Combination Chemotherapy and Rituximab in Treating Patients With Newly Diagnosed AIDS-Related B-Cell Non-Hodgkin's Lymphoma

• Sponsor: AIDS Malignancy Consortium (Other)
• Overall Status: Completed
• CT.gov ID: NCT00389818
• Collaborator: National Cancer Institute (NCI) (NIH), The Emmes Company, LLC (Industry)
• Enrollment: 43
• Locations: 14
• Arm: 1
• Duration (Months): 56
• Patients Per Site: 3.1
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

RATIONALE: Drugs used in chemotherapy work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as rituximab, can block cancer growth in different ways. Some find cancer cells and help kill them or carry cancer-killing substances to them. Others interfere with the ability of cancer cells to grow and spread. Giving combination chemotherapy together with rituximab may kill more cancer cells.

PURPOSE: This phase II trial is studying how well giving combination chemotherapy together with rituximab works in treating patients with newly diagnosed AIDS-related B-cell non-Hodgkin's lymphoma.

Condition or Disease	Intervention/Treatment	Phase
Lymphoma	Biological: filgrastim; Biological: pegfilgrastim; Biological: rituximab; Biological: sargramostim; Drug: cyclophosphamide; Drug: pegylated liposomal doxorubicin hydrochloride; Drug: prednisone; Drug: vincristine sulfate; Other: immunohistochemistry staining method; Other: laboratory biomarker analysis	Phase 2

Detailed Description

OBJECTIVES:

Primary

• Determine the complete response rate (complete response and complete response unconfirmed) in patients with newly diagnosed, AIDS-related B-cell non-Hodgkin's lymphoma treated with doxorubicin hydrochloride liposome, rituximab, cyclophosphamide, vincristine, and prednisone (DR-COP).

• Determine the duration of response (relapse-free survival) in patients treated with this regimen.

• Determine the median survival time of patients treated with this regimen.

• Determine rate of bacterial, fungal, and opportunistic infections in patients treated with this regimen.

Secondary

• Determine, preliminarily, the relationship between MDR-1 expression in tumor tissue and response to therapy in patients treated with this regimen.

• Determine, preliminarily, any relationship between response and survival and BCL-2 expression in tumor tissue in patients treated with this regimen.

• Determine any relationship between development of bacterial, fungal, and/or opportunistic infections and baseline CD4 lymphocyte count, HIV-1 RNA level, and quantitative immunoglobulin levels, or changes in quantitative immunoglobulin levels over time in patients treated with this regimen.

• Compare the results of positron emission tomography (PET) scanning with traditional CT scans in predicting response to therapy in these patients.

• Examine the relationship between chemotherapeutic drug levels and receipt of specific antiretroviral and/or anti-infective medications in these patients.

• Examine the mortality and the causes of death in patients treated with this regimen.

• Determine event-free survival at 1 year.

OUTLINE: This is a nonrandomized, multicenter study.

Patients receive doxorubicin hydrochloride liposome IV over 90 minutes, rituximab IV over 5-7 hours, cyclophosphamide IV over 1 hour, and vincristine IV over 1-2 minutes on day 1 and oral prednisone on days 1-5. Patients also receive filgrastim (G-CSF), sargramostim (GM-CSF), or pegfilgrastim beginning on day 3 and continuing until blood counts recover. Treatment repeats every 21-28 days for up to 8 courses in the absence of disease progression or unacceptable toxicity.

Patients undergo laboratory/biomarker studies at baseline and after every 2 courses of chemotherapy. Tissue is examined by immunohistochemistry for BCL-2, Ki67, and MDR-1, along with other markers.

After completion of study treatment, patients are followed periodically for 3 years.

PROJECTED ACCRUAL: A total of 44 patients will be accrued for this study.

Study Design

• Study Type: Interventional
• Actual Enrollment: 43 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Trial of Doxil, Rituximab, Cyclophosphamide, Vincristine, and Prednisone (DR-COP) in Patients With Newly Diagnosed AIDS-Associated B-Cell Non-Hodgkin's Lymphoma
• Study Start Date: Jan 1, 2007
• Actual Primary Completion Date: Sep 1, 2011
• Actual Study Completion Date: Sep 1, 2011

Arms and Interventions

Arm

Intervention/Treatment

Experimental: DR-COP Single arm interventional study: all subjects receive DR-COP regimen.

