Phase I of Histone Deacetylase (HDAC) Inhibitor Panobinostat With Ipilimumab With Unresectable III/IV Melanoma

• Sponsor: H. Lee Moffitt Cancer Center and Research Institute (Other)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT02032810
• Collaborator: Novartis (Industry)
• Enrollment: 17
• Location: 1
• Arm: 1
• Anticipated Duration (Months): 110.8
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The purpose of this study is to find out if an investigational drug called panobinostat can be given safely with another drug called ipilimumab. Investigators want to learn more about the side effects of this combination of drugs using different doses of panobinostat and the same dose of ipilimumab.

Condition or Disease	Intervention/Treatment	Phase
Melanoma; Skin Cancer	Drug: Panobinostat; Drug: Ipilimumab	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 17 participants
• Allocation: N/A
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 1 Study of HDAC Inhibitor Panobinostat (LBH 589) Administered in Combination With Ipilimumab in Subjects With Unresectable Stage III or Stage IV Melanoma
• Actual Study Start Date: Jan 7, 2014
• Actual Primary Completion Date: Sep 6, 2017
• Anticipated Study Completion Date: Apr 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Dose Escalation Dose Escalation of Panobinostat + Ipilimumab. Participants will be assigned to receive a certain dose of panobinostat (5, 10, 15, or 20 mg) along with a dose of ipilimumab of 3 mg per kg (mg/kg) of body weight.	Drug: Panobinostat; Participants will be assigned to receive a certain dose of panobinostat (5, 10, 15, or 20 mg). The dose of panobinostat will depend on the time point the participant enters the study and the side effects of other participants already on the study.; Other Names: LBH 589 ; Drug: Ipilimumab; Dose of ipilimumab of 3 mg per kg (mg/kg) of body weight.; Other Names: BMS-734016

Outcome Measures

Primary Outcome Measures

1. Maximum Tolerated Dose (MTD) [Up to 36 months]

   MTD and recommended Phase 2 dose (RP2D) of panobinostat (PAN), administered in combination with ipilimumab (IPI) in participants with unresectable Stage III or Stage IV melanoma. The goal is to enroll up to 36 patients for determination of the MTD, but will be successfully concluded earlier if 12 patients are accrued at the dose determined to be the MTD, with 3 dose limiting toxicities (DLTs). All participants who receive study any drug therapy will be evaluated for safety. Safety assessments will be based on medical review of adverse event reports and the results of vital sign measurements, physical examinations, and clinical laboratory tests. Triplicate 12-lead electrocardiograms (ECGs) will be collected prior to dosing on Day 1 of induction cycle 1. MTD of PAN in milligrams (mg), with IPI at 3 mg/kg.

Secondary Outcome Measures

1. Immune Related Overall Response Rate (ORR) [Up to 36 months]

   Tumor response by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and immune-related Response Criteria (irRC). RECIST: Best overall response from start of treatment until disease progression/recurrence. Immune-related Complete Response (irCR): Complete disappearance of all tumor lesions for at least 4 weeks from date of documentation of irCR. Immune-related Partial Response (irPR): Sum of the products of the 2 largest perpendicular diameters of all index lesions, measured and captured as the Sum of Product of Diameters (SPD) baseline. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for Progressive Disease (PD), taking as reference the smallest sum longest diameter (LD) since the treatment started. Immune-related Progressive Disease (irPD): At least a 25% increase in the SPD of all index lesions and new measurable lesions (irSPD) over the nadir SPD calculated for the index lesions.

2. Progression Free Survival (PFS) [Up to 6 months]

   Progression Free Survival (PFS): is defined for each participant as the time from first dosing to the first observation of disease progression or death due to any cause. If a subject has not progressed or died at the time of analysis, PFS will be censored on the date of the last disease assessment. PFS will be calculated by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Progressive Disease (PD) = 20% increase in the sum of the longest diameter of target lesions.

3. Overall Survival (OS) [36 months]

   Overall survival: The time from randomization until death from any cause.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Men and women ≥ 18 years old

• Participants must be ipilimumab naïve with progressive unresectable Stage III or Stage IV melanoma who are either treatment naïve or may have been treated with up to 3 prior treatments for melanoma (e.g., chemotherapy, biologic or targeted therapy or IL-2).

