Unresectable or Metastatic Adenocarcinoma of the Esophagus and Stomach
• Study Start Date: Sep 1, 2009
• Actual Primary Completion Date: May 1, 2014
• Actual Study Completion Date: May 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Everolimus Patients receive oral everolimus once daily on days 1-14. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity	Drug: everolimus; Other: laboratory biomarker analysis

Outcome Measures

Primary Outcome Measures

1. Overall Disease-control Rate in Patients With Previously Treated Unresectable or Metastatic Adenocarcinoma of the Upper Gastrointestinal Tract Treated With Everolimus. [Radiologic disease assessment was performed every 8 weeks (14 days = 1 cycle) treatment discontinuation.]

   Disease control rate (DCR), defined as complete response (CR) + partial response (PR) + stable disease (SD) according to Response Evaluation Criteria In Solid Tumors (RECIST) criteria.

Secondary Outcome Measures

1. Overall Survival [2.5 year]

   Overall Survival (OS), defined as the time from date of initial treatment to date of death. Survival function was estimated using the Kaplan-Meier method.

2. Efficacy in Terms of Progression Free Response [evry 3 months in year 1, every 6 months after that]

   Progression-free survival (PFS), was defined as the time from the date of initial treatment to first objective documentation of disease progression, or death. Estimated using the Kaplan-Meier method. Complete response (CR) + partial response (PR) + stable disease (SD) were determined according to Response Evaluation Criteria In Solid Tumors (RECIST) criteria. Radiologic disease assessments were utilized.

3. Observed Biomarkers [30 months]

   Potential correlations between clinical outcome and biomarkers of interest, including S6 protein overexpression and/or other mTOR-related proteins in tumor tissue samples from these patients.

4. Biomarker Correlations: Progression Free Survival [30 months]

   Potential correlations between progression free survival and S6 protein and mTOR-related proteins in tumor tissue samples from these patients.

5. Biomarker Correlations: Time to Progression [30 months]

   Potential correlations between time to progression and S6 protein and mTOR-related proteins in tumor tissue samples from these patients.

Eligibility Criteria

Criteria

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

Inclusion criteria:

• Diagnosis of adenocarcinoma of the upper gastrointestinal tract

• Metastatic or unresectable disease

• Received 1-2 prior chemotherapy or biological therapy regimens for unresectable or metastatic disease

• Measurable disease in ≥ 1 dimension by CT scan or MRI

• Patients whose only measurable lesion is a metastatic lymph node are eligible provided they have permission from the principal investigator

• ECOG performance status 0-1

• Life expectancy > 3 months

• ANC ≥ 1,500/mm^3

• Platelet count ≥ 100,000/mm^3

• Hemoglobin ≥ 9 g/dL

• Total bilirubin ≤ 1.5 times upper limit of normal (ULN)

• AST and ALT ≤ 2.5 times ULN (≤ 5.0 times ULN if there is liver metastasis)

• Creatinine clearance > 60 mL/min

• Fasting serum cholesterol < 300 mg/dL or < 7.75 mmol/L*

• Fasting triglycerides < 2.5 times ULN*

• INR ≤ 3.5 (for patients on warfarin)

• Negative pregnancy test

• Fertile patients must use effective contraception during and for ≥ 4 months after completion of study treatment (oral, implantable, or injectable contraceptives are not considered effective contraception for this study)

• More than 30 days since prior chemotherapy, surgery, radiotherapy, or investigational agents

Exclusion Criteria:

• uncontrolled diabetes mellitus, defined as fasting serum glucose > 1.5 times ULN

• severely impaired lung function

• known HV infection

• active, bleeding diathesis

• unstable angina pectoris, symptomatic congestive heart failure, or myocardial infarction within the past 6 months

• serious uncontrolled cardiac arrhythmia

• active or uncontrolled infection requiring parenteral antimicrobials

• known liver disease (e.g., cirrhosis, chronic active hepatitis, or chronic persistent hepatitis)

