Gefitinib, Trastuzumab, and Docetaxel in Treating Patients With Metastatic Breast Cancer

• Sponsor: City of Hope Medical Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT00086957
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 31
• Locations: 6
• Arm: 1
• Duration (Months): 139
• Patients Per Site: 5.2
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

RATIONALE: Gefitinib may stop the growth of tumor cells by blocking the enzymes necessary for their growth. Monoclonal antibodies such as trastuzumab can locate tumor cells and either kill them or deliver tumor-killing substances to them without harming normal cells. Drugs used in chemotherapy, such as docetaxel, work in different ways to stop tumor cells from dividing so they stop growing or die. Combining gefitinib and trastuzumab with docetaxel may kill more tumor cells.

PURPOSE: This phase I/II trial is studying the best dose of docetaxel when given together with gefitinib and trastuzumab in treating patients with metastatic breast cancer.

Condition or Disease	Intervention/Treatment	Phase
Breast Cancer	Biological: trastuzumab; Drug: docetaxel; Drug: gefitinib	Phase 1/Phase 2

Detailed Description

OBJECTIVES:

Primary

• Determine the safety and efficacy of gefitinib, trastuzumab (Herceptin®), and docetaxel, in terms of time to disease progression, in patients with HER2/neu-overexpressing metastatic adenocarcinoma of the breast.

Secondary

• Determine the objective tumor response rate in patients treated with this regimen.

• Correlate expression and/or degree of phosphorylation of epidermal growth factor receptor, HER2/neu, c-fos, Akt, ERK½, P13K, p53, p21, and p27 with outcome in patients treated with this regimen.

OUTLINE: This is a phase I, multicenter, dose-escalation study of docetaxel followed by a phase II study. Patients are stratified according to trastuzumab (Herceptin®)-naive vs trastuzumab-failure.

• Phase I: Patients receive oral gefitinib once daily on days 2-14. Patients also receive trastuzumab* IV over 30-90 minutes and docetaxel IV over 1 hour on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

NOTE: *Trastuzumab is given at a higher dose (loading dose) in course 1 and then at a lower dose in subsequent courses.

Cohorts of 3-6 patients receive docetaxel at dose level 1. If no dose-limiting toxicity (DLT) is observed in the first cohort of 3 patients, the dose of docetaxel remains the same. If 1 DLT is observed in the first cohort of 3 patients, 3 additional patients are added (for a total of 6 patients) to dose level 1. If no further DLTs are observed at dose level 1, the dose of docetaxel remains the same. If 2 of 3 or 2 of 6 patients experience DLT at dose level 1, the dose of docetaxel is considered above the maximum tolerated dose (MTD) and is subsequently reduced. If 2 of 3 or 2 of 6 patients experience DLT at the reduced dose of docetaxel, the study is stopped.

• Phase II: Patients receive docetaxel at the MTD and gefitinib and trastuzumab as in phase I.

Patients are followed for survival.

PROJECTED ACCRUAL: A total of 3-76 patients will be accrued for this study within 26 months.

Study Design

• Study Type: Interventional
• Actual Enrollment: 31 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase I/II Trial of ZD1839 (Iressa®), Trastuzumab (Herceptin®), and Docetaxel (Taxotere®) in Patients With erbB-2 (HER-2) Overexpressing, Stage IV Breast Carcinoma
• Study Start Date: Jan 1, 2004
• Actual Primary Completion Date: Aug 1, 2015
• Actual Study Completion Date: Aug 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: ZD1839, Trastuzumab and Docetaxel	Biological: trastuzumab; Cycle 1 loading dose of 8 mg/kg, followed by 6 mg/kg every 3 weeks for subsequent cycles.; Drug: docetaxel; 75 mg/m2 every three weeks, or 60 mg/m2 every three weeks depending on study findings; Drug: gefitinib; 250 mg daily or 250 mg daily on days 2 through 14 depending on study findings

Outcome Measures

Primary Outcome Measures

1. Number of Participants With at Least One Dose Limiting Toxicity in Phase I [4 weeks from start of treatment, up to 2 years]

   Dose Limiting Toxicity (DLT) defined as any treatment-related grade 3 or greater except for hematological toxicities which must be grade 4. Interstitial Lung Disease (ILD) related to treatment should be considered as a DLT regardless of the grade.

