Chemotherapy and Stem Cell Transplantation in Treating Patients With Stage IIIB Breast Cancer

• Sponsor: City of Hope Medical Center (Other)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT00003042
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 41
• Location: 1
• Arms: 2
• Anticipated Duration (Months): 307
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Combining chemotherapy with peripheral stem cell transplantation may allow the doctor to give higher doses of chemotherapy drugs and kill more tumor cells.

PURPOSE: This phase II trial is studying how well chemotherapy and stem cell transplantation work in treating patients with stage IIIB breast cancer.

Condition or Disease	Intervention/Treatment	Phase
Breast Cancer	Biological: filgrastim; Drug: cisplatin; Drug: cyclophosphamide; Drug: doxorubicin hydrochloride; Drug: melphalan; Drug: mesna; Drug: paclitaxel; Drug: tamoxifen citrate; Procedure: bone marrow ablation with stem cell support; Procedure: conventional surgery; Procedure: peripheral blood stem cell transplantation	Phase 2

Detailed Description

OBJECTIVES:

• Determine the effectiveness of neoadjuvant dose intensive sequential chemotherapy, followed by surgical resection, adjuvant therapy, and tandem high dose chemotherapy and stem cell rescue in patients with inflammatory stage IIIB breast cancer.

• Determine the clinical and pathological remission rate (complete, partial, and overall) following neoadjuvant dose dependent sequential chemotherapy in patients with inflammatory stage IIIB breast cancer.

• Determine the relapse and survival rate of these patients with the above therapy.

• Determine the potential correlations between inflammatory features and hereditary background.

OUTLINE: Patients are stratified according to those who have had no more than 1 cycle of neoadjuvant chemotherapy (stratum 1) and those who have had more than 1 cycle of neoadjuvant chemotherapy and/or modified radical mastectomy (stratum 2).

Patients in stratum 1 receive doxorubicin IV over 96 hours on days 1-4, 15-19, and 29-32. Paclitaxel is infused over 96 hours on days 43-47 and 57-60. Filgrastim (G-CSF) is administered on days 5-10, 20-25, 33-38, 48-55, and 61-68, and beyond if the granulocyte count is less than 1000/mm^3. A modified radical mastectomy is performed between days 70 and 80. All stratum 1 and stratum 2 patients then receive paclitaxel IV for 96 hours on days 100-104, and cyclophosphamide IV on day 121. Filgrastim is administered at one dose on days 105-110 and days 122-127 and at a higher dose on days 110-116 and days 128-135. Stem cells are harvested from the patient on days 113-116 and days 132-135.

High-dose chemotherapy is then administered to all patients in the study. Course 1 starts with doxorubicin IV on days -7 to -3. Paclitaxel IV is administered for 24 hours on day -2. Filgrastim is administered by IV on day -1 and continued until the granulocyte count is greater than 1000/mm^{3 for 3 days. Peripheral stem cells are reinfused on day 0. Course 2 starts 4-6 weeks after the start of course 1 with melphalan and cisplatin being infused on day -11. Filgrastim is administered IV on days -10 to -6. Melphalan and cisplatin are administered again on day -4. Stem cells are infused on day -3 and on day 0. Filgrastim is then administered until the granulocyte count is at least 1000/mm}3 for 3 days.

Radiation therapy is started 4-7 weeks after the beginning of course 2. Tamoxifen is started within 2 weeks of discharge following course 2 in patients with hormone receptor positive tumors.

Patients are followed every 3 months for two years and then annually for the next three years.

PROJECTED ACCRUAL: Approximately 60 patients will be accrued, at a rate of about 15 per year.