• Histologic or cytologic confirmation of stage III or stage IV melanoma

• Measurable disease at baseline as assessed by CT and/or MRI

• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1

• Screening laboratory values must meet the following criteria: white blood count (WBCs) ≥ 2000/μL; Neutrophils ≥ 1500/μL; Platelets ≥ 100 x 10^3/μL; Hemoglobin ≥ 9.0 g/dL; Creatinine Serum creatinine ≤ 1.5 x upper limit of normal (ULN) or creatinine clearance > 40 mL/minute (using Cockcroft/Gault formula); aspartic transaminase (AST) ≤ 3 x ULN; alanine transaminase (ALT) ≤ 3 x ULN; Total Bilirubin ≤ 1.5 x ULN (except those with Gilbert Syndrome who must have total bilirubin < 3.0 mg/dL)

• Men and women of childbearing potential (WOCBP) must be using an acceptable method of contraception to avoid pregnancy throughout the study and for at least 12 weeks after the last dose of investigational product in such a manner that the risk of pregnancy is minimized. Women must have a negative serum pregnancy test within 72 hours prior to the start of investigational product.

Exclusion Criteria:

• Known or suspected brain metastasis, or brain as the only site of disease, with the following exceptions: controlled brain metastasis (no radiographic progression at least 4 weeks following radiation and/or surgical treatment, off steroids for at least 4 weeks, and have no new or progressing neurological signs or symptoms); history of prior malignancy with the exception of carcinoma in situ of the cervix or other malignancy diagnosed > 2 years ago that has undergone potentially curative therapy with no evidence of disease for the last ≥ 2 years and that is deemed by the investigator to be at a low risk of recurrence

• Active autoimmune disease or a history of known or suspected autoimmune disease with the exception of subjects with isolated vitiligo, treated thyroiditis or resolved childhood asthma/atopy

• Known human immunodeficiency virus (HIV), active hepatitis A, or hepatitis B or C infection

• History of any hepatitis (e.g., alcohol or non-alcohol steatohepatitis (NASH), drug- related, autoimmune)

• Evidence of active infection that requires anti-bacterial, anti-viral, or anti-fungal therapy ≤ 7 days prior to initiation of study drug therapy

• History of acute diverticulitis, or current chronic diarrhea

• Active peptic ulcer disease even if asymptomatic

• History of adrenal insufficiency (including subjects using replacement therapy)

• Prior organ allograft or allogeneic bone marrow transplantation

• Uncontrolled or significant cardiovascular disease including, but not limited to, any of the following: Myocardial infarction within the past 6 months; Uncontrolled angina within the past 6 months; Any history of clinically significant ventricular arrhythmias (such as ventricular tachycardia, ventricular fibrillation or Torsades de pointes). Controlled atrial fibrillation by itself is not an exclusion criterion.; Baseline corrected QT interval (QTc) interval greater than 500 milliseconds

• Baseline toxicities from prior anti-cancer treatments > Grade 1

• Inability to be venipunctured and/or tolerate venous access

• Any major surgery within 4 weeks or a diagnostic procedure (e.g. incision, needle biopsy) within 1 day of study drug administration

• Any current or recent (within 3 months) gastrointestinal disease that could potentially impact the ability to swallow and/or absorb study drug (i.e., gastrointestinal surgery, malabsorption syndrome)

• Diabetes mellitus uncontrolled by medication

• Known drug or alcohol abuse

• Presence of underlying medical condition that in the opinion of the Investigator or Sponsor could adversely affect the ability of the subject to comply with or tolerate study procedures and/or study therapy, or confound the ability to interpret the tolerability of combined administration of panobinostat and ipilimumab in treated subjects

• History of allergy to components of ipilimumab or panobinostat, or known allergy to other antibody therapies.

• WOCBP who are unwilling or unable to use an acceptable method to minimize the risk of pregnancy for the entire study period and for at least 12 weeks after the last dose of investigational product

• Women who are pregnant or breastfeeding

• Women with a positive pregnancy test on enrollment or prior to investigational product administration

• Sexually active fertile men not using effective birth control if their partners are WOCBP

• Exposure to any investigational drug within 4 weeks of study drug administration.

