Doxil® + Melphalan + Velcade (DMV) in Relapsed/Refractory Multiple Myeloma

• Sponsor: University of California, San Francisco (Other)
• Overall Status: Terminated
• CT.gov ID: NCT00985907
• Collaborator: (none)
• Enrollment: 13
• Locations: 2
• Arm: 1
• Actual Duration (Months): 62.5
• Patients Per Site: 6.5
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The median overall survival (OS) of relapsed/refractory multiple myeloma (MM) is less than nine months. However, phase II data with the proteasome inhibitor bortezomib (Velcade®) has been heartening, with 35% overall response rates and median survival of 16 months. In-vitro data has shown that this agent dramatically increases the sensitivity to chemotherapeutic agents. Liposomal doxorubicin (Doxil), melphalan, and bortezomib all have different mechanisms of action and toxicity profiles. Clinical studies employing two drug combinations with these agents in patients with refractory MM have found favorable efficacy (nearly no progression of disease) and tolerance data. Thus, the investigators are initiating a phase I/II study to examine the safety and efficacy of combining all three agents into the regimen DMV (Doxil® + melphalan + Velcade).

Condition or Disease	Intervention/Treatment	Phase
Multiple Myeloma; Patient Participation	Drug: Doxil, melphalan, bortezomib	Phase 1/Phase 2

Detailed Description

Dose Level 1: Doxil 10 mg/m2, Melphalan 5 mg/m2, Velcade 0.7 mg/m2

Dose Level 2: Doxil 10 mg/m2, Melphalan 10 mg/m2, Velcade 0.7 mg/m2

Dose Level 3: Doxil 20 mg/m2, Melphalan 10 mg/m2, Velcade 0.7 mg/m2

Dose Level 4: Doxil 20 mg/m2, Melphalan 10 mg/m2, Velcade 1.0 mg/m2

Adjunctive therapy with a bisphosphonate, either pamidronate or zoledronic acid, will be given monthly.

Dose Escalation Schedule: Dose escalation will occur only after patients have completed at least two cycles at a given dose level.

1. If 0/3 experience DLT (as defined in attachment Section 6.0), the next three patients will be escalated by one dose level.

2. If 1/3 experience DLT, 3 additional patients enrolled at this dose level.

• If 0, 1, or 2 of these additional patients experience DLT (i.e. total 3/6), the dose will be escalated.

• If 3/3 experience DLT (i.e. total 4/6) then the next lower dose will be considered the MTD..

1. If 2/3 experience DLT, 3 additional patients enrolled at this dose level.

• If 0 or 1 of these additional patients experience DLT (i.e. total 3/6), the dose will be escalated.

• If 2 or more/3 experience DLT (i.e. total more than 3/6) then the next lower dose level is MTD

Study Design

• Study Type: Interventional
• Actual Enrollment: 13 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase I/II Study of Liposomal Doxorubicin (Doxil®)/Melphalan/Bortezomib (Velcade®) in Relapsed/Refractory Multiple Myeloma
• Actual Study Start Date: Oct 28, 2004
• Actual Primary Completion Date: Oct 7, 2008
• Actual Study Completion Date: Jan 12, 2010

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Doxil® + Melphalan + Velcade (DMV)

Drug: Doxil, melphalan, bortezomib; Doxil®: IV over 30-60 min, Day 1 q28d Melphalan: IV over 30 min, Day 1 q28d Velcade®: IV bolus, Day 1, 4, 8, 11 q28d Dose Level 1: Doxil 10 mg/m2, Melphalan 5 mg/m2, Velcade 0.7 mg/m2 Dose Level 2: Doxil 10 mg/m2, Melphalan 10 mg/m2, Velcade 0.7 mg/m2 Dose Level 3: Doxil 20 mg/m2, Melphalan 10 mg/m2, Velcade 0.7 mg/m2 Dose Level 4: Doxil 20 mg/m2, Melphalan 10 mg/m2, Velcade 1.0 mg/m2; Other Names: Doxil, melphalan, Velcade

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Dose Limiting Toxicities (DLT) (Phase 1) [Up to 2 cycles of treatment, approximately 56 days]

   Safety assessments will be evaluated as the proportion of patients experiencing the following: treatment-related grade 3 or higher toxicity (hematologic and nonhematologic) and treatment-related death.

