Ipilimumab With Lymphodepletion Plus Adoptive Cell Transfer and High Dose IL-2 in Melanoma Mets Pts

• Sponsor: H. Lee Moffitt Cancer Center and Research Institute (Other)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT01701674
• Collaborator: Bristol-Myers Squibb (Industry), Iovance Biotherapeutics, Inc. (Industry)
• Enrollment: 13
• Location: 1
• Arm: 1
• Anticipated Duration (Months): 121.7
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

Purpose of this Pilot Study: The investigators want to study the safety, side effects, and benefits of tumor infiltrating lymphocytes (TILs), when they are given with the drug ipilimumab. Ipilimumab is a type of immunotherapy - a drug that is used to boost the ability of the immune system to fight cancer, infection, and other diseases.

Condition or Disease	Intervention/Treatment	Phase
Metastatic Melanoma	Drug: Ipilimumab; Procedure: Tumor Infiltrating Lymphocytes (TIL); Drug: Administration of Lymphodepletion; Drug: Cyclophosphamide as Part of Lymphodepletion; Drug: Fludarabine as Part of Lymphodepletion; Drug: High Dose IL-2; Biological: Adoptive Cell Therapy with TIL	N/A

Detailed Description

The primary endpoints of this pilot trial will be the safety and feasibility of administering ipilimumab with Adoptive Cell Therapy (ACT) using TIL. The data analysis will mainly be descriptive. All study results will be preliminary and of exploratory in nature due to the pilot status and small sample size of the trial. Feasibility is defined as the ability to deliver at least 50% (i.e., two out of four) of the planned doses of ipilimumab and successfully treat at least 60% (i.e., ≥ 6/10) of the patients with TIL. All participants will be evaluable for toxicity from the time of their first protocol treatment. Toxicity will be reported by type and severity according to the National Cancer Institute Common Toxicity Criteria (NCI CTC) version 4.

Study Design

• Study Type: Interventional
• Actual Enrollment: 13 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Co-stimulation With Ipilimumab to Enhance Lymphodepletion Plus Adoptive Cell Transfer and High Dose IL-2 in Patients With Metastatic Melanoma
• Actual Study Start Date: Oct 9, 2012
• Actual Primary Completion Date: Apr 21, 2016
• Anticipated Study Completion Date: Dec 1, 2022

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Combination Therapy The combination of ipilimumab followed by lymphodepletion with chemotherapy, TIL infusion, and high dose IL-2.

Drug: Ipilimumab; Pre-treatment with ipilimumab (cycle 1): Before the participant's tumor sample is taken to send to the lab for growing the TILs, they will start their first cycle of ipilimumab. This drug is given as an intravenous infusion (through a vein) over a period of about 90 minutes (an hour and a half). Cycle 2 of ipilimumab: About a week after the sample of the participant's tumor was collected for TIL growth (and 3 weeks after their first cycle of ipilimumab), participants will have their second cycle of ipilimumab. This will be another IV infusion, lasting about 90 minutes.; Other Names: Yervoy ; Procedure: Tumor Infiltrating Lymphocytes (TIL); Tumor sample for TIL growth in the lab: About 2 weeks after the participant's first cycle of ipilimumab, a sample of their tumor will be collected and sent to the lab for TIL growth. Growing the TILs takes about 6 weeks. If their sample has grown enough TIL cells, participants will continue with the next part of the study. Depending on how long the TILs take to grow in the lab, they may need to repeat some of their laboratory and imaging tests (blood draws, X-rays, and CT or magnetic resonance imaging [MRI] scans). TIL Infusion (inpatient): After completing lymphodepletion, participants will be admitted back into the hospital for IV infusion of the TIL cells.; Drug: Administration of Lymphodepletion; Lymphodepletion (inpatient hospital stay for about 2 days plus outpatient drug dosing for 5 days): About 4 weeks after their second cycle of ipilimumab, participants will be admitted to the hospital for their first two days of receiving the chemotherapy drug, cyclophosphamide. This drug will be given as an intravenous (IV, meaning through the vein) infusion. After 2 days of receiving cyclophosphamide, if their study doctor thinks that they are well enough, you will be discharged from the hospital and will return for the next 5 days in a row for outpatient IV infusions of the second lymphodepletion chemotherapy, fludarabine.; Drug: Cyclophosphamide as Part of Lymphodepletion; Other Names: Cytoxan ; Drug: Fludarabine as Part of Lymphodepletion; Other Names: Fludara ; Drug: High Dose IL-2; High dose IL-2 (continued inpatient): Participants will remain in the hospital following TIL infusion for receiving high dose IL-2 and recovery. The IL-2 will be given three times per day for about 3-5 days as an IV bolus (meaning through the vein, more quickly than other infusions - in about 15 minutes each dose). Participants will remain in the hospital for approximately 7-14 days until they have recovered from the IL-2 treatments.; Other Names: Interleukin-2 Aldesleukin Proleukin ; Biological: Adoptive Cell Therapy with TIL; Other Names: ACT

