Everolimus and Combination Chemotherapy in Treating Patients With Metastatic Stomach or Esophageal Cancer

• Sponsor: City of Hope Medical Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT01231399
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 6
• Locations: 3
• Arm: 1
• Duration (Months): 53
• Patients Per Site: 2
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

RATIONALE: Everolimus may stop the growth of stomach or esophageal cancer by blocking blood flow to the tumor. Drugs used in chemotherapy, such as leucovorin calcium, fluorouracil, and oxaliplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing, or by stopping them from spreading. Giving everolimus together with combination chemotherapy may kill more tumor cells.

PURPOSE: This phase I trial is studying the side effects and best dose of everolimus when given together with combination chemotherapy in treating patients with metastatic stomach or esophageal cancer that has spread to other places in the body.

Condition or Disease	Intervention/Treatment	Phase
Adenocarcinoma of the Esophagus; Adenocarcinoma of the Gastroesophageal Junction; Diffuse Adenocarcinoma of the Stomach; Intestinal Adenocarcinoma of the Stomach; Mixed Adenocarcinoma of the Stomach; Recurrent Esophageal Cancer; Recurrent Gastric Cancer; Stage IV Esophageal Cancer; Stage IV Gastric Cancer	Drug: fluorouracil; Drug: leucovorin calcium; Drug: oxaliplatin; Drug: everolimus; Other: laboratory biomarker analysis; Other: immunohistochemistry staining method; Genetic: microarray analysis	Phase 1/Phase 2

Detailed Description

OBJECTIVES:

1. To determine the maximum tolerated dose of everolimus to use in combination with mFOLFOX6 [oxaliplatin, leucovorin (leucovorin calcium), 5-FU (fluorouracil)].

2. To better describe the toxicities associated with the combination of everolimus with mFOLFOX6.

3. To assess response rate and progression-free survival in this patient population.

4. To assess overall survival in patients with metastatic gastric, esophageal and gastroesophageal junction (GEJ) adenocarcinoma treated with the combination of mFOLFOX6 + everolimus.

OUTLINE: This is a dose-escalation study of everolimus. Patients receive fluorouracil intravenously (IV) continuously over 46 hours, leucovorin calcium IV over 2 hours, and oxaliplatin IV over 2 hours on day 1. Patients also receive oral everolimus once daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up periodically for 1 year.

Study Design

• Study Type: Interventional
• Actual Enrollment: 6 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase Ib Trial of mFOLFOX6 and Everolimus (NSC-733504) in Patients With Metastatic Gastroesophageal Adenocarcinoma
• Study Start Date: Feb 1, 2012
• Actual Primary Completion Date: Jul 1, 2016
• Actual Study Completion Date: Jul 1, 2016

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Arm I Patients receive fluorouracil IV continuously over 46 hours, leucovorin calcium IV over 2 hours, and oxaliplatin IV over 2 hours on day 1. Patients also receive oral everolimus once daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Drug: fluorouracil; Given IV; Other Names: 5-fluorouracil 5-Fluracil 5-FU Adrucil Efudex FU ; Drug: leucovorin calcium; Given IV; Other Names: calcium folinate CF CFR citrovorum factor LV Wellcovorin ; Drug: oxaliplatin; Given IV; Other Names: 1-OHP Dacotin Dacplat diaminocyclohexane oxalatoplatinum Eloxatin L-OHP ; Drug: everolimus; Given orally; Other Names: 42-O-(2-hydroxy)ethyl rapamycin Afinitor RAD001 ; Other: laboratory biomarker analysis; Correlative studies; Other: immunohistochemistry staining method; Correlative studies; Other Names: immunohistochemistry ; Genetic: microarray analysis; Correlative studies; Other Names: gene expression profiling

Outcome Measures

Primary Outcome Measures

1. Maximum Tolerated Dose (MTD) of Everolimus [Course 1 (first 28 days)]

   The highest dose tested in which fewer than 33% of patients experience an attributable DLT to the study drug, when at least 6 patients are treated at that dose and are evaluable for toxicity. Toxicities will be assessed using Common Terminology Criteria for Adverse Events (CTCAE) v4.0.

2. Number of Subject With Overall Response [Up to 5 years]

   Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR

3. Progression-free Survival [up to 5 years]

   Estimated using the product-limit method of Kaplan and Meier. From the date treatment started until the date of first documented progression or date of death from any cause, whichever came first. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.