2. Maximum Tolerated Dose (MTD) (Phase 1) [Up to 1 year]

   The MTD will be considered the dose below where <= 3 patients experience a DLT and the dose that two cycles can be given without meeting toxicity criteria.

Secondary Outcome Measures

1. Number of All Treatment-related Toxicities at the MTD (Phase 1) [5 years]

   NCI Common Terminology Criteria for Adverse Events (CTCAE) version 3 will be used to determine all treatment related toxicities at the MTD. Participants entered at the MTD Dose level from the phase I portion of the study will also be included in this analysis

2. Overall Response Rate [Up to 5 years]

   At each cycle, participants will be assessed for treatment response: Complete Response (CR), Near CR(nCR), Partial Response (PR), Minimal Response (MR), Stable Disease (SD), or Progressive Disease (PD) on at least 2 measurements at minimum of a 4 week interval. The overall response rate will use the best response of CR, nCR, PR, MR, or SD. In order to qualify for responses, the following events may NOT have occurred - new/increased size of plasmacytomas or bone lesions, recurrence or persistence of hypercalcemia. Collapse of bony structure from previous disease will not constitute progression or failure to respond. Participants entered at the MTD Dose level from the phase I portion of the study will also be included in this analysis

3. Time to Response (Phase 2) [28 days]

   Efficacy of DMV as determined by time to first observed response. Participants entered at the MTD Dose level from the phase I portion of the study will also be included in this analysis

4. Progression-free Survival (Phase 2) [Up to 5 years]

   Efficacy of DMV as determined by progression free survival. Participants entered at the MTD Dose level from the phase I portion of the study will also be included in this analysis

5. Overall Survival (Phase 2) [Up to 5 years]

   Overall survival is defined as the amount of time from start of study therapy until death, or study completion. Participants entered at the MTD Dose level from the phase I portion of the study will also be included in this analysis

Eligibility Criteria

Criteria

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

Inclusion Criteria:

Disease Characteristics:

1. Patient previously diagnosed with multiple myeloma; Durie-Salmon Stage I, II, or III based on standard criteria

2. Progressive disease. For non-secretory multiple myeloma, progressive disease is defined as bone marrow biopsy with > 25% increase in plasma cells or an absolute increase of at least 10% over prior known level. Alternatively, development of new or worsening of existing lytic bone lesions or soft tissue plasmacytomas, or hypercalcemia (serum calcium >11.5 mg/dL), or relapse from complete response.

Patient Characteristics:

1. 18 yrs or older

2. Patient has given voluntary written informed consent.

3. Unless post-menopausal or surgically sterilized, a female must be willing to use an acceptable method of birth control

4. Male patient must agree to use an acceptable method for contraception for the duration of the study.

5. Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2.

6. Life expectancy is at least 3 months.

7. • Absolute Neutrophil Count (ANC) over 1,000/ul without the use of colony stimulating factors

• Platelets over 50,000/ul without transfusion support 7 days

• Bilirubin 2.0 mg/dl or less

• aspartate aminotransferase (AST) 4 times or less upper limit normal Prior Therapy for Multiple Myeloma: Patients must have had at least 2 prior therapeutic regimens

Exclusion Criteria:

• Pregnant or breast feeding

• History of allergic reaction to compounds containing boron or mannitol.

• Active uncontrolled viral (including HIV), bacterial, or fungal infection.

• Grade III or IV toxicity due to previous anti-neoplastic therapy

• More than Grade 2 motor or sensory neuropathy

• Myocardial infarction within 6 months of enrollment or New York Heart Association (NYHA) Class III or IV heart failure, uncontrolled angina, severe uncontrolled arrhythmias, or electrocardiographic evidence of acute ischemia.

