Pyridoxine in Preventing Hand-Foot Syndrome in Patients Who Are Receiving Liposomal Doxorubicin for Cancer

• Sponsor: Case Comprehensive Cancer Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT00245050
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 34
• Locations: 8
• Arms: 2
• Duration (Months): 89
• Patients Per Site: 4.3
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

RATIONALE: Pyridoxine (vitamin B6) may prevent or lessen hand-foot syndrome caused by chemotherapy. It is not yet known whether pyridoxine is more effective than a placebo in preventing hand-foot syndrome.

PURPOSE: This randomized clinical trial is studying pyridoxine to see how well it works compared to a placebo in preventing hand-foot syndrome in patients who are receiving liposomal doxorubicin for recurrent ovarian, fallopian tube, or peritoneal cancer, metastatic breast cancer, or advanced endometrial cancer.

Condition or Disease	Intervention/Treatment	Phase
Breast Cancer; Drug/Agent Toxicity by Tissue/Organ; Endometrial Cancer; Fallopian Tube Cancer; Ovarian Cancer; Peritoneal Cavity Cancer	Dietary Supplement: pyridoxine hydrochloride; Drug: Placebo; Drug: doxorubicin HCL liposome	Phase 3

Detailed Description

OBJECTIVES:

Primary

• Compare the efficacy of pyridoxine vs placebo in preventing palmar-plantar erythrodysesthesia (PPE) in patients receiving doxorubicin HCl liposome for recurrent ovarian, fallopian tube, or peritoneal cavity cancer, metastatic breast cancer, or advanced endometrial cancer.

• Compare quality of life in patients treated with these regimens.

OUTLINE: This is a randomized, double-blind study. Patients are stratified according to cancer type (ovarian, fallopian tube, or peritoneal cavity cancer vs breast cancer vs endometrial cancer). Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive doxorubicin HCl liposome IV 40mg/m2 over 1 hour on day 1 and oral pyridoxine 100 mg twice daily on days 1-28.

• Arm II: Patients receive doxorubicin HCl liposome IV 40mg/m2 over 1 hour on day 1 and oral placebo 100 mg twice daily on days 1-28.

In both arms, treatment repeats every 4 weeks for up to 6 courses in the absence of disease progression or unacceptable toxicity.

Patients who develop grade 2-3 palmar-plantar erythrodysesthesia despite dose reduction of doxorubicin HCl liposome are unblinded and removed from the study (for patients in arm I) OR receive oral pyridoxine twice daily beginning day 1 of the next planned therapy (for patients in arm II).

Quality of life is assessed at baseline and after every third course of therapy.

After completion of study treatment, patients are followed periodically for 6 months.

PROJECTED ACCRUAL: A total of 60 patients will be accrued for this study.

Study Design

• Study Type: Interventional
• Actual Enrollment: 34 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Supportive Care
• Official Title: A Double-Blind Randomized Trial of Pyridoxine Versus Placebo for the Prevention of Doxil-Related Palmar-Plantar Erythrodysesthesia (Hand-Foot Syndrome)
• Study Start Date: Apr 1, 2004
• Actual Primary Completion Date: Apr 1, 2008
• Actual Study Completion Date: Sep 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Pyridoxine Arm I: Patients receive doxorubicin HCl liposome IV 40 mg/m2 over 1 hour on day 1 and oral pyridoxine 100 mg twice daily on days 1-28.	Dietary Supplement: pyridoxine hydrochloride; Arm I: Patients receive doxorubicin HCl liposome IV 40 mg/m2 over 1 hour on day 1 and oral pyridoxine twice 100 mg daily on days 1-28.; Drug: doxorubicin HCL liposome; IV, 40mg/m2
Placebo Comparator: Placebo Arm II: Patients receive doxorubicin HCl liposome IV 40 mg/m2 over 1 hour on day 1 and oral placebo twice 100 mg daily on days 1-28.	Drug: Placebo; Arm II: Patients receive doxorubicin HCl liposome IV 40 mg/m2 over 1 hour on day 1 and oral placebo 100 mg twice daily on days 1-28.; Drug: doxorubicin HCL liposome; IV, 40mg/m2

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Palmar-plantar Erythrodysesthesia (PPE) [Treatment repeats every 4 weeks for up to 6 courses in the absence of unacceptable toxicity.]

   Patients were monitored weekly with phone calls from the research nurse and monthly at clinic visits for overall (including pyridoxine) and specific doxorubicin HCl liposome related toxicities using the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE), version 3.0.