Study Design

• Study Type: Interventional
• Actual Enrollment: 41 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Dose-Intense Chemotherapy and Stem Cell Rescue in the Treatment of Inflammatory Breast Carcinoma
• Actual Study Start Date: May 30, 1997
• Anticipated Primary Completion Date: Dec 30, 2022
• Anticipated Study Completion Date: Dec 30, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 1 cycle of neoadjuvant chemotherapy Patients receive chemotherapy, surgical removal of the cancer followed by additional chemotherapy, followed by two treatment cycles of very high-dose chemotherapy, return of bone marrow derived cells, followed by radiation therapy and if indicated five years of tamoxifen treatment.	Biological: filgrastim; Drug: cisplatin; Drug: cyclophosphamide; Drug: doxorubicin hydrochloride; Drug: melphalan; Drug: mesna; Drug: paclitaxel; Drug: tamoxifen citrate; Procedure: bone marrow ablation with stem cell support; Procedure: conventional surgery; Procedure: peripheral blood stem cell transplantation
Experimental: More than 1 cycle of neoadjuvant chemotherapy Patients receive chemotherapy, followed by two treatment cycles of very high-dose chemotherapy, return of bone marrow derived cells, followed by radiation therapy and if indicated five years of tamoxifen treatment.	Biological: filgrastim; Drug: cisplatin; Drug: doxorubicin hydrochloride; Drug: melphalan; Drug: mesna; Drug: paclitaxel; Drug: tamoxifen citrate; Procedure: bone marrow ablation with stem cell support; Procedure: peripheral blood stem cell transplantation

Outcome Measures

Primary Outcome Measures

1. Three-year Relapse-free Survival [From date of mastectomy until date of relapse or death from any cause, 3 years post mastectomy.]

   Estimated using the product-limit method of Kaplan and Meier. Relapse defined as appearance of any new lesions during or after protocol treatment.

2. Five-year Overall Survival [From date of mastectomy until date of death, 5 years post mastectomy.]

   Estimated using the product-limit method of Kaplan and Meier. Endpoint is defined as death due to any cause.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 60 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

DISEASE CHARACTERISTICS:

• Histologically proven stage IIIB breast cancer with dermal/epidermal invasion or clinical features of inflammation, erythema, pain or hypersensitivity, edema, or thickening of the skin

• Diagnosis within the past 6 months

PATIENT CHARACTERISTICS:

Age:

• 60 and under

Performance status:

• Karnofsky 80-100%

Life expectancy:

• Not specified

Hematopoietic:

• Absolute neutrophil count at least 1,500/mm^3

• Platelet count at least 100,000/mm^3

Hepatic:

• Bilirubin less than 1.5 mg/dL

• SGOT or SGPT no greater than 1.5 times the upper limit of normal

Renal:

• Creatinine less than 1.2 mg/dL

• Creatinine clearance at least 80 mL/min

• No history of hemorrhagic cystitis

Cardiovascular:

• Left ventricular fraction at least 55% on MUGA scan

• No previous valvular heart disease or arrhythmia

Pulmonary:

• FEV_1 at least 60% predicted

• Room air pO_2 greater than 85 mmHg

• Room air pCO_2 no greater than 43 mmHg

• DLCO at least 60% of the lower limit of predicted value

Other:

• No history of malignant disease in the past 5 years, except for squamous or basal cell skin cancer and stage I or in situ cervical cancer

• No organic CNS dysfunction

• Not pregnant

• No known and potentially disabling psychosocial history

• Not positive for hepatitis B or HIV

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• Not specified

Chemotherapy:

• Stratum 1:

• No more than one cycle of chemotherapy

• Stratum 2:

• No greater than 225 mg/m^{2 doxorubicin and no greater than 250 mg/m}2 paclitaxel during previous chemotherapy

Endocrine therapy:

• Not specified

Radiotherapy:

• No prior radiation to the left chest wall

Surgery:

• Modified radical mastectomy allowed

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	City of Hope Comprehensive Cancer Center	Duarte	California	United States	91010-3000

Sponsors and Collaborators

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

Investigators

• Principal Investigator: George Somlo, MD, City of Hope Medical Center

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Dec 21, 2017

More Information

Publications

None provided.