4. Overall Survival [Up to 5 years.]

   Estimated using the product-limit method of Kaplan and Meier. From the date treatment started until the date of death from any cause.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 19 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patients must have histologically confirmed diagnosis of gastric, esophageal, and GEJ adenocarcinoma

• Patients must have metastatic disease

• Patients must not have received any chemotherapy for metastatic disease

• Patients may have received prior adjuvant chemotherapy; completion of chemotherapy must be greater than 6 months from date of recurrent disease

• Patients must have computed tomography (CT) or magnetic resonance imaging (MRI) scan; patients must have at least one measurable site of disease according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria that has not been previously irradiated; if the patient has had previous radiation to the marker lesion(s), there must be evidence of progression since the radiation

• Patients must have a ECOG Performance Status of 0-1

• Absolute neutrophil count (ANC) > 1,500/mcl

• Platelet count > 100,000/mcl

• Hemoglobin (Hg) > 9 g/dL

• Serum creatinine < 1.5 mg/dl and/or Creatinine clearance > 60 cc/min

• Bilirubin < 1.5 mg/dl

• Serum glutamic oxaloacetic transaminase (SGOT) and/or serum glutamic pyruvic transaminase (SGPT) =< 2.5 x institutional upper limit of normal (IULN) (=< 5 x upper limit of normal [ULN] in patients with liver metastases)

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

• Fasting triglycerides =< 2.5 x ULN; NOTE: in case one or both of these thresholds are exceeded, the patient can only be included after initiation of appropriate lipid lowering medication

• Patients should have controlled diabetes as evidenced by hemoglobin (Hb)A1C =< 8%

• International normalized ratio (INR) and partial thromboplastin time (PTT) =< 1.5; (anticoagulation is allowed if target INR =< 1.5 on a stable dose of warfarin or on a stable dose of low molecular weight [LMW] heparin for > 2 weeks at time of randomization)

• Due to the possibility of harm to a fetus or nursing infant from this treatment regimen, patients must not be pregnant or nursing (or plan to become pregnant); women and men of reproductive potential must have agreed to use a highly effective contraceptive method for at least 8 weeks after treatment

• Patients with risk factors for contraction hepatitis B or C should undergo screening prior to treatment on protocol. Patients with detectable viral titers are required to receive treatment for 4 weeks prior to starting protocol therapy.

• Patients must be able to swallow pills

• No other prior malignancy within the past 3 years is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated Stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease free for five years

• All patients must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines

• Patients must have pathology specimen available for submission

Exclusion Criteria:

• Patients currently receiving anticancer therapies or who have received anticancer therapies within 4 weeks of the start of study drug (including chemotherapy, radiation therapy, antibody based therapy, etc)

• Patients who have received prior treatment with an mammalian target of rapamycin (mTOR) inhibitor (sirolimus, temsirolimus, everolimus)

• Patients with a known hypersensitivity to everolimus or other rapamycins (sirolimus, temsirolimus) or to its excipients

• Patients, who have had a major surgery or significant traumatic injury within 4 weeks of start of study drug, patients who have not recovered from the side effects of any major surgery (defined as requiring general anesthesia) or patients that may require major surgery during the course of the study

• Prior treatment with any investigational drug within the preceding 4 weeks

• Patients receiving chronic, systemic treatment with corticosteroids (prednisone > 10 mg per day) or another immunosuppressive agent; topical or inhaled corticosteroids are allowed

• Patients should not receive immunization with attenuated live vaccines within one week of study entry or during study period

• Uncontrolled brain or leptomeningeal metastases, including patients who continue to require glucocorticoids for brain or leptomeningeal metastases

• Patients who have any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study such as:

• Symptomatic congestive heart failure of New York heart Association Class III or IV

• Unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction within 6 months of start of study drug, serious uncontrolled cardiac arrhythmia or any other clinically significant cardiac disease

• Severely impaired lung function as defined as spirometry and diffusion lung capacity of carbon monoxide (DLCO) that is 50% of the normal predicted value and/or 02 saturation that is 88% or less at rest on room air

• Uncontrolled diabetes as defined by fasting serum glucose > 1.5 x ULN

• Active (acute or chronic) or uncontrolled severe infections

• Liver disease such as cirrhosis, chronic active hepatitis or chronic persistent hepatitis

• A known history of human immunodeficiency virus (HIV) seropositivity

• Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of everolimus (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection)

• Patients with an active, bleeding diathesis; history of noncompliance to medical regimens

• Patients unwilling to or unable to comply with the protocol

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	City of Hope Medical Center	Duarte	California	United States	91010
2	South Pasadena Cancer Center	South Pasadena	California	United States	91030
3	H. Lee Moffitt Cancer Center and Research Institute	Tampa	Florida	United States	33612

