Phase 2 Study of Carfilzomib in Relapsed and Refractory Multiple Myeloma

• Sponsor: Amgen (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00511238
• Collaborator: (none)
• Enrollment: 312
• Locations: 34
• Arms: 2
• Duration (Months): 62
• Patients Per Site: 9.2
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

To evaluate the overall response rate and safety and tolerability of carfilzomib in subjects with relapsed and refractory multiple myeloma.

Patients must have received prior treatment with bortezomib and either thalidomide or lenalidomide and be refractory to their last treatment.

Condition or Disease	Intervention/Treatment	Phase
Multiple Myeloma	Drug: carfilzomib; Drug: carfilzomib	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 312 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-label, Single-arm, Phase 2 Study of Carfilzomib in Patients With Relapsed and Refractory Multiple Myeloma
• Study Start Date: Aug 1, 2007
• Actual Primary Completion Date: Nov 1, 2010
• Actual Study Completion Date: Oct 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: carfilzomib (A0)	Drug: carfilzomib; Subjects will receive carfilzomib 20 mg/m2 as an intravenous bolus over 2 minutes on Days 1, 2, 8, 9, 15, and 16 of 28 day cycles. A maximum of 12 cycles will be administered.; Other Names: PR-171 PR171 Kyprolis® (carfilzomib) for Injection
Experimental: carfilzomib (A1)	Drug: carfilzomib; Subjects will receive carfilzomib intravenously over up to 10 minutes on Days 1, 2, 8, 9, 15, and 16 of 28 day cycles. In cycle 1, the dose is 20 mg/m2. If all doses are administered and well-tolerated over Cycle 1, beginning with Cycle 2 the dose will escalate to 27 mg/m2 cycle. A maximum of 12 cycles will be administered.; Other Names: PR-171 PR171 Kyprolis® (carfilzomib) for Injection

Outcome Measures

Primary Outcome Measures

1. Best Overall Response Rate (ORR) [A0: Subjects evaluated for disease response on Day 24 of Cycles 2, 4, 6, 9, and 12. Onset of response measured on Day 15 of Cycle 1. A1: Subjects evaluated for disease response on Day 15 of Cycle 1, Day 1 of Cycles 2 through 12 and at End of Study.]

   For both A0 and A1, to evaluate the best overall response rate (stringent complete response [sCR]+ complete response [CR]+ very good partial response [VGPR]+ partial response [PR]) in patients with multiple myeloma who had previously received bortezomib and either thalidomide or lenalidomide, had relapsed after two or more therapies, and were refractory to the most recently received therapy

Secondary Outcome Measures

1. Clinical Benefit Response (CBR) (A0 Only) [Response assessments same as described in primary outcome measure]

   sCR, CR, VGPR, PR, and minimal response (MR)

2. Clinical Benefit Response (CBR) (A1 Only) [Response assessments same as described in primary outcome measure]

   sCR, CR, VGPR, PR, and minimal response (MR)

3. Duration of Response (A0 Only) [Response assessments same as described in primary outcome measure]

   Duration of response (DOR) was calculated separately for subjects with clinical benefit response or overall response. DOR is defined as the time from first evidence of PR or better (for overall response) and MR or better (for clinical benefit response) to start of disease progression or death.

4. Duration of Response (A1 Only) [Response assessments same as described in primary outcome measure]

   Duration of response (DOR) was calculated separately for subjects with clinical benefit response or overall response. DOR is defined as the time from first evidence of PR or better (for overall response) and MR or better (for clinical benefit response) to start of disease progression or death.

5. Time to Progression (A0 Only) [Response assessments same as described in primary outcome measure]

   Time to progression (TTP) is defined as the time from the study entry (first dose of carfilzomib) to disease progression.

6. Time to Progression (A1 Only) [Response assessments same as described in primary outcome measure]

   Time to progression (TTP) is defined as the time from the study entry (first dose of carfilzomib) to disease progression.

7. Progression-free Survival (A0 Only) [Response assessments same as described in primary outcome measure]

   The PFS was defined as the time from the start of treatment to progressive disease (PD) determined by PI or until death.

8. Progression-free Survival (A1 Only) [Response assessments same as described in primary outcome measure]

   The PFS was defined as the time from the start of treatment to progressive disease (PD) determined by PI or until death.

9. Overall Survival (A1 Only) [Patients were to be followed by telephone contact for disease progression and OS every 3 months after study discontinuation for the first year and every 6 months thereafter for up to 2 years]

   The time from start of treatment to death due to any cause OS was to be censored on the date the subject was last known to be alive for those who were alive or lost to follow-up as of a data analysis cutoff date.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Disease Related

• Multiple myeloma

• Subjects must have measurable disease defined as one of the following:

• Serum M-protein ≥ 1 g/dL

• Urine M-protein ≥ 200 mg/24 hours

• Serum FLC ≥ 10 mg/dL with abnormal ratio (A0 Only)

• Quantitative immunoglobulin levels using nephelometry or turbidometry (only if protein electrophoresis was felt to be unreliable for M-protein measurement) (A0 Only)

• Subjects must have been responsive (i.e., achieved an MR or better) to first-line, standard of care therapy

• Refractory to the most recently received therapy. Refractory disease is defined as ≤ 25% response or progression during therapy or within 60 days after completion of therapy.

