Regorafenib in Treating Patients With Locally Advanced Cancer of the Esophagus or Gastroesophageal Junction Who Have Completed Chemoradiation Therapy and Surgery

• Sponsor: Academic and Community Cancer Research United (Other)
• Overall Status: Terminated
• CT.gov ID: NCT02234180
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 3
• Locations: 10
• Arms: 2
• Duration (Months): 21.2
• Patients Per Site: 0.3
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

This randomized phase II trial studies how well regorafenib works in treating patients with cancer of the esophagus or gastroesophageal junction that has spread from where it started to nearby tissue or lymph nodes and have completed chemoradiation therapy and surgery. Regorafenib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Condition or Disease	Intervention/Treatment	Phase
Adenocarcinoma of the Gastroesophageal Junction; Stage IIB Esophageal Adenocarcinoma; Stage IIIA Esophageal Adenocarcinoma; Stage IIIB Esophageal Adenocarcinoma; Stage IIIC Esophageal Adenocarcinoma	Other: Placebo; Drug: Regorafenib	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. To compare the disease-free survival (DFS) for patients with resected esophageal and gastroesophageal (GE) junction adenocarcinoma treated with regorafenib vs. placebo in the adjuvant setting.

SECONDARY OBJECTIVES:

1. To compare the safety profile of adjuvant regorafenib vs. placebo in patients with locally advanced resectable esophageal and GE junction adenocarcinoma.

2. To compare the overall survival (OS) for patients with resected esophageal and GE junction adenocarcinoma treated with regorafenib vs. placebo in the adjuvant setting.

3. To compare the DFS in those patients that receive at least 1 cycle of therapy.

4. To collect tumor samples for future genomic analysis to explore the biology of locally advanced esophageal and GE junction adenocarcinoma.

5. DFS will be compared between the arms from the time of surgery as well.

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

ARM I: Within 6-12 weeks after surgery, patients receive regorafenib orally (PO) once daily (QD) on days 1-21.

ARM II: Within 6-12 weeks after surgery, patients receive placebo PO QD on days 1-21.

In both arms, courses repeat every 28 days for up to 1 year in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years, and every 6 months for up to 5 years.

Study Design

• Study Type: Interventional
• Actual Enrollment: 3 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double
• Primary Purpose: Treatment
• Official Title: Randomized Phase II Double Blind Study of Adjuvant Regorafenib vs Placebo in Patients With Node Positive Esophageal Cancer That Completed Pre-operative Therapy
• Study Start Date: Sep 1, 2014
• Actual Primary Completion Date: Jun 8, 2016
• Actual Study Completion Date: Jun 8, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm I (regorafenib) Within 6-12 weeks after surgery, patients receive regorafenib PO QD on days 1-21. Courses repeat every 28 days for up to 1 year in the absence of disease progression or unacceptable toxicity.	Drug: Regorafenib; Given PO; Other Names: BAY 73-4506 Stivarga
Placebo Comparator: Arm II (placebo) Within 6-12 weeks after surgery, patients receive placebo PO QD on days 1-21. Courses repeat every 28 days for up to 1 year in the absence of disease progression or unacceptable toxicity.	Other: Placebo; Given PO; Other Names: placebo therapy PLCB sham therapy

Outcome Measures

Primary Outcome Measures

1. Disease Free Survival (DFS) [Time from randomization to the first of either disease recurrence or death from any cause, assessed up to 1 year and 10 months]

   Disease free survival (DFS) is defined as the time from randomization to the first of either disease recurrence or death from any cause. The distribution of DFS will be estimated using the Kaplan Meier method.

Secondary Outcome Measures

1. Toxicity, Assessed Using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 (v4) [Up to 1 year and 10 months]

   The maximum grade for each type of toxicity will be recorded for each patient, and frequency tables will be reviewed to determine toxicity patterns within patient groups. In addition, we will review all adverse event data that is graded as 3, 4, or 5 and classified as either "unrelated" or "unlikely to be related" to study treatment in the event of an actual relationship developing. The overall toxicity rates (percentages) for grade 3 or higher adverse events considered at least possibly related to treatment are reported below.

2. Overall Survival (OS) [Time from randomization to death due to any cause, assessed up to 1 year and 10 months]

   Overall survival (OS) is defined as the time from randomization to death due to any cause.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Histological confirmation of node positive (any T stage N1-3) proximal esophageal, distal esophagus or gastroesophageal (GE) junction adenocarcinoma (Siewert I, II, or

1. after completing preoperative chemoradiation and surgery; supporting pathology report sufficient for registration; available tumor tissue from endoscopic biopsies prior to preoperative chemotherapy (chemo)/radiation therapy (RT), and tumor from surgical specimens will be submitted to Academic and Community Cancer Research United (ACCRU), but not be required prior registration; Note: if tissue is depleted, patient will still be eligible after discussion with the physician

• Imaging (computed tomography [CT] or magnetic resonance imaging [MRI]) =< 28 days of study registration negative for disease recurrence

• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1

• Absolute neutrophil count (ANC) >= 1500/mm^3

• Platelet count >= 100,000/mm^3

• Total bilirubin =< 1.5 x the upper limits of normal (ULN)

• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 x ULN (=< 5 x ULN for subjects with liver involvement of their cancer)

• Alkaline phosphatase limit =< 2.5 x ULN (=< 5 x ULN for subjects with liver involvement of their cancer)

• Lipase =< 1.5 x the ULN

• Serum creatinine =< 1.5 x the ULN

• International normalized ratio (INR)/partial thromboplastin time (PTT) =< 1.5 x ULN; Note-subjects who are therapeutically treated with an agent such as warfarin or heparin will be allowed to participate provided that their medication dose and INR/PTT are stable; close monitoring (day 1 of each cycle) is mandatory; if either of these values is above the therapeutic range, the doses should be modified and the assessments should be repeated weekly until they are stable

• Negative pregnancy test done =< 7 days prior to registration, for women of childbearing potential only

• Provide informed written consent

• Willing to return to enrolling institution for follow-up (during the Active Monitoring Phase of the study)

• Able to swallow and retain oral medications and begin therapy within 6 to 12 weeks post-surgery

• Provide blood samples for the mandatory correlative research purposes

Exclusion Criteria:

• Presence of metastatic or recurrent disease

• R1 or R2 resection

• Patients who have not recovered from serious adverse events (as determined by treating doctor of medicine [MD]) related to surgery

• Uncontrolled hypertension (systolic pressure > 140 mm Hg or diastolic pressure > 90 mm Hg on repeated measurement) despite optimal medical management per physician discretion

• Active or clinically significant cardiac disease including:

• Congestive heart failure - New York Heart Association (NYHA) > class II

• Active coronary artery disease

• Cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers or digoxin

• Unstable angina (anginal symptoms at rest), new-onset angina < 3 months before randomization, or myocardial infarction within 6 months before randomization

• Evidence or history of bleeding diathesis or coagulopathy

• Any hemorrhage or bleeding event >= National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4 grade 3 =< 4 weeks prior to registration

• Prior cancers < 3 years, with the exception of in-situ cervical cancer, low grade prostate cancer and basal or squamous cell skin cancers

• Subjects with thrombotic, embolic, venous, or arterial events, such as cerebrovascular accident (including transient ischemic attacks) deep vein thrombosis or pulmonary embolism =< 6 months prior to registration

• Receiving any medications or substances that are strong or moderate inhibitors of cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4); use of strong or moderate inhibitors are prohibited =< 7 days to registration

• Receiving any medications or substances that are inducers of CYP3A4; use of inducers are prohibited =< 7 days prior to registration

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Carle Cancer Center	Urbana	Illinois	United States	61801
2	Cancer Center of Kansas - Wichita	Wichita	Kansas	United States	67214
3	Ochsner Medical Center Jefferson	New Orleans	Louisiana	United States	70121
4	Mayo Clinic	Rochester	Minnesota	United States	55905
5	Missouri Valley Cancer Consortium	Omaha	Nebraska	United States	68106
6	Dartmouth Hitchcock Medical Center	Lebanon	New Hampshire	United States	03756
7	Memorial Sloan-Kettering Cancer Center	New York	New York	United States	10065
8	Comprehensive Cancer Center of Wake Forest University	Winston-Salem	North Carolina	United States	27157
9	Ohio State University Comprehensive Cancer Center	Columbus	Ohio	United States	43210
10	Toledo Clinic Cancer Centers-Toledo	Toledo	Ohio	United States	43623

Sponsors and Collaborators

• Academic and Community Cancer Research United
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Yelena Janjigian, Academic and Community Cancer Research United

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Academic and Community Cancer Research United
• ClinicalTrials.gov Identifier: NCT02234180
• Other Study ID Numbers: RU021212I; NCI-2015-01699; NCI-2014-01962; RU021212I; P30CA015083
• First Posted: Sep 9, 2014
• Last Update Posted: Oct 17, 2018
• Last Verified: Oct 1, 2018

• Additional relevant MeSH terms: Adenocarcinoma; Esophageal Neoplasms

Study Results

Participant Flow

Arm/Group Title	Arm I (Regorafenib)	Arm II (Placebo)
Arm/Group Description	Within 6-12 weeks after surgery, patients will receive regorafenib PO QD on days 1-21. Courses repeat every 28 days for up to 1 year in the absence of disease progression or unacceptable toxicity.	Within 6-12 weeks after surgery, patients will receive placebo PO QD on days 1-21. Courses repeat every 28 days for up to 1 year in the absence of disease progression or unacceptable toxicity.
Period Title: Overall Study
STARTED	2	1
COMPLETED	2	1
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Arm I/II (Regorafenib/Placebo)
Arm/Group Description	Within 6-12 weeks after surgery, patients receive regorafenib OR placebo PO QD on days 1-21. Courses repeat every 28 days for up to 1 year in the absence of disease progression or unacceptable toxicity.
Overall Participants	3
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	54.0
Sex: Female, Male (Count of Participants)
Female	0 0%
Male	3 100%
Region of Enrollment (Count of Participants)
United States	3 100%