Biological: filgrastim; Supportive therapy: GF therapy with G-CSF, GM-CSF, or pegfilgrastim will be used in all patients, beginning on Day 3 of each cycle, until post nadir of blood counts from each chemotherapy cycle.; Biological: pegfilgrastim; GF therapy with G-CSF, GM-CSF, or pegfilgrastim will be used in all patients, beginning on Day 3 of each cycle, until post nadir of blood counts from each chemotherapy cycle.; Biological: rituximab; 375 mg/m2 IV Day 1 of each cycle; Biological: sargramostim; GF therapy with G-CSF, GM-CSF, or pegfilgrastim will be used in all patients, beginning on Day 3 of each cycle, until post nadir of blood counts from each chemotherapy cycle.; Drug: cyclophosphamide; 750 mg/m2 IV Day 1 of each cycle; Drug: pegylated liposomal doxorubicin hydrochloride; 40 mg/m2 IV Day 1 of each cycle; Drug: prednisone; 100 mg PO Days 1-5 of each cycle; Drug: vincristine sulfate; 1.4 mg/m2 IV Day 1 (2.0 mg maximum) of each cycle; Other: immunohistochemistry staining method; tissue specimen collected at baseline; Other: laboratory biomarker analysis; tissue specimen collected at baseline

Outcome Measures

Primary Outcome Measures

1. Complete Response Rate (Complete Response and Complete Response Unconfirmed) Defined as Disappearance of All Evidence of Disease Based on Radiographic Findings on CT or MRI . [After cycles 2, 4, 6, 1 month after treatment discontinuation, every 2 months for 1 year after treatment discontinuation, every 6 months during the second and third years after treatment discontinuation]

2. Duration of Response [After cycles 2, 4, 6, 1 month after treatment discontinuation, every 2 months for 1 year after treatment discontinuation, every 6 months during the second and third years after treatment discontinuation]

3. Median Survival Time [After cycles 2, 4, 6, 1 month after treatment discontinuation, every 2 months for 1 year after treatment discontinuation, every 6 months during the second and third years after treatment discontinuation]

4. Rate of Bacterial, Fungal, and Opportunistic Infections [After every cycle of treatment, 1 month after treatment discontinuation, every 2 months for 1 year after treatment discontinuation, every 6 months during the second and third years after treatment discontinuation]

Secondary Outcome Measures

1. Relationship Between MDR-1 Expression and Response to Treatment [Baseline]

2. Relationship Between Response and Survival and BCL-2 Expression in Tumor Tissue [Baseline, after cycles 4 and 6, 1 month after treatment discontinuation]

3. Relationship Between Development of Bacterial, Fungal, and/or Opportunistic Infections and Baseline CD4 Lymphocyte Count, HIV-1 RNA Level, and Quantitative Immunoglobin Level, or Changes in Quantitative Immunoglobin Levels Over Time [After every cycle of treatment, 1 month after treatment discontinuation, every 2 months for 1 year after treatment discontinuation, every 6 months during the second and third years after treatment discontinuation]

4. Mortality and Cause of Death [At any time through the third year after treatment discontinuation]

5. Event-free Survival at 1 Year [1 year post-treatment]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 120 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

DISEASE CHARACTERISTICS:

• Histologically or cytologically confirmed AIDS-related B-cell non-Hodgkin's lymphoma (NHL), including any of the following subtypes:

• Grade III follicular large cell lymphoma

• Diffuse large B-cell lymphoma

• Immunoblastic lymphoma

• Plasmablastic lymphoma

• Primary effusion lymphoma

• Previously untreated disease

• Any stage disease

• CD20 positive disease

• Must have documented HIV infection

• Documentation may be by serology (enzyme-linked immunosorbent assay, western blot), culture, or quantitative polymerase chain reaction or branched DNA assays