• Subjects must have received ≥ 2 prior regimens for relapsed disease. Induction therapy and stem cell transplant will be considered as one regimen (A1 Only)

• Subjects must have received prior treatment with bortezomib, and either thalidomide or lenalidomide

• Subjects must have received an alkylating agent either alone or in combination with other myeloma treatments (history of stem cell transplant is acceptable) (A1 Only)

• Subjects must have received an anthracycline either alone or in combination with other myeloma treatments, unless not clinically indicated (A1 Only)

• Demographic

• Males and females > 18 years of age

• Life expectancy of more than three months

• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2

• Laboratory

• Adequate hepatic function, with bilirubin less than 2.0 times the upper limit of normal, and AST and ALT of less than 3.0 times the upper limit of normal

• Uric acid within normal range (A0 Only)

• Total white blood cell (WBC) count ≥ 2.0 × 109/L, absolute neutrophil count (ANC) ≥ 1.0 × 109/L, hemoglobin ≥ 8.0 g/dL, and platelet count ≥ 50.0 × 109/L (A0 Only)

• Absolute neutrophil count > 1,000/mm3, hemoglobin > 8.0 g/dL, and platelet count

50,000/mm3 (A1 Only)

• Subjects should be platelet transfusion independent

• Screening ANC should be independent of G-CSF or GM-CSF support for ≥ 1 week and of pegylated G-CSF for ≥ 2 weeks

• Subjects may receive red blood cell (RBC) or platelet transfusions or receive supportive care such as erythropoietin and darbepoetin in accordance with institutional guidelines

• Calculated and measured creatinine clearance of ≥ 30 mL/minute, calculated using the formula of Cockcroft and Gault [(140 - Age) X Mass (kg) / (72 X Creatinine mg/dL)]. Multiply result by 0.85 if female.

• Ethical / Other

• Written informed consent in accordance with federal, local, and institutional guidelines

• Female subjects of child-bearing potential must have a negative serum pregnancy test within seven days of the first dose and agree to use dual methods of contraception during and for 3 months following last dose of drug. Post menopausal females (> 45 years old and without menses for > 1 year) and surgically sterilized females are exempt from a pregnancy test. Male subjects must use an effective barrier method of contraception during study and for 3 months following the last dose if sexually active with a female of child-bearing potential.

Exclusion Criteria:

• Disease Related

• Multiple Myeloma IgM (A1 Only)

• Subjects who failed to achieve at least a confirmed MR(≥ 25% reduction in M-protein for ≥ 6 weeks) (A1 Only)

• Subjects with non-secretory multiple myeloma, defined as < 1 g/dL M-protein in serum and < 200 mg/24 hr M-protein in urine

• Subjects with disease measurable only by serum free light chain (SFLC) analysis (A1 Only)

• Glucocorticoid therapy (prednisone > 10 mg/day orally or equivalent) within the last three weeks

• POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes)

• Plasma cell leukemia

• Chemotherapy with approved or investigative anticancer therapeutics including steroid therapy within the three weeks prior to first dose

• Radiation therapy or immunotherapy in the previous four weeks; localized radiation therapy within 1 week prior to first dose

• Participation in an investigational therapeutic study within three weeks or within five drug half-lives (t1/2) prior to Day 1, whichever time is greater

• Prior treatment with carfilzomib

• Concurrent Conditions

• Major surgery within three weeks before Day 1

• Congestive heart failure (New York Heart Association class III to IV), symptomatic cardiac ischemia, cardiomyopathy, conduction abnormalities uncontrolled by conventional intervention, or myocardial infarction in the previous six months, LVEF < 40

• Acute active infection requiring systemic antibiotics, antivirals or antifungals within 2 weeks prior to first dose

• Known or suspected HIV infection or subjects who are HIV seropositive

• Active hepatitis A,B,or C infection

• Non-hematologic malignancy within the past three years except a) adequately treated basal cell or squamous cell skin cancer, b) carcinoma in situ of the cervix, or c) prostate cancer <Gleason Grade 6 with stable PSA

• Subjects with treatment related myelodysplastic syndrome

• Significant neuropathy (Grade 3, 4 or Grade 2 with pain) at the time of study initiation

• Subjects in whom the required program of oral and intravenous fluid hydration is contraindicated, e.g., due to pre-existing pulmonary, cardiac or renal impairment (A1 Only)

• Subjects with known or suspected amyloidosis (A1 Only)

• Subjects with pleural effusions requiring thoracentesis or ascites requiring paracentesis (A1 Only)

• Any clinically significant medical disease or condition that, in the Investigator's opinion, may interfere with protocol adherence or a subject's ability to give informed consent (A1 Only)

• Ethical / Other

• Female subjects who are pregnant or lactating

• Serious psychiatric or medical conditions that could interfere with treatment

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Southern Cancer Center	Mobile	Alabama	United States	36608
2	Mayo Clinic Scottsdale	Scottsdale	Arizona	United States	85259
3	Tower Cancer Research Foundation	Beverly Hills	California	United States	90211
4	City of Hope National Medical Center	Duarte	California	United States	91010
5	Scripps Clinic	La Jolla	California	United States	92037
6	University of California, San Francisco	San Francisco	California	United States	94143
7	Florida Cancer Specialists	Fort Myers	Florida	United States	33905
8	H. Lee Moffitt Cancer Center and Research Institute	Tampa	Florida	United States	33612
9	Emory University Winship Cancer Institute	Atlanta	Georgia	United States	30322
10	Northwestern Universtiy	Chicago	Illinois	United States	60605
11	Rush University Medical Center	Chicago	Illinois	United States	60612
12	University of Kentucky	Lexington	Kentucky	United States	40536
13	University of Michigan	Ann Arbor	Michigan	United States	48109
14	Barbara Ann Karmanos Cancer Institute	Detroit	Michigan	United States	48201
15	Mayo Clinic - Rochester	Rochester	Minnesota	United States	55905
16	Washington University School of Medicine	Saint Louis	Missouri	United States	63110
17	Hackensack University Medical Center	Hackensack	New Jersey	United States	07601
18	Roswell Park Cancer Institute	Buffalo	New York	United States	14263
19	St. Vincent Catholic Medical Center	New York	New York	United States	10011
20	Wake Forest University	Winston-Salem	North Carolina	United States	27157
21	Gabrail Cancer Center	Canton	Ohio	United States	44718
22	Oncology & Hematology Care	Cincinnati	Ohio	United States	45236
23	Cleveland Clinic	Cleveland	Ohio	United States	44195
24	University of Pennsylvania	Philadelphia	Pennsylvania	United States	19104
25	Sarah Cannon Research Institute	Nashville	Tennessee	United States	37203
26	MD Anderson Cancer Center	Houston	Texas	United States	77030
27	Northwest Cancer Center	Houston	Texas	United States	77090
28	University of Utah	Salt Lake City	Utah	United States	84132
29	University of Calgary	Calgary	Alberta	Canada	T2N 4N2
30	University of Alberta, Cross Cancer Institute	Edmonton	Alberta	Canada	T6G 1Z2
31	Leukemia/BMT Program of BC	Vancouver	British Columbia	Canada	V5Z 1M9
32	Princess Margaret Hospital	Toronto	Ontario	Canada	M5G 2C1
33	Royal Victoria Hospital	Montreal	Quebec	Canada	H3A 1A1
34	Jewish General Hospital	Montreal	Quebec	Canada	H3T 1E2