Secondary Outcome Measures

1. Quality of Life (QOL) as Measured by Functional Assessment of Cancer Therapy (FACT-G) [After Cycle 3 of chemotherapy (on average at 3 months)]

   QOL was measured with the FACT-G questionnaire following the third course of doxorubicin HCl liposome before the patient was seen by the treating physician and before chemotherapy was administered. The FACT-G, version 4, is a 27-item core questionnaire evaluating the domains of physical, functional, family-social, and emotional well-being (PWB, FWB, SWB, EWB). Total score ranges from 0-108 and higher scores indicate better QOL.

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A and Older
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

DISEASE CHARACTERISTICS:

• Diagnosis of 1 of the following:

• Recurrent ovarian, fallopian tube, or peritoneal cavity cancer

• Metastatic breast cancer

• Advanced endometrial cancer

• Planning to receive chemotherapy with doxorubicin HCl liposome at a dose of 40 mg/m^2

• Hormone receptor status:

• Not specified

PATIENT CHARACTERISTICS:

Sex

• Not specified

Menopausal status:

• Not specified

Performance status

• Karnofsky 60-100%

Life expectancy

• Not specified

Hematopoietic

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

• Platelet count ≥ 100,000/mm^3

• Hemoglobin ≥ 9.0 g/dL

Hepatic

• AST and ALT ≤ 2 times upper limit of normal (ULN)

• Alkaline phosphatase ≤ 2 times ULN

• Bilirubin normal

Renal

• Creatinine ≤ 2.0 mg/dL

Cardiovascular

• Ejection fraction ≥ 50% by MUGA or 2-D echocardiogram

• No history of cardiac disease

• No New York Heart Association class II-IV heart disease

• No clinical evidence of congestive heart failure

Other

• Not pregnant or nursing

• Fertile patients must use effective contraception during and for 3 months after completion of study treatment

• No active infection requiring antibiotics

• No history of hypersensitivity reaction attributed to a conventional formulation of doxorubicin HCl or doxorubicin HCl liposome and any of its components

• No other invasive malignancy within the past 5 years except nonmelanoma or basal cell skin cancer

PRIOR CONCURRENT THERAPY:

Biologic therapy

• At least 3 weeks since prior biologic or immunologic agents for this cancer

Chemotherapy

• Recovered from prior chemotherapy

• Alopecia or neuropathy allowed

• No prior doxorubicin HCl liposome

• Other concurrent chemotherapy allowed provided palmar-plantar erythrodysesthesia is not one of the side effects of the therapy

• No concurrent cytarabine, fluorouracil, liposomal daunorubicin, or capecitabine

• No concurrent pre-medication with corticosteroids as part of the chemotherapy regimen

Endocrine therapy

• See Chemotherapy

• At least 3 weeks since prior and no concurrent oral or topical corticosteroids

• At least 1 week since prior hormonal therapy for this cancer

• Concurrent hormone replacement therapy allowed

Radiotherapy

• At least 3 weeks since prior radiotherapy for this cancer and recovered

Surgery

• Recovered from prior surgery

Other

• At least 3 weeks since prior and no other concurrent forms of pyridoxine except what is included in a multivitamin

• No prior anticancer treatment that contraindicates study treatment

• No concurrent amifostine or other protective agents

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Geauga Regional Hospital	Cleveland	Ohio	United States	44024
2	Lake/University Ireland Cancer Center	Cleveland	Ohio	United States	44060
3	Case Medical Center, University Hospitals Seidman Cancer Center, Case Comprehensive Cancer Center	Cleveland	Ohio	United States	44106-5065
4	Southwest General Health Center	Cleveland	Ohio	United States	44130
5	University Suburban Health Center	Cleveland	Ohio	United States	44143
6	UHHS Westlake Medical Center	Cleveland	Ohio	United States	44145
7	Mercy Cancer Center at Mercy Medical Center	Cleveland	Ohio	United States	44708
8	UHHS Chagrin Highlands Medical Center	Cleveland	Ohio	United States	44708

Sponsors and Collaborators

• Case Comprehensive Cancer Center
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Vivian von Gruenigen, MD, Case Medical Center, University Hospitals Seidman Cancer Center, Case Comprehensive Cancer Center

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Case Comprehensive Cancer Center
• ClinicalTrials.gov Identifier: NCT00245050
• Other Study ID Numbers: CASE5Y03; P30CA043703; CASE5Y03
• First Posted: Oct 27, 2005
• Last Update Posted: Dec 30, 2011
• Last Verified: Dec 1, 2011