• Prior documentation of HIV seropositivity allowed

• Measurable or nonmeasurable disease

• Currently receiving effective highly active anti-retroviral therapy

• No primary CNS lymphoma, including parenchymal brain or spinal cord lymphoma

• No presence of leptomeningeal disease (positive cerebrospinal fluid for lymphoma) or presence of metastatic disease to brain, in terms of any mass lesion

PATIENT CHARACTERISTICS:

• ECOG performance status (PS) 0-2 OR Karnofsky PS 50-100%

• Life expectancy ≥ 2 months

• Absolute granulocyte (neutrophil) count ≥ 1,000/mm³ (unless secondary to lymphomatous involvement of bone marrow)

• Platelet count ≥ 75,000/mm³ (unless secondary to lymphomatous involvement of bone marrow or due to HIV-related thrombocytopenia)

• Bilirubin ≤ 2.0 mg/dL (unless elevated secondary to lymphomatous involvement of liver or biliary system or due to other HIV medications [e.g., indinavir, tenofavir, or atazanavir])

• SGOT ≤ 5 times upper limit of normal

• Creatinine ≤ 2.0 mg/dL OR creatinine clearance ≥ 60 mL/min (unless secondary to renal involvement by lymphoma)

• LVEF normal by MUGA or echocardiogram

• Not pregnant or nursing

• Negative pregnancy test

• Fertile patients must use effective contraception during and for 6 months after completion of study treatment

• No other malignancy, except nonmelanoma skin cancer, carcinoma in situ of the cervix, or Kaposi's sarcoma that does not require systemic therapy

• No serious, ongoing, nonmalignant disease or infection that would preclude study compliance, in the opinion of the investigator

• No history of cutaneous or mucocutaneous reactions, or diseases in the past, due to any cause, severe enough to cause hospitalization or an inability to eat or drink for ≥ 2 days

• No acute, intercurrent infection that would preclude study treatment

• Patients with Mycobacterium avium are eligible

• No cardiovascular problems, including any of the following:

• Myocardial infarction within the past 6 months

• New York Heart Association class II-IV heart failure

• Uncontrolled angina

• Severe uncontrolled ventricular arrhythmias

• Clinically significant pericardial disease

• ECG evidence of acute ischemic or active conduction system abnormalities.

• No shortness of breath at rest

• Arterial PO_2 ≥ 70 or pulse oximeter-derived O_2 saturation ≥ 94% on room air (unless due to lymphomatous involvement of the lungs)

• Able to comply with study and provide adequate informed consent

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics

• At least 4 weeks since prior major surgery (except diagnostic surgery)

• At least 12 months since prior rituximab unless it was only given for indications other than the treatment of aggressive lymphoma

• No prior cytotoxic chemotherapy or radiotherapy for this lymphoma

• Concurrent radiotherapy, with or without steroids, for emergency conditions secondary to lymphoma (i.e., CNS tumor or cord compression) allowed

• No zidovudine or zidovudine-containing regimen (including Combivir® or Trizivir®) during and for 2 months after completion of chemotherapy

• Concurrent erythropoietin or filgrastim (G-CSF) allowed

• Growth factor therapy must be discontinued ≥ 24 hours prior to study entry

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Rebecca and John Moores UCSD Cancer Center	La Jolla	California	United States	92093-0658
2	USC/Norris Comprehensive Cancer Center and Hospital	Los Angeles	California	United States	90089-9181
3	UCLA Clinical AIDS Research and Education (CARE) Center	Los Angeles	California	United States	90095-1793
4	University of Miami Sylvester Comprehensive Cancer Center - Miami	Miami	Florida	United States	33136
5	Robert H. Lurie Comprehensive Cancer Center at Northwestern University	Chicago	Illinois	United States	60611-3013
6	Ochsner Cancer Institute at Ochsner Clinic Foundation	New Orleans	Louisiana	United States	70121
7	Boston University Cancer Research Center	Boston	Massachusetts	United States	02118
8	Beth Israel Deaconess Medical Center	Boston	Massachusetts	United States	02215
9	Siteman Cancer Center at Barnes-Jewish Hospital - Saint Louis	Saint Louis	Missouri	United States	63110
10	Albert Einstein Cancer Center at Albert Einstein College of Medicine	Bronx	New York	United States	10461
11	Memorial Sloan-Kettering Cancer Center	New York	New York	United States	10065
12	Case Comprehensive Cancer Center	Cleveland	Ohio	United States	44106-5065
13	Joan Karnell Cancer Center at Pennsylvania Hospital	Philadelphia	Pennsylvania	United States	19106
14	Virginia Mason Medical Center	Seattle	Washington	United States	98101

