Safety Study of Elotuzumab in Combination With Thalidomide and Dexamethasone in Relapsed and/or Refractory Multiple Myeloma

• Sponsor: Bristol-Myers Squibb (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01632150
• Collaborator: AbbVie (Industry)
• Enrollment: 51
• Locations: 10
• Arm: 1
• Duration (Months): 46
• Patients Per Site: 5.1
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purpose of this study is to determine the safety and tolerability of elotuzumab administered in combination with thalidomide and dexamethasone in the treatment of relapsed and/or refractory multiple myeloma.

Condition or Disease	Intervention/Treatment	Phase
Relapsed and/or Refractory Multiple Myeloma	Biological: Elotuzumab; Biological: Thalidomide; Biological: Dexamethasone; Biological: Cyclophosphamide	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 51 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase 2a Single-Arm Safety Study of Elotuzumab in Combination With Thalidomide and Dexamethasone in Subjects With Relapsed and/or Refractory Multiple Myeloma
• Study Start Date: May 1, 2012
• Actual Primary Completion Date: Oct 1, 2013
• Actual Study Completion Date: Mar 1, 2016

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Elotuzumab + Thalidomide + Dexamethasone + Cyclophosphamide

Biological: Elotuzumab; Powder for solution, 400-mg vials, for infusion; Other Names: BMS-901608 HuLuc63 ; Biological: Thalidomide; 50-mg capsules administered orally; Other Names: Thalomid® ; Biological: Dexamethasone; 2- and 4-mg tablets (and various other strengths, as needed) administered orally and in 4- and 8-mg/mL (and various other strengths, as needed) solutions for intravenous administration; Other Names: Decadron® Dexamethasone Intensol® Dexpak® Taperpak® ; Biological: Cyclophosphamide; 50-mg tablets administered orally; Other Names: Cytoxan Endoxan Neosar

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants Who Received Treatment Including Cyclophosphamide and Had Grade 3 or Higher Nonhematologic Adverse Events (AEs) [From the first dose of study drug until the last dose of treatment, including cyclophosphamide treatment]

   AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Treatment-related=having certain, probable, possible, or unknown relationship to study drug. Grade (Gr) 1=Mild, Gr 2=Moderate, Gr 3=Severe, Gr 4=Life-threatening or disabling, Gr 5=Death.

2. Percentage of All Participants Who Received Treatment Without Cyclophosphamide and Had Grade 3 or Higher Nonhematologic Adverse Events (AEs) [From the first dose of study drug until the earlier of discontinuation from E-Td or the time when cyclophosphamide was initiated]

   AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Treatment-related=having certain, probable, possible, or unknown relationship to study drug. Grade (Gr) 1=Mild, Gr 2=Moderate, Gr 3=Severe, Gr 4=Life-threatening or disabling, Gr 5=Death.

Secondary Outcome Measures

1. Percentage of All Participants Who Received Treatment Including Cyclophosphamide and Had 1 Dose Reduction or Discontinued Due to an Adverse Event [From the first dose of study drug until the last dose of treatment, including cyclophosphamide treatment]

   Elotuzumab dose reduction was not permitted. Thalidomide dose reduction, delay, interruptions, or discontinuation was permitted in the event of toxicity. Dexamethasone dose reduction was also permitted in the event of toxicity and in the setting of infusion reactions;dose delays were allowed as clinically indicated at the discretion of the investigator. Cyclophosphamide dose reduction, delay, interruption, or discontinuation was permitted in the event of toxicity.

2. Percentage of All Participants Who Received Treatment Without Cyclophosphamide and Had 1 Dose Reduction or Discontinued Due to an Adverse Event [From the first dose of study drug until the earlier of discontinuation from E-Td or the time when cyclophosphamide was initiated]

   Elotuzumab dose reduction was not permitted. Thalidomide dose reduction, delay, interruptions, or discontinuation was permitted in the event of toxicity. Dexamethasone dose reduction was also permitted in the event of toxicity and in the setting of infusion reactions;dose delays were allowed as clinically indicated at the discretion of the investigator.

Eligibility Criteria

Criteria

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

For more information regarding BMS clinical trial participation, please visit www.BMSStudyConnect.com.