• For any patients whose lifetime cumulative doxorubicin dose exceeds 400mg/m2, patients with left ventricular ejection fraction (LVEF) less than 35% by multigated acquisition (MUGA) .

• Concurrent administration of liposomal doxorubicin, melphalan, and bortezomib (single or two drug combinations of these are permissible)

• Less than 3 weeks since most recent chemotherapy or concurrent chemotherapy

• Use of corticosteroids (mroe than 10 mg prednisone/day or equivalent)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of California, San Francisco	San Francisco	California	United States	94143
2	St. Vincent's Comprehensive Cancer Center	New York	New York	United States	10011

Sponsors and Collaborators

• University of California, San Francisco

Investigators

• Principal Investigator: Thomas Martin, MD, University of California, San Francisco

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: University of California, San Francisco
• ClinicalTrials.gov Identifier: NCT00985907
• Other Study ID Numbers: 04262; NCI-2011-01238
• First Posted: Sep 29, 2009
• Last Update Posted: Jun 17, 2020
• Last Verified: Jun 1, 2020

• 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
• Product Manufactured in and Exported from the U.S.: No
• Keywords provided by University of California, San Francisco: myeloma; DMV
• Additional relevant MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell; Bortezomib; Melphalan; Liposomal doxorubicin

Study Results

Participant Flow

Pre-assignment Detail	Arms/Groups are not separated by individual cohorts within Phase 1 as information was lost when it was transferred from our legacy system. Paper records were lost in a flood, so participants were only grouped electronically by which phase they were enrolled. The study was terminated and participants were not enrolled in Phase 2 part of the study.

Arm/Group Title	Phase 1
Arm/Group Description	Doxil, melphalan, bortezomib: Doxil®: IV over 30-60 min, Day 1 q28d Melphalan: IV over 30 min, Day 1 q28d Velcade®: IV bolus, Day 1, 4, 8, 11 q28d Dose Level 1: Doxil 10 mg/m2, Melphalan 5 mg/m2, Velcade 0.7 mg/m2 Dose Level 2: Doxil 10 mg/m2, Melphalan 10 mg/m2, Velcade 0.7 mg/m2 Dose Level 3: Doxil 20 mg/m2, Melphalan 10 mg/m2, Velcade 0.7 mg/m2 Dose Level 4: Doxil 20 mg/m2, Melphalan 10 mg/m2, Velcade 1.0 mg/m2
Period Title: Overall Study
STARTED	13
COMPLETED	0
NOT COMPLETED	13

Baseline Characteristics

Arm/Group Title	Doxil® + Melphalan + Velcade (DMV)
Arm/Group Description	Doxil, melphalan, bortezomib: Doxil®: IV over 30-60 min, Day 1 q28d Melphalan: IV over 30 min, Day 1 q28d Velcade®: IV bolus, Day 1, 4, 8, 11 q28d Dose Level 1: Doxil 10 mg/m2, Melphalan 5 mg/m2, Velcade 0.7 mg/m2 Dose Level 2: Doxil 10 mg/m2, Melphalan 10 mg/m2, Velcade 0.7 mg/m2 Dose Level 3: Doxil 20 mg/m2, Melphalan 10 mg/m2, Velcade 0.7 mg/m2 Dose Level 4: Doxil 20 mg/m2, Melphalan 10 mg/m2, Velcade 1.0 mg/m2
Overall Participants	13
Age, Customized (Count of Participants)
30-39 years old	1 7.7%
40-49 years old	1 7.7%
50-59 years old	6 46.2%
60-69 years old	3 23.1%
70-79 years old	2 15.4%
Sex: Female, Male (Count of Participants)
Female	6 46.2%
Male	7 53.8%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	4 30.8%
Not Hispanic or Latino	9 69.2%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	1 7.7%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	1 7.7%
White	9 69.2%
More than one race	0 0%
Unknown or Not Reported	2 15.4%
Region of Enrollment (participants) [Number]
United States	13 100%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Dose Limiting Toxicities (DLT) (Phase 1)
Description	Safety assessments will be evaluated as the proportion of patients experiencing the following: treatment-related grade 3 or higher toxicity (hematologic and nonhematologic) and treatment-related death.
Time Frame	Up to 2 cycles of treatment, approximately 56 days

