Cyclophosphamide, Carfilzomib, Thalidomide, and Dexamethasone in Treating Patients With Newly Diagnosed Active Multiple Myeloma

• Sponsor: Mayo Clinic (Other)
• Overall Status: Completed
• CT.gov ID: NCT01057225
• Collaborator: (none)
• Enrollment: 64
• Locations: 3
• Arm: 1
• Duration (Months): 90.2
• Patients Per Site: 21.3
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

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

PURPOSE: This phase I/II trial is studying the side effects and best dose of carfilzomib when given together with cyclophosphamide, thalidomide, and dexamethasone in treating patients with newly diagnosed active multiple myeloma.

Condition or Disease	Intervention/Treatment	Phase
Multiple Myeloma; Stage I Multiple Myeloma; Stage II Multiple Myeloma; Stage III Multiple Myeloma	Drug: carfilzomib; Drug: cyclophosphamide; Drug: thalidomide; Drug: dexamethasone	Phase 1/Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. To establish the maximum tolerated dose of carfilzomib given in combination with oral cyclophosphamide and thalidomide and dexamethasone. (Phase I) II. In newly diagnosed myeloma to evaluate the response rate (CR, nCR, and VGPR) to carfilzomib given in combination with oral cyclophosphamide and thalidomide and dexamethasone after four 28 day cycles. (Phase II)

SECONDARY OBJECTIVES:

1. Determine the overall response rate (CR, nCR, PR) after 4, 8, 12 cycles. II. Determine the duration of progression-free and overall survival for patients receiving this regimen.

2. To evaluate the incidence of toxicities for this regimen. IV. To evaluate the ability to successfully collect peripheral blood stem cells following four months of combination therapy.

OUTLINE: This is a phase I, dose escalation study of carfilzomib followed by a phase II study.

Patients receive carfilzomib IV on days 1, 2, 8, 9, 15, and 16; oral cyclophosphamide on days 1, 8, and 15; oral dexamethasone on days 1, 8, 15, and 22; and oral thalidomide on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed at 3 months, then every 3 months for 1 year, and then every 6 months for up to 3 years.

Study Design

• Study Type: Interventional
• Actual Enrollment: 64 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase I/II Trial of Cyclophosphamide, Carfilzomib, Thalidomide and Dexamethasone (CYCLONE) in Patients With Newly Diagnosed Active Multiple Myeloma
• Study Start Date: Mar 1, 2010
• Actual Primary Completion Date: Mar 1, 2014
• Actual Study Completion Date: Sep 5, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm I Patients receive carfilzomib IV on days 1, 2, 8, 9, 15, and 16; oral cyclophosphamide on days 1, 8, and 15; oral dexamethasone on days 1, 8, 15, and 22; and oral thalidomide on days 1-28.	Drug: carfilzomib; Given IV; Other Names: PR-171 ; Drug: cyclophosphamide; Given orally; Other Names: CPM CTX Cytoxan Endoxan Endoxana Enduxan ; Drug: thalidomide; Given orally; Other Names: alpha-phthalimidoglutarimide Contergan Kevadon Synovir THAL Thalomid ; Drug: dexamethasone; Given orally; Other Names: Aeroseb-Dex Decaderm Decadron Decaspray DM DXM

Outcome Measures

Primary Outcome Measures

1. Maximum Tolerated Dose (Phase I) [From baseline to end of active treatment, up to 12 28-day cycles.]

   To establish the maximum tolerated dose of carfilzomib given in combination with oral cyclophosphamide and thalidomide and dexamethasone. For this protocol, dose-limiting toxicity (DLT) will be defined as an adverse event attributed (definitely, probably, possibly) in the first or second cycle for patients enrolled to Dose Levels -1 and 0 and in the first cycle only for patients enrolled to Dose Levels 1 and 2. We are reporting the number of DLTs

2. Percentage of Patients Who Have at Least a Confirmed Very Good Partial Response (Phase II) [Following the first 4 cycles of treatment (28 day cycles)]