Key Inclusion Criteria:

• Confirmed diagnosis of previously treated multiple myeloma with progression documented by criteria of the International Myeloma Working Group after or during the most recent therapy

• Patient received 5 or fewer prior lines of therapy

• Eastern Cooperative Oncology Group performance status of 0 or 1 (safety lead-in cohort) or 0 to 2 (additional patients)

• Measurable disease as defined by at least 1 of the following:

• Serum immunoglobulin (Ig)G, IgA, IgM, or monoclonal (M) protein level ≥0.5 g/dL or serum IgD M protein level ≥0.05 g/dL; or

• Urine M protein level ≥200 mg excreted in a 24-hour collection sample; or

• Involved serum free light chain level ≥10 mg/dL, provided the free light chain ratio is abnormal

Key Exclusion Criteria:

• Solitary bone or solitary extramedullary plasmacytoma as the only evidence of plasma cell dyscrasia

• Monoclonal gammopathy of undetermined significance, smoldering myeloma, or Waldenström's macroglobulinemia

• Left ventricular ejection fraction by echocardiogram or Multi Gated Acquisition ≤50%

• Electrocardiogram finding of QTc ≥450 msec

• Active plasma cell leukemia (defined as either 20% of peripheral white blood cells, composed of plasma/CD138+ cells or an absolute plasma cell count of 2*10^9/L)

• Diagnosis of nonsecretory myeloma

• Active hepatitis A, B, or C virus infection

• Grade ≥2 neuropathy

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Local Institution	Barcelona		Spain	08035
2	Local Institution	Barcelona		Spain	08036
3	Local Institution	Barcelona		Spain	08041
4	Local Institution	Barcelona		Spain	08916
5	Local Institution	LaLaguna, S Cruz Tener		Spain	38320
6	Local Institution	Madrid		Spain	28034
7	Local Institution	Madrid		Spain	28041
8	Local Institution	Salamanca		Spain	37007
9	Local Institution	Sevilla		Spain	41013
10	Local Institution	Zaragoza		Spain	50009

Sponsors and Collaborators

• Bristol-Myers Squibb
• AbbVie

Investigators

• Study Director: Bristol-Myers Squibb, Bristol-Myers Squibb

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• BMS clinical trial educational resource
• BMS Clinical Trial Patient Recruiting

Publications

None provided.

• Responsible Party: Bristol-Myers Squibb
• ClinicalTrials.gov Identifier: NCT01632150
• Other Study ID Numbers: CA204-010; 2011-005121-49
• First Posted: Jul 2, 2012
• Last Update Posted: Apr 14, 2017
• Last Verified: Mar 1, 2017

• Additional relevant MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell; Thalidomide; Dexamethasone; Dexamethasone acetate; Cyclophosphamide; Elotuzumab; BB 1101

Study Results

Participant Flow

Pre-assignment Detail	Of 51 participants enrolled, 40 received treatment. Of those 40, 11 had cyclophosphamide added to their regimens.

Arm/Group Title	Thalidomide + Elotuzumab + Dexamethasone + Cyclophosphamide
Arm/Group Description	Participants received thalidomide in 28-day cycles: 50 mg, for the first 2 weeks, escalated to 100 mg for the next 2 weeks and beginning with Cycle 2, to 200 mg once daily. Elotuzumab, 10 mg/kg, was administered as an intravenous infusion weekly for the first 2 cycles and beginning with Cycle 3, every 2 weeks. Dexamethasone, 40 mg, was administered weekly on those weeks when elotuzumab was not administered. On weeks when elotuzumab was also given, participants received dexamethasone as a split dose of 28 mg, 3 to 24 hours before the elotuzumab infusion, and 8 mg intravenously at least 45 minutes before the infusion. Those patients with suboptimal response, defined as evidence of progressive disease between end of Cycle 2 and end of Cycle 4 or inability to achieve partial response or better by end of Cycle 4, also received cyclophosphamide, 50 mg. Cyclophosphamide could not be added beyond Cycle 5.
Period Title: Overall Study
STARTED	40
Received Cyclophosphamide	11
COMPLETED	0
NOT COMPLETED	40