• inability to swallow, impaired gastrointestinal (GI) function, or GI disease (e.g., ulcerative colitis, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection) that would significantly alter the absorption of study drugs or preclude the use of oral medications

• other malignancy within the past 5 years except for nonmelanoma skin cancer or cervical carcinoma in situ

• known hypersensitivity to everolimus, sirolimus, or temsirolimus or to their excipients

• other medical conditions that, in the opinion of the investigator, would preclude study participation

• prior mTOR inhibitors (e.g., rapamycin, CCI-779)

• concurrent chronic treatment with steroids or another immunosuppressive agent

• concurrent prophylactic use of hematopoietic growth factors

• concurrent anticancer agents or therapy (including radiotherapy)

• other concurrent experimental agents

• concurrent strong inhibitors or inducers of the isoenzyme CYP3A4

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Central Hematology Oncology Medical Group, Inc.	Alhambra	California	United States	91801
2	Comprehensive Blood and Cancer Center	Bakersfield	California	United States	93309
3	St. Jude Heritage Medical Group at Virginia K. Crosson Cancer Center	Fullerton	California	United States	92835
4	Antelope Valley Cancer Center	Lancaster	California	United States	93534
5	Pacific Shores Medical Group	Long Beach	California	United States	90813
6	Jonsson Comprehensive Cancer Center at UCLA	Los Angeles	California	United States	90095-1781
7	Translational Oncology Research International (TORI) Network	Los Angeles	California	United States	90095
8	North Valley Hematology/Oncology Medical Group	Northridge	California	United States	91328
9	Wilshire Oncology Medical Group, Inc.	Pomona	California	United States	91767
10	Cancer Care Associates Medical Group, Inc.	Redondo Beach	California	United States	90277
11	TORI REDONDO BEACH (Cancer Care Associates Medical Group, Inc.)	Redondo Beach	California	United States	90277
12	Sansum Medical Clinic	Santa Barbara	California	United States	93105
13	Santa Barbara Hematology Oncology Medical Group, Inc.	Santa Barbara	California	United States	93105
14	Central Coast Medical Oncology Corporation	Santa Maria	California	United States	93454
15	Trivalley Oncology Hematology	Westlake Village	California	United States	91361
16	Suburban Hematology-Oncology Associates, P.A.	Lawrenceville	Georgia	United States	30045
17	Northwest Georgia Oncology Centers, P.C.	Marietta	Georgia	United States	30060
18	Comprehensive Cancer Centers of Nevada	Las Vegas	Nevada	United States	89109

Sponsors and Collaborators

• Translational Oncology Research International
• National Cancer Institute (NCI)
• University of California, Los Angeles

Investigators

• Principal Investigator: Zev A. Wainberg, MD, Jonsson Comprehensive Cancer Center

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Translational Oncology Research International
• ClinicalTrials.gov Identifier: NCT00985192
• Other Study ID Numbers: CDR0000655574; UCLA-TRIO-TORI-GI-06; IRB# 09-07-061-01; NOVARTIS-UCLA-TRIO-TORI-GI-06
• First Posted: Sep 28, 2009
• Last Update Posted: Aug 5, 2020
• Last Verified: Feb 1, 2016

• Keywords provided by Translational Oncology Research International: adenocarcinoma of the esophagus; adenocarcinoma of the stomach; recurrent esophageal cancer; stage III esophageal cancer; stage IV esophageal cancer; recurrent gastric cancer; stage III gastric cancer; stage IV gastric cancer
• Additional relevant MeSH terms: Stomach Neoplasms; Esophageal Neoplasms; Everolimus

Study Results

Participant Flow

Pre-assignment Detail	A total of 49 patients were enrolled between December of 2007 and November of 2009 from 18 participating sites including the University of California Los Angeles hospitals and clinics participating in the TRIO-US Network.

