Vismodegib in Treating Patients With Steroid-Refractory Chronic Graft-Versus-Host Disease

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Terminated
• CT.gov ID: NCT02337517
• Collaborator: Genentech, Inc. (Industry)
• Enrollment: 6
• Locations: 2
• Arm: 1
• Actual Duration (Months): 33.6
• Patients Per Site: 3
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This pilot clinical trial studies how well vismodegib works in treating patients with chronic graft-versus-host disease that did not respond to previous steroid treatment. Chronic graft-versus-host disease can cause a build-up of scar tissue under the skin and lead to symptoms such as sclerodermatous skin changes, dry mouth, dry eye, narrowing of the esophagus, or vaginal graft-versus-host disease. Vismodegib may work against the build-up of scar tissue and be a better treatment for chronic graft-versus-host disease caused by a hematopoietic stem cell transplant.

Condition or Disease	Intervention/Treatment	Phase
Chronic Graft Versus Host Disease	Other: Laboratory Biomarker Analysis; Drug: Vismodegib	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. To determine the clinical effects of GDC-0449 (vismodegib), in steroid-refractory chronic graft-versus-host disease (GVHD).

SECONDARY OBJECTIVES:

1. To determine the safety of GDC-0449 in patients with steroid-refractory GVHD.

2. To determine the change in National Institutes of Health (NIH) Consensus Criteria (CC) global score of chronic GVHD at 6 and 12 months from baseline.

3. To determine one-year non relapse mortality (NRM) and one-year relapse rate.

4. To determine one-year failure free survival (FFS) and one-year overall survival (OS).

5. To determine baseline clinical characteristics that may be associated with decreased FFS.

OUTLINE:

Patients receive vismodegib orally (PO) daily, every other day, every three days, or twice weekly for 6-12 months in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 6 months.

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: Pilot Study for the Treatment of Steroid-Refractory Sclerodermatous Chronic Graft-Versus-Host Disease (GVHD) With GDC-0449 (GDC-0449)
• Actual Study Start Date: Sep 8, 2015
• Actual Primary Completion Date: Jun 28, 2018
• Actual Study Completion Date: Jun 28, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Supportive care (vismodegib) Patients receive vismodegib PO daily, every other day, every three days, or twice weekly for 6-12 months in the absence of disease progression or unacceptable toxicity.	Other: Laboratory Biomarker Analysis; Correlative studies; Drug: Vismodegib; Given PO; Other Names: Erivedge GDC-0449 Hedgehog Antagonist GDC-0449

Outcome Measures

Primary Outcome Measures

1. Failure Free Survival (FFS) [At 6 months]

   Defined as the count of participants at six months with an absence of non relapse mortality (NRM), no recurrent malignancy, steroid dose at 6 months =< 0.2 mg/kg/day of prednisone dose equivalent (PDE), and no addition of new systemic treatment for chronic graft-versus-host disease (GVHD) at six months after start of treatment.

Secondary Outcome Measures

1. Incidence of Adverse Events [Up to 1 month post last date of treatment (max time of approximately one year)]

   The count of participants who experience adverse events (AE) and serious adverse events (SAE) while on treatment or within one month after discontinuing treatment.

2. Chronic Graft-versus-host Disease Response [Baseline to up to 12 months after initiation of protocol therapy]

   Chronic graft-versus-host disease (GVHD) severity was assessed at baseline with the National Institutes of Health (NIH) global score of chronic GVHD, which was defined using the 2014 NIH consensus criteria for diagnosis and staging of chronic GVHD (see Baseline Characteristics). Following initiation of treatment, the response to therapy was assessed as complete response (CR) (complete resolution of GVHD in one or more organ system) , partial response (PR) (improvement of GVHD in one or more organ system), stable disease (SD) (no change in GVHD), or progressive disease (PD) (worsened GVHD in one or more organ system), based on 2014 NIH consensus criteria for response assessment. GVHD was assessed monthly, with defined study endpoints at 6 and 12 months. Additionally, best overall response on the study is being reported to include response for patients who did not remain on study long enough to be included in the 6 month assessment.