Outcome Measures

Primary Outcome Measures

1. Occurrence of Dose Limiting Toxicity (DLT) Events [3 months]

   Occurrence of adverse events with dose limiting toxicity, per adverse event category.

2. Rate of Meeting Feasibility Requirements [3 months]

   Number of participants who were successfully treated with at least 2 doses of ipilimumab and received TIL. Feasibility is defined as the ability to deliver at least 50% (i.e., two out of four) of the planned doses of ipilimumab and successfully treat at least 60% (i.e., ≥ 6/10) of the patients with TIL.

Secondary Outcome Measures

1. Overall Response Rate (ORR) [12 weeks]

   Overall Response: Complete Response (CR) + Partial Response (PR), per Response Evaluation Criteria In Solid Tumors Criteria (RECIST) v1.1 for target lesions and assessed by computed tomography (CT) scan. CR: Disappearance of all target lesions. PR: At least a 30% decrease in the sum of the longest diameter (LD) of target lesions..

2. Progression Free Survival (PFS) [42 months]

   Progression-free survival (PFS) per RECIST V1.1, defined as the time from study entry to disease progression, relapse or death due to any cause, whichever is earlier, will be summarized with the Kaplan-Meier curve. Progressive Disease (PD): At least a 20% increase in the sum of longest diameter (LD) of target lesions taking as reference the smallest sum recorded since the treatment started or the appearance of one or more new lesions.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Participants must have unresectable metastatic stage IV melanoma or stage III intransit or regional nodal disease, and in the opinion of the institutional PI is an acceptable candidate for ACT with high dose IL-2

• Residual measurable disease after resection of target lesion(s) for TIL growth

• Tumor may have a B-RAF V600 mutation or be BRAF wild type, and patients must not have been previously treated with ipilimumab

• Clinical performance status of Eastern Cooperative Oncology Group (ECOG) 0 - 1. ECOG performance status of 0-1 will be inferred if the patient's level of energy is ≥ 50% of baseline.

• May have been previously treated for metastatic disease, or may have not had prior systemic treatment. Patients with a V600 BRAF mutated tumor may have previously received a prior BRAF inhibitor.

• Women of childbearing potential (WOCBP) must have a negative serum pregnancy test within 7 days of screening.

• Adequate renal, hepatic and hematologic function, including creatinine of less than or equal to 1.7 gm/dL, total bilirubin less than or equal to 2.0 mg/dL, except in patients with Gilbert's Syndrome who must have a total bilirubin less than 3.0 mg/dL, aspartate aminotransferase (AST) and alanine transaminase (ALT) of less than 3 X institutional upper limit of normal, hemoglobin of 8 gm/dL or more, white blood count (WBC) of 3000 per mcL and total granulocytes of 1000 per mcL or more, and platelets of 100,000 per mcL or more.

• Must have a positive screening Epstein-Barr virus (EBV) antibody titre on screening test

• Potential participants with antibiotic allergies per se are not excluded; although the production of TIL for adoptive transfer includes antibiotics, extensive washing after harvest will minimize systemic exposure to antibiotics.

• At screening, patients with ≤ 3 untreated CNS metastases may be included provided none of the untreated lesions are > 1 cm in greatest dimension, and there is no peri-tumoral edema present on brain imaging (MRI or CT if MRI is contraindicated).

• At screening, patients with central nervous system (CNS) metastases treated with either surgical resection and/or radiation therapy may be included. Patients may be included if the largest lesion is ≤ 1 cm, and there is no evidence of progressive CNS disease on brain imaging at least 28 days after treatment.

• At screening, patients may be included if the largest lesion is > 1 cm or > 3 in number, and there is no evidence of progressive CNS disease on brain imaging at least 90 days after treatment with surgery and/or radiation therapy.

