Trial Outcomes & Findings for Cyclophosphamide, VELCADE, DOXIL, and Dexamethasone, (CVDD) in Newly Diagnosed Patients With Multiple Myeloma (MM) (NCT NCT00750815)

Last Updated: 2014-01-20

Results Overview

Maximum Phase II planned dose of cyclophosphamide when given in combination with bortezomib, pegylated liposomal doxorubicin and Dexamethasone (CVDD) in participants with newly diagnosed active multiple myeloma. Dose levels 1, 2, 3, 4 as outlined in Treatment Arm A. If no dose limiting toxicity (DLT) was reported in the first 3 participants at a dose level, that dose level was to be considered safe and 3 participants would be enrolled at the next dose level. If 1/3 participants in a cohort at a dose level had dose limiting toxicity (DLT), the dose level would be expanded to obtain 6 evaluable participants. MPD reflects the highest dose of drug that did not cause a DLT in 33% of participants.

Recruitment status

COMPLETED

Study phase

PHASE1/PHASE2

Target enrollment

58 participants

Primary outcome timeframe

9 months

Results posted on

2014-01-20

Participant Flow

Participants were recruited at Moffitt Cancer Center from September 2008 to August 2011.

Participant milestones

Participant milestones
Measure	A. Phase I - Dose Escalation Dose of Cyclophosphamide depended on how many patients we had treated. Three participants were treated at each level: * Dose Level 1: Cyclophosphamide 250 mg /m\^2 IV Day 1; VELCADE, 1.0 mg/m\^2 IV days 1,4,8, and 11; DOXIL 30 mg/m\^2 Day 4; Dexamethasone 20 mg orally daily on days 1-2,4-5,8-9,11-12 * Dose Level 2: Cyclophosphamide 500 mg /m\^2 IV Day 1; VELCADE, 1.0 mg/m\^2 IV days 1,4,8, and 11; DOXIL 30 mg/m\^2 Day 4; Dexamethasone 20 mg orally daily on days 1-2,4-5,8-9,11-12 * Dose Level 3: Cyclophosphamide 750 mg /m\^2 IV Day 1; VELCADE, 1.0 mg/m\^2 IV days 1,4,8, and 11; DOXIL 30 mg/m\^2 Day 4; Dexamethasone 20 mg orally daily on days 1-2,4-5,8-9,11-12 * Dose Level 4: Cyclophosphamide 750 mg /m\^2 IV Day 1; VELCADE, 1.3 mg/m\^2 IV days 1,4,8, and 11; DOXIL 30 mg/m\^2 Day 4; Dexamethasone 20 mg orally daily on days 1-2,4-5,8-9,11-12	B. Phase II - Maximum Planned Dose (MPD) Participants received Cyclophosphamide and VELCADE at Level 4 (the MPD) at the same schedule of the Phase I study. Pegylated doxorubicin and Dexamethasone were given at the same doses and schedule as the Phase I part of study.
Overall Study STARTED	12	46
Overall Study COMPLETED	12	46
Overall Study NOT COMPLETED	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Cyclophosphamide, VELCADE, DOXIL, and Dexamethasone, (CVDD) in Newly Diagnosed Patients With Multiple Myeloma (MM)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	A. Phase I - Dose Escalation n=12 Participants Dose of Cyclophosphamide depended on how many patients we had treated: * Dose Level 1: Cyclophosphamide 250 mg /m\^2 IV Day 1; VELCADE, 1.0 mg/m\^2 IV days 1,4,8, and 11; DOXIL 30 mg/m\^2 Day 4; Dexamethasone 20 mg orally daily on days 1-2,4-5,8-9,11-12 * Dose Level 2: Cyclophosphamide 500 mg /m\^2 IV Day 1; VELCADE, 1.0 mg/m\^2 IV days 1,4,8, and 11; DOXIL 30 mg/m\^2 Day 4; Dexamethasone 20 mg orally daily on days 1-2,4-5,8-9,11-12 * Dose Level 3: Cyclophosphamide 750 mg /m\^2 IV Day 1; VELCADE, 1.0 mg/m\^2 IV days 1,4,8, and 11; DOXIL 30 mg/m\^2 Day 4; Dexamethasone 20 mg orally daily on days 1-2,4-5,8-9,11-12 * Dose Level 4: Cyclophosphamide 750 mg /m\^2 IV Day 1; VELCADE, 1.3 mg/m\^2 IV days 1,4,8, and 11; DOXIL 30 mg/m\^2 Day 4; Dexamethasone 20 mg orally daily on days 1-2,4-5,8-9,11-12	B. Phase II - Maximum Planned Dose (MPD) n=46 Participants Participants received Cyclophosphamide and VELCADE at the MPD at the same schedule of the Phase I study. Pegylated doxorubicin and Dexamethasone were given at the same doses and schedule as the Phase I part of study.	Total n=58 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	8 Participants n=5 Participants	34 Participants n=7 Participants	42 Participants n=5 Participants
Age, Categorical >=65 years	4 Participants n=5 Participants	12 Participants n=7 Participants	16 Participants n=5 Participants
Age, Continuous	58.75 years n=5 Participants	57 years n=7 Participants	57 years n=5 Participants
Sex: Female, Male Female	4 Participants n=5 Participants	20 Participants n=7 Participants	24 Participants n=5 Participants
Sex: Female, Male Male	8 Participants n=5 Participants	26 Participants n=7 Participants	34 Participants n=5 Participants
Region of Enrollment United States	12 participants n=5 Participants	46 participants n=7 Participants	58 participants n=5 Participants

