Pegylated Liposomal Doxorubicin Hydrochloride, Bortezomib, Cyclophosphamide, and Dexamethasone in Treating Patients With Multiple Myeloma

• Sponsor: University of Washington (Other)
• Overall Status: Terminated
• CT.gov ID: NCT00849251
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 31
• Location: 1
• Arm: 1
• Duration (Months): 78.9
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

RATIONALE: Drugs used in chemotherapy, such as pegylated liposomal doxorubicin hydrochloride and cyclophosphamide, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Bortezomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the cancer. Giving pegylated liposomal doxorubicin hydrochloride together with bortezomib, cyclophosphamide, and dexamethasone may kill more cancer cells.

PURPOSE: This phase I/II trial is studying the side effects of giving pegylated liposomal doxorubicin hydrochloride together with bortezomib, cyclophosphamide, and dexamethasone and to see how well it works in treating patients with multiple myeloma

Condition or Disease	Intervention/Treatment	Phase
Refractory Multiple Myeloma; Stage I Multiple Myeloma; Stage II Multiple Myeloma; Stage III Multiple Myeloma	Drug: cyclophosphamide; Drug: pegylated liposomal doxorubicin hydrochloride; Drug: bortezomib; Drug: dexamethasone	Phase 1/Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. To determine efficacy of this novel combination in newly diagnosed patients with multiple myeloma.

SECONDARY OBJECTIVES:

1. To determine the toxicity of this novel combination regimen in previously treated patients and newly diagnosed patients with multiple myeloma.

OUTLINE:

Patients receive cyclophosphamide intravenously (IV) or orally (PO) over 1 hour, bortezomib IV over 3 minutes, and dexamethasone IV or PO on days 1, 8, and 15. Patients also receive pegylated liposomal doxorubicin hydrochloride IV over 1 hour on day 8. Treatment repeats every 28 days for up to 4 courses in the absence of disease progression or unacceptable toxicity.

After completion of treatment, patients are followed up every 3 months for 2 years, then annually up to 5 years.

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: Combination Pegylated Liposomal Doxorubicin, Bortezomib, Cyclophosphamide, and Dexamethasone for Multiple Myeloma (PLD-BCD)
• Study Start Date: Nov 1, 2008
• Actual Primary Completion Date: Dec 1, 2011
• Actual Study Completion Date: Jun 1, 2015

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Treatment (chemotherapy and enzyme inhibitor) Patients receive cyclophosphamide IV or PO over 1 hour, bortezomib IV over 3 minutes, and dexamethasone IV or PO on days 1, 8, and 15. Patients also receive pegylated liposomal doxorubicin hydrochloride IV over 1 hour on day 8. Treatment repeats every 28 days for up to 4 courses in the absence of disease progression or unacceptable toxicity.

Drug: cyclophosphamide; Given IV or PO; Other Names: CPM CTX Cytoxan Endoxan Endoxana ; Drug: pegylated liposomal doxorubicin hydrochloride; Given IV; Other Names: CAELYX Dox-SL DOXIL doxorubicin hydrochloride liposome LipoDox ; Drug: bortezomib; Given IV; Other Names: LDP 341 MLN341 VELCADE ; Drug: dexamethasone; Given IV or PO; Other Names: Aeroseb-Dex Decaderm Decadron DM DXM

Outcome Measures

Primary Outcome Measures

1. Maximum Tolerated Dose of This Combination of Drugs as Assessed by the NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 (Cohort 1) [MTD Cyclophosphamide, MTD Bortezmib, MTD Docxorubicin] [Up to 90 days after initiation of study treatment]

   If 3 patients of cohort 1 require dose reduction of one or more of the medications for toxicity attributed to the drug or drugs, then the starting dose level will be reduced for that drug or drugs for future patients. The initial dosing of drugs for cohort 2 will be permitted to be one dose level above the maximal tolerated doses of cohort 1. Note that this Outcome Measure shows MTD for cyclophosphamide, bortezomib and doxorubicin. MTD for dexamethasone is include in a separate table due to the different Unit of Measure.