Sponsors and Collaborators

• City of Hope Medical Center
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Vincent Chung, City of Hope Medical Center

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: City of Hope Medical Center
• ClinicalTrials.gov Identifier: NCT01231399
• Other Study ID Numbers: 10064; NCI-2010-02168
• First Posted: Nov 1, 2010
• Last Update Posted: May 31, 2017
• Last Verified: Apr 1, 2017

• Additional relevant MeSH terms: Adenocarcinoma; Stomach Neoplasms; Esophageal Neoplasms; Recurrence; Calcium, Dietary; Leucovorin; Fluorouracil; Oxaliplatin; Everolimus; Calcium; Levoleucovorin

Study Results

Participant Flow

Arm/Group Title	Dose Level 1 - 2.5 mg Everolimus Daily
Arm/Group Description	Patients receive 400 mg/m^2 fluorouracil (5-FU) IV slow push day 1, 2,400 mg/m^2 fluorouracil (5-FU) IV continuously over 46 hours days 1-2, 400 mg/m^2 leucovorin calcium IV over 2 hours, and 85 mg/m^2 oxaliplatin IV over 2 hours on day 1. Patients also receive 2.5 mg oral everolimus once daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. fluorouracil: Given IV leucovorin calcium: Given IV oxaliplatin: Given IV everolimus: Given orally
Period Title: Overall Study
STARTED	6
COMPLETED	6
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Dose Level 1 - 2.5 mg Everolimus Daily
Arm/Group Description	Patients receive 400 mg/m^2 fluorouracil (5-FU) IV slow push day 1, 2,400 mg/m^2 fluorouracil (5-FU) IV continuously over 46 hours days 1-2, 400 mg/m^2 leucovorin calcium IV over 2 hours, and 85 mg/m^2 oxaliplatin IV over 2 hours on day 1. Patients also receive 2.5 mg oral everolimus once daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. fluorouracil: Given IV leucovorin calcium: Given IV oxaliplatin: Given IV everolimus: Given orally
Overall Participants	6
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	58
Sex: Female, Male (Count of Participants)
Female	2 33.3%
Male	4 66.7%
Region of Enrollment (participants) [Number]
United States	6 100%

Outcome Measures

1. Primary Outcome

Title	Maximum Tolerated Dose (MTD) of Everolimus
Description	The highest dose tested in which fewer than 33% of patients experience an attributable DLT to the study drug, when at least 6 patients are treated at that dose and are evaluable for toxicity. Toxicities will be assessed using Common Terminology Criteria for Adverse Events (CTCAE) v4.0.
Time Frame	Course 1 (first 28 days)

Outcome Measure Data

Analysis Population Description

All patients observed for 28 days while receiving a full course of therapy or who experienced a DLT. Patients withdrawing before completion of the first course, for reasons other than DLT, were replaced.

Arm/Group Title	Dose Level 1 - 2.5 mg Everolimus
Arm/Group Description	Patients receive 400 mg/m^2 fluorouracil (5-FU) IV slow push day 1, 2,400 mg/m^2 fluorouracil (5-FU) IV continuously over 46 hours days 1-2, 400 mg/m^2 leucovorin calcium IV over 2 hours, and 85 mg/m^2 oxaliplatin IV over 2 hours on day 1. Patients also receive 2.5 mg oral everolimus once daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. fluorouracil: Given IV leucovorin calcium: Given IV oxaliplatin: Given IV everolimus: Given orally
Measure Participants	6
Number [mg]	2.5

2. Primary Outcome

Title	Number of Subject With Overall Response
Description	Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR
Time Frame	Up to 5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Dose Level 1 - 2.5 mg Everolimus Daily
Arm/Group Description	Patients receive 400 mg/m^2 fluorouracil (5-FU) IV slow push day 1, 2,400 mg/m^2 fluorouracil (5-FU) IV continuously over 46 hours days 1-2, 400 mg/m^2 leucovorin calcium IV over 2 hours, and 85 mg/m^2 oxaliplatin IV over 2 hours on day 1. Patients also receive 2.5 mg oral everolimus once daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. fluorouracil: Given IV leucovorin calcium: Given IV oxaliplatin: Given IV everolimus: Given orally
Measure Participants	6
Number [participants]	5 83.3%