• Responsible Party: City of Hope Medical Center
• ClinicalTrials.gov Identifier: NCT00003042
• Other Study ID Numbers: 96139; P30CA033572; CHNMC-96139; NCI-G97-1288; CDR0000065672
• First Posted: Jan 27, 2003
• Last Update Posted: Mar 2, 2022
• Last Verified: Feb 1, 2022

• Keywords provided by City of Hope Medical Center: stage IIIB breast cancer; inflammatory breast cancer
• Additional relevant MeSH terms: Breast Neoplasms; Tamoxifen; Paclitaxel; Cyclophosphamide; Doxorubicin; Liposomal doxorubicin; Melphalan

Study Results

Participant Flow

Arm/Group Title	Neoadjuvant Chemo Followed by Surgery & High-dose Chemo With PSC Rescue	High-dose Chemo With Rescue
Arm/Group Description	Patients receive chemotherapy, surgical removal of the cancer followed by additional chemotherapy, followed by two treatment cycles of very high-dose chemotherapy, return of bone marrow derived cells, followed by radiation therapy and if indicated five years of tamoxifen treatment. filgrastim cisplatin cyclophosphamide doxorubicin hydrochloride melphalan mesna paclitaxel tamoxifen citrate bone marrow ablation with stem cell support conventional surgery peripheral blood stem cell transplantation	Following surgery patients receive chemotherapy, followed by two treatment cycles of very high-dose chemotherapy, return of bone marrow derived cells, followed by radiation therapy and if indicated five years of tamoxifen treatment. filgrastim cisplatin doxorubicin hydrochloride melphalan mesna paclitaxel tamoxifen citrate bone marrow ablation with stem cell support peripheral blood stem cell transplantation
Period Title: Overall Study
STARTED	14	27
COMPLETED	14	27
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Neoadjuvant Chemo Followed by Surgery & High-dose Chemo With PSC Rescue	High-dose Chemo With Rescue	Total
Arm/Group Description	Patients receive chemotherapy, surgical removal of the cancer followed by additional chemotherapy, followed by two treatment cycles of very high-dose chemotherapy, return of bone marrow derived cells, followed by radiation therapy and if indicated five years of tamoxifen treatment. filgrastim cisplatin cyclophosphamide doxorubicin hydrochloride melphalan mesna paclitaxel tamoxifen citrate bone marrow ablation with stem cell support conventional surgery peripheral blood stem cell transplantation	Following surgery patients receive chemotherapy, followed by two treatment cycles of very high-dose chemotherapy, return of bone marrow derived cells, followed by radiation therapy and if indicated five years of tamoxifen treatment. filgrastim cisplatin doxorubicin hydrochloride melphalan mesna paclitaxel tamoxifen citrate bone marrow ablation with stem cell support peripheral blood stem cell transplantation	Total of all reporting groups
Overall Participants	14	27	41
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	49	50	50
Sex: Female, Male (Count of Participants)
Female	14 100%	27 100%	41 100%
Male	0 0%	0 0%	0 0%
Race/Ethnicity, Customized (Count of Participants)
White	13 92.9%	25 92.6%	38 92.7%
Hispanic	1 7.1%	1 3.7%	2 4.9%
Black	0 0%	1 3.7%	1 2.4%
Region of Enrollment (Count of Participants)
United States	14 100%	27 100%	41 100%