2. Disease Response Rate (Cohort II) [up to 28 days after last cycle of treatment]

   Disease response using Blade Multiple Myeloma Response Criteria in newly diagnosed (Cohort II) patients who completed at least one cycle of treatment. There were 24 evaluable patients in Cohort II.

3. Maximum Tolerated Dose of This Combination of Drugs as Assessed by the NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 (Cohort 1). [Dexamethasone MTD] [Up to 90 days after initiation of study treatment]

   If 3 patients of cohort 1 require dose reduction of one or more of the medications for toxicity attributed to the drug or drugs, then the starting dose level will be reduced for that drug or drugs for future patients. The initial dosing of drugs for cohort 2 will be permitted to be one dose level above the maximal tolerated doses of cohort 1. Note that this Outcome Measure will only describe the MTD for dexamethasone. Dexamethasone could not be reported with the MTD for the other three drugs due to a different Unit of Measure.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Cohort 1: Relapsed, refractory patients with multiple myeloma who have failed at least one prior regimen not including dexamethasone alone

• Cohort 2: Newly diagnosed patients with previously untreated multiple myeloma; prior dexamethasone permitted; not to exceed 320 mg

• Diagnosis of multiple myeloma with quantifiable monoclonal protein or light chain identified by serum protein electrophoresis (SPEP), urine protein electrophoresis (UPEP), or serum free light chain assay

• Eastern Cooperative Oncology Group (ECOG) performance status 0-2

• Absolute neutrophil count >= 1.5

• Platelet count >= 75,000 unless slightly lower due to disease with the approval of the principal investigator (PI)

• Serum creatinine =< 2.0 mg/dL

• Serum bilirubin =< 1.2

• Aspartate transaminase (AST)/alanine transaminase (ALT) =< 2.5 x upper limit of normal (ULN)

• Alkaline phosphatase =< 2.5 x ULN

• Voluntary written informed consent before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care

• Left ventricular ejection fraction greater than or equal to 50% by multi gated acquisition scan (MUGA)

• Female subjects must be post-menopausal, surgically sterilized, or willing to use an acceptable method of birth control (i.e., a hormonal contraceptive, intra-uterine device, diaphragm with spermicide, condom with spermicide, or abstinence) for the duration of the study; female patients of childbearing potential must have a negative serum pregnancy test within 2 weeks prior to enrollment

• Male patients must use an effective contraceptive method during the study and for a minimum of 6 months after study treatment

Exclusion Criteria:

• Current concomitant chemotherapy, radiation therapy, or immunotherapy other than as specified in the protocol

• Use of other anticancer therapy within 15 days or before study entry; the patient must have recovered from all acute non-hematological toxicities from any previous therapy

• Have any other severe concurrent disease, or have a history of serious organ dysfunction or disease involving the heart, kidney, liver, or other organ system that may place the patient at undue risk to undergo treatment, despite appropriate antibiotics or other treatment; for cardiac dysfunction, myocardial infarction within 6 months prior to enrollment or New York Heart Association (NYHA) Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities

• Patients with a systemic fungal, bacterial, viral, or other infection not controlled (defined as exhibiting ongoing signs/symptoms related to the infection) on antiviral, antibiotic and antifungal treatment

• Patient has >= Grade 2 peripheral neuropathy within 14 days before enrollment

• Patient has hypersensitivity to bortezomib, boron or mannitol

• Pregnant or lactating patients

• Cumulative dose of doxorubicin of 400 mg/m^2 or greater, or if this level would be exceeded during the current study

• Any significant concurrent illness, condition, or psychiatric disorder that would compromise patient safety or compliance, interfere with consent, study participation, follow up, or interpretation of study results

• Have had a diagnosis of another malignancy, unless the patient has been disease-free for at least 3 years following the completion of curative intent therapy including the following:

• Patients with treated non-melanoma skin cancer, in situ carcinoma, or cervical intraepithelial neoplasia, regardless of the disease-free duration, are eligible for this study if definitive treatment for the condition has been completed;

• Patients with organ-confined prostate cancer with no evidence of recurrent or progressive disease based on prostate-specific antigen (PSA) values are also eligible for this study if hormonal therapy has been initiated or a radical prostatectomy has been performed;