3. One-year Non Relapse Mortality (NRM) [At 1 year]

   Relapse will be defined as malignancy relapse or as the initiation of any unintended intervention including an unplanned taper of immunosuppressant therapy to prevent malignancy progression due to any signs of recurrent, residual or new malignant disease after transplantation. Non relapse mortality is the number of participant deaths due to any cause other than relapse.

4. One Year Relapse [Up to one year]

   Relapse will be defined as malignancy relapse or as the initiation of any unintended intervention including an unplanned taper of immunosuppressant therapy to prevent malignancy progression due to any signs of recurrent, residual or new malignant disease after transplantation. This measure is reported as the count of participants who experienced a relapse of their primary malignancy within one year of starting study therapy.

5. One-year Failure Free Survival (FFS) [At 1 year]

   Defined as the count of participants at one year with an absence of non relapse mortality (NRM), no recurrent malignancy, steroid dose at 6 months =< 0.2 mg/kg/day of prednisone dose equivalent (PDE), and no addition of new systemic treatment for chronic graft-versus-host disease (GVHD) at one year after start of treatment.

6. One-year Overall Survival [At 1 year]

   A count of participants who are not deceased at one year after initiation of study therapy.

7. Clinical Characteristics Associated With Failure Free Survival (FFS) [Up to 1 year]

   The study proposed to evaluate clinical characteristics that could be associated with FFS. Each patient was categorized as either having FFS greater than 6 months or less than 6 months. Factors evaluated were whether or not the patient had high intensity conditional with total-body irradiation (TBI) before bone marrow transplant, whether or not the patient had > 3 involved sites with chronic graft versus host disease (GVHD), whether or not the patient had lower gastrointestinal (GI) involvement by GVHD, and whether or not the patient had a Severe NIH global score at initiation of protocol treatment.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)

• Life expectancy of greater than 12 months

• Leukocytes >= 3,000/microliter (mcL)

• Absolute neutrophil count >= 1,500/mcL

• Platelets >= 50,000/mcL

• Total bilirubin within normal institutional limits

• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase (SGOT))/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase (SGPT)) =< 2.5 x institutional upper limit of normal

• Creatinine =< 1.5 mg/dl OR creatinine clearance >= 55 mL/min using the Cockcroft-Gault equation for patients with creatinine levels above 1.5 mg/dl

• Patients with chronic GVHD diagnosed within 3 years after hematopoietic stem cell transplant (HSCT) for any disease, with any graft, and any conditioning regimen with at least one manifestation secondary to fibrosis, including: sclerodermatous skin changes, dry mouth, dry eye, esophageal strictures, or vaginal GVHD

• Failure to respond to corticosteroids, defined as:

• Progression of chronic GVHD despite optimal first line therapy (> 0.5 mg/kg/day of prednisone dose equivalent (PDE) for two weeks) or

• No improvement after 4-8 weeks of sustained therapy; sustained therapy should include 2 weeks of > 0.5 mg/kg/day of PDE or

• Inability to taper steroid dosage to less than 0.5 mg/kg/day of PDE without worsening of chronic GVHD or

• Need for second or third line therapy beyond corticosteroids and calcineurin inhibitors or sirolimus, irrespective of other criteria

• Women of child-bearing potential and men must use two forms of contraception (i.e., barrier contraception and one other method of contraception) at least 4 weeks prior to study entry, for the duration of study participation, and for at least 24 months post-treatment; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately

• Women of childbearing potential are required to have a negative serum pregnancy test (with a sensitivity of at least 25 milli-international unit (mIU)/mL) within 7 days prior to the first dose of GDC-0449 (serum or urine); a pregnancy test (serum or urine) will be administered every 4 weeks if their menstrual cycles are regular or every 2 weeks if their cycles are irregular while on study within the 24-hour period prior to the administration of GDC-0449; a positive urine test must be confirmed by a serum pregnancy test; prior to dispensing GDC-0449, the investigator must confirm and document the patient's use of two contraceptive methods, dates of negative pregnancy test, and confirm the patient's understanding of GDC-0449 cause serious or life-threatening birth defects; patients must continue highly effective contraception during therapy and for 24 months after the last dose of GDC-0449