Outcome Measures

1. Primary Outcome

Title	Three-year Relapse-free Survival
Description	Estimated using the product-limit method of Kaplan and Meier. Relapse defined as appearance of any new lesions during or after protocol treatment.
Time Frame	From date of mastectomy until date of relapse or death from any cause, 3 years post mastectomy.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Neoadjuvant Chemo Followed by Surgery & High-dose Chemo With PSC Rescue	High-dose Chemo With Rescue
Arm/Group Description	Patients receive chemotherapy, surgical removal of the cancer followed by additional chemotherapy, followed by two treatment cycles of very high-dose chemotherapy, return of bone marrow derived cells, followed by radiation therapy and if indicated five years of tamoxifen treatment. filgrastim cisplatin cyclophosphamide doxorubicin hydrochloride melphalan mesna paclitaxel tamoxifen citrate bone marrow ablation with stem cell support conventional surgery peripheral blood stem cell transplantation	Following surgery patients receive chemotherapy, followed by two treatment cycles of very high-dose chemotherapy, return of bone marrow derived cells, followed by radiation therapy and if indicated five years of tamoxifen treatment. filgrastim cisplatin doxorubicin hydrochloride melphalan mesna paclitaxel tamoxifen citrate bone marrow ablation with stem cell support peripheral blood stem cell transplantation
Measure Participants	14	27
Number (95% Confidence Interval) [percentage of participants]	61.5 439.3%	77.8 288.1%

2. Primary Outcome

Title	Five-year Overall Survival
Description	Estimated using the product-limit method of Kaplan and Meier. Endpoint is defined as death due to any cause.
Time Frame	From date of mastectomy until date of death, 5 years post mastectomy.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Neoadjuvant Chemo Followed by Surgery & High-dose Chemo With PSC Rescue	High-dose Chemo With Rescue
Arm/Group Description	Patients receive chemotherapy, surgical removal of the cancer followed by additional chemotherapy, followed by two treatment cycles of very high-dose chemotherapy, return of bone marrow derived cells, followed by radiation therapy and if indicated five years of tamoxifen treatment. filgrastim cisplatin cyclophosphamide doxorubicin hydrochloride melphalan mesna paclitaxel tamoxifen citrate bone marrow ablation with stem cell support conventional surgery peripheral blood stem cell transplantation	Following surgery patients receive chemotherapy, followed by two treatment cycles of very high-dose chemotherapy, return of bone marrow derived cells, followed by radiation therapy and if indicated five years of tamoxifen treatment. filgrastim cisplatin doxorubicin hydrochloride melphalan mesna paclitaxel tamoxifen citrate bone marrow ablation with stem cell support peripheral blood stem cell transplantation
Measure Participants	14	27
Number (95% Confidence Interval) [percentage of participants]	69.2 494.3%	70.4 260.7%