• Keywords provided by Case Comprehensive Cancer Center: drug/agent toxicity by tissue/organ; fallopian tube cancer; peritoneal cavity cancer; recurrent ovarian epithelial cancer; recurrent endometrial carcinoma; stage III endometrial carcinoma; stage IV endometrial carcinoma; stage IV breast cancer; male breast cancer; recurrent breast cancer
• Additional relevant MeSH terms: Breast Neoplasms; Endometrial Neoplasms; Fallopian Tube Neoplasms; Hand-Foot Syndrome; Drug-Related Side Effects and Adverse Reactions; Pyridoxine; Vitamin B 6; Doxorubicin; Liposomal doxorubicin

Study Results

Participant Flow

Recruitment Details	Patients were recruited from the outpatient gynecologic oncology clinics at University Hospitals from May 2004 to December 2007.
Pre-assignment Detail	Patients were required to have discontinued corticosteroid therapy at least three weeks prior to enrollment and no corticosteroids were allowed for the duration of the trial. Patients must have discontinued pyridoxine therapy at least three weeks prior to enrollment.

Arm/Group Title	Pyridoxine	Placebo
Arm/Group Description	Arm I: Patients receive doxorubicin HCl liposome IV 40mg/m2 over 1 hour on day 1 and oral pyridoxine 100 mg twice daily on days 1-28.	Arm II: Patients receive doxorubicin HCl liposome IV 40mg/m2 over 1 hour on day 1 and oral placebo 100 mg twice daily on days 1-28.
Period Title: Overall Study
STARTED	18	16
COMPLETED	15	14
NOT COMPLETED	3	2

Baseline Characteristics

Arm/Group Title	Pyridoxine	Placebo	Total
Arm/Group Description	Arm I: Patients receive doxorubicin HCl liposome IV 40mg/m2 over 1 hour on day 1 and oral pyridoxine 100 mg twice daily on days 1-28.	Arm II: Patients receive doxorubicin HCl liposome IV 40mg/m2 over 1 hour on day 1 and oral placebo 100 mg twice daily on days 1-28.	Total of all reporting groups
Overall Participants	18	16	34
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	8 44.4%	6 37.5%	14 41.2%
>=65 years	10 55.6%	10 62.5%	20 58.8%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	62.9 (9.4)	65.9 (11.0)	64.3 (10.2)
Sex: Female, Male (Count of Participants)
Female	18 100%	16 100%	34 100%
Male	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	18 100%	16 100%	34 100%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Palmar-plantar Erythrodysesthesia (PPE)
Description	Patients were monitored weekly with phone calls from the research nurse and monthly at clinic visits for overall (including pyridoxine) and specific doxorubicin HCl liposome related toxicities using the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE), version 3.0.
Time Frame	Treatment repeats every 4 weeks for up to 6 courses in the absence of unacceptable toxicity.

Outcome Measure Data

Analysis Population Description

Patients were evaluable for PPE/HFS(Hand-Foot Syndrome) incidence and toxicity assessment if they received at least one course of chemotherapy. Intention to treat analysis was used.

Arm/Group Title	Pyridoxine	Placebo
Arm/Group Description	Arm I: Patients receive doxorubicin HCl liposome IV 40mg/m2 over 1 hour on day 1 and oral pyridoxine 100 mg twice daily on days 1-28.	Arm II: Patients receive doxorubicin HCl liposome IV 40mg/m2 over 1 hour on day 1 and oral placebo 100 mg twice daily on days 1-28.
Measure Participants	15	14
Grade 1 HFS	2 11.1%	3 18.8%
Grade 2 HFS	3 16.7%	3 18.8%
Grade 3 HFS	3 16.7%	1 6.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pyridoxine, Placebo
	Comments	Based on published literature, it is estimated that the incidence of HFS for all grades is 49%. A decrease of 50% or more in the incidence of HFS in patients receiving pyridoxine would be of clinical significance. A sample size of 27 patients per group was chosen as this would allow us to detect a difference between HFS incidence of 49% and 11.5% (alpha=0.05, two-sided, power=0.80). Interim analysis was conducted after 30 patients were enrolled and had evaluable HFS assessment data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.05
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	1.07
	Confidence Interval	(2-Sided) 95%; 0.536 to 2.16
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Quality of Life (QOL) as Measured by Functional Assessment of Cancer Therapy (FACT-G)
Description	QOL was measured with the FACT-G questionnaire following the third course of doxorubicin HCl liposome before the patient was seen by the treating physician and before chemotherapy was administered. The FACT-G, version 4, is a 27-item core questionnaire evaluating the domains of physical, functional, family-social, and emotional well-being (PWB, FWB, SWB, EWB). Total score ranges from 0-108 and higher scores indicate better QOL.
Time Frame	After Cycle 3 of chemotherapy (on average at 3 months)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pyridoxine	Placebo
Arm/Group Description	Arm I: Patients receive doxorubicin HCl liposome IV 40mg/m2 over 1 hour on day 1 and oral pyridoxine 100 mg twice daily on days 1-28.	Arm II: Patients receive doxorubicin HCl liposome IV 40mg/m2 over 1 hour on day 1 and oral placebo 100 mg twice daily on days 1-28.
Measure Participants	15	14
Mean (Standard Deviation) [Total scores on FACT-G scale]	84.9 (10.2)	84.4 (9.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pyridoxine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.916
	Comments
	Method	t-test, 2 sided
	Comments