Outcome Measure Data

Analysis Population Description

Only data for Phase 1, Cohort 1 DLT was collected

Arm/Group Title	Doxil® + Melphalan + Velcade (DMV)
Arm/Group Description	Doxil, melphalan, bortezomib: Doxil®: IV over 30-60 min, Day 1 q28d Melphalan: IV over 30 min, Day 1 q28d Velcade®: IV bolus, Day 1, 4, 8, 11 q28d Dose Level 1: Doxil 10 mg/m2, Melphalan 5 mg/m2, Velcade 0.7 mg/m2 Dose Level 2: Doxil 10 mg/m2, Melphalan 10 mg/m2, Velcade 0.7 mg/m2 Dose Level 3: Doxil 20 mg/m2, Melphalan 10 mg/m2, Velcade 0.7 mg/m2 Dose Level 4: Doxil 20 mg/m2, Melphalan 10 mg/m2, Velcade 1.0 mg/m2
Measure Participants	4
Count of Participants [Participants]	0 0%

2. Primary Outcome

Title	Maximum Tolerated Dose (MTD) (Phase 1)
Description	The MTD will be considered the dose below where <= 3 patients experience a DLT and the dose that two cycles can be given without meeting toxicity criteria.
Time Frame	Up to 1 year

Outcome Measure Data

Analysis Population Description

Data not collected

Arm/Group Title	Doxil® + Melphalan + Velcade (DMV)
Arm/Group Description	Doxil, melphalan, bortezomib: Doxil®: IV over 30-60 min, Day 1 q28d Melphalan: IV over 30 min, Day 1 q28d Velcade®: IV bolus, Day 1, 4, 8, 11 q28d Dose Level 1: Doxil 10 mg/m2, Melphalan 5 mg/m2, Velcade 0.7 mg/m2 Dose Level 2: Doxil 10 mg/m2, Melphalan 10 mg/m2, Velcade 0.7 mg/m2 Dose Level 3: Doxil 20 mg/m2, Melphalan 10 mg/m2, Velcade 0.7 mg/m2 Dose Level 4: Doxil 20 mg/m2, Melphalan 10 mg/m2, Velcade 1.0 mg/m2
Measure Participants	0

3. Secondary Outcome

Title	Number of All Treatment-related Toxicities at the MTD (Phase 1)
Description	NCI Common Terminology Criteria for Adverse Events (CTCAE) version 3 will be used to determine all treatment related toxicities at the MTD. Participants entered at the MTD Dose level from the phase I portion of the study will also be included in this analysis
Time Frame	5 years

Outcome Measure Data

Analysis Population Description

Data not collected

Arm/Group Title	Doxil® + Melphalan + Velcade (DMV)
Arm/Group Description	Doxil, melphalan, bortezomib: Doxil®: IV over 30-60 min, Day 1 q28d Melphalan: IV over 30 min, Day 1 q28d Velcade®: IV bolus, Day 1, 4, 8, 11 q28d Dose Level 1: Doxil 10 mg/m2, Melphalan 5 mg/m2, Velcade 0.7 mg/m2 Dose Level 2: Doxil 10 mg/m2, Melphalan 10 mg/m2, Velcade 0.7 mg/m2 Dose Level 3: Doxil 20 mg/m2, Melphalan 10 mg/m2, Velcade 0.7 mg/m2 Dose Level 4: Doxil 20 mg/m2, Melphalan 10 mg/m2, Velcade 1.0 mg/m2
Measure Participants	0