PRIMARY outcome

Timeframe: 9 months

Population: All participants in Arm A. Three participants at each dose level.

Outcome measures

Outcome measures
Measure	A. Phase I Dose Escalation n=12 Participants Dose of Cyclophosphamide depended on how many patients we had treated. Three participants were treated at each level: * Dose Level 1: Cyclophosphamide 250 mg /m\^2 IV Day 1; VELCADE, 1.0 mg/m\^2 IV days 1,4,8, and 11; DOXIL 30 mg/m\^2 Day 4; Dexamethasone 20 mg orally daily on days 1-2,4-5,8-9,11-12 * Dose Level 2: Cyclophosphamide 500 mg /m\^2 IV Day 1; VELCADE, 1.0 mg/m\^2 IV days 1,4,8, and 11; DOXIL 30 mg/m\^2 Day 4; Dexamethasone 20 mg orally daily on days 1-2,4-5,8-9,11-12 * Dose Level 3: Cyclophosphamide 750 mg /m\^2 IV Day 1; VELCADE, 1.0 mg/m\^2 IV days 1,4,8, and 11; DOXIL 30 mg/m\^2 Day 4; Dexamethasone 20 mg orally daily on days 1-2,4-5,8-9,11-12 * Dose Level 4: Cyclophosphamide 750 mg /m\^2 IV Day 1; VELCADE, 1.3 mg/m\^2 IV days 1,4,8, and 11; DOXIL 30 mg/m\^2 Day 4; Dexamethasone 20 mg orally daily on days 1-2,4-5,8-9,11-12	Standard-Risk Myeloma Participants eligible for risk stratification with Standard-Risk Myeloma. Arm A: * Level 1: Cyclophosphamide 250 mg /m\^2 IV Day 1; VELCADE, 1.0 mg/m\^2 IV days 1,4,8, and 11; DOXIL 30 mg/m\^2 Day 4; Dexamethasone 20 mg orally daily on days 1-2,4-5,8-9,11-12 * Level 2: Cyclophosphamide 500 mg /m\^2 IV Day 1; VELCADE, 1.0 mg/m\^2 IV days 1,4,8, and 11; DOXIL 30 mg/m\^2 Day 4; Dexamethasone 20 mg orally daily on days 1-2,4-5,8-9,11-12 * Level 3: Cyclophosphamide 750 mg /m\^2 IV Day 1; VELCADE, 1.0 mg/m\^2 IV days 1,4,8, and 11; DOXIL 30 mg/m\^2 Day 4; Dexamethasone 20 mg orally daily on days 1-2,4-5,8-9,11-12 * Level 4: Cyclophosphamide 750 mg /m\^2 IV Day 1; VELCADE, 1.3 mg/m\^2 IV days 1,4,8, and 11; DOXIL 30 mg/m\^2 Day 4; Dexamethasone 20 mg orally daily on days 1-2,4-5,8-9,11-12 Arm B: Cyclophosphamide and VELCADE at Level 4 (the MPD) at the same schedule of the Phase I study. Pegylated doxorubicin and Dexamethasone were given at the same doses and schedule Arm A.
Phase I - Maximum Planned Dose (MPD) Level	4 Dosing Level	—

PRIMARY outcome

Timeframe: Up to 6 months

Population: All Participants with Partial Response, Very Good Partial Response, or Complete Response.

