Study of Melphalan HCl for Injection (Propylene Glycol-free), Carmustine, Etoposide, Cytarabine (BEAM Regimen) and Autologous Stem Cell Transplantation for Lymphoma

• Sponsor: Washington University School of Medicine (Other)
• Overall Status: Completed
• CT.gov ID: NCT01969435
• Collaborator: (none)
• Enrollment: 50
• Location: 1
• Arm: 1
• Actual Duration (Months): 38.4
• Patients Per Site Per Month: 1.3

Study Details

Study Description

Brief Summary

Phase II study is being conducted to confirm the safety and efficacy of high-dose Melphalan HCl for Injection (Propylene Glycol-Free) when included in the BEAM regimen for myeloablative conditioning in lymphoma patients undergoing ASCT

Condition or Disease	Intervention/Treatment	Phase
Hodgkin Disease; Lymphoma, Non-Hodgkin	Drug: Carmustine; Drug: Etoposide phosphate; Drug: Cytarabine; Drug: Melphalan HCl (propylene glycol-free)	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 50 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Study of Melphalan HCl for Injection (Propylene Glycol-free), Combined With Carmustine, Etoposide, and Cytarabine (BEAM Regimen) for Myeloablative Conditioning in Lymphoma Patients Undergoing Autologous Stem Cell Transplantation
• Actual Study Start Date: Mar 19, 2014
• Actual Primary Completion Date: Sep 30, 2015
• Actual Study Completion Date: May 31, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Melphalan, carmustine, etoposide, cytarabine (BEAM) Day -7, carmustine intravenous (IV) infusion Days -6, -5, -4, and -3, etoposide and cytarabine (IV) infusions twice a day Day -2, melphalan HCl (propylene glycol-free)(IV) infusion Day 0, stem cell transplant.	Drug: Carmustine; Other Names: BCNU BiCNU® ; Drug: Etoposide phosphate; Other Names: VP-16 Vepesid ; Drug: Cytarabine; Other Names: Cytosar-U ® 1-β-Arabinofuranosylcytosine Arabinosylcytosine Cytosine arabinoside Ara-C ; Drug: Melphalan HCl (propylene glycol-free)

Outcome Measures

Primary Outcome Measures

1. Safety and Toxicity as Measured by Treatment Related Non-hematologic Adverse Events [Day -7 through Day 30]

   Adverse events will be assessed using the National Cancer Institute (NCI)-CTCAE version 4.0. Number of events, grade 2 or higher, occurring in 10% or greater of participants. Grade 2 diarrhea and Grade 2 nausea/vomiting were not recorded.

2. Treatment-related Mortality (TRM) [100 days]

   TRM is defined as death not due to progressive lymphoma prior to Day 100 after transplant

Secondary Outcome Measures

1. Efficacy as Measured by Response Rates [Up to Day 100]

   The response rates according to each category of response Complete Response (CR), Partial Response (PR), Stable Disease (SD), and Progressive Disease (PD) will be summarized by the proportion of patients meeting each criterion. Evaluated using PET or CT scan and Revised Response Criteria for Malignant Lymphoma

2. Disease-free Survival [1 year]

   Percentage of patients who survive without any signs or symptoms of cancer at 1 year.

3. Disease-free Survival [2 years]

   Percentage of patients who survive without any signs or symptoms of cancer at 2 years.

4. Time to Engraftment (Neutrophil) [Assessed up to day 30]

   Time from the date of the transplant to the date of neutrophil engraftment.

5. Time to Engraftment (Platelet) [Assessed up to day 100]

   Time from the date of transplant to the date of platelet engraftment.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Diagnosis of Hodgkin lymphoma or non-Hodgkin lymphoma.

• Eligible for autologous stem cell transplantation.

• 18 to 75 years of age at time of enrollment.

• Adequate autologous graft, defined as an unmanipulated, cryopreserved, peripheral blood stem cell graft containing at least 2 x 10^6 CD34+ cells/kg based on patient body weight

• ECOG performance status ≤ 2

• Normal organ function as defined below:

• Creatinine clearance > 40 ml/min

• Total bilirubin ≤2.0 x IULN

• AST(SGOT)/ALT(SGPT) ≤ 3.0 x IULN

• LVEF > 40% (by ECHO or MUGA)

• FEV1 > 50% of predicted and DLCO > or = 50% of predicted

• Women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control, abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately.