2. Recommended Phase II Dose [4 weeks from start of treatment, up to 2 years]

   The maximum tolerated dose (MTD): subjects received gefitinib 250 mg orally daily, trastuzumab 6 mg/kg intravenously every 3 weeks (after an initial dose of 8 mg/kg with cycle 1), and docetaxel 75 mg/m^2 intravenously every 3 weeks. This was to serve as the phase II dose if no dose-limiting toxicities (DLTs) occurred in the first three subjects. If one DLT occurred in the first three subjects, another three subjects where to be enrolled at this dose, whereas if two DLTs occurred in the first three subjects, the docetaxel dose was to be decreased to 60 mg/m^2. The study would then be continued only if no more than one patient had a DLT at this dose. Once the dose of docetaxel was established, all further subjects were to be treated at the phase II MTD dose.

Secondary Outcome Measures

1. Progression-free Survival [Until disease progression, up to 5 years.]

   Estimated using the product-limit method of Kaplan and Meier. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST), as a 20% increase in the sum of the longest diameter of target lesions, or the appearance of new lesions.

2. Objective Response Rate [After 3 cycles of treatment, up to 2 years.]

   Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Objective Response Rate defined as percentage of patients achieving a Best Response of either CR or PR.

3. Overall Survival [Until death from any cause, up to 5 years.]

   Estimated using the product-limit method of Kaplan and Meier.

Eligibility Criteria

Criteria

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

DISEASE CHARACTERISTICS:

• Histologically confirmed adenocarcinoma of the breast

• Metastatic disease

• HER-2/neu overexpression (3+ by immunohistochemistry OR 2+ by fluorescence in situ hybridization)

• Measurable or evaluable disease

• Hormone receptor status:

• Not specified

PATIENT CHARACTERISTICS:

Age

• 18 and over

Sex

• Male or female

Menopausal status

• Not specified

Performance status

• ECOG 0-2

Life expectancy

• Not specified

Hematopoietic

• Absolute granulocyte count ≥ 1,500/mm^3

• Platelet count ≥ 100,000/mm^3

Hepatic

• AST and ALT < 2.5 times upper limit of normal (ULN) (5.0 times ULN in the presence of liver metastases)

• Bilirubin < 1.5 times ULN

• No unstable or uncompensated hepatic disease

Renal

• Creatinine < 1.6 mg/dL

• No unstable or uncompensated renal disease

Cardiovascular

• LVEF > 45% by echocardiogram or MUGA

• No prior New York Heart Association class I-IV heart disease

• No prolonged PR interval or atrioventricular block on ECG

• No unstable or uncompensated cardiac disease

Pulmonary

• No unstable or uncompensated respiratory disease

• No clinically active interstitial lung disease

• Patients who are asymptomatic and have chronic stable radiographic changes are allowed

Immunologic

• No autoimmune disorders

• No conditions of immunosuppression

• No severe hypersensitivity to taxane or gefitinib or any of its excipients

Other

• Not pregnant or nursing

• Negative pregnancy test

• Fertile patients must use effective contraception

• No other prior or concurrent malignancy within the past 5 years except basal cell carcinoma or carcinoma in situ of the cervix

• No other severe or uncontrolled systemic disease

• No other acute or chronic medical condition that would preclude study participation

• No other significant clinical disorder or laboratory finding that would preclude study participation

• No psychiatric illness that would preclude study compliance

PRIOR CONCURRENT THERAPY:

Biologic therapy

• Prior adjuvant trastuzumab (Herceptin®) allowed if > 6 months elapsed before disease recurrence

• No prior trastuzumab for metastatic breast cancer

• No prior monoclonal antibodies directed at the epidermal growth factor receptor (EGFR)

Chemotherapy

• Prior adjuvant chemotherapy (or as first-line therapy for metastatic breast cancer) allowed

• Prior adjuvant taxane allowed if completed > 6 months before diagnosis of metastatic breast cancer

• No prior docetaxel for metastatic breast cancer

Endocrine therapy

• Prior adjuvant hormonal therapy (or as first-line therapy for metastatic breast cancer) allowed