• Any anti-cancer therapy (e.g., chemotherapy, biologics, radiotherapy, or hormonal treatment) within 4 weeks or at least 5 half-lives (whichever is longer) of study drug administration

• Prior therapy with an anti-CTLA4 antibody or an HDAC inhibitor

• Concurrent chemotherapy, hormonal therapy, immunotherapy regimens, or radiation therapy, standard or investigational

• Prisoners or subjects who are involuntarily incarcerated

• Subjects who are compulsorily detained for treatment of either a psychiatric or physical (e.g., infectious disease) illness

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
• Novartis

Investigators

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

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Dec 21, 2015

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: NCT02032810
• Other Study ID Numbers: MCC-17439
• First Posted: Jan 10, 2014
• Last Update Posted: May 10, 2022
• Last Verified: Apr 1, 2022

• Keywords provided by H. Lee Moffitt Cancer Center and Research Institute: Stage III Melanoma; Stage IV Melanoma; HDAC Inhibitor
• Additional relevant MeSH terms: Melanoma; Ipilimumab; Panobinostat

Study Results

Participant Flow

Recruitment Details	Participants were enrolled at Moffitt Cancer Center, November 2014 through November 2016.

Arm/Group Title	Panobinostat 5 mg	Panobinostat 10 mg
Arm/Group Description	Participants who received 5 mg of Panobinostat along with 3 mg Ipilimumab	Participants who received Panobinostat 10 mg along with 3 mg Ipilimumab
Period Title: Overall Study
STARTED	6	11
COMPLETED	6	11
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Panobinostat 5 mg	Panobinostat 10 mg	Total
Arm/Group Description	Participants who received 5 mg of Panobinostat along with 3 mg Ipililumab	Participants who received 10 mg of Panobinostat along with 3 mg Ipililumab	Total of all reporting groups
Overall Participants	6	11	17
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	64	66	66
Sex: Female, Male (Count of Participants)
Female	2 33.3%	2 18.2%	4 23.5%
Male	4 66.7%	9 81.8%	13 76.5%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	1 9.1%	1 5.9%
Not Hispanic or Latino	6 100%	10 90.9%	16 94.1%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	6 100%	11 100%	17 100%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	6 100%	11 100%	17 100%

Outcome Measures

1. Primary Outcome

Title	Maximum Tolerated Dose (MTD)
Description	MTD and recommended Phase 2 dose (RP2D) of panobinostat (PAN), administered in combination with ipilimumab (IPI) in participants with unresectable Stage III or Stage IV melanoma. The goal is to enroll up to 36 patients for determination of the MTD, but will be successfully concluded earlier if 12 patients are accrued at the dose determined to be the MTD, with 3 dose limiting toxicities (DLTs). All participants who receive study any drug therapy will be evaluated for safety. Safety assessments will be based on medical review of adverse event reports and the results of vital sign measurements, physical examinations, and clinical laboratory tests. Triplicate 12-lead electrocardiograms (ECGs) will be collected prior to dosing on Day 1 of induction cycle 1. MTD of PAN in milligrams (mg), with IPI at 3 mg/kg.
Time Frame	Up to 36 months

Outcome Measure Data

Analysis Population Description

All participants

Arm/Group Title	Dose Escalation of Panobinostat, Plus Ipilimumab
Arm/Group Description	Eligible participants with unresectable stage 3/4 MEL, up to 3 prior lines of therapy, and adequate laboratory values were treated with oral PAN 5 mg thrice weekly (TIW) plus IPI at 3 mg/kg IV every 3 weeks X 4 doses, followed by maintenance PAN until progression or intolerance. Using a modified Ji design, PAN dose escalation by 5 mg was planned in 3-12 participant cohorts up to a maximum dose of 20 mg TIW, without intra-participant dose escalation. Dose limiting toxicity (DLT) was assessed up to day 84 from start of therapy.
Measure Participants	17
Number [mg]	5

2. Secondary Outcome

Title	Immune Related Overall Response Rate (ORR)
Description	Tumor response by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and immune-related Response Criteria (irRC). RECIST: Best overall response from start of treatment until disease progression/recurrence. Immune-related Complete Response (irCR): Complete disappearance of all tumor lesions for at least 4 weeks from date of documentation of irCR. Immune-related Partial Response (irPR): Sum of the products of the 2 largest perpendicular diameters of all index lesions, measured and captured as the Sum of Product of Diameters (SPD) baseline. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for Progressive Disease (PD), taking as reference the smallest sum longest diameter (LD) since the treatment started. Immune-related Progressive Disease (irPD): At least a 25% increase in the SPD of all index lesions and new measurable lesions (irSPD) over the nadir SPD calculated for the index lesions.
Time Frame	Up to 36 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Panobinostat 5 mg	Panobinostat 10 mg
Arm/Group Description	Participants who received 5 mg of Panobinostat along with 3 mg Ipilimumab	Participants who received Panobinostat 10 mg along with 3 mg Ipilimumab
Measure Participants	6	11
Partial Response	1 16.7%	1 9.1%
Complete Response	0 0%	0 0%
Stable Disease	3 50%	3 27.3%