• Able to understand and willing to sign an IRB approved written informed consent document.

Exclusion Criteria:

• A history of other malignancy ≤ 5 years previous with the exception of basal cell or squamous cell carcinoma of the skin which were treated with local resection only or carcinoma in situ of the cervix.

• Currently receiving any other experimental therapy or has received any other experimental therapy within the 4 weeks prior to enrollment.

• A history of allergic reactions attributed to compounds of similar chemical or biologic composition to melphalan HCl for injection (propylene glycol-free), Captisol, or other agents used in the study.

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

• Pregnant and/or breastfeeding women. Women of childbearing potential must have a negative serum pregnancy test within 14 days of study entry.

• Known HIV-positivity. These patients are excluded because of the potential for pharmacokinetic interactions with the study regimen and their antiretroviral therapy and because these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy. .

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Washington University School of Medicine	Saint Louis	Missouri	United States	63110

Sponsors and Collaborators

• Washington University School of Medicine

Investigators

• Principal Investigator: Amanda Cashen, M.D., Washington University School of Medicine

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine

Publications

None provided.

• Responsible Party: Washington University School of Medicine
• ClinicalTrials.gov Identifier: NCT01969435
• Other Study ID Numbers: 201312115
• First Posted: Oct 25, 2013
• Last Update Posted: Feb 13, 2018
• Last Verified: Jan 1, 2018

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Lymphoma; Hodgkin Disease; Lymphoma, Non-Hodgkin; Cytarabine; Etoposide; Melphalan; Carmustine; Etoposide phosphate

Study Results

Participant Flow

Arm/Group Title	Melphalan, Carmustine, Etoposide, Cytarabine (BEAM)
Arm/Group Description	Day -7, carmustine intravenous (IV) infusion Days -6, -5, -4, and -3, etoposide and cytarabine (IV) infusions twice a day Day -2, melphalan HCl (propylene glycol-free)(IV) infusion Day 0, stem cell transplant.
Period Title: Overall Study
STARTED	50
COMPLETED	50
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Melphalan, Carmustine, Etoposide, Cytarabine (BEAM)
Arm/Group Description	Day -7, carmustine intravenous (IV) infusion Days -6, -5, -4, and -3, etoposide and cytarabine (IV) infusions twice a day Day -2, melphalan HCl (propylene glycol-free)(IV) infusion Day 0, stem cell transplant.
Overall Participants	50
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	51
Sex: Female, Male (Count of Participants)
Female	14 28%
Male	36 72%
Region of Enrollment (participants) [Number]
United States	50 100%
Diagnosis (participants) [Number]
Hodgkin lymphoma	17 34%
Diffuse large B-cell lymphoma	15 30%
Mantle cell lymphoma	8 16%
Other Non-Hodgkin Lymphoma	10 20%
Remission status prior to autologous stem cell transplant (participants) [Number]
Complete remission	23 46%
Partial remission	25 50%
Progressive disease	2 4%

Outcome Measures

1. Primary Outcome

Title	Safety and Toxicity as Measured by Treatment Related Non-hematologic Adverse Events
Description	Adverse events will be assessed using the National Cancer Institute (NCI)-CTCAE version 4.0. Number of events, grade 2 or higher, occurring in 10% or greater of participants. Grade 2 diarrhea and Grade 2 nausea/vomiting were not recorded.
Time Frame	Day -7 through Day 30

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Melphalan, Carmustine, Etoposide, Cytarabine (BEAM)
Arm/Group Description	Day -7, carmustine intravenous (IV) infusion Days -6, -5, -4, and -3, etoposide and cytarabine (IV) infusions twice a day Day -2, melphalan HCl (propylene glycol-free)(IV) infusion Day 0, stem cell transplant.
Measure Participants	50
Fever neutropenia	34 68%
Fever	6 12%
Bacteremia	7 14%
Clostridium difficile	3 6%
Respiratory infection	5 10%
Mucosal infection	7 14%
Skin infection	3 6%
Genito-urinary tract infection	3 6%
Hypotension	15 30%
Abdominal pain	5 10%
Diarrhea	8 16%
Mucositis oral	27 54%
Liver enzymes increased	5 10%
Bilirubin increased	5 10%
Dehydration	5 10%
Hyperglycemia	6 12%
Hypoalbuminemia	10 20%
Hypocalcemia	12 24%
Hypokalemia	14 28%
Hypophosphatemia	35 70%
Pain	10 20%
Headache	7 14%
Hypoxia	9 18%
Rash	8 16%