• No concurrent hormonal therapy

• Concurrent steroids allowed provided dose is stable

Radiotherapy

• Not specified

Surgery

• Fully recovered from prior oncologic or other major surgery

• No concurrent surgery within 7 days of gefitinib administration

Other

• Recovered from prior anticancer therapy (alopecia allowed)

• More than 30 days since prior non-approved drug or investigational agent

• No other prior EGFR-directed therapy (i.e., tyrosine kinase inhibitors)

• No concurrent use of any of the following medications:

• Phenytoin

• Carbamazepine

• Barbiturates

• Rifampin

• Hypericum perforatum (St. John's wort)

• No other concurrent anticancer therapy

• No concurrent cardioprotective drugs

• No concurrent oral retinoids

• Concurrent participation in the City of Hope indium-labeled trastuzumab imaging study allowed

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Tower Cancer Research Foundation	Beverly Hills	California	United States	90211-1850
2	City of Hope Comprehensive Cancer Center	Duarte	California	United States	91010-3000
3	Hematology Oncology Consultants-Hemet	Hemet	California	United States	92543
4	Breastlink Medical Group, Incorporated at Long Beach Memorial Medical Center	Long Beach	California	United States	90806
5	USC/Norris Comprehensive Cancer Center and Hospital	Los Angeles	California	United States	90089-9181
6	City of Hope Medical Group	Pasadena	California	United States	91105

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)

None provided.

More Information

Publications

None provided.

• Responsible Party: City of Hope Medical Center
• ClinicalTrials.gov Identifier: NCT00086957
• Other Study ID Numbers: 03049; P30CA033572; CHNMC-03049; ZENECA-1839US/0274; ZENECA-IRUSIRES0012; CDR0000371908
• First Posted: Jul 12, 2004
• Last Update Posted: Feb 27, 2017
• Last Verified: Jan 1, 2017

• Keywords provided by City of Hope Medical Center: stage IV breast cancer; male breast cancer; recurrent breast cancer
• Additional relevant MeSH terms: Breast Neoplasms; Docetaxel; Trastuzumab; Gefitinib

Study Results

Participant Flow

Arm/Group Title	Phase I - Docetaxel 75 mg/m^2	Phase I - Docetaxel 60 mg/m^2	Phase II - Docetaxel 60 mg/m^2
Arm/Group Description	Subjects receive gefitinib 250 mg orally daily, trastuzumab 6 mg/kg intravenously every 3 weeks (after an initial dose of 8 mg/kg with cycle 1), and docetaxel 75 mg/m^2 intravenously every 3 weeks.	Subjects receive gefitinib 250 mg orally daily or 250 mg daily on days 2 through 14 depending on study findings, trastuzumab 6 mg/kg intravenously every 3 weeks (after an initial dose of 8 mg/kg with cycle 1), and docetaxel 60 mg/m^2 intravenously every 3 weeks.	Subjects receive gefitinib 250 mg orally daily or 250 mg daily on days 2 through 14 depending on study findings, trastuzumab 6 mg/kg intravenously every 3 weeks (after an initial dose of 8 mg/kg with cycle 1), and docetaxel 60 mg/m^2 intravenously every 3 weeks.
Period Title: Overall Study
STARTED	2	7	22
COMPLETED	2	7	22
NOT COMPLETED	0	0	0

Baseline Characteristics

Arm/Group Title	Dose Levels 1 & 2 - Docetaxel 60 & 75 mg/m^2
Arm/Group Description	trastuzumab: Cycle 1 loading dose of 8 mg/kg, followed by 6 mg/kg every 3 weeks for subsequent cycles. docetaxel: 75 mg/m^2 every three weeks, or 60 mg/m^2 every three weeks depending on study findings gefitinib: 250 mg daily or 250 mg daily on days 2 through 14 depending on study findings
Overall Participants	31
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	52
Gender (Count of Participants)
Female	31 100%
Male	0 0%
Region of Enrollment (participants) [Number]
United States	31 100%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With at Least One Dose Limiting Toxicity in Phase I
Description	Dose Limiting Toxicity (DLT) defined as any treatment-related grade 3 or greater except for hematological toxicities which must be grade 4. Interstitial Lung Disease (ILD) related to treatment should be considered as a DLT regardless of the grade.
Time Frame	4 weeks from start of treatment, up to 2 years

Outcome Measure Data

Analysis Population Description

All patients receiving treatment were evaluated for DLT.