3. Secondary Outcome

Title	Progression Free Survival (PFS)
Description	Progression Free Survival (PFS): is defined for each participant as the time from first dosing to the first observation of disease progression or death due to any cause. If a subject has not progressed or died at the time of analysis, PFS will be censored on the date of the last disease assessment. PFS will be calculated by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Progressive Disease (PD) = 20% increase in the sum of the longest diameter of target lesions.
Time Frame	Up to 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Panobinostat 5 mg	Panobinostat 10 mg
Arm/Group Description	Participants who received 5 mg of Panobinostat along with 3 mg Ipilimumab	Participants who received 10 mg of Panobinostat along with 3 mg of Ipilimumab
Measure Participants	6	11
Median (95% Confidence Interval) [Months]	4.19	1.81

4. Secondary Outcome

Title	Overall Survival (OS)
Description	Overall survival: The time from randomization until death from any cause.
Time Frame	36 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Panobinostat 5 mg	Panobinostat 10 mg
Arm/Group Description	Participants who received 5 mg of Panobinostat along with 3 mg of Ipilimumab	Participants who received 10 mg Panobinostat along with 3 mg Ipilimumab
Measure Participants	6	11
Median (95% Confidence Interval) [Months]	25.91	12

Adverse Events

Time Frame	3 years, 9 months
Arm/Group Title	Panobinostat 5 mg		Panobinostat 10 mg
Arm/Group Description	Participants who received 5 mg of Panobinostat along with 3 mg Ipililumab		Participants who received 10 mg of Panobinostat along with 3 mg Ipililumab
All Cause Mortality
	Panobinostat 5 mg		Panobinostat 10 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/6 (16.7%)		0/11 (0%)
Serious Adverse Events
	Panobinostat 5 mg		Panobinostat 10 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/6 (66.7%)		7/11 (63.6%)
Blood and lymphatic system disorders
Anemia	1/6 (16.7%)	1	0/11 (0%)	0
Leukocytosis	0/6 (0%)	0	1/11 (9.1%)	1
Cardiac disorders
Sinus tachycardia	0/6 (0%)	0	1/11 (9.1%)	1
Endocrine disorders
Endocrine disorders - Other, Hypophysitis	0/6 (0%)	0	1/11 (9.1%)	1
Hypothyroidism	1/6 (16.7%)	1	0/11 (0%)	0
Gastrointestinal disorders
Diarrhea	0/6 (0%)	0	3/11 (27.3%)	3
Nausea	1/6 (16.7%)	1	3/11 (27.3%)	4
Vomiting	1/6 (16.7%)	1	2/11 (18.2%)	2
General disorders
Death NOS	1/6 (16.7%)	1	0/11 (0%)	0
Fatigue	0/6 (0%)	0	3/11 (27.3%)	3
Fever	0/6 (0%)	0	2/11 (18.2%)	3
Pain - Left groin/leg	0/6 (0%)	0	1/11 (9.1%)	1
Infections and infestations
Infections and infestations - Other, Tested positive for adenovirus	0/6 (0%)	0	1/11 (9.1%)	1
Lung infection - Pneumonia	0/6 (0%)	0	1/11 (9.1%)	1
Sepsis	0/6 (0%)	0	1/11 (9.1%)	1
Investigations
Investigations - Other, Hypophysitis	2/6 (33.3%)	2	0/11 (0%)	0