Sponsors and Collaborators

• AIDS Malignancy Consortium
• National Cancer Institute (NCI)
• The Emmes Company, LLC

Investigators

• Study Chair: Alexandra M. Levine, MD, City of Hope Comprehensive Cancer Center

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jan 21, 2011

More Information

Publications

None provided.

• Responsible Party: AIDS Malignancy Consortium
• ClinicalTrials.gov Identifier: NCT00389818
• Other Study ID Numbers: AMC-047; U01CA070019; CDR0000507634
• First Posted: Oct 19, 2006
• Last Update Posted: Jun 6, 2018
• Last Verified: May 1, 2018

• Keywords provided by AIDS Malignancy Consortium: contiguous stage II grade 3 follicular lymphoma; noncontiguous stage II grade 3 follicular lymphoma; stage I grade 3 follicular lymphoma; stage III grade 3 follicular lymphoma; stage IV grade 3 follicular lymphoma; AIDS-related diffuse large cell lymphoma; contiguous stage II adult diffuse large cell lymphoma; noncontiguous stage II adult diffuse large cell lymphoma; stage I adult diffuse large cell lymphoma; stage III adult diffuse large cell lymphoma; stage IV adult diffuse large cell lymphoma; AIDS-related immunoblastic large cell lymphoma; contiguous stage II adult immunoblastic large cell lymphoma; noncontiguous stage II adult immunoblastic large cell lymphoma; stage I adult immunoblastic large cell lymphoma; stage III adult immunoblastic large cell lymphoma; stage IV adult immunoblastic large cell lymphoma; AIDS-related peripheral/systemic lymphoma
• Additional relevant MeSH terms: Lymphoma; Lymphoma, Non-Hodgkin; Lymphoma, B-Cell; Prednisone; Cyclophosphamide; Rituximab; Doxorubicin; Liposomal doxorubicin; Vincristine; Sargramostim

Study Results

Participant Flow

Arm/Group Title	DR-COP
Arm/Group Description	Single arm interventional study: all subjects receive Doxil, Rituximab, Cyclophosphamide, Vincristine and Prednisone (DR-COP) regimen.
Period Title: Overall Study
STARTED	43
COMPLETED	40
NOT COMPLETED	3

Baseline Characteristics

Arm/Group Title	DR-COP
Arm/Group Description	Single arm interventional study: all subjects receive Doxil, Rituximab, Cyclophosphamide, Vincristine and Prednisone (DR-COP) regimen.
Overall Participants	40
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	39 97.5%
>=65 years	1 2.5%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	44.4 (8.3)
Sex: Female, Male (Count of Participants)
Female	10 25%
Male	30 75%
Region of Enrollment (participants) [Number]
United States	40 100%

Outcome Measures

1. Primary Outcome

Title	Complete Response Rate (Complete Response and Complete Response Unconfirmed) Defined as Disappearance of All Evidence of Disease Based on Radiographic Findings on CT or MRI .
Time Frame	After cycles 2, 4, 6, 1 month after treatment discontinuation, every 2 months for 1 year after treatment discontinuation, every 6 months during the second and third years after treatment discontinuation

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	DR-COP
Arm/Group Description	Single arm interventional study: all subjects receive Doxil, Rituximab, Cyclophosphamide, Vincristine and Prednisone (DR-COP) regimen.
Measure Participants	40
Number (95% Confidence Interval) [proportion of patients]	0.475

2. Primary Outcome

Title	Duration of Response
Time Frame	After cycles 2, 4, 6, 1 month after treatment discontinuation, every 2 months for 1 year after treatment discontinuation, every 6 months during the second and third years after treatment discontinuation