Best response to CVDD chemotherapy. Overall Response: Partial Response (PR) + Very Good Partial Response (VGPR) + Complete Response (CR). PR: ≥ 50% reduction of serum M-protein and reduction in 24 hour urinary M-protein by ≥ 90% or to \< 200 mg per 24 hours; VGPR: Serum and urine M-protein detectable by immunofixation but not on electrophoresis or 90% or greater reduction in serum M-protein with urine M-protein level \< 100 mg per 24 hours; CR: Negative immunofixation on the serum and urine, disappearance of any soft tissue plasmacytomas, and ≤ 5% plasma cells in bone marrow.

Outcome measures

Outcome measures
Measure	A. Phase I Dose Escalation n=54 Participants Dose of Cyclophosphamide depended on how many patients we had treated. Three participants were treated at each level: * Dose Level 1: Cyclophosphamide 250 mg /m\^2 IV Day 1; VELCADE, 1.0 mg/m\^2 IV days 1,4,8, and 11; DOXIL 30 mg/m\^2 Day 4; Dexamethasone 20 mg orally daily on days 1-2,4-5,8-9,11-12 * Dose Level 2: Cyclophosphamide 500 mg /m\^2 IV Day 1; VELCADE, 1.0 mg/m\^2 IV days 1,4,8, and 11; DOXIL 30 mg/m\^2 Day 4; Dexamethasone 20 mg orally daily on days 1-2,4-5,8-9,11-12 * Dose Level 3: Cyclophosphamide 750 mg /m\^2 IV Day 1; VELCADE, 1.0 mg/m\^2 IV days 1,4,8, and 11; DOXIL 30 mg/m\^2 Day 4; Dexamethasone 20 mg orally daily on days 1-2,4-5,8-9,11-12 * Dose Level 4: Cyclophosphamide 750 mg /m\^2 IV Day 1; VELCADE, 1.3 mg/m\^2 IV days 1,4,8, and 11; DOXIL 30 mg/m\^2 Day 4; Dexamethasone 20 mg orally daily on days 1-2,4-5,8-9,11-12	Standard-Risk Myeloma Participants eligible for risk stratification with Standard-Risk Myeloma. Arm A: * Level 1: Cyclophosphamide 250 mg /m\^2 IV Day 1; VELCADE, 1.0 mg/m\^2 IV days 1,4,8, and 11; DOXIL 30 mg/m\^2 Day 4; Dexamethasone 20 mg orally daily on days 1-2,4-5,8-9,11-12 * Level 2: Cyclophosphamide 500 mg /m\^2 IV Day 1; VELCADE, 1.0 mg/m\^2 IV days 1,4,8, and 11; DOXIL 30 mg/m\^2 Day 4; Dexamethasone 20 mg orally daily on days 1-2,4-5,8-9,11-12 * Level 3: Cyclophosphamide 750 mg /m\^2 IV Day 1; VELCADE, 1.0 mg/m\^2 IV days 1,4,8, and 11; DOXIL 30 mg/m\^2 Day 4; Dexamethasone 20 mg orally daily on days 1-2,4-5,8-9,11-12 * Level 4: Cyclophosphamide 750 mg /m\^2 IV Day 1; VELCADE, 1.3 mg/m\^2 IV days 1,4,8, and 11; DOXIL 30 mg/m\^2 Day 4; Dexamethasone 20 mg orally daily on days 1-2,4-5,8-9,11-12 Arm B: Cyclophosphamide and VELCADE at Level 4 (the MPD) at the same schedule of the Phase I study. Pegylated doxorubicin and Dexamethasone were given at the same doses and schedule Arm A.
Phase II: Overall Response Rate (ORR) Participants with Partial Response	16 participants	—
Phase II: Overall Response Rate (ORR) Participants with Very Good Partial Response	23 participants	—
Phase II: Overall Response Rate (ORR) Participants with Complete Response	15 participants	—