Arm/Group Title	Everolimus
Arm/Group Description	Patients receive oral everolimus once daily on days 1-14. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity everolimus laboratory biomarker analysis
Period Title: Overall Study
STARTED	49
COMPLETED	45
NOT COMPLETED	4

Baseline Characteristics

Arm/Group Title	Everolimus
Arm/Group Description	Patients receive oral everolimus once daily on days 1-14. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity everolimus laboratory biomarker analysis
Overall Participants	45
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	64
Sex: Female, Male (Count of Participants)
Female	8 17.8%
Male	37 82.2%
Race/Ethnicity, Customized (participants) [Number]
White	28 62.2%
Hispanic	10 22.2%
Asian	4 8.9%
Black	3 6.7%
Region of Enrollment (participants) [Number]
United States	45 100%
Disease Site (participants) [Number]
Gastric	21 46.7%
Gastroesophageal Junction	13 28.9%
Esophagus	11 24.4%
Eastern Cooperative Oncology Group (ECOG) score (participants) [Number]
0	15 33.3%
1	30 66.7%

Outcome Measures

1. Primary Outcome

Title	Overall Disease-control Rate in Patients With Previously Treated Unresectable or Metastatic Adenocarcinoma of the Upper Gastrointestinal Tract Treated With Everolimus.
Description	Disease control rate (DCR), defined as complete response (CR) + partial response (PR) + stable disease (SD) according to Response Evaluation Criteria In Solid Tumors (RECIST) criteria.
Time Frame	Radiologic disease assessment was performed every 8 weeks (14 days = 1 cycle) treatment discontinuation.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Everolimus
Arm/Group Description	Patients receive oral everolimus once daily on days 1-14. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity everolimus laboratory biomarker analysis
Measure Participants	45
Number (95% Confidence Interval) [percent subjects with disease control]	40

2. Secondary Outcome

Title	Overall Survival
Description	Overall Survival (OS), defined as the time from date of initial treatment to date of death. Survival function was estimated using the Kaplan-Meier method.
Time Frame	2.5 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Everolimus
Arm/Group Description	Patients receive oral everolimus once daily on days 1-14. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity everolimus laboratory biomarker analysis
Measure Participants	45
Median (95% Confidence Interval) [months]	3.4

3. Secondary Outcome

Title	Efficacy in Terms of Progression Free Response
Description	Progression-free survival (PFS), was defined as the time from the date of initial treatment to first objective documentation of disease progression, or death. Estimated using the Kaplan-Meier method. Complete response (CR) + partial response (PR) + stable disease (SD) were determined according to Response Evaluation Criteria In Solid Tumors (RECIST) criteria. Radiologic disease assessments were utilized.
Time Frame	evry 3 months in year 1, every 6 months after that

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Everolimus
Arm/Group Description	Patients receive oral everolimus once daily on days 1-14. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity everolimus laboratory biomarker analysis
Measure Participants	45
Median (95% Confidence Interval) [months]	1.8

4. Secondary Outcome

Title	Observed Biomarkers
Description	Potential correlations between clinical outcome and biomarkers of interest, including S6 protein overexpression and/or other mTOR-related proteins in tumor tissue samples from these patients.
Time Frame	30 months

Outcome Measure Data

Analysis Population Description

Exploratory analysis of translational endpoints in patient samples, Representative paraffin blocks were required for all participating patients. Tissue blocks were obtained on 39 patients. p-s6 and p-mTOR IHC expression in tumors

Arm/Group Title	Everolimus
Arm/Group Description	Patients receive oral everolimus once daily on days 1-14. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity everolimus laboratory biomarker analysis
Measure Participants	39
Tumor Grade 0, p-S6	4
Tumor Grade 1+, p-S6	15
Tumor Grade 2+, p-S6	8
Tumor Grade 3+, p-S6	9
Tumor Grade 4+, p-S6	3
Tumor Grade 0, p-mTOR	0
Tumor Grade 1+, p-mTOR	8
Tumor Grade 2+, p-mTOR	22
Tumor Grade 3+, p-mTOR	9
Tumor Grade 4+, p-mTOR	0