4. Secondary Outcome

Title	Overall Response Rate
Description	At each cycle, participants will be assessed for treatment response: Complete Response (CR), Near CR(nCR), Partial Response (PR), Minimal Response (MR), Stable Disease (SD), or Progressive Disease (PD) on at least 2 measurements at minimum of a 4 week interval. The overall response rate will use the best response of CR, nCR, PR, MR, or SD. In order to qualify for responses, the following events may NOT have occurred - new/increased size of plasmacytomas or bone lesions, recurrence or persistence of hypercalcemia. Collapse of bony structure from previous disease will not constitute progression or failure to respond. Participants entered at the MTD Dose level from the phase I portion of the study will also be included in this analysis
Time Frame	Up to 5 years

Outcome Measure Data

Analysis Population Description

Data not collected

Arm/Group Title	Doxil® + Melphalan + Velcade (DMV)
Arm/Group Description	Doxil, melphalan, bortezomib: Doxil®: IV over 30-60 min, Day 1 q28d Melphalan: IV over 30 min, Day 1 q28d Velcade®: IV bolus, Day 1, 4, 8, 11 q28d Dose Level 1: Doxil 10 mg/m2, Melphalan 5 mg/m2, Velcade 0.7 mg/m2 Dose Level 2: Doxil 10 mg/m2, Melphalan 10 mg/m2, Velcade 0.7 mg/m2 Dose Level 3: Doxil 20 mg/m2, Melphalan 10 mg/m2, Velcade 0.7 mg/m2 Dose Level 4: Doxil 20 mg/m2, Melphalan 10 mg/m2, Velcade 1.0 mg/m2
Measure Participants	0

5. Secondary Outcome

Title	Time to Response (Phase 2)
Description	Efficacy of DMV as determined by time to first observed response. Participants entered at the MTD Dose level from the phase I portion of the study will also be included in this analysis
Time Frame	28 days

Outcome Measure Data

Analysis Population Description

Data not collected

Arm/Group Title	Doxil® + Melphalan + Velcade (DMV)
Arm/Group Description	Doxil, melphalan, bortezomib: Doxil®: IV over 30-60 min, Day 1 q28d Melphalan: IV over 30 min, Day 1 q28d Velcade®: IV bolus, Day 1, 4, 8, 11 q28d Dose Level 1: Doxil 10 mg/m2, Melphalan 5 mg/m2, Velcade 0.7 mg/m2 Dose Level 2: Doxil 10 mg/m2, Melphalan 10 mg/m2, Velcade 0.7 mg/m2 Dose Level 3: Doxil 20 mg/m2, Melphalan 10 mg/m2, Velcade 0.7 mg/m2 Dose Level 4: Doxil 20 mg/m2, Melphalan 10 mg/m2, Velcade 1.0 mg/m2
Measure Participants	0

6. Secondary Outcome

Title	Progression-free Survival (Phase 2)
Description	Efficacy of DMV as determined by progression free survival. Participants entered at the MTD Dose level from the phase I portion of the study will also be included in this analysis
Time Frame	Up to 5 years

Outcome Measure Data

Analysis Population Description

Data not collected

Arm/Group Title	Doxil® + Melphalan + Velcade (DMV)
Arm/Group Description	Doxil, melphalan, bortezomib: Doxil®: IV over 30-60 min, Day 1 q28d Melphalan: IV over 30 min, Day 1 q28d Velcade®: IV bolus, Day 1, 4, 8, 11 q28d Dose Level 1: Doxil 10 mg/m2, Melphalan 5 mg/m2, Velcade 0.7 mg/m2 Dose Level 2: Doxil 10 mg/m2, Melphalan 10 mg/m2, Velcade 0.7 mg/m2 Dose Level 3: Doxil 20 mg/m2, Melphalan 10 mg/m2, Velcade 0.7 mg/m2 Dose Level 4: Doxil 20 mg/m2, Melphalan 10 mg/m2, Velcade 1.0 mg/m2
Measure Participants	0