• No evidence of ongoing cardiac dysrhythmia ≥ grade 2 (NCI Common Terminology Criteria for Adverse Events [CTCAE], v4.0)

• All laboratory and imaging studies must be completed and satisfactory within 30 days of signing the consent document, with the exceptions of: negative serum pregnancy test for women of child-bearing potential which must be negative within 7 days of screening, human leukocyte antigen (HLA) typing which will not be repeated if performed previously, and pulmonary function tests (PFTs)/cardiac stress tests whose results are valid for 6 months if performed previously.

Exclusion Criteria:

• Active systemic infections requiring intravenous antibiotics, coagulation disorders or other major medical illness of the cardiovascular, respiratory or immune system, which in the opinion of the principal investigator (PI) or treating coinvestigator is not acceptable risk for ACT, are excluded.

• Testing positive for HIV titre, Hepatitis B surface antigen, Hepatitis B core antibody, Hepatitis C antibody, Human T-Lymphotropic Virus (HTLV) I or II antibody, or both Rapid. Plasma Reagin (RPR) and fluorescent treponemal antibodies (FTA) positive are excluded.

• Pregnant or nursing

• Patients needing chronic, immunosuppressive systemic steroids are excluded

• History of autoimmune disease that require immunosuppressive medications at the time of screening

• Presence of a significant psychiatric disease, which in the opinion of the principal investigator or his designee, would prevent adequate informed consent or render immunotherapy unsafe or contraindicated

• Patients with > 3 untreated CNS metastases or evidence of peri-tumoral edema

• Patients with ≤ 3 untreated CNS metastases but with at least one lesion >1 cm or peri-tumoral edema

• Patients with invasive malignancy other than melanoma at the time of enrollment and within 2 years prior to the first TIL administration are excluded, except for adequately treated (with curative intent) basal or squamous cell carcinoma, in situ carcinoma of the cervix, in situ ductal adenocarcinoma of the breast, in situ prostate cancer, or limited stage bladder cancer or other cancers from which the patient has been disease-free for at least 2 years.

• Patients with treated CNS metastases > 1 cm or > 3 in number will be excluded if there is evidence of progressive CNS disease on brain imaging at least 90 days after treatment with surgery and/or radiation therapy.

• Unable to comprehend and give informed consent

• Male patients with WOCBP partners who do not agree to use two FDA-accepted forms of contraception during sexual intercourse with women of child-bearing potential from the start of ipilimumab and up to at least 6 months after ACT

• WOCBP who do not agree to use 2 FDA forms of contraception during sexual intercourse from the start of ipilimumab and up to at least 6 months after ACT

• Patients who have received ipilimumab in the past

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	H. Lee Moffitt Cancer Center and Research Institute	Tampa	Florida	United States	33612

Sponsors and Collaborators

• H. Lee Moffitt Cancer Center and Research Institute
• Bristol-Myers Squibb
• Iovance Biotherapeutics, Inc.

Investigators

• Principal Investigator: Amod Sarnaik, M.D., H. Lee Moffitt Cancer Center and Research Institute

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Moffitt Cancer Center Clinical Trials website

Publications

None provided.

• Responsible Party: H. Lee Moffitt Cancer Center and Research Institute
• ClinicalTrials.gov Identifier: NCT01701674
• Other Study ID Numbers: MCC-17057; CA184-213
• First Posted: Oct 5, 2012
• Last Update Posted: Jun 23, 2022
• Last Verified: Jun 1, 2022

• Keywords provided by H. Lee Moffitt Cancer Center and Research Institute: skin cancer
• Additional relevant MeSH terms: Melanoma; Aldesleukin; Cyclophosphamide; Fludarabine; Ipilimumab; Interleukin-2

Study Results

Participant Flow

Recruitment Details	Participants were enrolled at Moffitt Cancer Center, April 2013 through July 2014.

Arm/Group Title	Experimental: Combination Therapy
Arm/Group Description	The combination of ipilimumab followed by lymphodepletion with chemotherapy, TIL infusion, and high dose IL-2.
Period Title: Overall Study
STARTED	13
COMPLETED	12
NOT COMPLETED	1

Baseline Characteristics

Arm/Group Title	Experimental: Combination Therapy
Arm/Group Description	The combination of ipilimumab followed by lymphodepletion with chemotherapy, TIL infusion, and high dose IL-2.
Overall Participants	13
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	10 76.9%
>=65 years	3 23.1%
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	49
Sex: Female, Male (Count of Participants)
Female	6 46.2%
Male	7 53.8%
Region of Enrollment (Count of Participants)
United States	13 100%