Sponsors and Collaborators

• Amgen

Investigators

• Study Director: MD, Amgen

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Amgen
• ClinicalTrials.gov Identifier: NCT00511238
• Other Study ID Numbers: PX-171-003
• First Posted: Aug 3, 2007
• Last Update Posted: Aug 31, 2017
• Last Verified: Aug 1, 2017

• Keywords provided by Amgen: Onyx; PR171; carfilzomib; multiple myeloma; relapsed; refractory
• Additional relevant MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell

Study Results

Participant Flow

Recruitment Details	Results of this study are reported in 2 parts, depending on whether a patient was enrolled and treated under the original protocol (referred to as 'A0') or under Amendment 1 and subsequent amendments (referred to as 'A1').

Arm/Group Title	Carfilzomib (A0)	Carfilzomib (A1)
Arm/Group Description	Subjects will receive carfilzomib 20 mg/m2 intravenously on Days 1, 2, 8, 9, 15, and 16 of 28 day cycles	In Cycle 1, subjects will receive carfilzomib 20 mg/m2 intravenously on Days 1, 2, 8, 9, 15, and 16. If all doses are administered and well-tolerated over the 28-day cycle, beginning with Cycle 2 the dose will escalate to 27 mg/m2 intravenously on Days 1, 2, 8, 9, 15, and 16 for all subsequent cycles.
Period Title: Overall Study
STARTED	46	266
COMPLETED	4	40
NOT COMPLETED	42	226

Baseline Characteristics

Arm/Group Title	Carfilzomib (A0)	Carfilzomib (A1)	Total
Arm/Group Description	Subjects will receive carfilzomib 20 mg/m2 intravenously on Days 1, 2, 8, 9, 15, and 16 of 28 day cycle	In Cycle 1, subjects will receive carfilzomib 20 mg/m2 intravenously on Days 1, 2, 8, 9, 15, and 16. If all doses are administered and well-tolerated over the 28-day cycle, beginning with Cycle 2 the dose will escalate to 27 mg/m2 intravenously on Days 1, 2, 8, 9, 15, and 16 for all subsequent cycles.	Total of all reporting groups
Overall Participants	46	266	312
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	26 56.5%	146 54.9%	172 55.1%
>=65 years	20 43.5%	120 45.1%	140 44.9%
Sex: Female, Male (Count of Participants)
Female	21 45.7%	111 41.7%	132 42.3%
Male	25 54.3%	155 58.3%	180 57.7%

Outcome Measures

1. Primary Outcome

Title	Best Overall Response Rate (ORR)
Description	For both A0 and A1, to evaluate the best overall response rate (stringent complete response [sCR]+ complete response [CR]+ very good partial response [VGPR]+ partial response [PR]) in patients with multiple myeloma who had previously received bortezomib and either thalidomide or lenalidomide, had relapsed after two or more therapies, and were refractory to the most recently received therapy
Time Frame	A0: Subjects evaluated for disease response on Day 24 of Cycles 2, 4, 6, 9, and 12. Onset of response measured on Day 15 of Cycle 1. A1: Subjects evaluated for disease response on Day 15 of Cycle 1, Day 1 of Cycles 2 through 12 and at End of Study.

Outcome Measure Data

Analysis Population Description

Analysis population described in reporting groups below

Arm/Group Title	Carfilzomib (A0)	Carfilzomib (A1)
Arm/Group Description	Subjects will receive carfilzomib 20 mg/m2 intravenously on Days 1, 2, 8, 9, 15, and 16 of a 28 day cycle Response-evaluable Population: Enrolled patients who completed at least 1 cycle of carfilzomib and who underwent disease assessments at Screening, Cycle 1 Day 15, and Cycle 2 Day 24. This analysis set also included patients who discontinued treatment during this time due to an AE that was considered probably related to carfilzomib.	In Cycle 1, subjects will receive carfilzomib 20 mg/m2 intravenously on Days 1, 2, 8, 9, 15, and 16.If all doses are administered and well-tolerated over the 28-day cycle, beginning with Cycle 2 the dose will escalate to 27 mg/m2 intravenously on Days 1, 2, 8, 9, 15, and 16 for all subsequent cycles. Response-Evaluable Population: had measurable disease at Baseline received at least 1 dose of carfilzomib underwent baseline disease response assessments and at least 1 post-baseline disease assessment, or discontinued protocol treatment before Cycle 2 Day 1 due to an AE that was considered to be possibly or probably related to carfilzomib
Measure Participants	42	257
Number (95% Confidence Interval) [% of participants w/ PR or better]	16.7 36.3%	23.7 8.9%

2. Secondary Outcome

Title	Clinical Benefit Response (CBR) (A0 Only)
Description	sCR, CR, VGPR, PR, and minimal response (MR)
Time Frame	Response assessments same as described in primary outcome measure

Outcome Measure Data

Analysis Population Description

Response-evaluable Population: Enrolled patients who completed at least 1 cycle of carfilzomib and who underwent disease assessments at Screening, Cycle 1 Day 15, and Cycle 2 Day 24. This analysis set also included patients who discontinued treatment during this time due to an AE that was considered probably related to carfilzomib.