Baseline Characteristics

Arm/Group Title	Thalidomide + Elotuzumab + Dexamethasone + Cyclophosphamide
Arm/Group Description	Participants received thalidomide in 28-day cycles: 50 mg, for the first 2 weeks, escalated to 100 mg for the next 2 weeks and beginning with Cycle 2, to 200 mg once daily. Elotuzumab, 10 mg/kg, was administered as an intravenous infusion weekly for the first 2 cycles and beginning with Cycle 3, every 2 weeks. Dexamethasone, 40 mg, was administered weekly on those weeks when elotuzumab was not administered. On weeks when elotuzumab was also given, participants received dexamethasone as a split dose of 28 mg, 3 to 24 hours before the elotuzumab infusion, and 8 mg intravenously at least 45 minutes before the infusion. Those patients with suboptimal response, defined as evidence of progressive disease between end of Cycle 2 and end of Cycle 4 or inability to achieve partial response or better by end of Cycle 4, also received cyclophosphamide, 50 mg. Cyclophosphamide could not be added beyond Cycle 5.
Overall Participants	40
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	64.3 (8.47)
Age, Customized (Number) [Number]
Younger than 65 years	22 55%
65 years and older to younger than 75 years	12 30%
75 years and older	6 15%
Sex: Female, Male (Count of Participants)
Female	15 37.5%
Male	25 62.5%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	40 100%
More than one race	0 0%
Unknown or Not Reported	0 0%
Myeloma type (Number) [Number]
Immunoglobulin (Ig)G	15 37.5%
IGA	7 17.5%
IGM	0 0%
IGD	0 0%
Light chain disease	9 22.5%
Not reported	9 22.5%
Eastern Cooperative Oncology Group (ECOG) performance status (Number) [Number]
Score 0	17 42.5%
Score 1	21 52.5%
Score 2	2 5%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants Who Received Treatment Including Cyclophosphamide and Had Grade 3 or Higher Nonhematologic Adverse Events (AEs)
Description	AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Treatment-related=having certain, probable, possible, or unknown relationship to study drug. Grade (Gr) 1=Mild, Gr 2=Moderate, Gr 3=Severe, Gr 4=Life-threatening or disabling, Gr 5=Death.
Time Frame	From the first dose of study drug until the last dose of treatment, including cyclophosphamide treatment

Outcome Measure Data

Analysis Population Description

All participants who received thalidomide, elotuzumab, and dexamethasone (40) including those who had cyclophosphamide added to the regimen (11).

Arm/Group Title	Thalidomide + Elotuzumab + Dexamethasone + Cyclophosphamide
Arm/Group Description	Participants received thalidomide in 28-day cycles: 50 mg, for the first 2 weeks, escalated to 100 mg for the next 2 weeks and beginning with Cycle 2, to 200 mg once daily. Elotuzumab, 10 mg/kg, was administered as an intravenous infusion weekly for the first 2 cycles and beginning with Cycle 3, every 2 weeks. Dexamethasone, 40 mg, was administered weekly on those weeks when elotuzumab was not administered. On weeks when elotuzumab was also given, participants received dexamethasone as a split dose of 28 mg, 3 to 24 hours before the elotuzumab infusion, and 8 mg intravenously at least 45 minutes before the infusion. Those patients with suboptimal response, defined as evidence of progressive disease between end of Cycle 2 and end of Cycle 4 or inability to achieve partial response or better by end of Cycle 4, also received cyclophosphamide, 50 mg. Cyclophosphamide could not be added beyond Cycle 5.
Measure Participants	40
Number (90% Confidence Interval) [Percentage of participants]	62.5 156.3%

2. Secondary Outcome

Title	Percentage of All Participants Who Received Treatment Including Cyclophosphamide and Had 1 Dose Reduction or Discontinued Due to an Adverse Event
Description	Elotuzumab dose reduction was not permitted. Thalidomide dose reduction, delay, interruptions, or discontinuation was permitted in the event of toxicity. Dexamethasone dose reduction was also permitted in the event of toxicity and in the setting of infusion reactions;dose delays were allowed as clinically indicated at the discretion of the investigator. Cyclophosphamide dose reduction, delay, interruption, or discontinuation was permitted in the event of toxicity.
Time Frame	From the first dose of study drug until the last dose of treatment, including cyclophosphamide treatment

Outcome Measure Data

Analysis Population Description

All participants who received thalidomide, elotuzumab, and dexamethasone (40), including those who had cyclophosphamide added to the regimen (11).

Arm/Group Title	Thalidomide + Elotuzumab + Dexamethasone + Cyclophosphamide
Arm/Group Description	Participants received thalidomide in 28-day cycles: 50 mg, for the first 2 weeks, escalated to 100 mg for the next 2 weeks, then beginning with Cycle 2, to 200 mg once daily. Elotuzumab, 10 mg/kg, was administered as an intravenous infusion weekly for the first 2 cycles, then beginning with Cycle 3, every 2 weeks. Dexamethasone, 40 mg, was administered weekly on those weeks when elotuzumab was not administered. On weeks when elotuzumab was also given, participants received dexamethasone as a split dose of 28 mg, 3 to 24 hours before the elotuzumab infusion, and 8 mg intravenously at least 45 minutes before the infusion. Those patients with suboptimal response, defined as evidence of progressive disease between end of Cycle 2 and end of Cycle 4 or inability to achieve partial response or better by end of Cycle 4, also received cyclophosphamide, 50 mg. Cyclophosphamide could not be added beyond Cycle 5.
Measure Participants	40
Number (95% Confidence Interval) [Percentage of participants]	65.0 162.5%