• Women of childbearing potential are defined as follows:

• Patients with regular menses

• Patients with amenorrhea, irregular cycles, or using a contraceptive method that precludes withdrawal bleeding

• Women who have had a tubal ligation

• Women are considered not to be of childbearing potential for the following reasons:

• The patient has undergone hysterectomy and/or bilateral oophorectomy

• The patient is post-menopausal defined by amenorrhea for at least 12 months in a woman > 45 years old

• Male patients should use condoms with spermicide, even after a vasectomy, during sexual intercourse with female partners while being treated with GDC-0449 and for 3 months after the last dose to avoid exposing an embryo or fetus to GDC-0449

• Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are eligible provided that they meet the following criteria in addition to the other protocol criteria:

• Cancer as the only acquired immunodeficiency syndrome (AIDS)-defining condition

• Cluster of differentiation (CD)4 cell count >= 250

• Treatment sensitive HIV and prospects for long term survival on the basis of HIV disease alone

• Willing to take anti-HIV therapy that will have minimal potential for pharmacokinetic interactions with GDC-0449

Exclusion Criteria:

• Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier

• Patients who are receiving any other investigational agents

• Patients with known brain metastases should be excluded from this clinical trial

• History of allergic reactions attributed to compounds of similar chemical or biologic composition to GDC-0449

• Patients receiving any medications or substances that are strong inducers/inhibitors or substrates of cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4)/5, cytochrome P450, family 2, subfamily C, polypeptide 9 (CYP2C9), CYP2C8, or CYP2C19 are ineligible; as part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product

• Patients with malabsorption syndrome or other condition that would interfere with intestinal absorption; patients must be able to swallow capsules

• Patients with clinically important history of liver disease, including viral or other hepatitis or cirrhosis are ineligible

• Patients with uncontrolled hypocalcemia, hypomagnesemia, hyponatremia or hypokalemia defined as less than the lower limit of normal for the institution, despite adequate electrolyte supplementation are excluded from this study

• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements

• Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with GDC-0449

• More than 2 lines of therapy beyond corticosteroids with or without calcineurin inhibitors or sirolimus

• Relapsed malignancy after transplantation

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Michigan Comprehensive Cancer Center	Ann Arbor	Michigan	United States	48109
2	Huntsman Cancer Institute/University of Utah	Salt Lake City	Utah	United States	84112

Sponsors and Collaborators

• National Cancer Institute (NCI)
• Genentech, Inc.

Investigators

• Principal Investigator: Daniel R Couriel, Huntsman Cancer Institute/ University of Utah

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Apr 5, 2019

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT02337517
• Other Study ID Numbers: NCI-2014-02672; NCI-2014-02672; IIT 9664; 84584; 9664; 9664; P30CA042014
• First Posted: Jan 13, 2015
• Last Update Posted: Jul 19, 2021
• Last Verified: Jun 1, 2021

• Additional relevant MeSH terms: Graft vs Host Disease

Study Results

Participant Flow

Arm/Group Title	Supportive Care (Vismodegib)
Arm/Group Description	Patients receive vismodegib PO daily, every other day, every three days, or twice weekly for 6-12 months in the absence of disease progression or unacceptable toxicity.
Period Title: Overall Study
STARTED	6
COMPLETED	6
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Supportive Care (Vismodegib)
Arm/Group Description	Patients receive vismodegib PO daily, every other day, every three days, or twice weekly for 6-12 months in the absence of disease progression or unacceptable toxicity.
Overall Participants	6
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	5 83.3%
>=65 years	1 16.7%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	51.67 (12.16)
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	53
Sex: Female, Male (Count of Participants)
Female	2 33.3%
Male	4 66.7%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	6 100%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	6 100%
More than one race	0 0%
Unknown or Not Reported	0 0%
Baseline Chronic GVHD Grade (Count of Participants)
Mild GVHD	0 0%
Moderate GVHD	0 0%
Severe GVHD	6 100%