Arm/Group Title	Carfilzomib (A0)
Arm/Group Description	Subjects will receive carfilzomib 20 mg/m2 intravenously on Days 1, 2, 8, 9, 15, and 16 of 28 day cycle. Assessed by principal investigator.
Measure Participants	42
Clinical Benefit Response (sCR+CR+VGPR+PR+MR)	10 21.7%
Complete Response	0 0%
Very Good Partial Response	0 0%
Partial Response	7 15.2%
Minimal Response	3 6.5%

3. Secondary Outcome

Title	Clinical Benefit Response (CBR) (A1 Only)
Description	sCR, CR, VGPR, PR, and minimal response (MR)
Time Frame	Response assessments same as described in primary outcome measure

Outcome Measure Data

Analysis Population Description

Response-Evaluable Population: had measurable disease at Baseline received at least 1 dose of carfilzomib underwent baseline disease response assessments and at least 1 post-baseline disease assessment, or discontinued protocol treatment before Cycle 2 Day 1 due to an AE that was considered to be possibly or probably related to carfilzomib

Arm/Group Title	Carfilzomib (A1)
Arm/Group Description	In Cycle 1, subjects will receive carfilzomib 20 mg/m2 intravenously on Days 1, 2, 8, 9, 15, and 16. If all doses are administered and well-tolerated over the 28-day cycle, beginning with Cycle 2 the dose will escalate to 27 mg/m2 intravenously on Days 1, 2, 8, 9, 15, and 16 for all subsequent cycles. Assessed by Independent Review Committee
Measure Participants	257
Clinical Benefit Response (sCR+CR+VGPR+PR+MR)	95 206.5%
Complete Response	1 2.2%
Very Good Partial Response	13 28.3%
Partial Response	47 102.2%
Minimal Response	34 73.9%

4. Secondary Outcome

Title	Duration of Response (A0 Only)
Description	Duration of response (DOR) was calculated separately for subjects with clinical benefit response or overall response. DOR is defined as the time from first evidence of PR or better (for overall response) and MR or better (for clinical benefit response) to start of disease progression or death.
Time Frame	Response assessments same as described in primary outcome measure

Outcome Measure Data

Analysis Population Description

Subjects with overall response within the response-evaluable population were included in the analysis of DOR. See analysis population description of response-evaluable population above.

Arm/Group Title	Carfilzomib (A0) for (ORR)
Arm/Group Description	Subjects will receive carfilzomib 20 mg/m2 intravenously on Days 1, 2, 8, 9, 15, and 16 of a 28 day cycle
Measure Participants	7
Median (95% Confidence Interval) [days]	219

5. Secondary Outcome

Title	Duration of Response (A1 Only)
Description	Duration of response (DOR) was calculated separately for subjects with clinical benefit response or overall response. DOR is defined as the time from first evidence of PR or better (for overall response) and MR or better (for clinical benefit response) to start of disease progression or death.
Time Frame	Response assessments same as described in primary outcome measure

Outcome Measure Data

Analysis Population Description

Subjects with overall response within the response-evaluable population were included in the analysis of DOR. See overall analysis population description of response-evaluable population above.

Arm/Group Title	Carfilzomib (A1) for (ORR)	Carfilzomib (A1) for (CBR)
Arm/Group Description	In Cycle 1, subjects will receive carfilzomib 20 mg/m2 intravenously on Days 1, 2, 8, 9, 15, and 16. If all doses are administered and well-tolerated over the 28-day cycle, beginning with Cycle 2 the dose will escalate to 27 mg/m2 intravenously on Days 1, 2, 8, 9, 15, and 16 for all subsequent cycles. For subjects with ORR.	In Cycle 1, subjects will receive carfilzomib 20 mg/m2 intravenously on Days 1, 2, 8, 9, 15, and 16. If all doses are administered and well-tolerated over the 28-day cycle, beginning with Cycle 2 the dose will escalate to 27 mg/m2 intravenously on Days 1, 2, 8, 9, 15, and 16 for all subsequent cycles. For subjects with CBR.
Measure Participants	61	95
Median (95% Confidence Interval) [months]	7.8	8.3

6. Secondary Outcome

Title	Time to Progression (A0 Only)
Description	Time to progression (TTP) is defined as the time from the study entry (first dose of carfilzomib) to disease progression.
Time Frame	Response assessments same as described in primary outcome measure

Outcome Measure Data

Analysis Population Description

Response-evaluable Population: Enrolled patients who completed at least 1 cycle of carfilzomib and who underwent disease assessments at Screening, Cycle 1 Day 15, and Cycle 2 Day 24. This analysis set also included patients who discontinued treatment during this time due to an AE that was considered probably related to carfilzomib.