Arm/Group Title	Phase I: Dose Level 1 - Docetaxel 75 mg/m^2	Phase I: Dose Level 2 - Docetaxel 60 mg/m^2
Arm/Group Description	Subjects receive gefitinib 250 mg orally daily, trastuzumab 6 mg/kg intravenously every 3 weeks (after an initial dose of 8 mg/kg with cycle 1), and docetaxel 75 mg/m^2 intravenously every 3 weeks.	Subjects receive gefitinib 250 mg orally daily, trastuzumab 6 mg/kg intravenously every 3 weeks (after an initial dose of 8 mg/kg with cycle 1), and docetaxel 60 mg/m^2 intravenously every 3 weeks.
Measure Participants	2	7
Number [participants with DLTs]	2 6.5%	0 NaN

2. Primary Outcome

Title	Recommended Phase II Dose
Description	The maximum tolerated dose (MTD): subjects received gefitinib 250 mg orally daily, trastuzumab 6 mg/kg intravenously every 3 weeks (after an initial dose of 8 mg/kg with cycle 1), and docetaxel 75 mg/m^2 intravenously every 3 weeks. This was to serve as the phase II dose if no dose-limiting toxicities (DLTs) occurred in the first three subjects. If one DLT occurred in the first three subjects, another three subjects where to be enrolled at this dose, whereas if two DLTs occurred in the first three subjects, the docetaxel dose was to be decreased to 60 mg/m^2. The study would then be continued only if no more than one patient had a DLT at this dose. Once the dose of docetaxel was established, all further subjects were to be treated at the phase II MTD dose.
Time Frame	4 weeks from start of treatment, up to 2 years

Outcome Measure Data

Analysis Population Description

All patients observed for 21 days while receiving a full course of therapy or who experienced a DLT. Patients withdrawing before completion of the first course, for reasons other than DLT, were replaced.

Arm/Group Title	Phase I
Arm/Group Description	All patients enrolled on the Phase I (dose-finding) portion of the study.
Measure Participants	9
Number [mg/m^2]	60

3. Secondary Outcome

Title	Progression-free Survival
Description	Estimated using the product-limit method of Kaplan and Meier. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST), as a 20% increase in the sum of the longest diameter of target lesions, or the appearance of new lesions.
Time Frame	Until disease progression, up to 5 years.

Outcome Measure Data

Analysis Population Description

All patients treated at the phase II docetaxel dose (7 in the phase I portion, 22 in the phase II portion).

Arm/Group Title	Dose Level 2 - Docetaxel 60 mg/m^2
Arm/Group Description	Subjects receive gefitinib 250 mg orally daily or 250 mg daily on days 2 through 14 depending on study findings, trastuzumab 6 mg/kg intravenously every 3 weeks (after an initial dose of 8 mg/kg with cycle 1), and docetaxel 60 mg/m2 intravenously every 3 weeks.
Measure Participants	29
Median (95% Confidence Interval) [Months]	12.7

4. Secondary Outcome

Title	Objective Response Rate
Description	Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Objective Response Rate defined as percentage of patients achieving a Best Response of either CR or PR.
Time Frame	After 3 cycles of treatment, up to 2 years.

Outcome Measure Data

Analysis Population Description

All patients treated at the phase II docetaxel dose (7 in the phase I portion, 22 in the phase II portion). Patients who complete 3 cycles of treatment or who terminate treatment for reasons of toxicity, or who progress prior to the completion of 3 cycles of therapy on the Phase II portion of the study.

Arm/Group Title	Dose Level 2 - Docetaxel 60 mg/m^2
Arm/Group Description	Subjects receive gefitinib 250 mg orally daily or 250 mg daily on days 2 through 14 depending on study findings, trastuzumab 6 mg/kg intravenously every 3 weeks (after an initial dose of 8 mg/kg with cycle 1), and docetaxel 60 mg/m^2 intravenously every 3 weeks.
Measure Participants	29
Number [percentage of participants]	64 206.5%

5. Secondary Outcome

Title	Overall Survival
Description	Estimated using the product-limit method of Kaplan and Meier.
Time Frame	Until death from any cause, up to 5 years.