Outcome Measures

1. Primary Outcome

Title	Failure Free Survival (FFS)
Description	Defined as the count of participants at six months with an absence of non relapse mortality (NRM), no recurrent malignancy, steroid dose at 6 months =< 0.2 mg/kg/day of prednisone dose equivalent (PDE), and no addition of new systemic treatment for chronic graft-versus-host disease (GVHD) at six months after start of treatment.
Time Frame	At 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Supportive Care (Vismodegib)
Arm/Group Description	Patients receive vismodegib PO daily, every other day, every three days, or twice weekly for 6-12 months in the absence of disease progression or unacceptable toxicity.
Measure Participants	6
Count of Participants [Participants]	3 50%

2. Secondary Outcome

Title	Incidence of Adverse Events
Description	The count of participants who experience adverse events (AE) and serious adverse events (SAE) while on treatment or within one month after discontinuing treatment.
Time Frame	Up to 1 month post last date of treatment (max time of approximately one year)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Supportive Care (Vismodegib)
Arm/Group Description	Patients receive vismodegib PO daily, every other day, every three days, or twice weekly for 6-12 months in the absence of disease progression or unacceptable toxicity.
Measure Participants	6
Participants with any AE	6 100%
Participants with any SAE	4 66.7%

3. Secondary Outcome

Title	Chronic Graft-versus-host Disease Response
Description	Chronic graft-versus-host disease (GVHD) severity was assessed at baseline with the National Institutes of Health (NIH) global score of chronic GVHD, which was defined using the 2014 NIH consensus criteria for diagnosis and staging of chronic GVHD (see Baseline Characteristics). Following initiation of treatment, the response to therapy was assessed as complete response (CR) (complete resolution of GVHD in one or more organ system) , partial response (PR) (improvement of GVHD in one or more organ system), stable disease (SD) (no change in GVHD), or progressive disease (PD) (worsened GVHD in one or more organ system), based on 2014 NIH consensus criteria for response assessment. GVHD was assessed monthly, with defined study endpoints at 6 and 12 months. Additionally, best overall response on the study is being reported to include response for patients who did not remain on study long enough to be included in the 6 month assessment.
Time Frame	Baseline to up to 12 months after initiation of protocol therapy

Outcome Measure Data

Analysis Population Description

Only 3 participants had NIH GVHD assessment for response at 6 months. Only 1 participant had NIH GVHD assessment for response at 12 months.

Arm/Group Title	Supportive Care (Vismodegib)
Arm/Group Description	Patients receive vismodegib PO daily, every other day, every three days, or twice weekly for 6-12 months in the absence of disease progression or unacceptable toxicity.
Measure Participants	6
Partial Response (PR)	6 100%
CR, SD, and PD	0 0%
Partial Response (PR)	3 50%
CR, SD, and PD	0 0%
Partial Response (PR)	1 16.7%
CR, SD, and PD	0 0%

4. Secondary Outcome

Title	One-year Non Relapse Mortality (NRM)
Description	Relapse will be defined as malignancy relapse or as the initiation of any unintended intervention including an unplanned taper of immunosuppressant therapy to prevent malignancy progression due to any signs of recurrent, residual or new malignant disease after transplantation. Non relapse mortality is the number of participant deaths due to any cause other than relapse.
Time Frame	At 1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Supportive Care (Vismodegib)
Arm/Group Description	Patients receive vismodegib PO daily, every other day, every three days, or twice weekly for 6-12 months in the absence of disease progression or unacceptable toxicity.
Measure Participants	6
Count of Participants [Participants]	0 0%

5. Secondary Outcome

Title	One Year Relapse
Description	Relapse will be defined as malignancy relapse or as the initiation of any unintended intervention including an unplanned taper of immunosuppressant therapy to prevent malignancy progression due to any signs of recurrent, residual or new malignant disease after transplantation. This measure is reported as the count of participants who experienced a relapse of their primary malignancy within one year of starting study therapy.
Time Frame	Up to one year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Supportive Care (Vismodegib)
Arm/Group Description	Patients receive vismodegib PO daily, every other day, every three days, or twice weekly for 6-12 months in the absence of disease progression or unacceptable toxicity.
Measure Participants	6
Count of Participants [Participants]	1 16.7%