Adverse Events

Time Frame	Adverse events were assessed during all cycles of chemotherapy treatment (up to 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	Neoadjuvant Chemo Followed by Surgery & High-dose Chemo With PSC Rescue		High-dose Chemo With Rescue
Arm/Group Description	Patients receive chemotherapy, surgical removal of the cancer followed by additional chemotherapy, followed by two treatment cycles of very high-dose chemotherapy, return of bone marrow derived cells, followed by radiation therapy and if indicated five years of tamoxifen treatment. filgrastim cisplatin cyclophosphamide doxorubicin hydrochloride melphalan mesna paclitaxel tamoxifen citrate bone marrow ablation with stem cell support conventional surgery peripheral blood stem cell transplantation		Following surgery patients receive chemotherapy, followed by two treatment cycles of very high-dose chemotherapy, return of bone marrow derived cells, followed by radiation therapy and if indicated five years of tamoxifen treatment. filgrastim cisplatin doxorubicin hydrochloride melphalan mesna paclitaxel tamoxifen citrate bone marrow ablation with stem cell support peripheral blood stem cell transplantation
All Cause Mortality
	Neoadjuvant Chemo Followed by Surgery & High-dose Chemo With PSC Rescue		High-dose Chemo With Rescue
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	10/14 (71.4%)		14/27 (51.9%)
Serious Adverse Events
	Neoadjuvant Chemo Followed by Surgery & High-dose Chemo With PSC Rescue		High-dose Chemo With Rescue
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/14 (0%)		2/27 (7.4%)
Infections and infestations
Skin infection	0/14 (0%)	0	1/27 (3.7%)	1
Metabolism and nutrition disorders
Alkalosis	0/14 (0%)	0	1/27 (3.7%)	1
Other (Not Including Serious) Adverse Events
	Neoadjuvant Chemo Followed by Surgery & High-dose Chemo With PSC Rescue		High-dose Chemo With Rescue
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	13/14 (92.9%)		23/27 (85.2%)
Blood and lymphatic system disorders
Clinical Coagulation	2/14 (14.3%)	2	7/27 (25.9%)	12
Disseminated intravascular coagulation	0/14 (0%)	0	1/27 (3.7%)	1
Febrile neutropenia	5/14 (35.7%)	6	11/27 (40.7%)	15
Hemoglobin decreased	0/14 (0%)	0	3/27 (11.1%)	5
Lymphatic disorder	1/14 (7.1%)	2	0/27 (0%)	0
Cardiac disorders
Dysrhythmias	4/14 (28.6%)	8	9/27 (33.3%)	15
Ischemia	4/14 (28.6%)	8	9/27 (33.3%)	15
Pericardial	4/14 (28.6%)	8	9/27 (33.3%)	15
Arrhythmia	0/14 (0%)	0	1/27 (3.7%)	1
Arrhythmia supraventricular	0/14 (0%)	0	1/27 (3.7%)	1
EF/CHF	4/14 (28.6%)	8	9/27 (33.3%)	15
Left ventricular failure	3/14 (21.4%)	4	4/27 (14.8%)	4