Outcome Measure Data

Analysis Population Description

All patients treated at the phase II docetaxel dose (7 in the phase I portion, 22 in the phase II portion).

Arm/Group Title	Dose Level 2 - Docetaxel 60 mg/m^2
Arm/Group Description	Subjects receive gefitinib 250 mg orally daily or 250 mg daily on days 2 through 14 depending on study findings, trastuzumab 6 mg/kg intravenously every 3 weeks (after an initial dose of 8 mg/kg with cycle 1), and docetaxel 60 mg/m^2 intravenously every 3 weeks.
Measure Participants	29
Median (95% Confidence Interval) [Months]	43.2

Adverse Events

Time Frame	Adverse events occurred over a period of 5 years and 3 months.
Adverse Event Reporting Description	"Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.
Arm/Group Title	Dose Level 1 - Docetaxel 75 mg/m^2		Dose Level 2 - Docetaxel 60 mg/m^2
Arm/Group Description	Subjects receive gefitinib 250 mg orally daily, trastuzumab 6 mg/kg intravenously every 3 weeks (after an initial dose of 8 mg/kg with cycle 1), and docetaxel 75 mg/m^2 intravenously every 3 weeks.		Subjects receive gefitinib 250 mg orally daily or 250 mg daily on days 2 through 14 depending on study findings, trastuzumab 6 mg/kg intravenously every 3 weeks (after an initial dose of 8 mg/kg with cycle 1), and docetaxel 60 mg/m^2 intravenously every 3 weeks.
All Cause Mortality
	Dose Level 1 - Docetaxel 75 mg/m^2		Dose Level 2 - Docetaxel 60 mg/m^2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Dose Level 1 - Docetaxel 75 mg/m^2		Dose Level 2 - Docetaxel 60 mg/m^2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/2 (100%)		7/29 (24.1%)
Blood and lymphatic system disorders
Febrile neutropenia	2/2 (100%)	2	1/29 (3.4%)	1
Haemorrhage NOS	0/2 (0%)	0	1/29 (3.4%)	1
Gastrointestinal disorders
Abdominal pain	0/2 (0%)	0	1/29 (3.4%)	1
Diarrhea	0/2 (0%)	0	2/29 (6.9%)	2
Melaena	0/2 (0%)	0	1/29 (3.4%)	1
Mucositis oral	0/2 (0%)	0	1/29 (3.4%)	1
Nausea	0/2 (0%)	0	1/29 (3.4%)	1
Vomiting	0/2 (0%)	0	1/29 (3.4%)	1
Infections and infestations
Catheter related infection	0/2 (0%)	0	1/29 (3.4%)	1
Infection NOS	0/2 (0%)	0	2/29 (6.9%)	2
Investigations
Leukopenia	1/2 (50%)	1	0/29 (0%)	0
Neutrophil count decreased	1/2 (50%)	1	0/29 (0%)	0
Metabolism and nutrition disorders
Anorexia	0/2 (0%)	0	1/29 (3.4%)	1
Dehydration	0/2 (0%)	0	2/29 (6.9%)	2
Musculoskeletal and connective tissue disorders
Musculoskeletal disorder	0/2 (0%)	0	1/29 (3.4%)	1
Other (Not Including Serious) Adverse Events