6. Secondary Outcome

Title	One-year Failure Free Survival (FFS)
Description	Defined as the count of participants at one year with an absence of non relapse mortality (NRM), no recurrent malignancy, steroid dose at 6 months =< 0.2 mg/kg/day of prednisone dose equivalent (PDE), and no addition of new systemic treatment for chronic graft-versus-host disease (GVHD) at one year after start of treatment.
Time Frame	At 1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Supportive Care (Vismodegib)
Arm/Group Description	Patients receive vismodegib PO daily, every other day, every three days, or twice weekly for 6-12 months in the absence of disease progression or unacceptable toxicity.
Measure Participants	6
Count of Participants [Participants]	1 16.7%

7. Secondary Outcome

Title	One-year Overall Survival
Description	A count of participants who are not deceased at one year after initiation of study therapy.
Time Frame	At 1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Supportive Care (Vismodegib)
Arm/Group Description	Patients receive vismodegib PO daily, every other day, every three days, or twice weekly for 6-12 months in the absence of disease progression or unacceptable toxicity.
Measure Participants	6
Count of Participants [Participants]	5 83.3%

8. Secondary Outcome

Title	Clinical Characteristics Associated With Failure Free Survival (FFS)
Description	The study proposed to evaluate clinical characteristics that could be associated with FFS. Each patient was categorized as either having FFS greater than 6 months or less than 6 months. Factors evaluated were whether or not the patient had high intensity conditional with total-body irradiation (TBI) before bone marrow transplant, whether or not the patient had > 3 involved sites with chronic graft versus host disease (GVHD), whether or not the patient had lower gastrointestinal (GI) involvement by GVHD, and whether or not the patient had a Severe NIH global score at initiation of protocol treatment.
Time Frame	Up to 1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Supportive Care (Vismodegib)
Arm/Group Description	Patients receive vismodegib PO daily, every other day, every three days, or twice weekly for 6-12 months in the absence of disease progression or unacceptable toxicity.
Measure Participants	6
Had Factor and FFS > 6 months	1 16.7%
Did not have factor and FFS > 6 months	2 33.3%
Had factor and FFS < 6 months	1 16.7%
Did not have factor and FFS < 6 months	2 33.3%
Had Factor and FFS > 6 months	1 16.7%
Did not have factor and FFS > 6 months	2 33.3%
Had factor and FFS < 6 months	2 33.3%
Did not have factor and FFS < 6 months	1 16.7%
Had Factor and FFS > 6 months	2 33.3%
Did not have factor and FFS > 6 months	1 16.7%
Had factor and FFS < 6 months	2 33.3%
Did not have factor and FFS < 6 months	1 16.7%
Had Factor and FFS > 6 months	3 50%
Did not have factor and FFS > 6 months	0 0%
Had factor and FFS < 6 months	3 50%
Did not have factor and FFS < 6 months	0 0%