Myocardial ischemia	2/14 (14.3%)	2	0/27 (0%)	0
Pericardial effusion	0/14 (0%)	0	1/27 (3.7%)	2
Sinus bradycardia	1/14 (7.1%)	1	1/27 (3.7%)	1
Sinus tachycardia	5/14 (35.7%)	7	10/27 (37%)	13
Ventricular arrhythmia	0/14 (0%)	0	1/27 (3.7%)	1
Ear and labyrinth disorders
Ear disorder	0/14 (0%)	0	1/27 (3.7%)	1
Hearing	4/14 (28.6%)	7	10/27 (37%)	16
Hearing loss	1/14 (7.1%)	1	1/27 (3.7%)	1
Eye disorders
Vision	4/14 (28.6%)	7	10/27 (37%)	19
Gastrointestinal disorders
Haematemesis	0/14 (0%)	0	1/27 (3.7%)	1
Abdominal pain	2/14 (14.3%)	3	8/27 (29.6%)	9
Constipation	5/14 (35.7%)	16	18/27 (66.7%)	30
Diarrhea	6/14 (42.9%)	18	13/27 (48.1%)	25
Diarrhea (Somlo COH)	2/14 (14.3%)	2	7/27 (25.9%)	10
Dry mouth	0/14 (0%)	0	3/27 (11.1%)	3
Dyspepsia	1/14 (7.1%)	2	1/27 (3.7%)	2
Dysphagia	1/14 (7.1%)	1	0/27 (0%)	0
Dysphagia, esophagitis, odynophagia (Somlo COH)	1/14 (7.1%)	1	1/27 (3.7%)	2
Esophagitis	1/14 (7.1%)	1	3/27 (11.1%)	3
Gastrointestinal disorder	1/14 (7.1%)	6	3/27 (11.1%)	4
Haematochezia	0/14 (0%)	0	1/27 (3.7%)	1
Incontinence NOS	2/14 (14.3%)	2	2/27 (7.4%)	3
Melaena	1/14 (7.1%)	1	0/27 (0%)	0
Mucositis oral	2/14 (14.3%)	2	3/27 (11.1%)	4
Nausea	10/14 (71.4%)	26	18/27 (66.7%)	34
Nausea (Somlo COH)	2/14 (14.3%)	2	7/27 (25.9%)	11
Proctitis	0/14 (0%)	0	1/27 (3.7%)	2
Stomatitis/phayngitis (Somlo COH)	2/14 (14.3%)	2	7/27 (25.9%)	10
Vomiting	10/14 (71.4%)	25	19/27 (70.4%)	35
Vomiting (Somlo COH)	1/14 (7.1%)	1	7/27 (25.9%)	11
General disorders
Stomatitis	5/14 (35.7%)	24	10/27 (37%)	26
Chest pain	1/14 (7.1%)	1	5/27 (18.5%)	5
Chills	3/14 (21.4%)	4	9/27 (33.3%)	9
Fatigue	8/14 (57.1%)	14	8/27 (29.6%)	11
Fever	2/14 (14.3%)	4	5/27 (18.5%)	6
Fever (no infection)	4/14 (28.6%)	11	10/27 (37%)	21
General symptom	2/14 (14.3%)	2	1/27 (3.7%)	1
Injection site reaction	0/14 (0%)	0	4/27 (14.8%)	5
Irritability	1/14 (7.1%)	2	0/27 (0%)	0
Oedema NOS	5/14 (35.7%)	6	11/27 (40.7%)	14
Pain	4/14 (28.6%)	7	8/27 (29.6%)	12
Hepatobiliary disorders
Hepatobiliary disease	1/14 (7.1%)	1	1/27 (3.7%)	1
Immune system disorders
Allergy	5/14 (35.7%)	24	10/27 (37%)	26
Hypersensitivity	0/14 (0%)	0	2/27 (7.4%)	2
Infections and infestations
Infection	6/14 (42.9%)	25	11/27 (40.7%)	27
Catheter related infection	1/14 (7.1%)	1	3/27 (11.1%)	3
Infection, Bacterial (COH)	0/14 (0%)	0	1/27 (3.7%)	1
Injury, poisoning and procedural complications
Wound dehiscence	0/14 (0%)	0	2/27 (7.4%)	2
Investigations
AGC	5/14 (35.7%)	20	10/27 (37%)	25
Activated partial thromboplastin time prolonged	5/14 (35.7%)	6	10/27 (37%)	15
Alanine aminotransferase increased	1/14 (7.1%)	2	5/27 (18.5%)	6
Alk Phos (Somlo COH)	1/14 (7.1%)	1	1/27 (3.7%)	1
