Bortezomib, Doxorubicin Hydrochloride Liposome, and Dexamethasone Followed by Thalidomide and Dexamethasone With or Without Bortezomib in Treating Patients With Multiple Myeloma

• Sponsor: Memorial Sloan Kettering Cancer Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT00458705
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 45
• Location: 1
• Arm: 1
• Duration (Months): 53
• Patients Per Site Per Month: 0.8

Study Details

Study Description

Brief Summary

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

PURPOSE: This phase II trial is studying the side effects and how well giving bortezomib together with doxorubicin hydrochloride liposome and dexamethasone followed by thalidomide and dexamethasone with or without bortezomib works in treating patients with multiple myeloma.

Condition or Disease	Intervention/Treatment	Phase
Multiple Myeloma and Plasma Cell Neoplasm	Drug: bortezomib; Drug: dexamethasone; Drug: pegylated liposomal doxorubicin hydrochloride; Drug: thalidomide	Phase 2

Detailed Description

OBJECTIVES:

• Determine the efficacy and safety of bortezomib, pegylated doxorubicin hydrochloride liposome, and dexamethasone followed by thalidomide and dexamethasone with or without bortezomib in patients with symptomatic high-risk or primary resistant multiple myeloma.

OUTLINE: Patients receive BDD comprising bortezomib IV on days 1, 4, 8, and 11; pegylated doxorubicin hydrochloride liposome IV over 60-90 minutes on day 4; and oral dexamethasone on day 1, 2, 4, 5, 8, 9, 11, and 12. Treatment repeats every 21 days for 3 courses in the absence of disease progression or unacceptable toxicity.

Patients achieving response to BDD receive oral thalidomide on days 1-28 and oral dexamethasone on days 1-4, 9-12, and 17-20. Treatment repeats every 28 days for 2 courses in the absence of disease progression or unacceptable toxicity.

Patients experiencing stable or progressive disease on BDD receive oral thalidomide on days 1-28; oral dexamethasone on days 1, 2, 4, 5, 8, 9, 11, 12, and 17-21; and bortezomib IV on days 1, 4, 8, and 11. Treatment repeats every 28 days for 2 courses in the absence of disease progression or unacceptable toxicity.

Study Design

• Study Type: Interventional
• Actual Enrollment: 45 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Bortezomib + Pegylated Liposomal Doxorubicin (Doxil) + Dexamethasone Followed by Thalidomide + Dexamethasone or Bortezomib + Thalidomide + Dexamethasone for Patients With Symptomatic Untreated High-Risk or Primary Resistant Multiple Myeloma
• Study Start Date: Nov 1, 2006
• Actual Primary Completion Date: Apr 1, 2011
• Actual Study Completion Date: Apr 1, 2011

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Combination therapy Combination therapy with bortezomib, pegylated liposomal doxorubicin and dexamethasone (BDD) followed by either thalidomide and dexamethasone (TD) or bortezomib, thalidomide and dexamethasone in patients with symptomatic untreated high-risk or primary resistant multiple myeloma. Three cycles of BDD will be administered. Patients who respond after three cycles will receive two cycles of TD. Patients with stable or progressive disease after three cycles of BDD receive two cycles of bortezomib, thalidomide and dexamethasone. If at any point during the study a patient achieves a complete response (CR), the patient will be given the option to discontinue treatment on-study.

Drug: bortezomib; Drug: dexamethasone; Drug: pegylated liposomal doxorubicin hydrochloride; Drug: thalidomide

Outcome Measures

Primary Outcome Measures

1. Disease Response [2 years]

   The response of myeloma to BDDTD will be assessed by standard electrophoretic and immunofixation tests of blood and urine for a monoclonal protein (M protein), and bone marrow aspirate and biopsy. These tests will be performed at enrollment and at the conclusion of therapy.

Eligibility Criteria

Criteria

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

DISEASE CHARACTERISTICS:

• Histologically and serologically confirmed multiple myeloma meeting one of the following criteria:

• High-risk myeloma, defined as symptomatic International Staging System (ISS) stage 2 or 3 multiple myeloma

• Soft-tissue involvement with myeloma in the form of a soft-tissue plasmacytoma

• Extension of a plasmacytoma into soft tissues

• Primary resistant myeloma, defined as unchanged or progressive myeloma despite two courses of standard treatment

• No ISS stage 1 multiple myeloma without soft-tissue involvement

• No smoldering myeloma

PATIENT CHARACTERISTICS:

• ECOG performance status 0-3

• Life expectancy > 16 weeks

• Absolute granulocyte count ≥ 1,500/mm³ (unless low granulocyte counts are due to multiple myeloma)