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

3. Primary Outcome

Title	Median Survival Time
Time Frame	After cycles 2, 4, 6, 1 month after treatment discontinuation, every 2 months for 1 year after treatment discontinuation, every 6 months during the second and third years after treatment discontinuation

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

4. Primary Outcome

Title	Rate of Bacterial, Fungal, and Opportunistic Infections
Time Frame	After every cycle of treatment, 1 month after treatment discontinuation, every 2 months for 1 year after treatment discontinuation, every 6 months during the second and third years after treatment discontinuation

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

5. Secondary Outcome

Title	Relationship Between MDR-1 Expression and Response to Treatment
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

6. Secondary Outcome

Title	Relationship Between Response and Survival and BCL-2 Expression in Tumor Tissue
Time Frame	Baseline, after cycles 4 and 6, 1 month after treatment discontinuation

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

7. Secondary Outcome

Title	Relationship Between Development of Bacterial, Fungal, and/or Opportunistic Infections and Baseline CD4 Lymphocyte Count, HIV-1 RNA Level, and Quantitative Immunoglobin Level, or Changes in Quantitative Immunoglobin Levels Over Time
Time Frame	After every cycle of treatment, 1 month after treatment discontinuation, every 2 months for 1 year after treatment discontinuation, every 6 months during the second and third years after treatment discontinuation

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

8. Secondary Outcome

Title	Mortality and Cause of Death
Time Frame	At any time through the third year after treatment discontinuation