• Prior autologous stem cell transplant (Cohort 2 only);

• Prior allogeneic stem cell transplant;

• Patient has received other investigational drugs within 14 days before enrollment

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium	Seattle	Washington	United States	98109

Sponsors and Collaborators

• University of Washington
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Pamela Becker, Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Pamela S Becker, Principal Investigator, University of Washington
• ClinicalTrials.gov Identifier: NCT00849251
• Other Study ID Numbers: 6817; NCI-2009-01665
• First Posted: Feb 23, 2009
• Last Update Posted: Sep 8, 2017
• Last Verified: Aug 1, 2017

• Additional relevant MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell; Dexamethasone; Cyclophosphamide; Doxorubicin; Liposomal doxorubicin; Bortezomib

Study Results

Participant Flow

Arm/Group Title	Relapsed Disease (Cohort I)	Newly Diagnosed Disease (Cohort II)
Arm/Group Description	Patients with relapsed multiple myeloma receive cyclophosphamide IV or PO over 1 hour, bortezomib IV over 3 minutes, and dexamethasone IV or PO on days 1, 8, and 15. Patients also receive pegylated liposomal doxorubicin hydrochloride IV over 1 hour on day 8. Treatment repeats every 28 days for up to 4 courses in the absence of disease progression or unacceptable toxicity. cyclophosphamide: Given IV or PO pegylated liposomal doxorubicin hydrochloride: Given IV bortezomib: Given IV dexamethasone: Given IV or PO	Patients with newly diagnosed multiple myeloma receive cyclophosphamide IV or PO over 1 hour, bortezomib IV over 3 minutes, and dexamethasone IV or PO on days 1, 8, and 15. Patients also receive pegylated liposomal doxorubicin hydrochloride IV over 1 hour on day 8. Treatment repeats every 28 days for up to 4 courses in the absence of disease progression or unacceptable toxicity. cyclophosphamide: Given IV or PO pegylated liposomal doxorubicin hydrochloride: Given IV bortezomib: Given IV dexamethasone: Given IV or PO
Period Title: Overall Study
STARTED	6	25
COMPLETED	5	24
NOT COMPLETED	1	1

Baseline Characteristics

Arm/Group Title	Treatment (Chemotherapy and Enzyme Inhibitor)
Arm/Group Description	Patients receive cyclophosphamide IV or PO over 1 hour, bortezomib IV over 3 minutes, and dexamethasone IV or PO on days 1, 8, and 15. Patients also receive pegylated liposomal doxorubicin hydrochloride IV over 1 hour on day 8. Treatment repeats every 28 days for up to 4 courses in the absence of disease progression or unacceptable toxicity. cyclophosphamide: Given IV or PO pegylated liposomal doxorubicin hydrochloride: Given IV bortezomib: Given IV dexamethasone: Given IV or PO
Overall Participants	31
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	25 80.6%
>=65 years	6 19.4%
Sex: Female, Male (Count of Participants)
Female	17 54.8%
Male	14 45.2%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	2 6.5%
Not Hispanic or Latino	24 77.4%
Unknown or Not Reported	5 16.1%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	1 3.2%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	1 3.2%
White	29 93.5%
More than one race	0 0%
Unknown or Not Reported	0 0%

Outcome Measures

1. Primary Outcome

Title	Maximum Tolerated Dose of This Combination of Drugs as Assessed by the NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 (Cohort 1) [MTD Cyclophosphamide, MTD Bortezmib, MTD Docxorubicin]
Description	If 3 patients of cohort 1 require dose reduction of one or more of the medications for toxicity attributed to the drug or drugs, then the starting dose level will be reduced for that drug or drugs for future patients. The initial dosing of drugs for cohort 2 will be permitted to be one dose level above the maximal tolerated doses of cohort 1. Note that this Outcome Measure shows MTD for cyclophosphamide, bortezomib and doxorubicin. MTD for dexamethasone is include in a separate table due to the different Unit of Measure.
Time Frame	Up to 90 days after initiation of study treatment

Outcome Measure Data

Analysis Population Description

Patients with relapsed multiple myeloma who received cyclophosphomide, bortezomib, liposomal doxorubicin and dexamethasone. Note that the MTD for dexamethasone is in a separate table due to the different dosing unit.