• Platelet count ≥ 100,000/mm³ (unless low platelet counts are due to multiple myeloma)

• Bilirubin ≤ 2.0 mg/dL

• AST and ALT < 3 times upper limit of normal (ULN)

• Alkaline phosphatase < 3 times ULN

• LVEF ≥ 50% by MUGA or ECHO

• Not pregnant or nursing

• Negative pregnancy test

• Fertile patients must use effective barrier contraception 4 months prior to, during, and for 4 weeks after completion of study treatment

• No active thromboembolic disease on anticoagulation

• No active angina or myocardial infarction within the past 6 months

• No pre-existing neuropathy or sensory or neuropathic pain ≥ grade 2

• No concurrent active malignancy other than nonmelanoma skin cancer or carcinoma in situ of the cervix

• Prior malignancies that have not required antitumor treatment within the past 24 months allowed

• Patients with a history of stage I or II (T1a/b) prostate cancer (detected incidentally at transurethral resection of prostate [TURP] and comprising < 5% of resected tissue) allowed if the prostate-specific antigen has remained normal since TURP

• No known HIV positivity or AIDS-related illness

• No other medical condition or reason that, in the opinion of the investigator, would preclude study compliance

• No history of hypersensitivity reactions attributed to a conventional formulation of doxorubicin hydrochloride or to components of pegylated doxorubicin hydrochloride liposome, bortezomib, boron, or mannitol

PRIOR CONCURRENT THERAPY:

• Prior radiotherapy allowed

• No more than 2 courses of prior initial chemotherapy for multiple myeloma

• No prior bortezomib

• No prior high-dose steroids (not including taper) for more than 1 month in duration for emergent indications, such as hypercalcemia or life-threatening lesions (e.g., spinal cord compromise) (in high-risk patients)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Memorial Sloan-Kettering Cancer Center	New York	New York	United States	10065

Sponsors and Collaborators

• Memorial Sloan Kettering Cancer Center
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Heather Landau, MD, Memorial Sloan Kettering Cancer Center

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Memorial Sloan Kettering Cancer Center
• ClinicalTrials.gov Identifier: NCT00458705
• Other Study ID Numbers: 06-067; P30CA008748; MSKCC-06067
• First Posted: Apr 11, 2007
• Last Update Posted: Jan 22, 2016
• Last Verified: Dec 1, 2015

• Keywords provided by Memorial Sloan Kettering Cancer Center: stage I multiple myeloma; stage II multiple myeloma; stage III multiple myeloma; refractory multiple myeloma
• Additional relevant MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell; Plasmacytoma; Thalidomide; Dexamethasone; Doxorubicin; Liposomal doxorubicin; Bortezomib

Study Results

Participant Flow

Arm/Group Title	Combination Therapy
Arm/Group Description	Combination therapy with bortezomib, pegylated liposomal doxorubicin and dexamethasone (BDD) followed by either thalidomide and dexamethasone (TD) or bortezomib, thalidomide and dexamethasone in patients with symptomatic untreated high-risk or primary resistant multiple myeloma. Three cycles of BDD will be administered. Patients who respond after three cycles will receive two cycles of TD. Patients with stable or progressive disease after three cycles of BDD receive two cycles of bortezomib, thalidomide and dexamethasone. If at any point during the study a patient achieves a complete response (CR), the patient will be given the option to discontinue treatment on-study.
Period Title: Overall Study
STARTED	45
COMPLETED	40
NOT COMPLETED	5

Baseline Characteristics

Arm/Group Title	Combination Therapy
Arm/Group Description	Combination therapy with bortezomib, pegylated liposomal doxorubicin and dexamethasone (BDD) followed by either thalidomide and dexamethasone (TD) or bortezomib, thalidomide and dexamethasone in patients with symptomatic untreated high-risk or primary resistant multiple myeloma. Three cycles of BDD will be administered. Patients who respond after three cycles will receive two cycles of TD. Patients with stable or progressive disease after three cycles of BDD receive two cycles of bortezomib, thalidomide and dexamethasone. If at any point during the study a patient achieves a complete response (CR), the patient will be given the option to discontinue treatment on-study.
Overall Participants	45
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	35 77.8%
>=65 years	10 22.2%
Sex: Female, Male (Count of Participants)
Female	15 33.3%
Male	30 66.7%
Region of Enrollment (participants) [Number]
United States	45 100%