Outcome Measures

1. Primary Outcome

Title	Occurrence of Dose Limiting Toxicity (DLT) Events
Description	Occurrence of adverse events with dose limiting toxicity, per adverse event category.
Time Frame	3 months

Outcome Measure Data

Analysis Population Description

All participants

Arm/Group Title	Experimental: Combination Therapy
Arm/Group Description	The combination of ipilimumab followed by lymphodepletion with chemotherapy, TIL infusion, and high dose IL-2.
Measure Participants	13
Eye-related: Uveitis	1
Gastrointestinal: Colitis	1

2. Primary Outcome

Title	Rate of Meeting Feasibility Requirements
Description	Number of participants who were successfully treated with at least 2 doses of ipilimumab and received TIL. Feasibility is defined as the ability to deliver at least 50% (i.e., two out of four) of the planned doses of ipilimumab and successfully treat at least 60% (i.e., ≥ 6/10) of the patients with TIL.
Time Frame	3 months

Outcome Measure Data

Analysis Population Description

All participants

Arm/Group Title	Experimental: Combination Therapy
Arm/Group Description	The combination of ipilimumab followed by lymphodepletion with chemotherapy, TIL infusion, and high dose IL-2.
Measure Participants	13
Count of Participants [Participants]	12 92.3%

3. Secondary Outcome

Title	Overall Response Rate (ORR)
Description	Overall Response: Complete Response (CR) + Partial Response (PR), per Response Evaluation Criteria In Solid Tumors Criteria (RECIST) v1.1 for target lesions and assessed by computed tomography (CT) scan. CR: Disappearance of all target lesions. PR: At least a 30% decrease in the sum of the longest diameter (LD) of target lesions..
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

All participants.

Arm/Group Title	Experimental: Combination Therapy
Arm/Group Description	The combination of ipilimumab followed by lymphodepletion with chemotherapy, TIL infusion, and high dose IL-2.
Measure Participants	13
Number [percentage of participants]	38.5 296.2%

4. Secondary Outcome

Title	Progression Free Survival (PFS)
Description	Progression-free survival (PFS) per RECIST V1.1, defined as the time from study entry to disease progression, relapse or death due to any cause, whichever is earlier, will be summarized with the Kaplan-Meier curve. Progressive Disease (PD): At least a 20% increase in the sum of longest diameter (LD) of target lesions taking as reference the smallest sum recorded since the treatment started or the appearance of one or more new lesions.
Time Frame	42 months

Outcome Measure Data

Analysis Population Description

All participants.

Arm/Group Title	Experimental: Combination Therapy
Arm/Group Description	The combination of ipilimumab followed by lymphodepletion with chemotherapy, TIL infusion, and high dose IL-2.
Measure Participants	13
Median (Full Range) [months]	7.4