Arm/Group Title	Carfilzomib (A0)
Arm/Group Description	Subjects will receive carfilzomib 20 mg/m2 intravenously on Days 1, 2, 8, 9, 15, and 16 of a 28 day cycle. Assesed by principal investigator.
Measure Participants	42
Median (95% Confidence Interval) [months]	3.5

7. Secondary Outcome

Title	Time to Progression (A1 Only)
Description	Time to progression (TTP) is defined as the time from the study entry (first dose of carfilzomib) to disease progression.
Time Frame	Response assessments same as described in primary outcome measure

Outcome Measure Data

Analysis Population Description

Response-Evaluable Population: had measurable disease at Baseline received at least 1 dose of carfilzomib underwent baseline disease response assessments and at least 1 post-baseline disease assessment, or discontinued protocol treatment before Cycle 2 Day 1 due to an AE that was considered to be possibly or probably related to carfilzomib

Arm/Group Title	Carfilzomib (A1)
Arm/Group Description	In Cycle 1, subjects will receive carfilzomib 20 mg/m2 intravenously on Days 1, 2, 8, 9, 15, and 16. If all doses are administered and well-tolerated over the 28-day cycle, beginning with Cycle 2 the dose will escalate to 27 mg/m2 intravenously on Days 1, 2, 8, 9, 15, and 16 for all subsequent cycles. Assessed by Independent Review Committee
Measure Participants	257
Median (95% Confidence Interval) [months]	3.9

8. Secondary Outcome

Title	Progression-free Survival (A0 Only)
Description	The PFS was defined as the time from the start of treatment to progressive disease (PD) determined by PI or until death.
Time Frame	Response assessments same as described in primary outcome measure

Outcome Measure Data

Analysis Population Description

Response-evaluable Population: Enrolled patients who completed at least 1 cycle of carfilzomib and who underwent disease assessments at Screening, Cycle 1 Day 15, and Cycle 2 Day 24. This analysis set also included patients who discontinued treatment during this time due to an AE that was considered probably related to carfilzomib.

Arm/Group Title	Carfilzomib (A0)
Arm/Group Description	Subjects will receive carfilzomib 20 mg/m2 intravenously on Days 1, 2, 8, 9, 15, and 16 of a 28 day cycle
Measure Participants	42
Median (95% Confidence Interval) [months]	3.5

9. Secondary Outcome

Title	Progression-free Survival (A1 Only)
Description	The PFS was defined as the time from the start of treatment to progressive disease (PD) determined by PI or until death.
Time Frame	Response assessments same as described in primary outcome measure

Outcome Measure Data

Analysis Population Description

Response-Evaluable Population: had measurable disease at Baseline received at least 1 dose of carfilzomib underwent baseline disease response assessments and at least 1 post-baseline disease assessment, or discontinued protocol treatment before Cycle 2 Day 1 due to an AE that was considered to be possibly or probably related to carfilzomib

Arm/Group Title	Carfilzomib (A1)
Arm/Group Description	In Cycle 1, subjects will receive carfilzomib 20 mg/m2 intravenously on Days 1, 2, 8, 9, 15, and 16.If all doses are administered and well-tolerated over the 28-day cycle, beginning with Cycle 2 the dose will escalate to 27 mg/m2 intravenously on Days 1, 2, 8, 9, 15, and 16 for all subsequent cycles.
Measure Participants	257
Median (95% Confidence Interval) [months]	3.7

10. Secondary Outcome

Title	Overall Survival (A1 Only)
Description	The time from start of treatment to death due to any cause OS was to be censored on the date the subject was last known to be alive for those who were alive or lost to follow-up as of a data analysis cutoff date.
Time Frame	Patients were to be followed by telephone contact for disease progression and OS every 3 months after study discontinuation for the first year and every 6 months thereafter for up to 2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Carfilzomib (A1) - Safety Population	Carfilzomib (A1) - Response-evaluable Population
Arm/Group Description	In Cycle 1, subjects will receive carfilzomib 20 mg/m2 intravenously on Days 1, 2, 8, 9, 15, and 16. If all doses are administered and well-tolerated over the 28-day cycle, beginning with Cycle 2 the dose will escalate to 27 mg/m2 intravenously on Days 1, 2, 8, 9, 15, and 16 for all subsequent cycles. Safety population: The safety population was used for the analysis of safety data in this study. The safety population consists of all enrolled patients who received at least 1 dose of carfilzomib. However, for some safety analyses, at least 1 laboratory, neurological, electrocardiogram, or vital sign measurement obtained subsequent to at least 1 dose of carfilzomib was required for inclusion in the analysis of a safety specific parameter. To assess change from baseline, a baseline measurement was also required.	In Cycle 1, subjects will receive carfilzomib 20 mg/m2 intravenously on Days 1, 2, 8, 9, 15, and 16. If all doses are administered and well-tolerated over the 28-day cycle, beginning with Cycle 2 the dose will escalate to 27 mg/m2 intravenously on Days 1, 2, 8, 9, 15, and 16 for all subsequent cycles. Response-Evaluable Population(the primary analysis population) was defined as all patients who had measurable disease at Baseline by either M-protein (serum and/or urine) or by quantitative serum Ig for certain patients with IgA myeloma received at least 1 dose of carfilzomib underwent baseline disease response assessments and at least 1 post-baseline disease assessment, or patients who discontinued protocol treatment before Cycle 2 Day 1 due to an AE that was considered to be possibly or probably related to carfilzomib-irrespective of availability of baseline and post-baseline assessment
Measure Participants	266	257
Number (95% Confidence Interval) [months]	15.4	15.6