3. Primary Outcome

Title	Progression-free Survival
Description	Estimated using the product-limit method of Kaplan and Meier. From the date treatment started until the date of first documented progression or date of death from any cause, whichever came first. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
Time Frame	up to 5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Dose Level 1 - 2.5 mg Everolimus Daily
Arm/Group Description	Patients receive 400 mg/m^2 fluorouracil (5-FU) IV slow push day 1, 2,400 mg/m^2 fluorouracil (5-FU) IV continuously over 46 hours days 1-2, 400 mg/m^2 leucovorin calcium IV over 2 hours, and 85 mg/m^2 oxaliplatin IV over 2 hours on day 1. Patients also receive 2.5 mg oral everolimus once daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. fluorouracil: Given IV leucovorin calcium: Given IV oxaliplatin: Given IV everolimus: Given orally
Measure Participants	6
Median (95% Confidence Interval) [Months]	14.5

4. Primary Outcome

Title	Overall Survival
Description	Estimated using the product-limit method of Kaplan and Meier. From the date treatment started until the date of death from any cause.
Time Frame	Up to 5 years.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Dose Level 1 - 2.5 mg Everolimus Daily
Arm/Group Description	Patients receive 400 mg/m^2 fluorouracil (5-FU) IV slow push day 1, 2,400 mg/m^2 fluorouracil (5-FU) IV continuously over 46 hours days 1-2, 400 mg/m^2 leucovorin calcium IV over 2 hours, and 85 mg/m^2 oxaliplatin IV over 2 hours on day 1. Patients also receive 2.5 mg oral everolimus once daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. fluorouracil: Given IV leucovorin calcium: Given IV oxaliplatin: Given IV everolimus: Given orally
Measure Participants	6
Median (95% Confidence Interval) [Months]	20.3