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

9. Secondary Outcome

Title	Event-free Survival at 1 Year
Time Frame	1 year post-treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Arm/Group Title	DR-COP
Arm/Group Description	Single arm interventional study: all subjects receive Doxil, Rituximab, Cyclophosphamide, Vincristine and Prednisone (DR-COP) regimen.
All Cause Mortality
	DR-COP
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	DR-COP
	Affected / at Risk (%)	# Events
Total	26/40 (65%)
Blood and lymphatic system disorders
Anemia	2/40 (5%)	2
Febrile Neutropenia	3/40 (7.5%)	4
Eye disorders
Optic nerve disorder	1/40 (2.5%)	3
Gastrointestinal disorders
Abdominal pain	2/40 (5%)	3
Constipation	1/40 (2.5%)	1
Dysphagia	1/40 (2.5%)	1
Gastric hemorrhage	1/40 (2.5%)	1
Ileal obstruction	1/40 (2.5%)	1
Ileal perforation	1/40 (2.5%)	1
Ileus	1/40 (2.5%)	1
Nausea	3/40 (7.5%)	3
Small intestinal obstruction	1/40 (2.5%)	1
Vomiting	3/40 (7.5%)	5
General disorders
Death	12/40 (30%)	12
Fever	1/40 (2.5%)	1
Non-cardiac chest pain	1/40 (2.5%)	1
Pain	1/40 (2.5%)	1
Infections and infestations
Abdominal infection	1/40 (2.5%)	1
Cather related infection	2/40 (5%)	2
Lung infection	1/40 (2.5%)	1
Skin infection	1/40 (2.5%)	1
Investigations
Neutrophil count decreased	6/40 (15%)	9
Platelet count decreased	3/40 (7.5%)	4
Weight loss	2/40 (5%)	3
White blood cell decreased	3/40 (7.5%)	3
Metabolism and nutrition disorders
Dehydration	2/40 (5%)	2
Hyperuricemia	1/40 (2.5%)	1
Hypocalcemia	1/40 (2.5%)	1
Hypokalemia	1/40 (2.5%)	1
Musculoskeletal and connective tissue disorders
Bone pain	1/40 (2.5%)	1
Pain in extremity	1/40 (2.5%)	2
Nervous system disorders
Headache	1/40 (2.5%)	1
Intracranial hemorrhage	1/40 (2.5%)	1
Leukoencephalopathy	1/40 (2.5%)	1
Peripheral motor neuropathy	2/40 (5%)	5
Peripheral sensory neuropathy	1/40 (2.5%)	1
Seizure	1/40 (2.5%)	1
Delirium	1/40 (2.5%)	1
Psychiatric disorders
Confusion	1/40 (2.5%)	1
Renal and urinary disorders
Cystitis noninfective	1/40 (2.5%)	1
Renal and urinary disorders, other	1/40 (2.5%)	1
Respiratory, thoracic and mediastinal disorders
Bronchospasm	1/40 (2.5%)	1
Dyspnea	4/40 (10%)	6
Hypoxia	3/40 (7.5%)	3
Pleural effusion	1/40 (2.5%)	1
Vascular disorders
Hypotension	1/40 (2.5%)	1
Other (Not Including Serious) Adverse Events
	DR-COP
	Affected / at Risk (%)	# Events
Total	38/40 (95%)
Blood and lymphatic system disorders
Anemia	13/40 (32.5%)	19
Blood and lymphatic system disorders, other	3/40 (7.5%)	6
Cardiac disorders
Sinus tachycardia	2/40 (5%)	2
Ear and labyrinth disorders
Ear and labyrinth disorders, other	2/40 (5%)	2
Gastrointestinal disorders
Abdominal pain	5/40 (12.5%)	6
Nausea	13/40 (32.5%)	19
Vomiting	12/40 (30%)	17
Constipation	11/40 (27.5%)	14
Diarrhea	7/40 (17.5%)	8
Dysphagia	3/40 (7.5%)	3
Gastric ulcer	2/40 (5%)	2
Mucositis, oral	6/40 (15%)	10
General disorders
Chills	6/40 (15%)	6
Edema, limbs	5/40 (12.5%)	6
Fatigue	14/40 (35%)	19
Fever	8/40 (20%)	10
Non-cardiac chest pain	2/40 (5%)	2
Pain	3/40 (7.5%)	4
Infections and infestations
Infections and investigations, other	4/40 (10%)	4
Mucosal infections	5/40 (12.5%)	5
Upper respiratory infection	2/40 (5%)	2
Urinary tract infection	2/40 (5%)	2
Investigations
Alanine aminotransferase increased	3/40 (7.5%)	4
Alkaline phosphatase increased	3/40 (7.5%)	3
Aspartate aminotransferase increased	3/40 (7.5%)	3
Lymphocyte count decreased	6/40 (15%)	18
Neutrophil count decreased	22/40 (55%)	54
Platelet count decreased	3/40 (7.5%)	4
Weight gain	2/40 (5%)	3
Weight loss	7/40 (17.5%)	10
White blood cell decreased	10/40 (25%)	30
Metabolism and nutrition disorders
Anorexia	6/40 (15%)	8
Dehydration	3/40 (7.5%)	3
Hyperglycemia	2/40 (5%)	3
Musculoskeletal and connective tissue disorders
Bone pain	3/40 (7.5%)	4
Myalgia	3/40 (7.5%)	3
Pain in extremity	5/40 (12.5%)	6
Nervous system disorders
Headache	8/40 (20%)	13
Leukoencephalopathy	2/40 (5%)	2
Memory impairment	2/40 (5%)	2
Peripheral motor neuropathy	3/40 (7.5%)	4
Peripheral sensory neuropathy	13/40 (32.5%)	19
Psychiatric disorders
Anxiety	3/40 (7.5%)	3
Depression	2/40 (5%)	3
Insomnia	5/40 (12.5%)	5
Renal and urinary disorders
Urinary frequency	2/40 (5%)	2
Respiratory, thoracic and mediastinal disorders
Cough	7/40 (17.5%)	8
Dyspnea	3/40 (7.5%)	5
Pharyngolaryngeal pain	5/40 (12.5%)	6
Skin and subcutaneous tissue disorders
Alopecia	5/40 (12.5%)	5
Dry skin	4/40 (10%)	4
Hyperhidrosis	2/40 (5%)	3
Nail loss	2/40 (5%)	2
Palmar-plantar erythrodysesthesia syndrome	5/40 (12.5%)	10
Pruritus	4/40 (10%)	4
Skin and subcutaneous tissue disorders, other	4/40 (10%)	5
Skin hyperpigmentation	4/40 (10%)	4

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT 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.