   The proportion of patients who have at least a confirmed very good partial response will be calculated by taking the number of patients with a very good partial response or a complete response divided by the total number of patients. A complete response is defined as: Negative immunofixation of the serum and urine If at on study, only the measurable non-bone marrow parameter was FLC, normalization of FLC ratio < 5% plasma cells in bone marrow Disappearance of any soft tissue plasmacytomas A very good partial response is defined as: Serum and urine M-component detectable by immunofixation but not on electrophoresis or If at on study, serum measurable, ≥ 90% or greater reduction in serum Mcomponent Urine M-component <100 mg per 24 hour

Secondary Outcome Measures

1. Progression-free Survival (Phase II) [From baseline to progression or death up to 3 years]

   PFS was defined as the time from registration to progression or death due to any cause. Progression was defined as any one or more of the following: • Increase of 25% from lowest confirmed response in: Serum M-component (absolute increase must be ≥ 0.5 g/dl)c Urine M-component (absolute increase must be ≥ 200 mg/24 hour) If at on study, only the measurable non-bone marrow parameter was FLC, the difference between involved and uninvolved FLC levels (absolute increase must be >10 mg/dl) Bone marrow plasma cell percentage (absolute % must be 10%)d Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing bone lesions or soft tissue plasmacytomas • Development of hypercalcemia (corrected serum calcium >11.5 mg/dl) that can be attributed solely to the plasma cell proliferative disorder

2. Time to Treatment Failure [From baseline to end of active treatment]

   The time from the date of registration to the date at which the patient is removed from treatment due to progression, adverse events, or refusal. If the patient is considered to be a major treatment violation or is taken off study as a non-protocol failure, the patient will be censored on the date they were removed from treatment. The distribution of time to treatment failure will be estimated using the method of Kaplan-Meier

3. Stem Cell Collection and Engraftment (Phase II) [Following the first 4 courses of treatment]

   For patients going on to stem cell collection, the total number of CD34 positive cells collected per collection, days to platelets over 20,000 without transfusion and ANC over 1000 will be recorded. If a patient fails to collect adequate stem cells for transplant, this will be recorded as such. The number of patients with successful stem cell mobilization are reported.

4. Complete Response (Phase II) [Following the first 4 courses of treatment]

   In patients continuing beyond 4 cycles the ability to induce complete response will be evaluated at completion of planned therapy.

5. Survival Time (Phase II) [From baseline to death]

   Survival time is defined as the time from registration to death due to any cause. The distribution of survival time will be estimated using the method of Kaplan-Meier

6. Progression Free Survival (12 Month) [12 months]

   Progression-free survival time is defined as the time from registration to the earliest date of documentation of disease progression. If a patient dies without a documentation of disease progression the patient will be considered to have had disease progression at the time of their death. If the patient is declared to be a major treatment violation, the patient will be censored on the date the treatment violation was declared to have occurred. In the case of a patient starting treatment and then never returning for any evaluations, the patient will be censored for progression 1 day post-registration. This is reported as the percentage of patients alive and progression free at the 12 month mark.

7. Progession Free Survival (24 Month) [24 months]

   Progression-free survival time is defined as the time from registration to the earliest date of documentation of disease progression. If a patient dies without a documentation of disease progression the patient will be considered to have had disease progression at the time of their death. If the patient is declared to be a major treatment violation, the patient will be censored on the date the treatment violation was declared to have occurred. In the case of a patient starting treatment and then never returning for any evaluations, the patient will be censored for progression 1 day post-registration. This is reported as the percentage of patients alive and progression free at the 24 month mark.