Arm/Group Title	Relapsed Disease
Arm/Group Description	Patients with relapsed multiple myeloma receive cyclophosphamide IV or PO over 1 hour, bortezomib IV over 3 minutes, and dexamethasone IV or PO on days 1, 8, and 15. Patients also receive pegylated liposomal doxorubicin hydrochloride IV over 1 hour on day 8. Treatment repeats every 28 days for up to 4 courses in the absence of disease progression or unacceptable toxicity. cyclophosphamide: Given IV or PO pegylated liposomal doxorubicin hydrochloride: Given IV bortezomib: Given IV dexamethasone: Given IV or PO
Measure Participants	6
MTD cyclophosphamide	300
MTD bortezomib	1.6
MTD liposomal doxorubicin	30

2. Primary Outcome

Title	Disease Response Rate (Cohort II)
Description	Disease response using Blade Multiple Myeloma Response Criteria in newly diagnosed (Cohort II) patients who completed at least one cycle of treatment. There were 24 evaluable patients in Cohort II.
Time Frame	up to 28 days after last cycle of treatment

Outcome Measure Data

Analysis Population Description

Newly diagnosed patients (cohort II)

Arm/Group Title	Newly Diagnosed Patients
Arm/Group Description	Patients with newly diagnosed multiple myeloma receive cyclophosphamide IV or PO over 1 hour, bortezomib IV over 3 minutes, and dexamethasone IV or PO on days 1, 8, and 15. Patients also receive pegylated liposomal doxorubicin hydrochloride IV over 1 hour on day 8. Treatment repeats every 28 days for up to 4 courses in the absence of disease progression or unacceptable toxicity. cyclophosphamide: Given IV or PO pegylated liposomal doxorubicin hydrochloride: Given IV bortezomib: Given IV dexamethasone: Given IV or PO
Measure Participants	24
Complete response (CR)	2 6.5%
Near complete response (nCR)	2 6.5%
Very good partial response (VGPR)	3 9.7%
Partial response (PR)	11 35.5%
Stable disease (SD)	6 19.4%

3. Primary Outcome

Title	Maximum Tolerated Dose of This Combination of Drugs as Assessed by the NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 (Cohort 1). [Dexamethasone MTD]
Description	If 3 patients of cohort 1 require dose reduction of one or more of the medications for toxicity attributed to the drug or drugs, then the starting dose level will be reduced for that drug or drugs for future patients. The initial dosing of drugs for cohort 2 will be permitted to be one dose level above the maximal tolerated doses of cohort 1. Note that this Outcome Measure will only describe the MTD for dexamethasone. Dexamethasone could not be reported with the MTD for the other three drugs due to a different Unit of Measure.
Time Frame	Up to 90 days after initiation of study treatment

Outcome Measure Data

Analysis Population Description

Patients with relapsed multiple myeloma who received cyclophosphomide, bortezomib, liposomal doxorubicin and dexamethasone. Note that this Outcome Measure will only describe the MTD for dexamethasone. Dexamethasone could not be reported with the MTD for the other three drugs due to a different Unit of Measure.

Arm/Group Title	Relapsed Disease (Cohort I)
Arm/Group Description	Patients with relapsed multiple myeloma receive cyclophosphamide IV or PO over 1 hour, bortezomib IV over 3 minutes, and dexamethasone IV or PO on days 1, 8, and 15. Patients also receive pegylated liposomal doxorubicin hydrochloride IV over 1 hour on day 8. Treatment repeats every 28 days for up to 4 courses in the absence of disease progression or unacceptable toxicity. cyclophosphamide: Given IV or PO pegylated liposomal doxorubicin hydrochloride: Given IV bortezomib: Given IV dexamethasone: Given IV or PO
Measure Participants	6
Number [mg]	40