SECONDARY outcome

Timeframe: Up to 50.9 months

Progression-free survival after CVDD in participants with newly diagnosed active multiple myeloma. PFS: time from the initiation of therapy to progression, relapse or death from any causes. Progressive Disease (PD): Progressive Disease requires any one or more of the following: Increase of ≥ 25% from baseline in: * serum M-component and /or (the absolute increase must be ≥ 0.5 g/dL) * urine M-component and/or (the absolute increase must be ≥ 200 mg/24 h)

Outcome measures

Outcome measures
Measure	A. Phase I Dose Escalation n=58 Participants Dose of Cyclophosphamide depended on how many patients we had treated. Three participants were treated at each level: * Dose Level 1: Cyclophosphamide 250 mg /m\^2 IV Day 1; VELCADE, 1.0 mg/m\^2 IV days 1,4,8, and 11; DOXIL 30 mg/m\^2 Day 4; Dexamethasone 20 mg orally daily on days 1-2,4-5,8-9,11-12 * Dose Level 2: Cyclophosphamide 500 mg /m\^2 IV Day 1; VELCADE, 1.0 mg/m\^2 IV days 1,4,8, and 11; DOXIL 30 mg/m\^2 Day 4; Dexamethasone 20 mg orally daily on days 1-2,4-5,8-9,11-12 * Dose Level 3: Cyclophosphamide 750 mg /m\^2 IV Day 1; VELCADE, 1.0 mg/m\^2 IV days 1,4,8, and 11; DOXIL 30 mg/m\^2 Day 4; Dexamethasone 20 mg orally daily on days 1-2,4-5,8-9,11-12 * Dose Level 4: Cyclophosphamide 750 mg /m\^2 IV Day 1; VELCADE, 1.3 mg/m\^2 IV days 1,4,8, and 11; DOXIL 30 mg/m\^2 Day 4; Dexamethasone 20 mg orally daily on days 1-2,4-5,8-9,11-12	Standard-Risk Myeloma Participants eligible for risk stratification with Standard-Risk Myeloma. Arm A: * Level 1: Cyclophosphamide 250 mg /m\^2 IV Day 1; VELCADE, 1.0 mg/m\^2 IV days 1,4,8, and 11; DOXIL 30 mg/m\^2 Day 4; Dexamethasone 20 mg orally daily on days 1-2,4-5,8-9,11-12 * Level 2: Cyclophosphamide 500 mg /m\^2 IV Day 1; VELCADE, 1.0 mg/m\^2 IV days 1,4,8, and 11; DOXIL 30 mg/m\^2 Day 4; Dexamethasone 20 mg orally daily on days 1-2,4-5,8-9,11-12 * Level 3: Cyclophosphamide 750 mg /m\^2 IV Day 1; VELCADE, 1.0 mg/m\^2 IV days 1,4,8, and 11; DOXIL 30 mg/m\^2 Day 4; Dexamethasone 20 mg orally daily on days 1-2,4-5,8-9,11-12 * Level 4: Cyclophosphamide 750 mg /m\^2 IV Day 1; VELCADE, 1.3 mg/m\^2 IV days 1,4,8, and 11; DOXIL 30 mg/m\^2 Day 4; Dexamethasone 20 mg orally daily on days 1-2,4-5,8-9,11-12 Arm B: Cyclophosphamide and VELCADE at Level 4 (the MPD) at the same schedule of the Phase I study. Pegylated doxorubicin and Dexamethasone were given at the same doses and schedule Arm A.
Phase II: Progression-Free Survival (PFS)	31.3 months Interval 24.5 to Has not been reached	—

SECONDARY outcome

Timeframe: 2 years

Population: Participants with cytogenetics and fluorescence in situ hybridisation (FISH) results available for risk stratification.

Overall survival by disease risk stratification after CVDD. OS: time from initiation of therapy until death from any cause.