3. Primary Outcome

Title	Percentage of All Participants Who Received Treatment Without Cyclophosphamide and Had Grade 3 or Higher Nonhematologic Adverse Events (AEs)
Description	AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Treatment-related=having certain, probable, possible, or unknown relationship to study drug. Grade (Gr) 1=Mild, Gr 2=Moderate, Gr 3=Severe, Gr 4=Life-threatening or disabling, Gr 5=Death.
Time Frame	From the first dose of study drug until the earlier of discontinuation from E-Td or the time when cyclophosphamide was initiated

Outcome Measure Data

Analysis Population Description

All participants who received thalidomide + elotuzumab + dexamethasone regimen, from first dose of study drug until discontinuation or until cyclophosphamide was initiated, whichever came first.

Arm/Group Title	Thalidomide + Elotuzumab + Dexamethasone
Arm/Group Description	Participants received thalidomide in 28-day cycles: 50 mg, for the first 2 weeks, escalated to 100 mg for the next 2 weeks and beginning with Cycle 2, to 200 mg once daily. Elotuzumab, 10 mg/kg, was administered as an intravenous infusion weekly for the first 2 cycles, then beginning with Cycle 3, every 2 weeks. Dexamethasone, 40 mg, was administered weekly on those weeks when elotuzumab was not administered. On weeks when elotuzumab was also given, participants received dexamethasone as a split dose of 28 mg, 3 to 24 hours before the elotuzumab infusion, and 8 mg intravenously at least 45 minutes before the infusion.
Measure Participants	40
Number (90% Confidence Interval) [Percentage of participants]	55.0 137.5%

4. Secondary Outcome

Title	Percentage of All Participants Who Received Treatment Without Cyclophosphamide and Had 1 Dose Reduction or Discontinued Due to an Adverse Event
Description	Elotuzumab dose reduction was not permitted. Thalidomide dose reduction, delay, interruptions, or discontinuation was permitted in the event of toxicity. Dexamethasone dose reduction was also permitted in the event of toxicity and in the setting of infusion reactions;dose delays were allowed as clinically indicated at the discretion of the investigator.
Time Frame	From the first dose of study drug until the earlier of discontinuation from E-Td or the time when cyclophosphamide was initiated

Outcome Measure Data

Analysis Population Description

All participants who received thalidomide + elotuzumab + dexamethasone regimen, from first dose of study drug until discontinuation or until cyclophosphamide was initiated, whichever came first.

Arm/Group Title	Thalidomide + Elotuzumab + Dexamethasone
Arm/Group Description	Participants received thalidomide in 28-day cycles: 50 mg, for the first 2 weeks, escalated to 100 mg for the next 2 weeks, then beginning with Cycle 2, to 200 mg once daily. Elotuzumab, 10 mg/kg, was administered as an intravenous infusion weekly for the first 2 cycles, then beginning with Cycle 3, every 2 weeks. Dexamethasone, 40 mg, was administered weekly on those weeks when elotuzumab was not administered. On weeks when elotuzumab was also given, participants received dexamethasone as a split dose of 28 mg, 3 to 24 hours before the elotuzumab infusion, and 8 mg intravenously at least 45 minutes before the infusion.
Measure Participants	40
Number (95% Confidence Interval) [Percentage of participants]	57.5 143.8%