Platelet count decreased	0/6 (0%)	0	1/11 (9.1%)	1
Serum amylase increased	0/6 (0%)	0	1/11 (9.1%)	1
Metabolism and nutrition disorders
Anorexia	0/6 (0%)	0	1/11 (9.1%)	1
Dehydration	1/6 (16.7%)	1	1/11 (9.1%)	1
Hypocalcemia	0/6 (0%)	0	1/11 (9.1%)	1
Hypokalemia	0/6 (0%)	0	1/11 (9.1%)	1
Hyponatremia	1/6 (16.7%)	1	1/11 (9.1%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms - Other, basal cell carcinoma	0/6 (0%)	0	1/11 (9.1%)	1
Nervous system disorders
Dizziness	0/6 (0%)	0	1/11 (9.1%)	1
Psychiatric disorders
Confusion	0/6 (0%)	0	2/11 (18.2%)	2
Renal and urinary disorders
Acute kidney injury	0/6 (0%)	0	3/11 (27.3%)	3
Renal and urinary disorders - Other, Hydronephrosis	1/6 (16.7%)	1	0/11 (0%)	0
Urinary retention	0/6 (0%)	0	1/11 (9.1%)	1
Respiratory, thoracic and mediastinal disorders
Cough	0/6 (0%)	0	1/11 (9.1%)	1
Dyspnea	0/6 (0%)	0	1/11 (9.1%)	1
Skin and subcutaneous tissue disorders
Rash maculopapular	0/6 (0%)	0	2/11 (18.2%)	2
Vascular disorders
Hypotension	0/6 (0%)	0	2/11 (18.2%)	2
Other (Not Including Serious) Adverse Events
	Panobinostat 5 mg		Panobinostat 10 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/6 (100%)		11/11 (100%)
Blood and lymphatic system disorders
Anemia	1/6 (16.7%)	1	1/11 (9.1%)	1
Cardiac disorders
Cardiac disorders - Other	0/6 (0%)	0	1/11 (9.1%)	1
Palpitations	0/6 (0%)	0	1/11 (9.1%)	3
Sinus bradycardia	1/6 (16.7%)	1	0/11 (0%)	0
Ear and labyrinth disorders
Ear pain	0/6 (0%)	0	1/11 (9.1%)	1
Vertigo	1/6 (16.7%)	1	0/11 (0%)	0
Endocrine disorders
Hypothyroidism	2/6 (33.3%)	2	4/11 (36.4%)	5
Endocrine disorders - Other	2/6 (33.3%)	3	3/11 (27.3%)	6
Adrenal insufficiency	1/6 (16.7%)	1	0/11 (0%)	0
Eye disorders
Conjunctivitis	0/6 (0%)	0	1/11 (9.1%)	1
Dry eye	0/6 (0%)	0	1/11 (9.1%)	1
Eye disorders - Other	0/6 (0%)	0	1/11 (9.1%)	1
Gastrointestinal disorders
Diarrhea	5/6 (83.3%)	6	9/11 (81.8%)	33
Nausea	5/6 (83.3%)	8	8/11 (72.7%)	14
Vomiting	4/6 (66.7%)	6	5/11 (45.5%)	12
Abdominal pain	4/6 (66.7%)	4	3/11 (27.3%)	6
Constipation	2/6 (33.3%)	2	4/11 (36.4%)	4
Dry mouth	1/6 (16.7%)	1	3/11 (27.3%)	4
Bloating	1/6 (16.7%)	1	1/11 (9.1%)	1
Colitis	1/6 (16.7%)	1	1/11 (9.1%)	1
Gastrointestinal disorders - Other	1/6 (16.7%)	1	1/11 (9.1%)	2
Mucositis oral	0/6 (0%)	0	1/11 (9.1%)	1
General disorders
Fatigue	5/6 (83.3%)	11	10/11 (90.9%)	20
Pain	1/6 (16.7%)	1	3/11 (27.3%)	4
Fever	1/6 (16.7%)	1	2/11 (18.2%)	4
General disorders and administration site conditions - Other	2/6 (33.3%)	2	0/11 (0%)	0
Malaise	1/6 (16.7%)	1	1/11 (9.1%)	2
Chills	0/6 (0%)	0	1/11 (9.1%)	1
Edema limbs	0/6 (0%)	0	1/11 (9.1%)	1
Flu like symptoms	0/6 (0%)	0	1/11 (9.1%)	1
Infusion related reaction	1/6 (16.7%)	1	0/11 (0%)	0
Localized edema	0/6 (0%)	0	1/11 (9.1%)	1
Non-cardiac chest pain	0/6 (0%)	0	1/11 (9.1%)	1
Immune system disorders
Immune system disorders - Other	0/6 (0%)	0	1/11 (9.1%)	1