Alkaline Phosphatase	4/14 (28.6%)	8	7/27 (25.9%)	7
Alkaline phosphatase increased	2/14 (14.3%)	4	5/27 (18.5%)	7
Amylase	3/14 (21.4%)	5	1/27 (3.7%)	1
Aspartate aminotransferase increased	3/14 (21.4%)	3	1/27 (3.7%)	1
Bilirubin	4/14 (28.6%)	8	7/27 (25.9%)	7
Bilirubin (Somlo COH)	1/14 (7.1%)	1	0/27 (0%)	0
Creatinine	2/14 (14.3%)	2	3/27 (11.1%)	3
Creatinine increased	3/14 (21.4%)	3	4/27 (14.8%)	5
HGB/HCT	4/14 (28.6%)	13	8/27 (29.6%)	8
Hyperbilirubinemia	0/14 (0%)	0	1/27 (3.7%)	1
Hypercholesterolemia	0/14 (0%)	0	1/27 (3.7%)	1
INR increased	6/14 (42.9%)	8	13/27 (48.1%)	17
Leukopenia	1/14 (7.1%)	1	1/27 (3.7%)	1
Lymphopenia	0/14 (0%)	0	2/27 (7.4%)	4
Neutrophil count decreased	3/14 (21.4%)	6	3/27 (11.1%)	6
Neutrophils (ANC) (Somlo COH)	3/14 (21.4%)	5	8/27 (29.6%)	14
	7/14 (50%)	39	9/27 (33.3%)	53
Partial Thromboplastin Time	2/14 (14.3%)	2	7/27 (25.9%)	11
Platelet count decreased	2/14 (14.3%)	4	5/27 (18.5%)	8
Platelets	5/14 (35.7%)	20	10/27 (37%)	25
Platelets (Somlo COH)	3/14 (21.4%)	4	8/27 (29.6%)	14
Prothrombin Time	2/14 (14.3%)	2	7/27 (25.9%)	12
SGOT (Somlo COH)	1/14 (7.1%)	1	0/27 (0%)	0
SGOT/SGT	4/14 (28.6%)	8	7/27 (25.9%)	7
SGPT (Somlo COH)	0/14 (0%)	0	2/27 (7.4%)	2
WBC	4/14 (28.6%)	13	8/27 (29.6%)	8
Weight gain	3/14 (21.4%)	4	3/27 (11.1%)	3
Weight loss	1/14 (7.1%)	2	3/27 (11.1%)	3
Metabolism and nutrition disorders
Weight (Food Intake)	5/14 (35.7%)	16	9/27 (33.3%)	9
Anorexia	4/14 (28.6%)	5	9/27 (33.3%)	14
Blood bicarbonate decreased	0/14 (0%)	0	1/27 (3.7%)	2
Dehydration	0/14 (0%)	0	2/27 (7.4%)	2
Hypercalcemia	4/14 (28.6%)	10	10/27 (37%)	22
Hyperglycemia	12/14 (85.7%)	24	23/27 (85.2%)	43
Hypermagnesemia	0/14 (0%)	0	1/27 (3.7%)	1
Hyperuricemia	0/14 (0%)	0	2/27 (7.4%)	2
Hypoalbuminemia	1/14 (7.1%)	1	2/27 (7.4%)	4
Hypocalcemia	12/14 (85.7%)	22	22/27 (81.5%)	42
Hypoglycemia	4/14 (28.6%)	10	10/27 (37%)	22
Hypokalemia	1/14 (7.1%)	1	2/27 (7.4%)	3
Hypomagnesemia	10/14 (71.4%)	17	21/27 (77.8%)	37
Hyponatremia	0/14 (0%)	0	2/27 (7.4%)	2
Hypophosphatemia	1/14 (7.1%)	1	2/27 (7.4%)	3
Musculoskeletal and connective tissue disorders
Arthritis	0/14 (0%)	0	1/27 (3.7%)	2
Bone pain	1/14 (7.1%)	1	5/27 (18.5%)	5
Joint pain	1/14 (7.1%)	2	1/27 (3.7%)	1
Musculoskeletal disorder	1/14 (7.1%)	1	0/27 (0%)	0
Myalgia	3/14 (21.4%)	3	5/27 (18.5%)	6
Nervous system disorders
Cerebellar	4/14 (28.6%)	7	10/27 (37%)	19
Ataxia	0/14 (0%)	0	1/27 (3.7%)	1
Cortical/State of Consciousness	4/14 (28.6%)	7	11/27 (40.7%)	20
Depressed level of consciousness	2/14 (14.3%)	2	2/27 (7.4%)	2
Dizziness	1/14 (7.1%)	1	5/27 (18.5%)	5
Extrapyramidal disorder	1/14 (7.1%)	1	2/27 (7.4%)	2