Adverse Events

Time Frame	All adverse events (AEs) should be reported from the time the subject signs consent through 30 days post-last dose of study drug or initiation of a new anti-cancer therapy, whichever occurs first.
Arm/Group Title	Carfilzomib (A0)		Carfilzomib (A1)
Arm/Group Description	Subjects will receive carfilzomib 20 mg/m2 intravenously on Days 1, 2, 8, 9, 15, and 16 of a 28 day cycle		In Cycle 1, subjects will receive carfilzomib 20 mg/m2 intravenously on Days 1, 2, 8, 9, 15, and 16.If all doses are administered and well-tolerated over the 28-day cycle, beginning with Cycle 2 the dose will escalate to 27 mg/m2 intravenously on Days 1, 2, 8, 9, 15, and 16 for all subsequent cycles.
All Cause Mortality
	Carfilzomib (A0)		Carfilzomib (A1)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Carfilzomib (A0)		Carfilzomib (A1)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	20/46 (43.5%)		126/266 (47.4%)
Blood and lymphatic system disorders
Anaemia	0/46 (0%)		5/266 (1.9%)
Thrombocytopenia	0/46 (0%)		5/266 (1.9%)
Febrile neutropenia	0/46 (0%)		2/266 (0.8%)
Cardiac disorders
Cardiac failure congestive	2/46 (4.3%)		8/266 (3%)
Cardiac failure	1/46 (2.2%)		0/266 (0%)
Cardiomyopathy	1/46 (2.2%)		0/266 (0%)
Myocardial ischaemia	1/46 (2.2%)		2/266 (0.8%)
Supraventricular tachycardia	1/46 (2.2%)		0/266 (0%)
Cardiac arrest	0/46 (0%)		4/266 (1.5%)
Atrial fibrillation	0/46 (0%)		2/266 (0.8%)
Acute coronary syndrome	0/46 (0%)		1/266 (0.4%)
Acute myocardial infarction	0/46 (0%)		1/266 (0.4%)
Aortic valve stenosis	0/46 (0%)		1/266 (0.4%)
Arrhythmia	0/46 (0%)		1/266 (0.4%)
Atrial flutter	0/46 (0%)		1/266 (0.4%)
Congestive cardiomyopathy	0/46 (0%)		1/266 (0.4%)
Ventricular dysfunction	0/46 (0%)		1/266 (0.4%)
Endocrine disorders
Hypercalcaemia of malignancy	0/46 (0%)		1/266 (0.4%)
Eye disorders
Diplopia	0/46 (0%)		1/266 (0.4%)
Gastrointestinal disorders
Abdominal discomfort	0/46 (0%)		1/266 (0.4%)
Diarrhoea	0/46 (0%)		1/266 (0.4%)
Dysphagia	0/46 (0%)		1/266 (0.4%)
Intra-abdominal haemorrhage	0/46 (0%)		1/266 (0.4%)
Pancreatitis	0/46 (0%)		1/266 (0.4%)
Vomiting	0/46 (0%)		1/266 (0.4%)
General disorders
Disease progression	5/46 (10.9%)		16/266 (6%)
Multi-organ failure	1/46 (2.2%)		0/266 (0%)
Non-cardiac chest pain	1/46 (2.2%)		3/266 (1.1%)
Pyrexia	1/46 (2.2%)		8/266 (3%)
Asthenia	0/46 (0%)		1/266 (0.4%)
Chills	0/46 (0%)		1/266 (0.4%)
Death	0/46 (0%)		1/266 (0.4%)
Infusion related reaction	0/46 (0%)		1/266 (0.4%)
Pain	0/46 (0%)		1/266 (0.4%)
Hepatobiliary disorders
Hepatic failure	0/46 (0%)		2/266 (0.8%)
Immune system disorders
Hypersensitivity	0/46 (0%)		1/266 (0.4%)
Infections and infestations
Pneumonia	5/46 (10.9%)		23/266 (8.6%)
Bacteraemia	2/46 (4.3%)		1/266 (0.4%)
Clostridium colitis	1/46 (2.2%)		0/266 (0%)
Klebsiella sepsis	1/46 (2.2%)		0/266 (0%)
Lobar pneumonia	1/46 (2.2%)		2/266 (0.8%)
Sepsis	1/46 (2.2%)		4/266 (1.5%)
Cellulitis	0/46 (0%)		2/266 (0.8%)
Upper respiratory tract infection	0/46 (0%)		2/266 (0.8%)
Central line infection	0/46 (0%)		1/266 (0.4%)
Chronic sinusitis	0/46 (0%)		1/266 (0.4%)
Ear infection	0/46 (0%)		1/266 (0.4%)
Escherichia bacteraemia	0/46 (0%)		1/266 (0.4%)
Fusobacterium infection	0/46 (0%)		1/266 (0.4%)
Gastroenteritis viral	0/46 (0%)		1/266 (0.4%)
Infection	0/46 (0%)		1/266 (0.4%)
Otitis media	0/46 (0%)		1/266 (0.4%)
Parainfluenzae virus infection	0/46 (0%)		1/266 (0.4%)
Pneumonia respiratory syncytial viral	0/46 (0%)		1/266 (0.4%)
Respiratory syncytial virus infection	0/46 (0%)		1/266 (0.4%)
Septic shock	0/46 (0%)		1/266 (0.4%)
Injury, poisoning and procedural complications
Post procedural haemorrhage	1/46 (2.2%)		0/266 (0%)
Subdural haematoma	0/46 (0%)		1/266 (0.4%)
Investigations
Blood creatinine increased	0/46 (0%)		5/266 (1.9%)
Alanine aminotransferase increased	0/46 (0%)		1/266 (0.4%)
Aspartate aminotransferase increased	0/46 (0%)		1/266 (0.4%)
Hepatic enzyme abnormal	0/46 (0%)		1/266 (0.4%)