8. Overall Survival (12 Month) [From baseline to death]

   12 Month Overall survival is defined as the proportion of patients to still be alive after 12 months.

9. Overall Survival (24 Month) [From baseline to death]

   24 Month Overall survival is defined as the proportion of patients to still be alive after 24 months.

Eligibility Criteria

Criteria

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

Inclusion

• Creatinine =< 2 mg/dL

• Calculated Creatinine Clearance >= 30 mL/min

• Total Bilirubin =< 2.0 mg/dL

• Alkaline Phosphatase =< 3 x ULN

• ALT =< 3 x ULN

• Absolute neutrophil count >= 1000/uL

• Platelet >= 75000/uL

• Hemoglobin >= 8.0 g/dL

• Untreated symptomatic myeloma: Prior non-systemic therapy for the treatment of solitary plasmacytoma is permitted, but >= 1 month should have elapsed from the last day of radiation; prior therapy with clarithromycin, DHEA, anakinra, pamidronate or zoledronic acid is permitted; any additional agents not listed must be approved by the Principal Investigator

• Prior high dose corticosteroid therapy for twelve days (480 mg total dose) or less is permitted for emergent complications from newly diagnosed multiple myeloma

• Measurable disease of multiple myeloma, as defined by at least ONE of the following:

• Serum monoclonal protein >= 1.0 g by protein electrophoresis

• OR > 200 mg of monoclonal protein in the urine on 24 hour electrophoresis

• OR serum immunoglobulin free light chain >= 10 mg/dL AND abnormal serum immunoglobulin kappa to lambda free light chain ratio; OR monoclonal bone marrow plasmacytosis >= 30% (evaluable disease)

• ECOG performance status (PS) 0, 1, 2; ECOG PS of 3 will be allowed if secondary to pain in the opinion of the Investigator

• Willingness and able to provide informed written consent

• Negative serum pregnancy test done =< 7 days prior to registration, for women of childbearing potential only

• Willingness to return to Mayo Clinic enrolling institution for follow-up

Exclusion

• MGUS or smoldering myeloma

• Peripheral sensory neuropathy >= Grade 2 as defined by CTEP Active Version of the CTCAE

• Active malignancy with the exception of non melanoma skin cancer or in situ cervical or breast cancer

• Pregnant women or women of reproductive ability who are unwilling to use effective contraception

• Nursing women

• Men who are unwilling to use a condom (even if they have undergone a prior vasectomy) while having intercourse with any woman, while taking the drug and for 4 weeks after stopping treatment

• Known hypersensitivity, allergy or inability to tolerate any of the agents employed

• Active, uncontrolled infection

• Severe cardiac comorbidity

• New York Heart Association Class III or IV Heart Failure

• Recent history of myocardial infarction in the six months prior to registration

• Uncontrolled angina or electrocardiographic evidence of acute ischemia

• Severe uncontrolled ventricular arrhythmias or electrocardiographic evidence of active conduction system abnormalities

• Cardiac amyloidosis with hypotension (systolic BP less than 100 mmHg)

• Other concurrent chemotherapy, radiotherapy, or any ancillary therapy considered investigational; NOTE: Bisphosphonates are considered to be supportive care rather than therapy, and are thus allowed while on protocol treatment

• The following medications are not permitted during the trial: any other investigational treatment; any cytotoxic chemotherapy; any other systemic anti-neoplastic therapy including, but not limited to, immunotherapy, hormonal therapy, or monoclonal antibody therapy

• Palliative radiation therapy is permitted if clinically indicated and not indicative of progressive disease

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic in Arizona	Scottsdale	Arizona	United States	85259
2	Mayo Clinic	Rochester	Minnesota	United States	55905
3	Medical University of South Carolina	Charleston	South Carolina	United States	29425-6350

Sponsors and Collaborators

• Mayo Clinic

Investigators

• Study Chair: Joseph R. Mikhael, M.D., Mayo Clinic

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Mayo Clinic
• ClinicalTrials.gov Identifier: NCT01057225
• Other Study ID Numbers: MC0982; NCI-2009-01699; PT-171-502; 09-004091; MC0982
• First Posted: Jan 27, 2010
• Last Update Posted: Dec 12, 2017
• Last Verified: Nov 1, 2017