Adverse Events

Time Frame	3 years, 6 months
Arm/Group Title	Experimental: Combination Therapy
Arm/Group Description	The combination of ipilimumab followed by lymphodepletion with chemotherapy, TIL infusion, and high dose IL-2.
All Cause Mortality
	Experimental: Combination Therapy
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Experimental: Combination Therapy
	Affected / at Risk (%)	# Events
Total	9/13 (69.2%)
Endocrine disorders
Hypothyroidism	1/13 (7.7%)	1
Eye disorders
Uveitis	1/13 (7.7%)	1
Gastrointestinal disorders
Abdominal pain	1/13 (7.7%)	1
Colonic perforation	1/13 (7.7%)	1
Constipation	1/13 (7.7%)	1
Diarrhea	1/13 (7.7%)	1
Small intestinal obstruction	1/13 (7.7%)	1
Immune system disorders
Autoimmune disorder	1/13 (7.7%)	1
Infections and infestations
Abdominal infection	1/13 (7.7%)	1
Appendicitis	1/13 (7.7%)	1
Catheter related infection	1/13 (7.7%)	1
Injury, poisoning and procedural complications
Fracture	1/13 (7.7%)	1
Vascular access complication	1/13 (7.7%)	1
Investigations
Investigations - Other, SIADH	1/13 (7.7%)	1
Metabolism and nutrition disorders
Dehydration	2/13 (15.4%)	2
Hyponatremia	1/13 (7.7%)	1
Musculoskeletal and connective tissue disorders
Chest wall pain	1/13 (7.7%)	1
Nervous system disorders
Presyncope	1/13 (7.7%)	1
Syncope	1/13 (7.7%)	1
Psychiatric disorders
Anxiety	1/13 (7.7%)	1
Renal and urinary disorders
Cystitis non-infective	2/13 (15.4%)	2
Renal and urinary disorders - Other, Cistitis infective	1/13 (7.7%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnea	2/13 (15.4%)	2
Vascular disorders
Hypotension	1/13 (7.7%)	1
Other (Not Including Serious) Adverse Events
	Experimental: Combination Therapy
	Affected / at Risk (%)	# Events
Total	13/13 (100%)
Blood and lymphatic system disorders
Anemia	12/13 (92.3%)	82
Blood and lymphatic system disorders - Other	1/13 (7.7%)	1
Febrile neutropenia	10/13 (76.9%)	10
Cardiac disorders
Atrial fibrillation	1/13 (7.7%)	1
Cardiac disorders - Other	3/13 (23.1%)	4
Palpitations	1/13 (7.7%)	1
Sinus bradycardia	1/13 (7.7%)	2
Sinus tachycardia	9/13 (69.2%)	12
Ventricular tachycardia	1/13 (7.7%)	1
Endocrine disorders
Endocrine disorders - Other	3/13 (23.1%)	4
Hypothyroidism	1/13 (7.7%)	2
Eye disorders
Blurred vision	3/13 (23.1%)	3
Cataract	1/13 (7.7%)	1
Conjunctivitis	1/13 (7.7%)	1
Dry eye	2/13 (15.4%)	2
Eye disorders - Other	3/13 (23.1%)	4
Eye pain	1/13 (7.7%)	1
Uveitis	1/13 (7.7%)	2
Gastrointestinal disorders
Abdominal pain	5/13 (38.5%)	8
Bloating	2/13 (15.4%)	2
Colitis	2/13 (15.4%)	3
Constipation	7/13 (53.8%)	10
Diarrhea	11/13 (84.6%)	30
Dry mouth	1/13 (7.7%)	1
Dysphagia	1/13 (7.7%)	1
Gastroesophageal reflux disease	2/13 (15.4%)	2
Gastrointestinal disorders - Other	5/13 (38.5%)	6
Mucositis oral	4/13 (30.8%)	6
Nausea	13/13 (100%)	31
Vomiting	9/13 (69.2%)	11
General disorders
Chills	10/13 (76.9%)	16
Edema limbs	5/13 (38.5%)	8
Fatigue	11/13 (84.6%)	33
Fever	7/13 (53.8%)	12
Flu like symptoms	3/13 (23.1%)	4
General disorders and administration site conditions - Other	7/13 (53.8%)	15
Localized edema	2/13 (15.4%)	2
Malaise	1/13 (7.7%)	1
Non-cardiac chest pain	2/13 (15.4%)	2
Pain	7/13 (53.8%)	13
Immune system disorders
Allergic reaction	1/13 (7.7%)	1
Immune system disorders - Other	2/13 (15.4%)	2
Infections and infestations
Bronchial infection	1/13 (7.7%)	1
Infections and infestations - Other	5/13 (38.5%)	5
Mucosal infection	1/13 (7.7%)	1
Penile infection	1/13 (7.7%)	2
Upper respiratory infection	3/13 (23.1%)	3
Urinary tract infection	2/13 (15.4%)	2
Wound infection	1/13 (7.7%)	1
Injury, poisoning and procedural complications
Bruising	2/13 (15.4%)	2
Fall	1/13 (7.7%)	2