Transaminases increased	0/46 (0%)		1/266 (0.4%)
Metabolism and nutrition disorders
Hypercalcaemia	2/46 (4.3%)		6/266 (2.3%)
Hyponatraemia	1/46 (2.2%)		1/266 (0.4%)
Dehydration	0/46 (0%)		3/266 (1.1%)
Fluid overload	0/46 (0%)		2/266 (0.8%)
Hyperkalaemia	0/46 (0%)		1/266 (0.4%)
Musculoskeletal and connective tissue disorders
Bone pain	1/46 (2.2%)		2/266 (0.8%)
Pathological fracture	1/46 (2.2%)		8/266 (3%)
Back pain	0/46 (0%)		1/266 (0.4%)
Shoulder pain	0/46 (0%)		1/266 (0.4%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumour lysis syndrome	2/46 (4.3%)		0/266 (0%)
Plasmacytoma	1/46 (2.2%)		2/266 (0.8%)
Nervous system disorders
Spinal cord compression	0/46 (0%)		6/266 (2.3%)
Syncope	0/46 (0%)		2/266 (0.8%)
Haemorrhage intracranial	0/46 (0%)		1/266 (0.4%)
Hepatic encephalopathy	0/46 (0%)		1/266 (0.4%)
Migraine	0/46 (0%)		1/266 (0.4%)
Neuropathy	0/46 (0%)		1/266 (0.4%)
Syncope vasovagal	0/46 (0%)		1/266 (0.4%)
Transient ischaemic attack	0/46 (0%)		1/266 (0.4%)
Psychiatric disorders
Mental status changes	0/46 (0%)		2/266 (0.8%)
Confusional state	0/46 (0%)		1/266 (0.4%)
Delirium	0/46 (0%)		1/266 (0.4%)
Renal and urinary disorders
Renal failure acute	4/46 (8.7%)		9/266 (3.4%)
Nephrolithiasis	1/46 (2.2%)		0/266 (0%)
Renal failure	1/46 (2.2%)		3/266 (1.1%)
Haematuria	0/46 (0%)		1/266 (0.4%)
Renal impairment	0/46 (0%)		1/266 (0.4%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	1/46 (2.2%)		5/266 (1.9%)
Pulmonary oedema	1/46 (2.2%)		2/266 (0.8%)
Respiratory failure	1/46 (2.2%)		1/266 (0.4%)
Pleural effusion	0/46 (0%)		3/266 (1.1%)
Hypoxia	0/46 (0%)		2/266 (0.8%)
Pulmonary embolism	0/46 (0%)		2/266 (0.8%)
Acute pulmonary oedema	0/46 (0%)		1/266 (0.4%)
Cough	0/46 (0%)		1/266 (0.4%)
Haemoptysis	0/46 (0%)		1/266 (0.4%)
Pneumonitis	0/46 (0%)		1/266 (0.4%)
Pulmonary alveolar haemorrhage	0/46 (0%)		1/266 (0.4%)
Vascular disorders
Hypotension	0/46 (0%)		4/266 (1.5%)
Deep vein thrombosis	0/46 (0%)		2/266 (0.8%)
Hypertension	0/46 (0%)		1/266 (0.4%)
Other (Not Including Serious) Adverse Events
	Carfilzomib (A0)		Carfilzomib (A1)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	46/46 (100%)		266/266 (100%)
Blood and lymphatic system disorders
Anaemia	34/46 (73.9%)		122/266 (45.9%)
Thrombocytopenia	23/46 (50%)		103/266 (38.7%)
Lymphopenia	16/46 (34.8%)		62/266 (23.3%)
Leukopenia	10/46 (21.7%)		37/266 (13.9%)
Neutropenia	10/46 (21.7%)		48/266 (18%)
Gastrointestinal disorders
Nausea	16/46 (34.8%)		119/266 (44.7%)
Diarrhoea	15/46 (32.6%)		86/266 (32.3%)
Vomiting	8/46 (17.4%)		59/266 (22.2%)
Constipation	6/46 (13%)		56/266 (21.1%)
Abdominal pain	5/46 (10.9%)		16/266 (6%)
Dyspepsia	5/46 (10.9%)		26/266 (9.8%)
Dry mouth	3/46 (6.5%)		4/266 (1.5%)
General disorders
Fatigue	32/46 (69.6%)		130/266 (48.9%)
Pyrexia	15/46 (32.6%)		83/266 (31.2%)
Asthenia	7/46 (15.2%)		40/266 (15%)
Oedema peripheral	9/46 (19.6%)		62/266 (23.3%)
Chest discomfort	5/46 (10.9%)		6/266 (2.3%)
Chills	5/46 (10.9%)		42/266 (15.8%)
Disease progression	5/46 (10.9%)		17/266 (6.4%)
Injection site irritation	4/46 (8.7%)		4/266 (1.5%)
Infusion site pain	2/46 (4.3%)		24/266 (9%)
Pain	2/46 (4.3%)		24/266 (9%)
Hepatobiliary disorders
Hyperbilirubinaemia	3/46 (6.5%)		3/266 (1.1%)
Infections and infestations
Upper respiratory tract infection	17/46 (37%)		71/266 (26.7%)
Pneumonia	5/46 (10.9%)		32/266 (12%)
Nasopharyngitis	3/46 (6.5%)		13/266 (4.9%)
Urinary tract infection	0/46 (0%)		19/266 (7.1%)
Injury, poisoning and procedural complications
Contusion	2/46 (4.3%)		14/266 (5.3%)
Investigations
Blood creatinine increased	16/46 (34.8%)		67/266 (25.2%)
Blood bicarbonate decreased	14/46 (30.4%)		6/266 (2.3%)
Aspartate aminotransfersae increased	9/46 (19.6%)		27/266 (10.2%)
Blood chloride increased	8/46 (17.4%)		1/266 (0.4%)
Blood urea increased	7/46 (15.2%)		4/266 (1.5%)
Blood uric acid increased	7/46 (15.2%)		15/266 (5.6%)
Blood glucose increased	5/46 (10.9%)		2/266 (0.8%)