7. Secondary Outcome

Title	Overall Survival (Phase 2)
Description	Overall survival is defined as the amount of time from start of study therapy until death, or study completion. Participants entered at the MTD Dose level from the phase I portion of the study will also be included in this analysis
Time Frame	Up to 5 years

Outcome Measure Data

Analysis Population Description

Data not collected

Arm/Group Title	Doxil® + Melphalan + Velcade (DMV)
Arm/Group Description	Doxil, melphalan, bortezomib: Doxil®: IV over 30-60 min, Day 1 q28d Melphalan: IV over 30 min, Day 1 q28d Velcade®: IV bolus, Day 1, 4, 8, 11 q28d Dose Level 1: Doxil 10 mg/m2, Melphalan 5 mg/m2, Velcade 0.7 mg/m2 Dose Level 2: Doxil 10 mg/m2, Melphalan 10 mg/m2, Velcade 0.7 mg/m2 Dose Level 3: Doxil 20 mg/m2, Melphalan 10 mg/m2, Velcade 0.7 mg/m2 Dose Level 4: Doxil 20 mg/m2, Melphalan 10 mg/m2, Velcade 1.0 mg/m2
Measure Participants	0

Adverse Events

Time Frame	Up to 5 years
Adverse Event Reporting Description	Arms are not separated by individual cohorts within Phase 1 as information was lost when it was transferred from legacy system. When legacy patient data was transferred, it was decided that only mortality and serious adverse event data should be retained and transferred. Other adverse event (AE) data was not electronically transferred. Paper records were lost in a flood, so participants AE data could not be recovered. The study was terminated and participants not enrolled in Phase 2.
Arm/Group Title	Phase 1 Doxil® + Melphalan + Velcade (DMV)
Arm/Group Description	Doxil, melphalan, bortezomib: Doxil®: IV over 30-60 min, Day 1 q28d Melphalan: IV over 30 min, Day 1 q28d Velcade®: IV bolus, Day 1, 4, 8, 11 q28d Dose Level 1: Doxil 10 mg/m2, Melphalan 5 mg/m2, Velcade 0.7 mg/m2 Dose Level 2: Doxil 10 mg/m2, Melphalan 10 mg/m2, Velcade 0.7 mg/m2 Dose Level 3: Doxil 20 mg/m2, Melphalan 10 mg/m2, Velcade 0.7 mg/m2 Dose Level 4: Doxil 20 mg/m2, Melphalan 10 mg/m2, Velcade 1.0 mg/m2
All Cause Mortality
	Phase 1 Doxil® + Melphalan + Velcade (DMV)
	Affected / at Risk (%)	# Events
Total	2/13 (15.4%)
Serious Adverse Events
	Phase 1 Doxil® + Melphalan + Velcade (DMV)
	Affected / at Risk (%)	# Events
Total	6/13 (46.2%)
Hepatobiliary disorders
Cholecystitis	1/13 (7.7%)	1
Infections and infestations
Infection	1/13 (7.7%)	1
Lung Infection	1/13 (7.7%)	1
Investigations
Hyperbilirubinemia	1/13 (7.7%)	1
Musculoskeletal and connective tissue disorders
Bone Fracture	1/13 (7.7%)	1
Nervous system disorders
Neurological disorder NOS	1/13 (7.7%)	1
Vascular disorders
Hypotension	1/13 (7.7%)	1
Thrombosis	1/13 (7.7%)	1
Other (Not Including Serious) Adverse Events
	Phase 1 Doxil® + Melphalan + Velcade (DMV)
	Affected / at Risk (%)	# Events
Total	0/0 (NaN)

Limitations/Caveats

Enrollment was terminated early due to low accrual in Phase 1. No participants were enrolled in Phase 2. Participant flow, baseline, and adverse event data was electronically transferred from a legacy clinical trials database by phase group only.

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.