Adverse Events

Time Frame	From date of first dose to 60 days post last dose
Arm/Group Title	All Treated Subjects
Arm/Group Description
All Cause Mortality
	All Treated Subjects
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	All Treated Subjects
	Affected / at Risk (%)	# Events
Total	23/40 (57.5%)
Cardiac disorders
Cardio-respiratory arrest	1/40 (2.5%)
Myocarditis	1/40 (2.5%)
Gastrointestinal disorders
Pancreatitis	1/40 (2.5%)
General disorders
Cardiac death	1/40 (2.5%)
Disease progression	1/40 (2.5%)
Sudden death	1/40 (2.5%)
Infections and infestations
Aspergillus infection	1/40 (2.5%)
Bronchopulmonary aspergillosis	1/40 (2.5%)
Cellulitis	1/40 (2.5%)
Herpes zoster	2/40 (5%)
Lung infection	1/40 (2.5%)
Pneumonia	2/40 (5%)
Respiratory tract infection	4/40 (10%)
Septic shock	3/40 (7.5%)
Upper respiratory tract infection	1/40 (2.5%)
Injury, poisoning and procedural complications
Femur fracture	1/40 (2.5%)
Spinal fracture	1/40 (2.5%)
Investigations
Aspiration bronchial	1/40 (2.5%)
Musculoskeletal and connective tissue disorders
Back pain	1/40 (2.5%)
Spinal pain	1/40 (2.5%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Malignant neoplasm progression	2/40 (5%)
Plasma cell myeloma	2/40 (5%)
Nervous system disorders
Spinal cord compression	1/40 (2.5%)
Psychiatric disorders
Confusional state	2/40 (5%)
Renal and urinary disorders
Acute kidney injury	1/40 (2.5%)
Renal failure	1/40 (2.5%)
Respiratory, thoracic and mediastinal disorders
Epistaxis	1/40 (2.5%)
Pneumonitis	2/40 (5%)
Pulmonary embolism	1/40 (2.5%)
Pulmonary oedema	1/40 (2.5%)
Respiratory failure	1/40 (2.5%)
Vascular disorders
Hypertension	1/40 (2.5%)
Other (Not Including Serious) Adverse Events
	All Treated Subjects
	Affected / at Risk (%)	# Events
Total	39/40 (97.5%)
Blood and lymphatic system disorders
Anaemia	15/40 (37.5%)
Neutropenia	6/40 (15%)
Thrombocytopenia	9/40 (22.5%)
Eye disorders
Diplopia	2/40 (5%)
Vision blurred	2/40 (5%)
Gastrointestinal disorders
Abdominal distension	2/40 (5%)
Abdominal pain	2/40 (5%)
Constipation	8/40 (20%)
Diarrhoea	3/40 (7.5%)
Dysphagia	2/40 (5%)
Nausea	2/40 (5%)
Vomiting	2/40 (5%)
General disorders
Asthenia	17/40 (42.5%)
Chest pain	2/40 (5%)
Chills	2/40 (5%)
Crepitations	2/40 (5%)
Fatigue	3/40 (7.5%)
Gait disturbance	2/40 (5%)
Oedema peripheral	12/40 (30%)
Pain	3/40 (7.5%)
Pyrexia	13/40 (32.5%)
Infections and infestations
Gastroenteritis	2/40 (5%)
Herpes zoster	3/40 (7.5%)
Influenza	4/40 (10%)
Lower respiratory tract infection	2/40 (5%)
Nasopharyngitis	5/40 (12.5%)
Respiratory tract infection	9/40 (22.5%)
Upper respiratory tract infection	5/40 (12.5%)
Investigations
Blood creatinine increased	3/40 (7.5%)
Blood glucose increased	2/40 (5%)
Laboratory test abnormal	2/40 (5%)
Weight decreased	3/40 (7.5%)
Metabolism and nutrition disorders
Decreased appetite	4/40 (10%)
Hyperglycaemia	8/40 (20%)
Iron deficiency	2/40 (5%)
Musculoskeletal and connective tissue disorders
Arthralgia	2/40 (5%)
Back pain	12/40 (30%)
Bone pain	5/40 (12.5%)
Muscle spasms	2/40 (5%)
Muscular weakness	2/40 (5%)
Musculoskeletal chest pain	2/40 (5%)
Myalgia	2/40 (5%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Plasmacytoma	2/40 (5%)
Nervous system disorders
Dizziness	7/40 (17.5%)
Neuropathy peripheral	11/40 (27.5%)
Paraesthesia	5/40 (12.5%)
Somnolence	4/40 (10%)
Tremor	5/40 (12.5%)
Psychiatric disorders
Anxiety	5/40 (12.5%)
Confusional state	2/40 (5%)
Respiratory, thoracic and mediastinal disorders
Catarrh	2/40 (5%)
Cough	9/40 (22.5%)
Dyspnoea	5/40 (12.5%)
Productive cough	2/40 (5%)
Vascular disorders
Deep vein thrombosis	4/40 (10%)
Hypertension	4/40 (10%)
Hypotension	2/40 (5%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

Bristol-Myers Squibb Co. agreements with investigators vary; constant is our right to embargo communications regarding trial results prior to public release for a period ≤60 days from submittal for review. We will not prohibit investigators from publishing, but will prohibit the disclosure of previously undisclosed confidential information other than study results, and request postponement of single-center publications until after disclosure of the clinical trial's primary publication.