2. Primary Outcome

Title	Treatment-related Mortality (TRM)
Description	TRM is defined as death not due to progressive lymphoma prior to Day 100 after transplant
Time Frame	100 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Melphalan, Carmustine, Etoposide, Cytarabine (BEAM)
Arm/Group Description	Day -7, carmustine intravenous (IV) infusion Days -6, -5, -4, and -3, etoposide and cytarabine (IV) infusions twice a day Day -2, melphalan HCl (propylene glycol-free)(IV) infusion Day 0, stem cell transplant.
Measure Participants	50
Number [percentage of participants]	0 0%

3. Secondary Outcome

Title	Efficacy as Measured by Response Rates
Description	The response rates according to each category of response Complete Response (CR), Partial Response (PR), Stable Disease (SD), and Progressive Disease (PD) will be summarized by the proportion of patients meeting each criterion. Evaluated using PET or CT scan and Revised Response Criteria for Malignant Lymphoma
Time Frame	Up to Day 100

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Melphalan, Carmustine, Etoposide, Cytarabine (BEAM)
Arm/Group Description	Day -7, carmustine intravenous (IV) infusion Days -6, -5, -4, and -3, etoposide and cytarabine (IV) infusions twice a day Day -2, melphalan HCl (propylene glycol-free)(IV) infusion Day 0, stem cell transplant.
Measure Participants	50
Complete response	84 168%
Partial response	4 8%
Stable disease	0 0%
Progressive disease	12 24%

4. Secondary Outcome

Title	Disease-free Survival
Description	Percentage of patients who survive without any signs or symptoms of cancer at 1 year.
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Melphalan, Carmustine, Etoposide, Cytarabine (BEAM)
Arm/Group Description	Day -7, carmustine intravenous (IV) infusion Days -6, -5, -4, and -3, etoposide and cytarabine (IV) infusions twice a day Day -2, melphalan HCl (propylene glycol-free)(IV) infusion Day 0, stem cell transplant.
Measure Participants	50
Number (95% Confidence Interval) [percentage of participants]	70 140%

5. Secondary Outcome

Title	Disease-free Survival
Description	Percentage of patients who survive without any signs or symptoms of cancer at 2 years.
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Melphalan, Carmustine, Etoposide, Cytarabine (BEAM)
Arm/Group Description	Day -7, carmustine intravenous (IV) infusion Days -6, -5, -4, and -3, etoposide and cytarabine (IV) infusions twice a day Day -2, melphalan HCl (propylene glycol-free)(IV) infusion Day 0, stem cell transplant.
Measure Participants	50
Number [percentage of participants]	64 128%

6. Secondary Outcome

Title	Time to Engraftment (Neutrophil)
Description	Time from the date of the transplant to the date of neutrophil engraftment.
Time Frame	Assessed up to day 30

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Melphalan, Carmustine, Etoposide, Cytarabine (BEAM)
Arm/Group Description	Day -7, carmustine intravenous (IV) infusion Days -6, -5, -4, and -3, etoposide and cytarabine (IV) infusions twice a day Day -2, melphalan HCl (propylene glycol-free)(IV) infusion Day 0, stem cell transplant.
Measure Participants	50
Median (Full Range) [days]	10

7. Secondary Outcome

Title	Time to Engraftment (Platelet)
Description	Time from the date of transplant to the date of platelet engraftment.
Time Frame	Assessed up to day 100