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

Study Results

Participant Flow

Arm/Group Title	Phase I: Dose Level -1	Phase I: Dose Level 0	Phase I: Dose Level 1	Phase I: Dose Level 2	Phase II: Dose Level 0	Phase II: Dose Level 1
Arm/Group Description	Patients receive: Oral 300 mg/m^2 cyclophosphamide on days 1, 8, and 15; Oral 40 mg dexamethasone on days 1, 8, 15, and 22; Oral 100 mg thalidomide on days 1-28. Patients also recieve 15 mg/m^2 carfilzomib IV on days 1, 2, 8, 9, 15, and 16 in cycle 1, and 20 mg/m^2 on days 1, 2, 8, 9, 15, and 16 in subsequent cycles.	Patients receive: Oral 300 mg/m^2 cyclophosphamide on days 1, 8, and 15; Oral 40 mg dexamethasone on days 1, 8, 15, and 22; Oral 100 mg thalidomide on days 1-28. Patients also recieve 20 mg/m^2 carfilzomib IV on days 1, 2, 8, 9, 15, and 16 in cycle 1, and 27 mg/m^2 on days 1, 2, 8, 9, 15, and 16 in subsequent cycles.	Patients receive: Oral 300 mg/m^2 cyclophosphamide on days 1, 8, and 15; Oral 40 mg dexamethasone on days 1, 8, 15, and 22; Oral 100 mg thalidomide on days 1-28. Patients also recieve 20 mg/m^2 carfilzomib IV on days 1, 2, 8, 9, 15, and 16 in cycle 1, and 36 mg/m^2 on days 1, 2, 8, 9, 15, and 16 in subsequent cycles.	Patients receive: Oral 300 mg/m^2 cyclophosphamide on days 1, 8, and 15; Oral 40 mg dexamethasone on days 1, 8, 15, and 22; Oral 100 mg thalidomide on days 1-28. Patients also recieve 20 mg/m^2 carfilzomib IV on days 1, 2, 8, 9, 15, and 16 in cycle 1, and 45 mg/m^2 on days 1, 2, 8, 9, 15, and 16 in subsequent cycles.	Patients receive: Oral 300 mg/m^2 cyclophosphamide on days 1, 8, and 15; Oral 40 mg dexamethasone on days 1, 8, 15, and 22; Oral 100 mg thalidomide on days 1-28. Patients also recieve 20 mg/m^2 carfilzomib IV on days 1, 2, 8, 9, 15, and 16 in cycle 1, and 27 mg/m^2 on days 1, 2, 8, 9, 15, and 16 in subsequent cycles.	Patients receive: Oral 300 mg/m^2 cyclophosphamide on days 1, 8, and 15; Oral 40 mg dexamethasone on days 1, 8, 15, and 22; Oral 100 mg thalidomide on days 1-28. Patients also recieve 20 mg/m^2 carfilzomib IV on days 1, 2, 8, 9, 15, and 16 in cycle 1, and 36 mg/m^2 on days 1, 2, 8, 9, 15, and 16 in subsequent cycles.
Period Title: Overall Study
STARTED	3	3	6	7	22	23
COMPLETED	3	3	6	7	22	23
NOT COMPLETED	0	0	0	0	0	0

Baseline Characteristics

Arm/Group Title	All Treated Patients
Arm/Group Description	Patients receive carfilzomib IV on days 1, 2, 8, 9, 15, and 16; oral cyclophosphamide on days 1, 8, and 15; oral dexamethasone on days 1, 8, 15, and 22; and oral thalidomide on days 1-28.
Overall Participants	64
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	62.5
Sex: Female, Male (Count of Participants)
Female	30 46.9%
Male	34 53.1%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	1 1.6%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	4 6.3%
White	54 84.4%
More than one race	0 0%
Unknown or Not Reported	5 7.8%
Region of Enrollment (participants) [Number]
United States	64 100%