5. Secondary Outcome

Title	Biomarker Correlations: Progression Free Survival
Description	Potential correlations between progression free survival and S6 protein and mTOR-related proteins in tumor tissue samples from these patients.
Time Frame	30 months

Outcome Measure Data

Analysis Population Description

Exploratory analysis of translational endpoints in patient samples, Representative paraffin blocks were required for all participating patients. Tissue blocks were obtained on 39 patients. p-s6 and p-mTOR IHC expression in tumors

Arm/Group Title	Everolimus
Arm/Group Description	Patients receive oral everolimus once daily on days 1-14. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity everolimus laboratory biomarker analysis
Measure Participants	39
p-S6 level 0-2	1.8
p-S6 level >2	3.5
p-mTOR level 0-2	1.8
p-mTOR level >2	2.6

6. Secondary Outcome

Title	Biomarker Correlations: Time to Progression
Description	Potential correlations between time to progression and S6 protein and mTOR-related proteins in tumor tissue samples from these patients.
Time Frame	30 months

Outcome Measure Data

Analysis Population Description

Exploratory analysis of translational endpoints in patient samples, Representative paraffin blocks were required for all participating patients. Tissue blocks were obtained on 39 patients. p-s6 and p-mTOR IHC expression in tumors

Arm/Group Title	Everolimus
Arm/Group Description	Patients receive oral everolimus once daily on days 1-14. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity everolimus laboratory biomarker analysis
Measure Participants	39
p-S6 level 0-2	1.75
p-S6 level >2	3.4
p-mTOR level 0-2	1.8
p-mTOR level >2	2.6