	Dose Level 1 - Docetaxel 75 mg/m^2		Dose Level 2 - Docetaxel 60 mg/m^2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/2 (100%)		29/29 (100%)
Blood and lymphatic system disorders
Febrile neutropenia	0/2 (0%)	0	1/29 (3.4%)	1
Hemoglobin decreased	2/2 (100%)	9	25/29 (86.2%)	196
Lymphatic disorder	0/2 (0%)	0	9/29 (31%)	18
Packed red blood cell transfusion	0/2 (0%)	0	1/29 (3.4%)	1
Cardiac disorders
Arrhythmia	0/2 (0%)	0	1/29 (3.4%)	1
Atrial fibrillation	0/2 (0%)	0	1/29 (3.4%)	1
Cardiac disorder	0/2 (0%)	0	2/29 (6.9%)	3
Left ventricular failure	1/2 (50%)	1	5/29 (17.2%)	8
Myocardial ischemia	0/2 (0%)	0	3/29 (10.3%)	3
Palpitations	0/2 (0%)	0	1/29 (3.4%)	2
Sinus bradycardia	0/2 (0%)	0	1/29 (3.4%)	1
Sinus tachycardia	2/2 (100%)	3	8/29 (27.6%)	24
Ear and labyrinth disorders
Ear disorder	0/2 (0%)	0	1/29 (3.4%)	3
Ear pain	1/2 (50%)	2	3/29 (10.3%)	4
External ear inflammation	1/2 (50%)	1	1/29 (3.4%)	1
Hearing loss	1/2 (50%)	2	1/29 (3.4%)	1
Endocrine disorders
Hypothyroidism	1/2 (50%)	1	0/29 (0%)	0
Eye disorders
Dry eye syndrome	0/2 (0%)	0	2/29 (6.9%)	2
Eye disorder	0/2 (0%)	0	4/29 (13.8%)	7
Vision blurred	1/2 (50%)	1	1/29 (3.4%)	1
Watering eyes	0/2 (0%)	0	3/29 (10.3%)	4
Gastrointestinal disorders
Haematemesis	0/2 (0%)	0	1/29 (3.4%)	1
Abdominal pain	0/2 (0%)	0	8/29 (27.6%)	18
Constipation	1/2 (50%)	1	6/29 (20.7%)	16
Diarrhea	2/2 (100%)	5	26/29 (89.7%)	129
Dry mouth	1/2 (50%)	1	2/29 (6.9%)	2
Dyspepsia	0/2 (0%)	0	3/29 (10.3%)	9
Dysphagia	0/2 (0%)	0	1/29 (3.4%)	1
Esophagitis	1/2 (50%)	1	0/29 (0%)	0
Gastritis	0/2 (0%)	0	3/29 (10.3%)	4
Gastrointestinal disorder	1/2 (50%)	2	9/29 (31%)	44
Melaena	0/2 (0%)	0	1/29 (3.4%)	1
Mucositis oral	2/2 (100%)	4	15/29 (51.7%)	32
Nausea	2/2 (100%)	5	18/29 (62.1%)	44
	0/2 (0%)	0	2/29 (6.9%)	8
Rectal bleeding/hematochezia	0/2 (0%)	0	2/29 (6.9%)	4
Vomiting	0/2 (0%)	0	11/29 (37.9%)	17
General disorders
Chest pain	1/2 (50%)	1	3/29 (10.3%)	10
Chills	2/2 (100%)	3	8/29 (27.6%)	12
Edema	0/2 (0%)	0	2/29 (6.9%)	3
Fatigue	2/2 (100%)	3	28/29 (96.6%)	158
Fever	0/2 (0%)	0	11/29 (37.9%)	17
General symptom	0/2 (0%)	0	3/29 (10.3%)	5
Injection site reaction	0/2 (0%)	0	1/29 (3.4%)	1
Oedema NOS	2/2 (100%)	5	6/29 (20.7%)	9
Pain	2/2 (100%)	5	16/29 (55.2%)	60
Hepatobiliary disorders
Hepatobiliary disease	0/2 (0%)	0	1/29 (3.4%)	2
Immune system disorders
Hypersensitivity	0/2 (0%)	0	1/29 (3.4%)	1
Immune system disorder	0/2 (0%)	0	3/29 (10.3%)	4
Infections and infestations
Infection	1/2 (50%)	2	5/29 (17.2%)	7
Infection NOS	1/2 (50%)	2	9/29 (31%)	15
Infection with unknown ANC	0/2 (0%)	0	1/29 (3.4%)	1
Infection without neutropenia	0/2 (0%)	0	3/29 (10.3%)	3