Injury, poisoning and procedural complications - Other	1/13 (7.7%)	1
Vascular access complication	1/13 (7.7%)	1
Wound dehiscence	1/13 (7.7%)	1
Investigations
Activated partial thromboplastin time prolonged	3/13 (23.1%)	4
Alanine aminotransferase increased	11/13 (84.6%)	24
Alkaline phosphatase increased	9/13 (69.2%)	18
Aspartate aminotransferase increased	12/13 (92.3%)	26
Blood bilirubin increased	5/13 (38.5%)	11
Cardiac troponin T increased	1/13 (7.7%)	1
CPK increased	6/13 (46.2%)	9
Creatinine increased	3/13 (23.1%)	5
INR increased	1/13 (7.7%)	1
Investigations - Other	2/13 (15.4%)	7
Lipase increased	1/13 (7.7%)	1
Lymphocyte count decreased	12/13 (92.3%)	45
Lymphocyte count increased	2/13 (15.4%)	2
Neutrophil count decreased	12/13 (92.3%)	32
Platelet count decreased	12/13 (92.3%)	61
Serum amylase increased	1/13 (7.7%)	1
Weight gain	1/13 (7.7%)	4
White blood cell decreased	12/13 (92.3%)	49
Metabolism and nutrition disorders
Acidosis	1/13 (7.7%)	1
Anorexia	8/13 (61.5%)	10
Dehydration	2/13 (15.4%)	2
Hypercalcemia	1/13 (7.7%)	2
Hyperglycemia	2/13 (15.4%)	9
Hyperkalemia	4/13 (30.8%)	7
Hypermagnesemia	1/13 (7.7%)	1
Hypoalbuminemia	12/13 (92.3%)	37
Hypocalcemia	3/13 (23.1%)	8
Hypokalemia	3/13 (23.1%)	3
Hypomagnesemia	4/13 (30.8%)	7
Hyponatremia	10/13 (76.9%)	32
Hypophosphatemia	12/13 (92.3%)	21
Musculoskeletal and connective tissue disorders
Arthralgia	3/13 (23.1%)	4
Arthritis	1/13 (7.7%)	3
Bone pain	1/13 (7.7%)	1
Generalized muscle weakness	1/13 (7.7%)	1
Myalgia	2/13 (15.4%)	2
Myositis	2/13 (15.4%)	2
Pain in extremity	5/13 (38.5%)	6
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other	2/13 (15.4%)	2
Tumor pain	3/13 (23.1%)	4
Nervous system disorders
Dizziness	7/13 (53.8%)	10
Dysarthria	1/13 (7.7%)	1
Dysgeusia	2/13 (15.4%)	2
Headache	10/13 (76.9%)	12
Nervous system disorders - Other	1/13 (7.7%)	1
Paresthesia	3/13 (23.1%)	3
Peripheral sensory neuropathy	1/13 (7.7%)	1
Somnolence	1/13 (7.7%)	1
Syncope	1/13 (7.7%)	1
Psychiatric disorders
Agitation	1/13 (7.7%)	1
Anxiety	1/13 (7.7%)	1
Depression	1/13 (7.7%)	1
Insomnia	3/13 (23.1%)	4
Renal and urinary disorders
Acute kidney injury	1/13 (7.7%)	2
Bladder spasm	1/13 (7.7%)	2
Cystitis non-infective	1/13 (7.7%)	1
Hematuria	2/13 (15.4%)	2
Renal and urinary disorders - Other	1/13 (7.7%)	4
Urinary frequency	1/13 (7.7%)	1
Urinary tract pain	1/13 (7.7%)	2
Urine discoloration	1/13 (7.7%)	1
Reproductive system and breast disorders
Erectile dysfunction	1/13 (7.7%)	1
Scrotal pain	1/13 (7.7%)	3
Vaginal discharge	1/13 (7.7%)	1
Vaginal hemorrhage	1/13 (7.7%)	1
Respiratory, thoracic and mediastinal disorders
Allergic rhinitis	2/13 (15.4%)	3
Bronchospasm	1/13 (7.7%)	1
Cough	8/13 (61.5%)	12
Dyspnea	10/13 (76.9%)	18
Epistaxis	2/13 (15.4%)	2
Hiccups	2/13 (15.4%)	2
Hypoxia	3/13 (23.1%)	3
Nasal congestion	2/13 (15.4%)	2
Postnasal drip	1/13 (7.7%)	1
Productive cough	2/13 (15.4%)	3
Pulmonary edema	5/13 (38.5%)	7
Respiratory, thoracic and mediastinal disorders - Other	4/13 (30.8%)	4
Sore throat	3/13 (23.1%)	4
Skin and subcutaneous tissue disorders
Alopecia	5/13 (38.5%)	7
Dry skin	3/13 (23.1%)	3
Erythema multiforme	2/13 (15.4%)	3
Pruritus	8/13 (61.5%)	18
Rash acneiform	1/13 (7.7%)	1
Rash maculo-papular	8/13 (61.5%)	22
Skin and subcutaneous tissue disorders - Other	7/13 (53.8%)	9
Surgical and medical procedures
Surgical and medical procedures - Other	2/13 (15.4%)	2
Vascular disorders
Capillary leak syndrome	4/13 (30.8%)	4
Flushing	1/13 (7.7%)	1
Hot flashes	1/13 (7.7%)	1
Hypertension	1/13 (7.7%)	2
Hypotension	9/13 (69.2%)	14
Lymphedema	3/13 (23.1%)	3
Vascular disorders - Other	1/13 (7.7%)	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.