Blood lactate dehydrogenase increased	4/46 (8.7%)		8/266 (3%)
Carbon dioxide decreased	4/46 (8.7%)		2/266 (0.8%)
Alanine aminotransferase decreased	3/46 (6.5%)		1/266 (0.4%)
Alanine aminotransferase increased	3/46 (6.5%)		20/266 (7.5%)
Neutrophil percentage increased	3/46 (6.5%)		0/266 (0%)
White blood cell count decreased	3/46 (6.5%)		5/266 (1.9%)
Weight decreased	1/46 (2.2%)		20/266 (7.5%)
Blood albumin decreased	3/46 (6.5%)		4/266 (1.5%)
Blood calcium increased	3/46 (6.5%)		5/266 (1.9%)
Blood sodium decreased	3/46 (6.5%)		0/266 (0%)
Blood phosphorus decreased	3/46 (6.5%)		12/266 (4.5%)
Lymphocyte percentage decreased	3/46 (6.5%)		1/266 (0.4%)
Metabolism and nutrition disorders
Hypocalcaemia	16/46 (34.8%)		14/266 (5.3%)
Hypoalbuminaemia	12/46 (26.1%)		14/266 (5.3%)
Anorexia	10/46 (21.7%)		35/266 (13.2%)
Hypercalcaemia	7/46 (15.2%)		36/266 (13.5%)
Hypokalaemia	7/46 (15.2%)		29/266 (10.9%)
Hyperphosphataemia	6/46 (13%)		7/266 (2.6%)
Hypophosphataemia	6/46 (13%)		32/266 (12%)
Hypermagnesaemia	5/46 (10.9%)		3/266 (1.1%)
Decreased appetite	4/46 (8.7%)		19/266 (7.1%)
Hypoglycaemia	3/46 (6.5%)		6/266 (2.3%)
Hyponatraemia	10/46 (21.7%)		31/266 (11.7%)
Hyperglycaemia	12/46 (26.1%)		26/266 (9.8%)
Dehydration	1/46 (2.2%)		18/266 (6.8%)
Hyperkalaemia	9/46 (19.6%)		14/266 (5.3%)
Hyperuricaemia	9/46 (19.6%)		11/266 (4.1%)
Hypomagnesaemia	10/46 (21.7%)		28/266 (10.5%)
Musculoskeletal and connective tissue disorders
Chest wall pain	8/46 (17.4%)		32/266 (12%)
Muscle spasms	8/46 (17.4%)		32/266 (12%)
Pain in extremity	8/46 (17.4%)		31/266 (11.7%)
Arthralgia	6/46 (13%)		49/266 (18.4%)
Back pain	6/46 (13%)		63/266 (23.7%)
Bone pain	5/46 (10.9%)		23/266 (8.6%)
Shoulder pain	5/46 (10.9%)		28/266 (10.5%)
Pain in jaw	3/46 (6.5%)		1/266 (0.4%)
Myalgia	1/46 (2.2%)		22/266 (8.3%)
Pathological fracture	2/46 (4.3%)		17/266 (6.4%)
Nervous system disorders
Headache	12/46 (26.1%)		74/266 (27.8%)
Hypoaesthesia	5/46 (10.9%)		25/266 (9.4%)
Areflexia	4/46 (8.7%)		14/266 (5.3%)
Neuropathic pain	4/46 (8.7%)		9/266 (3.4%)
Neuropathy peripheral	4/46 (8.7%)		17/266 (6.4%)
Dizziness	3/46 (6.5%)		30/266 (11.3%)
Hyporeflexia	3/46 (6.5%)		18/266 (6.8%)
Neuropathy	3/46 (6.5%)		9/266 (3.4%)
Paraesthesia	3/46 (6.5%)		20/266 (7.5%)
Psychiatric disorders
Insomnia	12/46 (26.1%)		39/266 (14.7%)
Confusional state	6/46 (13%)		17/266 (6.4%)
Anxiety	2/46 (4.3%)		16/266 (6%)
Depression	2/46 (4.3%)		14/266 (5.3%)
Renal and urinary disorders
Renal failure acute	4/46 (8.7%)		13/266 (4.9%)
Proteinuria	3/46 (6.5%)		0/266 (0%)
Renal failure	3/46 (6.5%)		10/266 (3.8%)
Respiratory, thoracic and mediastinal disorders
Cough	13/46 (28.3%)		65/266 (24.4%)
Dyspnoea	13/46 (28.3%)		90/266 (33.8%)
Crackles lung	4/46 (8.7%)		9/266 (3.4%)
Dyspnoea exertional	1/46 (2.2%)		33/266 (12.4%)
Epistaxis	4/46 (8.7%)		29/266 (10.9%)
Rhinorrhoea	3/46 (6.5%)		21/266 (7.9%)
Pharyngolaryngeal pain	7/46 (15.2%)		20/266 (7.5%)
Nasal congestion	2/46 (4.3%)		17/266 (6.4%)
Productive cough	4/46 (8.7%)		16/266 (6%)
Pleural effusion	1/46 (2.2%)		14/266 (5.3%)
Bronchospasm	3/46 (6.5%)		0/266 (0%)
Dysphonia	3/46 (6.5%)		3/266 (1.1%)
Pulmonary oedema	4/46 (8.7%)		5/266 (1.9%)
Skin and subcutaneous tissue disorders
Rash	3/46 (6.5%)		20/266 (7.5%)
Pruritus	1/46 (2.2%)		17/266 (6.4%)
Vascular disorders
Hypertension	4/46 (8.7%)		39/266 (14.7%)
Hypotension	4/46 (8.7%)		21/266 (7.9%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

After the study is completed and all case report forms have been sent to Sponsor, Institution shall have the right to publish or otherwise make public any data resulting from the study under this agreement after publication of a multi-center publication coordinated by Sponsor with respect to the data resulting from the study, or 12 months after the Study is completed at all participating sites if a multi-center publication is not submitted by Sponsor for publication within such 12 month period.