Infection, Viral (COH)	0/2 (0%)	0	1/29 (3.4%)	1
Wound infection	1/2 (50%)	1	1/29 (3.4%)	3
Injury, poisoning and procedural complications
Bruising	0/2 (0%)	0	2/29 (6.9%)	2
Intraoperative gastrointestinal injury - Teeth	0/2 (0%)	0	1/29 (3.4%)	1
Investigations
Activated partial thromboplastin time prolonged	0/2 (0%)	0	6/29 (20.7%)	45
Alanine aminotransferase increased	1/2 (50%)	2	25/29 (86.2%)	97
Alkaline phosphatase increased	1/2 (50%)	1	14/29 (48.3%)	30
Amylase increased	0/2 (0%)	0	1/29 (3.4%)	1
Aspartate aminotransferase increased	2/2 (100%)	5	25/29 (86.2%)	150
Bilirubin increased	0/2 (0%)	0	1/29 (3.4%)	1
Creatinine increased	0/2 (0%)	0	4/29 (13.8%)	4
Hyperbilirubinemia	0/2 (0%)	0	1/29 (3.4%)	1
Hypercholesterolemia	1/2 (50%)	3	1/29 (3.4%)	1
INR increased	2/2 (100%)	4	14/29 (48.3%)	92
Laboratory test abnormal	0/2 (0%)	0	9/29 (31%)	26
Leukocyte count decreased	0/2 (0%)	0	12/29 (41.4%)	65
Leukopenia	2/2 (100%)	6	16/29 (55.2%)	103
Lymphocyte count decreased	0/2 (0%)	0	13/29 (44.8%)	93
Lymphopenia	2/2 (100%)	5	12/29 (41.4%)	107
Neutrophil count decreased	2/2 (100%)	4	24/29 (82.8%)	142
Platelet count decreased	1/2 (50%)	1	5/29 (17.2%)	5
Weight gain	1/2 (50%)	2	7/29 (24.1%)	26
Weight loss	1/2 (50%)	3	9/29 (31%)	20
Metabolism and nutrition disorders
Acidosis	0/2 (0%)	0	1/29 (3.4%)	1
Anorexia	1/2 (50%)	1	8/29 (27.6%)	15
Blood bicarbonate decreased	1/2 (50%)	1	5/29 (17.2%)	6
Blood glucose increased	0/2 (0%)	0	11/29 (37.9%)	42
Blood uric acid increased	0/2 (0%)	0	1/29 (3.4%)	1
Dehydration	1/2 (50%)	1	3/29 (10.3%)	3
Hypercalcemia	0/2 (0%)	0	5/29 (17.2%)	8
Hyperglycemia	1/2 (50%)	1	13/29 (44.8%)	53
Hyperkalemia	0/2 (0%)	0	2/29 (6.9%)	2
Hypertriglyceridemia	1/2 (50%)	1	1/29 (3.4%)	1
Hyperuricemia	0/2 (0%)	0	4/29 (13.8%)	7
Hypoalbuminemia	2/2 (100%)	4	13/29 (44.8%)	55
Hypocalcemia	2/2 (100%)	5	11/29 (37.9%)	30
Hypoglycemia	0/2 (0%)	0	3/29 (10.3%)	4
Hypokalemia	2/2 (100%)	2	10/29 (34.5%)	29
Hypomagnesemia	0/2 (0%)	0	9/29 (31%)	22
Hyponatremia	1/2 (50%)	1	5/29 (17.2%)	5
Hypophosphatemia	2/2 (100%)	2	14/29 (48.3%)	54
Serum albumin decreased	0/2 (0%)	0	8/29 (27.6%)	25
Serum calcium decreased	0/2 (0%)	0	6/29 (20.7%)	8
Serum calcium increased	0/2 (0%)	0	3/29 (10.3%)	8
Serum glucose decreased	0/2 (0%)	0	2/29 (6.9%)	2
Serum magnesium decreased	0/2 (0%)	0	7/29 (24.1%)	25
Serum magnesium increased	0/2 (0%)	0	2/29 (6.9%)	2
Serum phosphate decreased	0/2 (0%)	0	6/29 (20.7%)	15
Serum potassium decreased	0/2 (0%)	0	10/29 (34.5%)	23
Serum sodium decreased	0/2 (0%)	0	2/29 (6.9%)	3