Outcome measures

Outcome measures
Measure	A. Phase I Dose Escalation n=12 Participants Dose of Cyclophosphamide depended on how many patients we had treated. Three participants were treated at each level: * Dose Level 1: Cyclophosphamide 250 mg /m\^2 IV Day 1; VELCADE, 1.0 mg/m\^2 IV days 1,4,8, and 11; DOXIL 30 mg/m\^2 Day 4; Dexamethasone 20 mg orally daily on days 1-2,4-5,8-9,11-12 * Dose Level 2: Cyclophosphamide 500 mg /m\^2 IV Day 1; VELCADE, 1.0 mg/m\^2 IV days 1,4,8, and 11; DOXIL 30 mg/m\^2 Day 4; Dexamethasone 20 mg orally daily on days 1-2,4-5,8-9,11-12 * Dose Level 3: Cyclophosphamide 750 mg /m\^2 IV Day 1; VELCADE, 1.0 mg/m\^2 IV days 1,4,8, and 11; DOXIL 30 mg/m\^2 Day 4; Dexamethasone 20 mg orally daily on days 1-2,4-5,8-9,11-12 * Dose Level 4: Cyclophosphamide 750 mg /m\^2 IV Day 1; VELCADE, 1.3 mg/m\^2 IV days 1,4,8, and 11; DOXIL 30 mg/m\^2 Day 4; Dexamethasone 20 mg orally daily on days 1-2,4-5,8-9,11-12	Standard-Risk Myeloma n=42 Participants Participants eligible for risk stratification with Standard-Risk Myeloma. Arm A: * Level 1: Cyclophosphamide 250 mg /m\^2 IV Day 1; VELCADE, 1.0 mg/m\^2 IV days 1,4,8, and 11; DOXIL 30 mg/m\^2 Day 4; Dexamethasone 20 mg orally daily on days 1-2,4-5,8-9,11-12 * Level 2: Cyclophosphamide 500 mg /m\^2 IV Day 1; VELCADE, 1.0 mg/m\^2 IV days 1,4,8, and 11; DOXIL 30 mg/m\^2 Day 4; Dexamethasone 20 mg orally daily on days 1-2,4-5,8-9,11-12 * Level 3: Cyclophosphamide 750 mg /m\^2 IV Day 1; VELCADE, 1.0 mg/m\^2 IV days 1,4,8, and 11; DOXIL 30 mg/m\^2 Day 4; Dexamethasone 20 mg orally daily on days 1-2,4-5,8-9,11-12 * Level 4: Cyclophosphamide 750 mg /m\^2 IV Day 1; VELCADE, 1.3 mg/m\^2 IV days 1,4,8, and 11; DOXIL 30 mg/m\^2 Day 4; Dexamethasone 20 mg orally daily on days 1-2,4-5,8-9,11-12 Arm B: Cyclophosphamide and VELCADE at Level 4 (the MPD) at the same schedule of the Phase I study. Pegylated doxorubicin and Dexamethasone were given at the same doses and schedule Arm A.
Phase II: Two Year Overall Survival (OS)	88.9 percentage of participants Interval 43.3 to 98.4	91.1 percentage of participants Interval 78.0 to 96.6

Adverse Events

Dose Level 1

Serious events: 2 serious events

Other events: 3 other events

Deaths: 0 deaths

Dose Level 2

Serious events: 1 serious events

Other events: 3 other events

Deaths: 0 deaths

Dose Level 3

Serious events: 0 serious events

Other events: 3 other events

Deaths: 0 deaths

Maximum Tolerated Dose

Serious events: 18 serious events

Other events: 48 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Melissa Alsina, M.D.