Outcome Measure Data

Analysis Population Description

One patient did not have platelet engraftment by Day 100

Arm/Group Title	Melphalan, Carmustine, Etoposide, Cytarabine (BEAM)
Arm/Group Description	Day -7, carmustine intravenous (IV) infusion Days -6, -5, -4, and -3, etoposide and cytarabine (IV) infusions twice a day Day -2, melphalan HCl (propylene glycol-free)(IV) infusion Day 0, stem cell transplant.
Measure Participants	49
Median (Full Range) [days]	19

8. Post-Hoc Outcome

Title	Progression-free Survival (PFS) Rate
Description	PFS - Time from start of treatment to the time of progression or death, whichever occurs first.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Melphalan, Carmustine, Etoposide, Cytarabine (BEAM)
Arm/Group Description	Day -7, carmustine intravenous (IV) infusion Days -6, -5, -4, and -3, etoposide and cytarabine (IV) infusions twice a day Day -2, melphalan HCl (propylene glycol-free)(IV) infusion Day 0, stem cell transplant.
Measure Participants	50
Median (95% Confidence Interval) [percentage of participants]	84 168%

9. Post-Hoc Outcome

Title	Progression-free Survival Rate (PFS)
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Melphalan, Carmustine, Etoposide, Cytarabine (BEAM)
Arm/Group Description	Day -7, carmustine intravenous (IV) infusion Days -6, -5, -4, and -3, etoposide and cytarabine (IV) infusions twice a day Day -2, melphalan HCl (propylene glycol-free)(IV) infusion Day 0, stem cell transplant.
Measure Participants	50
Median (95% Confidence Interval) [percentage of participants]	70 140%

10. Post-Hoc Outcome

Title	Relapse Free Survival
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Melphalan, Carmustine, Etoposide, Cytarabine (BEAM)
Arm/Group Description	Day -7, carmustine intravenous (IV) infusion Days -6, -5, -4, and -3, etoposide and cytarabine (IV) infusions twice a day Day -2, melphalan HCl (propylene glycol-free)(IV) infusion Day 0, stem cell transplant.
Measure Participants	50
Number [percentage of participants]	0 0%

11. Post-Hoc Outcome

Title	Overall Survival (OS) Rate
Time Frame	Median follow-up 15.4 months (range 4.7-24.6)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Melphalan, Carmustine, Etoposide, Cytarabine (BEAM)
Arm/Group Description	Day -7, carmustine intravenous (IV) infusion Days -6, -5, -4, and -3, etoposide and cytarabine (IV) infusions twice a day Day -2, melphalan HCl (propylene glycol-free)(IV) infusion Day 0, stem cell transplant.
Measure Participants	50
Number [percentage of participants]	10 20%