Headache	10/14 (71.4%)	15	17/27 (63%)	29
Motor Activity	4/14 (28.6%)	7	10/27 (37%)	19
Neuralgia	0/14 (0%)	0	2/27 (7.4%)	2
Neurological disorder NOS	2/14 (14.3%)	3	1/27 (3.7%)	1
Peripheral Nervous System Sensory	4/14 (28.6%)	7	10/27 (37%)	19
Peripheral motor neuropathy	3/14 (21.4%)	4	7/27 (25.9%)	9
Peripheral sensory neuropathy	6/14 (42.9%)	9	12/27 (44.4%)	19
Speech disorder	1/14 (7.1%)	2	1/27 (3.7%)	1
Taste alteration	0/14 (0%)	0	3/27 (11.1%)	3
Psychiatric disorders
Anxiety	4/14 (28.6%)	7	7/27 (25.9%)	7
Confusion	0/14 (0%)	0	1/27 (3.7%)	1
Depression	1/14 (7.1%)	1	6/27 (22.2%)	7
Hallucination NOS	0/14 (0%)	0	2/27 (7.4%)	2
Ideation	4/14 (28.6%)	7	10/27 (37%)	19
Insomnia	3/14 (21.4%)	4	5/27 (18.5%)	5
Mood	4/14 (28.6%)	7	10/27 (37%)	19
Personality change	1/14 (7.1%)	1	0/27 (0%)	0
Renal and urinary disorders
Fluid Retention	5/14 (35.7%)	24	10/27 (37%)	26
Blood urine present	3/14 (21.4%)	3	2/27 (7.4%)	2
Hematuria	2/14 (14.3%)	2	3/27 (11.1%)	3
Proteinuria	2/14 (14.3%)	2	3/27 (11.1%)	3
Urinary frequency	0/14 (0%)	0	1/27 (3.7%)	1
Urinary retention	0/14 (0%)	0	1/27 (3.7%)	1
Urine discoloration	0/14 (0%)	0	1/27 (3.7%)	1
Reproductive system and breast disorders
Vaginal hemorrhage	0/14 (0%)	0	1/27 (3.7%)	1
Respiratory, thoracic and mediastinal disorders
Pulmonary	5/14 (35.7%)	24	10/27 (37%)	26
Allergic rhinitis	0/14 (0%)	0	1/27 (3.7%)	2
Cough	3/14 (21.4%)	3	7/27 (25.9%)	8
Dyspnea	4/14 (28.6%)	4	6/27 (22.2%)	6
Haemoptysis	0/14 (0%)	0	1/27 (3.7%)	1
Hemorrhage nasal	4/14 (28.6%)	5	6/27 (22.2%)	7
Hiccough	1/14 (7.1%)	1	2/27 (7.4%)	2
Hypoxia	2/14 (14.3%)	2	6/27 (22.2%)	7
Pleural effusion	0/14 (0%)	0	1/27 (3.7%)	1
Pneumonitis	0/14 (0%)	0	1/27 (3.7%)	1
Respiratory disorder	6/14 (42.9%)	7	5/27 (18.5%)	5
Voice alteration	1/14 (7.1%)	1	1/27 (3.7%)	1
Skin and subcutaneous tissue disorders
Alopecia	6/14 (42.9%)	12	9/27 (33.3%)	9
Dry skin	0/14 (0%)	0	1/27 (3.7%)	1
Erythema multiforme	0/14 (0%)	0	1/27 (3.7%)	2
Extensive Skin Rash	2/14 (14.3%)	5	7/27 (25.9%)	9
Local Skin Rash	2/14 (14.3%)	5	7/27 (25.9%)	9
Nail disorder	0/14 (0%)	0	1/27 (3.7%)	1
Petechiae	1/14 (7.1%)	1	2/27 (7.4%)	2
Pruritus	2/14 (14.3%)	2	1/27 (3.7%)	1
Rash desquamating	1/14 (7.1%)	2	5/27 (18.5%)	7
Skin discolouration	0/14 (0%)	0	1/27 (3.7%)	1
Skin disorder	5/14 (35.7%)	9	6/27 (22.2%)	7
Sweating	2/14 (14.3%)	2	0/27 (0%)	0
Urticaria	0/14 (0%)	0	1/27 (3.7%)	1
Vascular disorders
Flushing	3/14 (21.4%)	3	3/27 (11.1%)	3
Hemorrhage	7/14 (50%)	26	13/27 (48.1%)	29
Hypertension	5/14 (35.7%)	6	17/27 (63%)	23
Hypotension	7/14 (50%)	8	17/27 (63%)	24

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.