Infections and infestations
Lung infection	0/6 (0%)	0	1/11 (9.1%)	2
Upper respiratory infection	0/6 (0%)	0	1/11 (9.1%)	2
Urinary tract infection	0/6 (0%)	0	1/11 (9.1%)	1
Injury, poisoning and procedural complications
Fracture	0/6 (0%)	0	1/11 (9.1%)	1
Postoperative hemorrhage	0/6 (0%)	0	1/11 (9.1%)	1
Investigations
Platelet count decreased	0/6 (0%)	0	3/11 (27.3%)	8
Lipase increased	1/6 (16.7%)	4	2/11 (18.2%)	4
Serum amylase increased	1/6 (16.7%)	1	2/11 (18.2%)	2
Weight loss	0/6 (0%)	0	3/11 (27.3%)	3
Creatinine increased	2/6 (33.3%)	2	0/11 (0%)	0
Investigations - Other	2/6 (33.3%)	3	0/11 (0%)	0
Alanine aminotransferase increased	0/6 (0%)	0	1/11 (9.1%)	1
Aspartate aminotransferase increased	0/6 (0%)	0	1/11 (9.1%)	1
Electrocardiogram QT corrected interval prolonged	0/6 (0%)	0	1/11 (9.1%)	1
Metabolism and nutrition disorders
Anorexia	3/6 (50%)	4	9/11 (81.8%)	10
Dehydration	2/6 (33.3%)	2	3/11 (27.3%)	3
Hyponatremia	1/6 (16.7%)	4	3/11 (27.3%)	9
Hypokalemia	0/6 (0%)	0	1/11 (9.1%)	1
Hyperglycemia	0/6 (0%)	0	1/11 (9.1%)	2
Hypoalbuminemia	0/6 (0%)	0	1/11 (9.1%)	1
Musculoskeletal and connective tissue disorders
Myalgia	0/6 (0%)	0	4/11 (36.4%)	4
Back pain	1/6 (16.7%)	1	2/11 (18.2%)	3
Arthralgia	0/6 (0%)	0	2/11 (18.2%)	2
Arthritis	0/6 (0%)	0	1/11 (9.1%)	1
Generalized muscle weakness	1/6 (16.7%)	1	0/11 (0%)	0
Pain in extremity	0/6 (0%)	0	1/11 (9.1%)	1
Nervous system disorders
Dizziness	1/6 (16.7%)	5	2/11 (18.2%)	4
Dysgeusia	0/6 (0%)	0	2/11 (18.2%)	2
Headache	1/6 (16.7%)	2	1/11 (9.1%)	3
Amnesia	1/6 (16.7%)	1	0/11 (0%)	0
Concentration impairment	1/6 (16.7%)	1	0/11 (0%)	0
Nervous system disorders - Other	0/6 (0%)	0	1/11 (9.1%)	2
Syncope	1/6 (16.7%)	1	0/11 (0%)	0
Psychiatric disorders
Confusion	1/6 (16.7%)	1	1/11 (9.1%)	1
Insomnia	1/6 (16.7%)	1	2/11 (18.2%)	2
Anxiety	1/6 (16.7%)	1	0/11 (0%)	0
Depression	0/6 (0%)	0	1/11 (9.1%)	1
Renal and urinary disorders
Hematuria	0/6 (0%)	0	3/11 (27.3%)	3
Urinary frequency	1/6 (16.7%)	1	2/11 (18.2%)	2
Acute kidney injury	0/6 (0%)	0	1/11 (9.1%)	1
Urinary retention	0/6 (0%)	0	1/11 (9.1%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnea	2/6 (33.3%)	2	5/11 (45.5%)	6
Cough	2/6 (33.3%)	2	2/11 (18.2%)	2
Productive cough	2/6 (33.3%)	2	0/11 (0%)	0
Hoarseness	0/6 (0%)	0	1/11 (9.1%)	1
Pneumonitis	0/6 (0%)	0	1/11 (9.1%)	1
Respiratory, thoracic and mediastinal disorders - Other	0/6 (0%)	0	1/11 (9.1%)	1
Sore throat	0/6 (0%)	0	1/11 (9.1%)	1
Skin and subcutaneous tissue disorders
Rash maculopapular	1/6 (16.7%)	1	4/11 (36.4%)	5
Pruritus	1/6 (16.7%)	1	3/11 (27.3%)	3
Dry skin	0/6 (0%)	0	1/11 (9.1%)	1
Skin and subcutaneous tissue disorders - Other	0/6 (0%)	0	1/11 (9.1%)	3
Skin ulceration	0/6 (0%)	0	1/11 (9.1%)	1
Vascular disorders
Hypotension	0/6 (0%)	0	2/11 (18.2%)	4
Hot flashes	1/6 (16.7%)	1	0/11 (0%)	0

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.