Adverse Events

Time Frame	Reportable adverse events were collected from the first dose of study treatment (Day -7) through the Day +30 visit.
Adverse Event Reporting Description	Reportable adverse events are events grade 2 or higher. Hematologic adverse events are expected and therefore the following adverse events were not collected/reported regardless of grade: anemia, white blood cell decreased, neutrophil count decreased, lymphocyte count decreased, and platelet count decreased. In addition, the following grade 2 non-hematologic adverse events were expected and not collected/reported: nausea, vomiting, diarrhea, anorexia, fatigue, and alopecia.
Arm/Group Title	Melphalan, Carmustine, Etoposide, Cytarabine (BEAM)
Arm/Group Description	Day -7, carmustine intravenous (IV) infusion Days -6, -5, -4, and -3, etoposide and cytarabine (IV) infusions twice a day Day -2, melphalan HCl (propylene glycol-free)(IV) infusion Day 0, stem cell transplant.
All Cause Mortality
	Melphalan, Carmustine, Etoposide, Cytarabine (BEAM)
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Melphalan, Carmustine, Etoposide, Cytarabine (BEAM)
	Affected / at Risk (%)	# Events
Total	1/50 (2%)
General disorders
Multi-organ failure due to sepsis	1/50 (2%)
Other (Not Including Serious) Adverse Events
	Melphalan, Carmustine, Etoposide, Cytarabine (BEAM)
	Affected / at Risk (%)	# Events
Total	50/50 (100%)
Cardiac disorders
Atrial fibrillation	3/50 (6%)
Heart failure	1/50 (2%)
Sinus tachycardia	1/50 (2%)
Supraventricular tachycardia	1/50 (2%)
Gastrointestinal disorders
Abdominal pain	5/50 (10%)
Colitis	2/50 (4%)
Constipation	1/50 (2%)
Diarrhea	8/50 (16%)
Esophageal spasm	1/50 (2%)
Gastric hemorrhage	1/50 (2%)
Gastroesophageal reflux disease	3/50 (6%)
Hemorrhoids	4/50 (8%)
Ileal obstruction	1/50 (2%)
Lower gastrointestinal hemorrhage	1/50 (2%)
Mucositis oral	27/50 (54%)
Nausea	2/50 (4%)
Rectal pain	2/50 (4%)
Vomiting	1/50 (2%)
General disorders
Chills	2/50 (4%)
Edema limbs	2/50 (4%)
Fever	6/50 (12%)
Localized edema	1/50 (2%)
Non-cardiac chest pain	4/50 (8%)
Immune system disorders
Allergic reaction	2/50 (4%)
Infections and infestations
Blood-Coagulase-negative staphylococcus	3/50 (6%)
Blood-Enterobacter clocae/streptococcus mitis	1/50 (2%)
Blood-Klebsiella pneumoniae	2/50 (4%)
Catheter related infection	1/50 (2%)
Clostridium difficile	3/50 (6%)
Febrile neutropenia	34/50 (68%)
HSV (oral)	2/50 (4%)
Lung infection	1/50 (2%)
Mucosal infection (oral candidiasis)	5/50 (10%)
Parainfluenaza virus type 3	1/50 (2%)
Sinusitis	2/50 (4%)
Skin infection	3/50 (6%)
Upper respiratory infection	1/50 (2%)
Urinary tract infection	2/50 (4%)
Vaginal infection	1/50 (2%)
Injury, poisoning and procedural complications
Fall	1/50 (2%)
Investigations
Alanine aminotransferase increased	3/50 (6%)
Alkaline phosphatase increased	1/50 (2%)
Aspartate aminotransferase increased	1/50 (2%)
Blood bilirubin increased	5/50 (10%)
Creatinine increased	1/50 (2%)
Electrocardiogram QT corrected interval prolonged	3/50 (6%)
Weight gain	1/50 (2%)
Weight loss	4/50 (8%)
Metabolism and nutrition disorders
Anorexia	3/50 (6%)
Dehydration	5/50 (10%)
Hyperglycemia	6/50 (12%)
Hypernatremia	1/50 (2%)
Hypoalbuminemia	10/50 (20%)
Hypocalcemia	12/50 (24%)
Hypokalemia	14/50 (28%)
Hypomagnesemia	1/50 (2%)
Hyponatremia	1/50 (2%)
Hypophosphatemia	35/50 (70%)
Musculoskeletal and connective tissue disorders
Back pain	2/50 (4%)
Bone pain	3/50 (6%)
Generalized muscle weakness	4/50 (8%)
Hip pain	1/50 (2%)
Pain in extremity	4/50 (8%)
Nervous system disorders
Dizziness	1/50 (2%)
Headache	7/50 (14%)
Lethargy	1/50 (2%)
Syncope	1/50 (2%)
Psychiatric disorders
Insomnia	1/50 (2%)
Renal and urinary disorders
Hematuria	1/50 (2%)
Urinary retention	1/50 (2%)
Respiratory, thoracic and mediastinal disorders
Atelectasis	1/50 (2%)
BCNU pulmonary toxicity	1/50 (2%)
Cough	1/50 (2%)
Dyspnea	1/50 (2%)
Hypoxia	9/50 (18%)
Nasal congestion	1/50 (2%)
Pleural effusion	1/50 (2%)
Productive cough	1/50 (2%)
Respiratory failure	1/50 (2%)
Sore throat	2/50 (4%)
Skin and subcutaneous tissue disorders
Folliculitis	1/50 (2%)
Pruritus	1/50 (2%)
Rash maculo-papular	8/50 (16%)
Subcutaneous nodule	1/50 (2%)
Vascular disorders
Flushing	2/50 (4%)
Hypertension	1/50 (2%)
Hypotension	15/50 (30%)
Thromboembolic event	2/50 (4%)

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.