Adverse Events

Time Frame	Patients were monitored weekly with phone calls from the research nurse and monthly at clinic visits for overall (including pyridoxine) and specific PLD-related toxicities using the NCI CTCAE, version 3.0
Arm/Group Title	Pyridoxine		Placebo
Arm/Group Description	Arm I: Patients receive doxorubicin HCl liposome IV 40mg/m2 over 1 hour on day 1 and oral pyridoxine 100 mg twice daily on days 1-28.		Arm II: Patients receive doxorubicin HCl liposome IV 40mg/m2 over 1 hour on day 1 and oral placebo 100 mg twice daily on days 1-28.
All Cause Mortality
	Pyridoxine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Pyridoxine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/15 (53.3%)		6/14 (42.9%)
Blood and lymphatic system disorders
Blood/bone marrow	1/15 (6.7%)	4	2/14 (14.3%)	4
Hemorrhage/bleeding	1/15 (6.7%)	1	0/14 (0%)	0
Lymphatics	0/15 (0%)	0	0/14 (0%)	0
Gastrointestinal disorders
Gastrointestinal	2/15 (13.3%)	2	0/14 (0%)	0
General disorders
Constitutional symptoms	0/15 (0%)	0	1/14 (7.1%)	1
Pain	0/15 (0%)	0	0/14 (0%)	0
Immune system disorders
Allergy/immunologic	0/15 (0%)	0	1/14 (7.1%)	1
Infections and infestations
Infection	1/15 (6.7%)	1	0/14 (0%)	0
Metabolism and nutrition disorders
Metabolic/laboratory	0/15 (0%)	0	1/14 (7.1%)	1
Nervous system disorders
Neurology	1/15 (6.7%)	1	0/14 (0%)	0
Renal and urinary disorders
Renal/genitourinary	0/15 (0%)	0	0/14 (0%)	0
Respiratory, thoracic and mediastinal disorders
Pulmonary/upper respiratory	1/15 (6.7%)	1	0/14 (0%)	0
Vascular disorders
Vascular	1/15 (6.7%)	1	1/14 (7.1%)	1
Other (Not Including Serious) Adverse Events
	Pyridoxine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	13/15 (86.7%)		10/14 (71.4%)
Blood and lymphatic system disorders
Blood/bone marrow	7/15 (46.7%)	36	8/14 (57.1%)	42
Lymphatics	2/15 (13.3%)	2	2/14 (14.3%)	2
Gastrointestinal disorders
Gastrointestinal	9/15 (60%)	11	5/14 (35.7%)	7
General disorders
Constitutional symptoms	7/15 (46.7%)	7	5/14 (35.7%)	8
Pain	5/15 (33.3%)	5	2/14 (14.3%)	6
Hepatobiliary disorders
Hepatic/pancreas	0/15 (0%)	0	2/14 (14.3%)	2
Infections and infestations
Infection	2/15 (13.3%)	2	1/14 (7.1%)	3
Metabolism and nutrition disorders
Metabolic/laboratory	1/15 (6.7%)	3	1/14 (7.1%)	6
Musculoskeletal and connective tissue disorders
Musculoskeletal/soft tissue	0/15 (0%)	0	2/14 (14.3%)	2
Nervous system disorders
Neurology	3/15 (20%)	3	1/14 (7.1%)	1
Renal and urinary disorders
Renal/genitourinary	2/15 (13.3%)	3	3/14 (21.4%)	3
Respiratory, thoracic and mediastinal disorders
Pulmonary/upper respiratory	2/15 (13.3%)	2	4/14 (28.6%)	5

Limitations/Caveats

Interim analysis was conducted after 30 patients were enrolled and had evaluable PPE assessment data. Due to decreased accrual and similar PPE rates between groups, the trial was closed for enrollment after the interim analyses was completed.

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.