Adverse Events

Time Frame	Adverse events occurred over a period of 2 years, 6 months
Adverse Event Reporting Description	"Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.
Arm/Group Title	Dose Level 1 - 2.5 mg Everolimus Daily
Arm/Group Description	Patients receive 400 mg/m^2 fluorouracil (5-FU) IV slow push day 1, 2,400 mg/m^2 fluorouracil (5-FU) IV continuously over 46 hours days 1-2, 400 mg/m^2 leucovorin calcium IV over 2 hours, and 85 mg/m^2 oxaliplatin IV over 2 hours on day 1. Patients also receive 2.5 mg oral everolimus once daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. fluorouracil: Given IV leucovorin calcium: Given IV oxaliplatin: Given IV everolimus: Given orally
All Cause Mortality
	Dose Level 1 - 2.5 mg Everolimus Daily
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Dose Level 1 - 2.5 mg Everolimus Daily
	Affected / at Risk (%)	# Events
Total	2/6 (33.3%)
Gastrointestinal disorders
Mucositis oral	1/6 (16.7%)	2
General disorders
Chills	1/6 (16.7%)	1
Fever	1/6 (16.7%)	1
Flu like symptoms	1/6 (16.7%)	1
Infections and infestations
Catheter related infection	1/6 (16.7%)	1
Other (Not Including Serious) Adverse Events
	Dose Level 1 - 2.5 mg Everolimus Daily
	Affected / at Risk (%)	# Events
Total	6/6 (100%)
Blood and lymphatic system disorders
Anemia	6/6 (100%)	66
Cardiac disorders
Sinus bradycardia	2/6 (33.3%)	5
Sinus tachycardia	3/6 (50%)	8
Eye disorders
Watering eyes	1/6 (16.7%)	1
Gastrointestinal disorders
Abdominal pain	3/6 (50%)	25
Bloating	1/6 (16.7%)	1
Constipation	4/6 (66.7%)	21
Diarrhea	3/6 (50%)	6
Dry mouth	2/6 (33.3%)	3
Dyspepsia	3/6 (50%)	6
Dysphagia	2/6 (33.3%)	5
Esophageal pain	1/6 (16.7%)	1
Flatulence	1/6 (16.7%)	1
Gastroesophageal reflux disease	2/6 (33.3%)	9
Gastrointestinal disorders - Other, spec	2/6 (33.3%)	3
Hemorrhoids	1/6 (16.7%)	3
Mucositis oral	4/6 (66.7%)	14
Nausea	6/6 (100%)	34
Oral pain	1/6 (16.7%)	1
Rectal hemorrhage	1/6 (16.7%)	2
Vomiting	3/6 (50%)	5
General disorders
Chills	1/6 (16.7%)	2
Edema face	1/6 (16.7%)	1
Fatigue	6/6 (100%)	56
Fever	2/6 (33.3%)	4
Flu like symptoms	1/6 (16.7%)	1
Gait disturbance	1/6 (16.7%)	1
Infusion related reaction	1/6 (16.7%)	1
Injection site reaction	2/6 (33.3%)	3
Pain	2/6 (33.3%)	4
Infections and infestations
Mucosal infection	1/6 (16.7%)	1
Skin infection	1/6 (16.7%)	3
Upper respiratory infection	1/6 (16.7%)	1
Urinary tract infection	1/6 (16.7%)	1
Wound infection	1/6 (16.7%)	2
Injury, poisoning and procedural complications
Fall	2/6 (33.3%)	2
Investigations
Hyperglycemia	4/6 (66.7%)	8
Hypocalcemia	3/6 (50%)	15
Activated partial thromboplastin time pr	2/6 (33.3%)	10
Alanine aminotransferase increased	5/6 (83.3%)	31
Alkaline phosphatase increased	5/6 (83.3%)	35
Aspartate aminotransferase increased	5/6 (83.3%)	37
CPK increased	1/6 (16.7%)	2
Cholesterol high	5/6 (83.3%)	32
Creatinine increased	1/6 (16.7%)	2
Haptoglobin decreased	1/6 (16.7%)	1
INR increased	1/6 (16.7%)	8
Lymphocyte count decreased	3/6 (50%)	8
Lymphocyte count increased	1/6 (16.7%)	1
Neutrophil count decreased	6/6 (100%)	29
Platelet count decreased	5/6 (83.3%)	30
Weight gain	2/6 (33.3%)	3
Weight loss	3/6 (50%)	17
White blood cell decreased	6/6 (100%)	28
Metabolism and nutrition disorders
Anorexia	4/6 (66.7%)	17
Dehydration	1/6 (16.7%)	1
Hypernatremia	1/6 (16.7%)	2
Hypertriglyceridemia	4/6 (66.7%)	37
Hyperuricemia	1/6 (16.7%)	3
Hypoalbuminemia	4/6 (66.7%)	11
Hypokalemia	2/6 (33.3%)	2
Hyponatremia	3/6 (50%)	19
Obesity	3/6 (50%)	17
Musculoskeletal and connective tissue disorders
Arthralgia	3/6 (50%)	4
Back pain	3/6 (50%)	20
Bone pain	3/6 (50%)	3
Flank pain	1/6 (16.7%)	1
Generalized muscle weakness	1/6 (16.7%)	1
Muscle weakness trunk	1/6 (16.7%)	1
Musculoskeletal and connective tissue di	1/6 (16.7%)	1
Myalgia	1/6 (16.7%)	1
Neck pain	1/6 (16.7%)	1
Pain in extremity	1/6 (16.7%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumor pain	1/6 (16.7%)	5
Nervous system disorders
Akathisia	1/6 (16.7%)	1
Ataxia	1/6 (16.7%)	2
Cognitive disturbance	1/6 (16.7%)	1
Dysarthria	2/6 (33.3%)	2
Dysgeusia	3/6 (50%)	10
Dysphasia	1/6 (16.7%)	1
Headache	2/6 (33.3%)	2
Memory impairment	1/6 (16.7%)	2
Paresthesia	4/6 (66.7%)	12
Peripheral motor neuropathy	2/6 (33.3%)	6
Peripheral sensory neuropathy	5/6 (83.3%)	30
Somnolence	1/6 (16.7%)	1
Tremor	1/6 (16.7%)	13
Psychiatric disorders
Agitation	1/6 (16.7%)	1
Anxiety	2/6 (33.3%)	11
Confusion	2/6 (33.3%)	3
Depression	3/6 (50%)	20
Insomnia	2/6 (33.3%)	23
Restlessness	1/6 (16.7%)	1
Suicidal ideation	1/6 (16.7%)	1
Renal and urinary disorders
Hematuria	3/6 (50%)	11
Proteinuria	3/6 (50%)	9
Urinary frequency	1/6 (16.7%)	1
Urinary tract pain	1/6 (16.7%)	1
Reproductive system and breast disorders
Erectile dysfunction	1/6 (16.7%)	4
Respiratory, thoracic and mediastinal disorders
Cough	3/6 (50%)	3
Pharyngolaryngeal pain	1/6 (16.7%)	1
Respiratory, thoracic and mediastinal di	2/6 (33.3%)	3
Sore throat	2/6 (33.3%)	2
Skin and subcutaneous tissue disorders
Hyperhidrosis	1/6 (16.7%)	1
Photosensitivity	1/6 (16.7%)	1
Rash maculo-papular	3/6 (50%)	9
Skin and subcutaneous tissue disorders -	1/6 (16.7%)	1
Vascular disorders
Hypertension	6/6 (100%)	74

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.