H. Lee Moffitt Cancer Center and Research Institute

Phone: 813-745-6886

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Dose Level 1 n=3 participants at risk Participants at Dose Level 1	Dose Level 2 n=3 participants at risk Participants at Dose Level 2	Dose Level 3 n=3 participants at risk Participants at Dose Level 3	Maximum Tolerated Dose n=49 participants at risk Participants at Dose Level 4
Blood and lymphatic system disorders Low Hemoglobin	0.00% 0/3 • Up to 6 months per participant	0.00% 0/3 • Up to 6 months per participant	0.00% 0/3 • Up to 6 months per participant	4.1% 2/49 • Number of events 3 • Up to 6 months per participant
Blood and lymphatic system disorders Low Leukocytes (total WBC)	0.00% 0/3 • Up to 6 months per participant	0.00% 0/3 • Up to 6 months per participant	0.00% 0/3 • Up to 6 months per participant	2.0% 1/49 • Number of events 2 • Up to 6 months per participant
Blood and lymphatic system disorders Low Neutrophils/granulocytes (ANC/AGC)	0.00% 0/3 • Up to 6 months per participant	0.00% 0/3 • Up to 6 months per participant	0.00% 0/3 • Up to 6 months per participant	4.1% 2/49 • Number of events 2 • Up to 6 months per participant
Cardiac disorders Hypotension	0.00% 0/3 • Up to 6 months per participant	0.00% 0/3 • Up to 6 months per participant	0.00% 0/3 • Up to 6 months per participant	2.0% 1/49 • Number of events 1 • Up to 6 months per participant
General disorders Fatigue (asthenia, lethargy, malaise)	0.00% 0/3 • Up to 6 months per participant	0.00% 0/3 • Up to 6 months per participant	0.00% 0/3 • Up to 6 months per participant	2.0% 1/49 • Number of events 1 • Up to 6 months per participant
General disorders Fever (in the absence of neutropenia)	0.00% 0/3 • Up to 6 months per participant	0.00% 0/3 • Up to 6 months per participant	0.00% 0/3 • Up to 6 months per participant	6.1% 3/49 • Number of events 5 • Up to 6 months per participant
Gastrointestinal disorders Constipation	0.00% 0/3 • Up to 6 months per participant	0.00% 0/3 • Up to 6 months per participant	0.00% 0/3 • Up to 6 months per participant	4.1% 2/49 • Number of events 3 • Up to 6 months per participant
Gastrointestinal disorders Dehydration	0.00% 0/3 • Up to 6 months per participant	0.00% 0/3 • Up to 6 months per participant	0.00% 0/3 • Up to 6 months per participant	6.1% 3/49 • Number of events 4 • Up to 6 months per participant
Infections and infestations Colitis, infectious (e.g., Clostridium difficile)	0.00% 0/3 • Up to 6 months per participant	0.00% 0/3 • Up to 6 months per participant	0.00% 0/3 • Up to 6 months per participant	2.0% 1/49 • Number of events 1 • Up to 6 months per participant
Infections and infestations Infection - Other	0.00% 0/3 • Up to 6 months per participant	0.00% 0/3 • Up to 6 months per participant	0.00% 0/3 • Up to 6 months per participant	6.1% 3/49 • Number of events 3 • Up to 6 months per participant
Infections and infestations Infection with normal ANC or Grade 1 or 2 neutrophils - Blood	0.00% 0/3 • Up to 6 months per participant	0.00% 0/3 • Up to 6 months per participant	0.00% 0/3 • Up to 6 months per participant	4.1% 2/49 • Number of events 2 • Up to 6 months per participant
Infections and infestations Infection with normal ANC or Grade 1 or 2 neutrophils - Lung (pneumonia)	0.00% 0/3 • Up to 6 months per participant	0.00% 0/3 • Up to 6 months per participant	0.00% 0/3 • Up to 6 months per participant	2.0% 1/49 • Number of events 1 • Up to 6 months per participant
Infections and infestations Infection with normal ANC or Grade 1 or 2 neutrophils - Urinary tract NOS	0.00% 0/3 • Up to 6 months per participant	0.00% 0/3 • Up to 6 months per participant	0.00% 0/3 • Up to 6 months per participant	2.0% 1/49 • Number of events 1 • Up to 6 months per participant