Outcome Measures

1. Primary Outcome

Title	Maximum Tolerated Dose (Phase I)
Description	To establish the maximum tolerated dose of carfilzomib given in combination with oral cyclophosphamide and thalidomide and dexamethasone. For this protocol, dose-limiting toxicity (DLT) will be defined as an adverse event attributed (definitely, probably, possibly) in the first or second cycle for patients enrolled to Dose Levels -1 and 0 and in the first cycle only for patients enrolled to Dose Levels 1 and 2. We are reporting the number of DLTs
Time Frame	From baseline to end of active treatment, up to 12 28-day cycles.

Outcome Measure Data

Analysis Population Description

All patients registered to a dose escalation Phase I group were analyzed for this endpoint.

Arm/Group Title	Phase I: Dose Level -1	Phase I: Dose Level 0	Phase I: Dose Level 1	Phase I: Dose Level 2
Arm/Group Description	Patients receive: Oral 300 mg/m^2 cyclophosphamide on days 1, 8, and 15; Oral 40 mg dexamethasone on days 1, 8, 15, and 22; Oral 100 mg thalidomide on days 1-28. Patients also recieve 15 mg/m^2 carfilzomib IV on days 1, 2, 8, 9, 15, and 16 in cycle 1, and 20 mg/m^2 on days 1, 2, 8, 9, 15, and 16 in subsequent cycles.	Patients receive: Oral 300 mg/m^2 cyclophosphamide on days 1, 8, and 15; Oral 40 mg dexamethasone on days 1, 8, 15, and 22; Oral 100 mg thalidomide on days 1-28. Patients also recieve 20 mg/m^2 carfilzomib IV on days 1, 2, 8, 9, 15, and 16 in cycle 1, and 27 mg/m^2 on days 1, 2, 8, 9, 15, and 16 in subsequent cycles.	Patients receive: Oral 300 mg/m^2 cyclophosphamide on days 1, 8, and 15; Oral 40 mg dexamethasone on days 1, 8, 15, and 22; Oral 100 mg thalidomide on days 1-28. Patients also recieve 20 mg/m^2 carfilzomib IV on days 1, 2, 8, 9, 15, and 16 in cycle 1, and 36 mg/m^2 on days 1, 2, 8, 9, 15, and 16 in subsequent cycles.	Patients receive: Oral 300 mg/m^2 cyclophosphamide on days 1, 8, and 15; Oral 40 mg dexamethasone on days 1, 8, 15, and 22; Oral 100 mg thalidomide on days 1-28. Patients also recieve 20 mg/m^2 carfilzomib IV on days 1, 2, 8, 9, 15, and 16 in cycle 1, and 45 mg/m^2 on days 1, 2, 8, 9, 15, and 16 in subsequent cycles.
Measure Participants	3	3	6	7
Number [participants]	0 0%	0 NaN	0 NaN	3 NaN

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Phase I: Dose Level -1, Phase I: Dose Level 0, Phase I: Dose Level 1, Phase I: Dose Level 2
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Dose Level
	Estimated Value	1
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments	Using a cohort of 3 design, it was determined the maximum tolerated dose of carfilzomib is Dose Level 1: 20 mg/m^2 for the first cycle and 36 mg/m^2 for subsequent cycles.

2. Primary Outcome

Title	Percentage of Patients Who Have at Least a Confirmed Very Good Partial Response (Phase II)
Description	The proportion of patients who have at least a confirmed very good partial response will be calculated by taking the number of patients with a very good partial response or a complete response divided by the total number of patients. A complete response is defined as: Negative immunofixation of the serum and urine If at on study, only the measurable non-bone marrow parameter was FLC, normalization of FLC ratio < 5% plasma cells in bone marrow Disappearance of any soft tissue plasmacytomas A very good partial response is defined as: Serum and urine M-component detectable by immunofixation but not on electrophoresis or If at on study, serum measurable, ≥ 90% or greater reduction in serum Mcomponent Urine M-component <100 mg per 24 hour
Time Frame	Following the first 4 cycles of treatment (28 day cycles)

Outcome Measure Data

Analysis Population Description

All enrolled patients who began treatment were evaluated for safety and response.