Outcome Measures

1. Primary Outcome

Title	Disease Response
Description	The response of myeloma to BDDTD will be assessed by standard electrophoretic and immunofixation tests of blood and urine for a monoclonal protein (M protein), and bone marrow aspirate and biopsy. These tests will be performed at enrollment and at the conclusion of therapy.
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Combination Therapy
Arm/Group Description	Combination therapy with bortezomib, pegylated liposomal doxorubicin and dexamethasone (BDD) followed by either thalidomide and dexamethasone (TD) or bortezomib, thalidomide and dexamethasone in patients with symptomatic untreated high-risk or primary resistant multiple myeloma. Three cycles of BDD will be administered. Patients who respond after three cycles will receive two cycles of TD. Patients with stable or progressive disease after three cycles of BDD receive two cycles of bortezomib, thalidomide and dexamethasone. If at any point during the study a patient achieves a complete response (CR), the patient will be given the option to discontinue treatment on-study.
Measure Participants	40
Complete Response	10 22.2%
Near Complete Response	8 17.8%
Partial Response	10 22.2%
Stable Disease	2 4.4%
Progression of Disease	3 6.7%
Very Good Partial Response	7 15.6%

Adverse Events

Arm/Group Title	Combination Therapy
Arm/Group Description	Combination therapy with bortezomib, pegylated liposomal doxorubicin and dexamethasone (BDD) followed by either thalidomide and dexamethasone (TD) or bortezomib, thalidomide and dexamethasone in patients with symptomatic untreated high-risk or primary resistant multiple myeloma. Three cycles of BDD will be administered. Patients who respond after three cycles will receive two cycles of TD. Patients with stable or progressive disease after three cycles of BDD receive two cycles of bortezomib, thalidomide and dexamethasone. If at any point during the study a patient achieves a complete response (CR), the patient will be given the option to discontinue treatment on-study.
All Cause Mortality
	Combination Therapy
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Combination Therapy
	Affected / at Risk (%)	# Events
Total	22/45 (48.9%)
Cardiac disorders
Atrial fibrillation	1/45 (2.2%)	1
Gastrointestinal disorders
Constipation	2/45 (4.4%)	2
Diarrhea	2/45 (4.4%)	2
Lower gastrointestinal hemorrhage	1/45 (2.2%)	1
Abdominal pain	1/45 (2.2%)	1
General disorders
Death not assoc w CTCAE term- Multi-organ failure	1/45 (2.2%)	1
Fever	1/45 (2.2%)	1
Hepatobiliary disorders
Hepatobiliary disorders -other, specify	1/45 (2.2%)	1
Hepatic failure	1/45 (2.2%)	1
Infections and infestations
Sepsis	1/45 (2.2%)	1
Infection	3/45 (6.7%)	3
Investigations
Creatinine increased	1/45 (2.2%)	1
Lymphocyte count decrease	1/45 (2.2%)	1
Metabolism and nutrition disorders
Acidosis	1/45 (2.2%)	1
Hypocalcemia	1/45 (2.2%)	1
Dehydration	1/45 (2.2%)	1
Hyperglycemia	3/45 (6.7%)	3
Hyperkalemia	1/45 (2.2%)	1
Hyponatremia	1/45 (2.2%)	1
Musculoskeletal and connective tissue disorders
Back pain	2/45 (4.4%)	2
Nervous system disorders
Peripheral sensory neuropathy	1/45 (2.2%)	1
Neuralgia	1/45 (2.2%)	1
Vasovagal reaction	1/45 (2.2%)	1
Renal and urinary disorders
Renal and urinary disorders -other, specify, Renal failure	5/45 (11.1%)	5
Urinary retention	1/45 (2.2%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnea	3/45 (6.7%)	5
Hypoxia	1/45 (2.2%)	1
Pneumonia	3/45 (6.7%)	3
Pleural effusion	1/45 (2.2%)	1
Respiratory, thoracic and mediastinal disorders-other, specify	1/45 (2.2%)	1
Vascular disorders
Hypotension	1/45 (2.2%)	1
Thrombosis/thrombus/embolism	6/45 (13.3%)	7
Other (Not Including Serious) Adverse Events
	Combination Therapy
	Affected / at Risk (%)	# Events
Total	23/45 (51.1%)
Gastrointestinal disorders
Constipation	5/45 (11.1%)	5
Diarrhea	4/45 (8.9%)	4
Musculoskeletal and connective tissue disorders
Back pain	3/45 (6.7%)	3
Nervous system disorders
Peripheral sensory neuropathy	4/45 (8.9%)	6
Neuralgia	4/45 (8.9%)	6
Renal and urinary disorders
Renal and urinary disorders -other, specify-Renal failure	4/45 (8.9%)	4
Respiratory, thoracic and mediastinal disorders
Pneumonia	3/45 (6.7%)	3
Vascular disorders
Thrombosis/thrombus/embolism	8/45 (17.8%)	11

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.