Adverse Events

Time Frame	From the first dose of study treatment until 30 days after the last dose, up to one year.
Adverse Event Reporting Description	The occurrence of adverse events (AEs) was sought by non-directive questioning of the patient at each visit or phone contact during the study. Adverse events may also have been detected when they were volunteered by the patient during or between visits or through physical examination, laboratory test, or other assessments.
Arm/Group Title	Supportive Care (Vismodegib)
Arm/Group Description	Patients receive vismodegib PO daily, every other day, every three days, or twice weekly for 6-12 months in the absence of disease progression or unacceptable toxicity.
All Cause Mortality
	Supportive Care (Vismodegib)
	Affected / at Risk (%)	# Events
Total	1/6 (16.7%)
Serious Adverse Events
	Supportive Care (Vismodegib)
	Affected / at Risk (%)	# Events
Total	4/6 (66.7%)
Gastrointestinal disorders
Pneumatosis	1/6 (16.7%)
Infections and infestations
Sepsis	1/6 (16.7%)	2
Injury, poisoning and procedural complications
Fracture	1/6 (16.7%)
Investigations
Weight loss	1/6 (16.7%)
Respiratory, thoracic and mediastinal disorders
Pleural effusion	1/6 (16.7%)
Vascular disorders
Hypotension	1/6 (16.7%)
Other (Not Including Serious) Adverse Events
	Supportive Care (Vismodegib)
	Affected / at Risk (%)	# Events
Total	6/6 (100%)
Blood and lymphatic system disorders
Anemia	1/6 (16.7%)	2
elevated neutrophils	1/6 (16.7%)
Cardiac disorders
Chest pain - cardiac	1/6 (16.7%)
Coronary atherosclerosis	1/6 (16.7%)
Endocrine disorders
Adrenal insufficiency	2/6 (33.3%)
Eye disorders
conjunctival irritation lower eye	1/6 (16.7%)
Gastrointestinal disorders
Abdominal pain	1/6 (16.7%)
Bloating	2/6 (33.3%)
crown of tooth detached	1/6 (16.7%)
Dental caries	1/6 (16.7%)
Diarrhea	5/6 (83.3%)
Dry mouth	2/6 (33.3%)
Dysphagia	1/6 (16.7%)	2
Flatulence	1/6 (16.7%)
Gastritis	1/6 (16.7%)
gastrointestinal disorder	1/6 (16.7%)
Nausea	5/6 (83.3%)
Stomach pain	1/6 (16.7%)
General disorders
Fatigue	2/6 (33.3%)
Fever	1/6 (16.7%)
Flu like symptoms	1/6 (16.7%)
Infections and infestations
Epstein Barr Virus	1/6 (16.7%)
leg ulceration	1/6 (16.7%)
Rhinitis infective	1/6 (16.7%)
Skin infection	1/6 (16.7%)
Injury, poisoning and procedural complications
Fall	2/6 (33.3%)
Fracture	2/6 (33.3%)
Investigations
Alkaline phosphatase increased	1/6 (16.7%)
Creatinine increased	1/6 (16.7%)
Lymphocyte count decreased	1/6 (16.7%)
Neutrophil count decreased	1/6 (16.7%)
Weight loss	3/6 (50%)	6
Metabolism and nutrition disorders
Anorexia	1/6 (16.7%)
BUN elevated	1/6 (16.7%)
Hypernatremia	1/6 (16.7%)
Hypokalemia	1/6 (16.7%)
Hyponatremia	1/6 (16.7%)
Hypophosphatemia	2/6 (33.3%)
Increased Appetite	1/6 (16.7%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/6 (16.7%)
Arthritis	1/6 (16.7%)
Back pain	1/6 (16.7%)	2
Chest wall pain	1/6 (16.7%)
Generalized muscle weakness	2/6 (33.3%)
Muscle cramps	1/6 (16.7%)
Muscle weakness lower limb	1/6 (16.7%)
Myalgia	2/6 (33.3%)	3
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
colonic polyps	1/6 (16.7%)
Nervous system disorders
Concentration impairment	1/6 (16.7%)
Dizziness	1/6 (16.7%)
Dysgeusia	4/6 (66.7%)	7
Encephalopathy	1/6 (16.7%)
Movements involuntary	3/6 (50%)	6
Spasticity	1/6 (16.7%)
Syncope	1/6 (16.7%)
Tremor	2/6 (33.3%)	3
Psychiatric disorders
Agitation	1/6 (16.7%)
Confusion	2/6 (33.3%)
Depression	1/6 (16.7%)
Insomnia	2/6 (33.3%)	3
Renal and urinary disorders
Acute kidney injury	1/6 (16.7%)
Respiratory, thoracic and mediastinal disorders
Atelectasis	1/6 (16.7%)
Cough	2/6 (33.3%)
Dyspnea	1/6 (16.7%)	2
Productive cough	1/6 (16.7%)
Skin and subcutaneous tissue disorders
Alopecia	4/6 (66.7%)	7
Bullous dermatitis	1/6 (16.7%)
Erythema multiforme	1/6 (16.7%)
Hyperhidrosis	1/6 (16.7%)
Skin hyperpigmentation	1/6 (16.7%)
Vascular disorders
Hypertension	1/6 (16.7%)
Hypotension	1/6 (16.7%)
Vasculitis	1/6 (16.7%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.