Outcome Measures

1. Primary Outcome

Title	Disease Free Survival (DFS)
Description	Disease free survival (DFS) is defined as the time from randomization to the first of either disease recurrence or death from any cause. The distribution of DFS will be estimated using the Kaplan Meier method.
Time Frame	Time from randomization to the first of either disease recurrence or death from any cause, assessed up to 1 year and 10 months

Outcome Measure Data

Analysis Population Description

Only 1 patient was registered to the placebo arm. Due to protected health information, listing only 1 patient's results is contraindicated. The data below is descriptive and shouldn't be trusted because of the small sample size.

Arm/Group Title	Arm I/II (Regorafenib/Placebo)
Arm/Group Description	Within 6-12 weeks after surgery, patients receive regorafenib OR placebo PO QD on days 1-21. Courses repeat every 28 days for up to 1 year in the absence of disease progression or unacceptable toxicity.
Measure Participants	3
Median (95% Confidence Interval) [months]	4.83

2. Secondary Outcome

Title	Toxicity, Assessed Using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 (v4)
Description	The maximum grade for each type of toxicity will be recorded for each patient, and frequency tables will be reviewed to determine toxicity patterns within patient groups. In addition, we will review all adverse event data that is graded as 3, 4, or 5 and classified as either "unrelated" or "unlikely to be related" to study treatment in the event of an actual relationship developing. The overall toxicity rates (percentages) for grade 3 or higher adverse events considered at least possibly related to treatment are reported below.
Time Frame	Up to 1 year and 10 months

Outcome Measure Data

Analysis Population Description

Only 1 patient was registered to the placebo arm. Due to protected health information, listing only 1 patient's results is contraindicated. The data below is descriptive and shouldn't be trusted because of the small sample size.

Arm/Group Title	Arm I/II (Regorafenib/Placebo)
Arm/Group Description	Within 6-12 weeks after surgery, patients receive regorafenib OR placebo PO QD on days 1-21. Courses repeat every 28 days for up to 1 year in the absence of disease progression or unacceptable toxicity.
Measure Participants	3
Number [percentage of grade 3+ AEs]	0

3. Secondary Outcome

Title	Overall Survival (OS)
Description	Overall survival (OS) is defined as the time from randomization to death due to any cause.
Time Frame	Time from randomization to death due to any cause, assessed up to 1 year and 10 months

Outcome Measure Data

Analysis Population Description

Only 1 patient was registered to the placebo arm. Due to protected health information, listing only 1 patient's results is contraindicated. The data below is descriptive and shouldn't be trusted because of the small sample size.

Arm/Group Title	Arm I/II (Regorafenib/Placebo)
Arm/Group Description	Within 6-12 weeks after surgery, patients receive regorafenib OR placebo PO QD on days 1-21. Courses repeat every 28 days for up to 1 year in the absence of disease progression or unacceptable toxicity.
Measure Participants	3
Median (95% Confidence Interval) [months]	NA

Adverse Events

Time Frame	Up to 1 year and 10 months
Adverse Event Reporting Description	The descriptions & grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting. Each CTCAE term in the current version is a unique representation of a specific event used for medical documentation & scientific analysis & is a single MedDRA Lowest Level Term (LLT). Only 1 patient was registered to the placebo arm. Due to protected health information, listing only 1 patient's results is contraindicated.
Arm/Group Title	Arm I/II (Regorafenib/Placebo)
Arm/Group Description	Within 6-12 weeks after surgery, patients receive regorafenib OR placebo PO QD on days 1-21. Courses repeat every 28 days for up to 1 year in the absence of disease progression or unacceptable toxicity.
All Cause Mortality
	Arm I/II (Regorafenib/Placebo)
	Affected / at Risk (%)	# Events
Total	0/3 (0%)
Serious Adverse Events
	Arm I/II (Regorafenib/Placebo)
	Affected / at Risk (%)	# Events
Total	1/3 (33.3%)
Vascular disorders
Thromboembolic event	1/3 (33.3%)	1
Other (Not Including Serious) Adverse Events
	Arm I/II (Regorafenib/Placebo)
	Affected / at Risk (%)	# Events
Total	3/3 (100%)
Gastrointestinal disorders
Diarrhea	2/3 (66.7%)	6
Vomiting	1/3 (33.3%)	2
General disorders
Fatigue	1/3 (33.3%)	3
Skin and subcutaneous tissue disorders
Palmar-plantar erythrodysesthesia syndrome	2/3 (66.7%)	7
Vascular disorders
Hypertension	2/3 (66.7%)	6

Limitations/Caveats

[Not Specified]

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.