Infections and infestations Infection with normal ANC or Grade 1 or 2 neutrophils - Vulva	0.00% 0/3 • Up to 6 months per participant	0.00% 0/3 • Up to 6 months per participant	0.00% 0/3 • Up to 6 months per participant	2.0% 1/49 • Number of events 1 • Up to 6 months per participant
Infections and infestations Infection with unknown ANC - Lung (pneumonia)	0.00% 0/3 • Up to 6 months per participant	0.00% 0/3 • Up to 6 months per participant	0.00% 0/3 • Up to 6 months per participant	4.1% 2/49 • Number of events 2 • Up to 6 months per participant
Infections and infestations Infection with unknown ANC - Lymphatic	0.00% 0/3 • Up to 6 months per participant	0.00% 0/3 • Up to 6 months per participant	0.00% 0/3 • Up to 6 months per participant	2.0% 1/49 • Number of events 1 • Up to 6 months per participant
Blood and lymphatic system disorders Edema: limb	0.00% 0/3 • Up to 6 months per participant	0.00% 0/3 • Up to 6 months per participant	0.00% 0/3 • Up to 6 months per participant	4.1% 2/49 • Number of events 2 • Up to 6 months per participant
Metabolism and nutrition disorders Glucose, serum-low (hypoglycemia)	0.00% 0/3 • Up to 6 months per participant	0.00% 0/3 • Up to 6 months per participant	0.00% 0/3 • Up to 6 months per participant	4.1% 2/49 • Number of events 2 • Up to 6 months per participant
Musculoskeletal and connective tissue disorders Fracture	0.00% 0/3 • Up to 6 months per participant	33.3% 1/3 • Number of events 1 • Up to 6 months per participant	0.00% 0/3 • Up to 6 months per participant	2.0% 1/49 • Number of events 1 • Up to 6 months per participant
Psychiatric disorders Mental status	0.00% 0/3 • Up to 6 months per participant	0.00% 0/3 • Up to 6 months per participant	0.00% 0/3 • Up to 6 months per participant	2.0% 1/49 • Number of events 1 • Up to 6 months per participant
General disorders Syncope (fainting)	0.00% 0/3 • Up to 6 months per participant	0.00% 0/3 • Up to 6 months per participant	0.00% 0/3 • Up to 6 months per participant	6.1% 3/49 • Number of events 3 • Up to 6 months per participant
General disorders Pain - Other - rib cage	0.00% 0/3 • Up to 6 months per participant	0.00% 0/3 • Up to 6 months per participant	0.00% 0/3 • Up to 6 months per participant	2.0% 1/49 • Number of events 1 • Up to 6 months per participant
Respiratory, thoracic and mediastinal disorders Dyspnea (shortness of breath)	0.00% 0/3 • Up to 6 months per participant	0.00% 0/3 • Up to 6 months per participant	0.00% 0/3 • Up to 6 months per participant	2.0% 1/49 • Number of events 1 • Up to 6 months per participant
Respiratory, thoracic and mediastinal disorders Pneumonitis/pulmonary infiltrates	66.7% 2/3 • Number of events 2 • Up to 6 months per participant	0.00% 0/3 • Up to 6 months per participant	0.00% 0/3 • Up to 6 months per participant	2.0% 1/49 • Number of events 1 • Up to 6 months per participant
Respiratory, thoracic and mediastinal disorders Pulmonary/Upper Respiratory - Other	0.00% 0/3 • Up to 6 months per participant	0.00% 0/3 • Up to 6 months per participant	0.00% 0/3 • Up to 6 months per participant	2.0% 1/49 • Number of events 1 • Up to 6 months per participant
Renal and urinary disorders Renal/Genitourinary - Other	0.00% 0/3 • Up to 6 months per participant	0.00% 0/3 • Up to 6 months per participant	0.00% 0/3 • Up to 6 months per participant	2.0% 1/49 • Number of events 1 • Up to 6 months per participant
Vascular disorders Thrombosis/embolism (vascular access-related)	0.00% 0/3 • Up to 6 months per participant	0.00% 0/3 • Up to 6 months per participant	0.00% 0/3 • Up to 6 months per participant	2.0% 1/49 • Number of events 1 • Up to 6 months per participant
Vascular disorders Thrombosis/thrombus/embolism	0.00% 0/3 • Up to 6 months per participant	0.00% 0/3 • Up to 6 months per participant	0.00% 0/3 • Up to 6 months per participant	6.1% 3/49 • Number of events 3 • Up to 6 months per participant