Adverse Events

Time Frame	Adverse Event data collected continuously for subjects. Subjects evaluated every 14 days until 30 days after last drug dose. Up to 2.5 years.
Adverse Event Reporting Description	Systemic adverse event assessment occurred every 14 days through investigator assessment during Treatment.
Arm/Group Title	Everolimus
Arm/Group Description	Patients receive oral everolimus once daily on days 1-14. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity everolimus laboratory biomarker analysis
All Cause Mortality
	Everolimus
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Everolimus
	Affected / at Risk (%)	# Events
Total	24/47 (51.1%)
Blood and lymphatic system disorders
Anemia	5/47 (10.6%)	5
Thrombocytopenia	9/47 (19.1%)	9
Hyperglycemia	1/47 (2.1%)	1
Hyperlipidemia	2/47 (4.3%)	2
General disorders
Fatigue	9/47 (19.1%)	9
Metabolism and nutrition disorders
Anorexia	5/47 (10.6%)	5
Musculoskeletal and connective tissue disorders
Mucositis	2/47 (4.3%)	2
Other (Not Including Serious) Adverse Events
	Everolimus
	Affected / at Risk (%)	# Events
Total	47/47 (100%)
Blood and lymphatic system disorders
ALT	2/47 (4.3%)	2
Anemia	17/47 (36.2%)	31
Hypercholesteremia	9/47 (19.1%)	10
Hyperglycemia	7/47 (14.9%)	13
Hyperlipidemia	1/47 (2.1%)	1
Hypertriglyceridemia	5/47 (10.6%)	5
Hypocalcemia	2/47 (4.3%)	3
Hypokalemia	1/47 (2.1%)	1
LDL - elevated	4/47 (8.5%)	5
Leukopenia	3/47 (6.4%)	5
Lymphopenia	1/47 (2.1%)	1
Neutropenia	5/47 (10.6%)	7
Thrombocytopenia	18/47 (38.3%)	39
Cardiac disorders
Cardiac Infarction	1/47 (2.1%)	1
Cardiopulmonary Arrest	1/47 (2.1%)	1
Tachycardia	1/47 (2.1%)	1
Ear and labyrinth disorders
Dizziness	2/47 (4.3%)	2
Nasal/paranasal reactions	1/47 (2.1%)	2
Stomatitis	2/47 (4.3%)	3
Gastrointestinal disorders
Constipation	4/47 (8.5%)	4
Diarrhea	11/47 (23.4%)	11
Flatulence	1/47 (2.1%)	1
Nausea	13/47 (27.7%)	15
Pain - Stomach	1/47 (2.1%)	1
Vomiting	8/47 (17%)	10
General disorders
Bloating	1/47 (2.1%)	1
Cachexia	1/47 (2.1%)	1
Dehydration	2/47 (4.3%)	4
Dry Mouth	1/47 (2.1%)	1
Dysphagia	1/47 (2.1%)	1
Fatigue	22/47 (46.8%)	39
Halitosis	1/47 (2.1%)	1
Hot flashes	1/47 (2.1%)	1
Insomnia	1/47 (2.1%)	1
Muscle weakness - generalized	1/47 (2.1%)	1
Performance status decrease	6/47 (12.8%)	8
Sweating	1/47 (2.1%)	1
Taste alteration	1/47 (2.1%)	1
Weakness	2/47 (4.3%)	2
Weight loss	3/47 (6.4%)	4
Hepatobiliary disorders
AST	4/47 (8.5%)	4
Infections and infestations
Fever	2/47 (4.3%)	2
Infection - Kidney	1/47 (2.1%)	1
Infection - Lung	1/47 (2.1%)	1
Infection - urinary tract NOS	1/47 (2.1%)	1
Metabolism and nutrition disorders
Anorexia	14/47 (29.8%)	18
Musculoskeletal and connective tissue disorders
Mucositis - oral cavity	11/47 (23.4%)	17
Nervous system disorders
Neuropathy-sensory	2/47 (4.3%)	2
Pain - abdomen	8/47 (17%)	11
Pain - back	1/47 (2.1%)	1
Pain - body	1/47 (2.1%)	1
Pain - chest/thorax NOS	1/47 (2.1%)	1
Pain - extremity-limb	1/47 (2.1%)	1
Pain - eye	1/47 (2.1%)	1
Pain - head	2/47 (4.3%)	2
Pain - hip	1/47 (2.1%)	1
Pain - NOS	1/47 (2.1%)	1
Pain - oral cavity	1/47 (2.1%)	1
Pain - shoulder	1/47 (2.1%)	1
Pain - throat	2/47 (4.3%)	2
Psychiatric disorders
Mood alteration - anxiety	1/47 (2.1%)	1
Mood alteration - depression	1/47 (2.1%)	1
Respiratory, thoracic and mediastinal disorders
Bronchospasm	1/47 (2.1%)	1
Cough	5/47 (10.6%)	5
Dyspnea	4/47 (8.5%)	6
Pneumonitis	1/47 (2.1%)	3
Skin and subcutaneous tissue disorders
Alkaline phosphatase	3/47 (6.4%)	3
Distension	1/47 (2.1%)	1
Dry skin	6/47 (12.8%)	6
Ecchymosis	1/47 (2.1%)	1
Edema - limb	1/47 (2.1%)	1
Pruritus	5/47 (10.6%)	5
Rash	11/47 (23.4%)	17
Surgical and medical procedures
Hemorrhage pulmonary - nose	4/47 (8.5%)	4
Vascular disorders
Hemorrhage, GI - abdomen NOS	1/47 (2.1%)	1
Hypotension	1/47 (2.1%)	1

Limitations/Caveats

This study had several limitations with the major weakness being that it was a single- rm, non-comparative study. At the time this study was launched, a Japanese report indicating a DCR was 50 % was not yet reported.

More Information

Certain Agreements

Principal Investigators are NOT 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.