Musculoskeletal and connective tissue disorders
Bone pain	1/2 (50%)	1	8/29 (27.6%)	19
Joint pain	0/2 (0%)	0	4/29 (13.8%)	4
Muscle weakness	0/2 (0%)	0	5/29 (17.2%)	5
Musculoskeletal disorder	1/2 (50%)	1	8/29 (27.6%)	12
Myalgia	0/2 (0%)	0	5/29 (17.2%)	16
Pain in extremity	0/2 (0%)	0	1/29 (3.4%)	1
Nervous system disorders
Ataxia	1/2 (50%)	1	0/29 (0%)	0
Dizziness	2/2 (100%)	2	5/29 (17.2%)	10
Headache	1/2 (50%)	2	10/29 (34.5%)	22
Neuralgia	0/2 (0%)	0	5/29 (17.2%)	7
Neurological disorder NOS	0/2 (0%)	0	6/29 (20.7%)	7
Peripheral motor neuropathy	0/2 (0%)	0	2/29 (6.9%)	2
Peripheral sensory neuropathy	0/2 (0%)	0	9/29 (31%)	26
Syncope	0/2 (0%)	0	1/29 (3.4%)	1
Taste alteration	0/2 (0%)	0	8/29 (27.6%)	11
Psychiatric disorders
Anxiety	0/2 (0%)	0	10/29 (34.5%)	13
Depression	0/2 (0%)	0	7/29 (24.1%)	9
Insomnia	0/2 (0%)	0	1/29 (3.4%)	2
Personality change	0/2 (0%)	0	1/29 (3.4%)	1
Renal and urinary disorders
Bladder pain	1/2 (50%)	1	5/29 (17.2%)	6
Protein urine positive	0/2 (0%)	0	1/29 (3.4%)	1
Urinary frequency	0/2 (0%)	0	1/29 (3.4%)	1
Urinary retention	0/2 (0%)	0	1/29 (3.4%)	1
Urine discoloration	0/2 (0%)	0	1/29 (3.4%)	1
Urogenital disorder	0/2 (0%)	0	3/29 (10.3%)	3
Reproductive system and breast disorders
Reproductive tract disorder	0/2 (0%)	0	1/29 (3.4%)	3
Vaginal dryness	0/2 (0%)	0	1/29 (3.4%)	2
Vaginal hemorrhage	0/2 (0%)	0	1/29 (3.4%)	1
Vaginal inflammation	0/2 (0%)	0	2/29 (6.9%)	3
Respiratory, thoracic and mediastinal disorders
Allergic rhinitis	1/2 (50%)	1	4/29 (13.8%)	6
Cough	2/2 (100%)	3	12/29 (41.4%)	36
Dyspnea	1/2 (50%)	2	12/29 (41.4%)	27
Hemorrhage nasal	0/2 (0%)	0	4/29 (13.8%)	5
Hypoxia	1/2 (50%)	1	1/29 (3.4%)	1
Pneumonitis	0/2 (0%)	0	1/29 (3.4%)	1
Pneumothorax	0/2 (0%)	0	1/29 (3.4%)	1
Respiratory disorder	0/2 (0%)	0	9/29 (31%)	21
Voice alteration	1/2 (50%)	2	4/29 (13.8%)	6
Skin and subcutaneous tissue disorders
Alopecia	0/2 (0%)	0	9/29 (31%)	24
Dry skin	0/2 (0%)	0	11/29 (37.9%)	16
Nail disorder	0/2 (0%)	0	7/29 (24.1%)	15
Pigmentation changes (e.g., vitiligo)	0/2 (0%)	0	2/29 (6.9%)	2
Pruritus	1/2 (50%)	2	9/29 (31%)	9
Rash desquamating	2/2 (100%)	5	24/29 (82.8%)	77
Skin discolouration	0/2 (0%)	0	1/29 (3.4%)	1
Skin disorder	1/2 (50%)	1	12/29 (41.4%)	30
Urticaria	0/2 (0%)	0	1/29 (3.4%)	1
Vascular disorders
Flushing	1/2 (50%)	2	4/29 (13.8%)	9
Hemorrhage	0/2 (0%)	0	1/29 (3.4%)	1
Hot flashes	0/2 (0%)	0	2/29 (6.9%)	3
Hypertension	1/2 (50%)	5	3/29 (10.3%)	4
Hypotension	1/2 (50%)	1	7/29 (24.1%)	8
Thrombosis	0/2 (0%)	0	1/29 (3.4%)	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.