Adverse Events

Time Frame	Through 45 days after the last dose of study drug.
Adverse Event Reporting Description	>= grade 2 events are recorded
Arm/Group Title	Treatment (Chemotherapy and Enzyme Inhibitor)
Arm/Group Description	Patients receive cyclophosphamide IV or PO over 1 hour, bortezomib IV over 3 minutes, and dexamethasone IV or PO on days 1, 8, and 15. Patients also receive pegylated liposomal doxorubicin hydrochloride IV over 1 hour on day 8. Treatment repeats every 28 days for up to 4 courses in the absence of disease progression or unacceptable toxicity. cyclophosphamide: Given IV or PO pegylated liposomal doxorubicin hydrochloride: Given IV bortezomib: Given IV dexamethasone: Given IV or PO
All Cause Mortality
	Treatment (Chemotherapy and Enzyme Inhibitor)
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Treatment (Chemotherapy and Enzyme Inhibitor)
	Affected / at Risk (%)	# Events
Total	1/31 (3.2%)
Vascular disorders
Thromboembolic event	1/31 (3.2%)	1
Other (Not Including Serious) Adverse Events
	Treatment (Chemotherapy and Enzyme Inhibitor)
	Affected / at Risk (%)	# Events
Total	31/31 (100%)
Blood and lymphatic system disorders
Anemia	8/31 (25.8%)	8
Eye disorders
Vomiting	3/31 (9.7%)	3
Gastrointestinal disorders
Gastrointestinal hemorrhage	2/31 (6.5%)	2
Nausea	10/31 (32.3%)	10
Constipation	10/31 (32.3%)	10
Diarrhea	3/31 (9.7%)	3
Mucositis	1/31 (3.2%)	1
General disorders
Non-cardiac chest pain	2/31 (6.5%)	2
Jaw pain	1/31 (3.2%)	1
Upper arm pain	1/31 (3.2%)	1
Fatigue	18/31 (58.1%)	18
Chest tightness	1/31 (3.2%)	1
Leg pain	2/31 (6.5%)	2
Edema limbs	1/31 (3.2%)	1
Weakness	1/31 (3.2%)	1
Shoulder pain	1/31 (3.2%)	1
Back pain	3/31 (9.7%)	3
Hiccoughs	1/31 (3.2%)	1
Infections and infestations
Hand foot and mouth disease	4/31 (12.9%)	4
Urinary tract infection	1/31 (3.2%)	1
Infection without neutropenia	2/31 (6.5%)	2
Candidas	1/31 (3.2%)	1
Upper respiratory infection	1/31 (3.2%)	1
Fungal skin infection	1/31 (3.2%)	1
Investigations
Weight loss	1/31 (3.2%)	1
Transaminitis	1/31 (3.2%)	1
Hypoalbuminemia	5/31 (16.1%)	5
Leukopenia	4/31 (12.9%)	4
Neutropenia	5/31 (16.1%)	5
Hypophosphatemia	3/31 (9.7%)	3
Hyponatremia	1/31 (3.2%)	1
Hypocalcemia	3/31 (9.7%)	3
Lymphopenia	1/31 (3.2%)	1
Metabolism and nutrition disorders
Dehydration	2/31 (6.5%)	2
Musculoskeletal and connective tissue disorders
Muscle cramps	1/31 (3.2%)	1
Muscle pain	1/31 (3.2%)	1
Nervous system disorders
Peripheral neuropathy	7/31 (22.6%)	7
Dizziness	1/31 (3.2%)	1
Cognitive disturbance	1/31 (3.2%)	1
Psychiatric disorders
Insomnia	3/31 (9.7%)	3
Anxiety	1/31 (3.2%)	1
Renal and urinary disorders
Urinary incontinence	1/31 (3.2%)	1
Respiratory, thoracic and mediastinal disorders
Acute exacerbation of COPD	1/31 (3.2%)	1
Dyspnea	2/31 (6.5%)	2
Lung infection	1/31 (3.2%)	1
Laryngeal inflammation	1/31 (3.2%)	1
Epistaxis	1/31 (3.2%)	1
Skin and subcutaneous tissue disorders
Blistering hands	1/31 (3.2%)	1
Peeling hands	1/31 (3.2%)	1
Rash	2/31 (6.5%)	2
Skin changes	1/31 (3.2%)	1
Hives	1/31 (3.2%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.