Arm/Group Title	Arm I
Arm/Group Description	Patients receive carfilzomib IV on days 1, 2, 8, 9, 15, and 16; oral cyclophosphamide on days 1, 8, and 15; oral dexamethasone on days 1, 8, 15, and 22; and oral thalidomide on days 1-28.
Measure Participants	64
Number [percentage of participants]	91 142.2%

3. Secondary Outcome

Title	Progression-free Survival (Phase II)
Description	PFS was defined as the time from registration to progression or death due to any cause. Progression was defined as any one or more of the following: • Increase of 25% from lowest confirmed response in: Serum M-component (absolute increase must be ≥ 0.5 g/dl)c Urine M-component (absolute increase must be ≥ 200 mg/24 hour) If at on study, only the measurable non-bone marrow parameter was FLC, the difference between involved and uninvolved FLC levels (absolute increase must be >10 mg/dl) Bone marrow plasma cell percentage (absolute % must be 10%)d Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing bone lesions or soft tissue plasmacytomas • Development of hypercalcemia (corrected serum calcium >11.5 mg/dl) that can be attributed solely to the plasma cell proliferative disorder
Time Frame	From baseline to progression or death up to 3 years

Outcome Measure Data

Analysis Population Description

All of the 64 participants that were eligible and began treatment were evaluated.

Arm/Group Title	Arm I
Arm/Group Description	Patients receive carfilzomib IV on days 1, 2, 8, 9, 15, and 16; oral cyclophosphamide on days 1, 8, and 15; oral dexamethasone on days 1, 8, 15, and 22; and oral thalidomide on days 1-28.
Measure Participants	64
Number (95% Confidence Interval) [months]	NA

4. Secondary Outcome

Title	Time to Treatment Failure
Description	The time from the date of registration to the date at which the patient is removed from treatment due to progression, adverse events, or refusal. If the patient is considered to be a major treatment violation or is taken off study as a non-protocol failure, the patient will be censored on the date they were removed from treatment. The distribution of time to treatment failure will be estimated using the method of Kaplan-Meier
Time Frame	From baseline to end of active treatment

Outcome Measure Data

Analysis Population Description

All enrolled patients who began treatment were evaluated for safety and response.

Arm/Group Title	Arm I
Arm/Group Description	Patients receive carfilzomib IV on days 1, 2, 8, 9, 15, and 16; oral cyclophosphamide on days 1, 8, and 15; oral dexamethasone on days 1, 8, 15, and 22; and oral thalidomide on days 1-28.
Measure Participants	64
Number (95% Confidence Interval) [months]	NA

5. Secondary Outcome

Title	Stem Cell Collection and Engraftment (Phase II)
Description	For patients going on to stem cell collection, the total number of CD34 positive cells collected per collection, days to platelets over 20,000 without transfusion and ANC over 1000 will be recorded. If a patient fails to collect adequate stem cells for transplant, this will be recorded as such. The number of patients with successful stem cell mobilization are reported.
Time Frame	Following the first 4 courses of treatment

Outcome Measure Data

Analysis Population Description

Of the 64 patients that began protocol treatment, stem cell harvesting was attempted on 42 patients.

Arm/Group Title	All Treated Patients
Arm/Group Description	Patients receive carfilzomib IV on days 1, 2, 8, 9, 15, and 16; oral cyclophosphamide on days 1, 8, and 15; oral dexamethasone on days 1, 8, 15, and 22; and oral thalidomide on days 1-28.
Measure Participants	42
Number [participants]	42 65.6%

6. Secondary Outcome

Title	Complete Response (Phase II)
Description	In patients continuing beyond 4 cycles the ability to induce complete response will be evaluated at completion of planned therapy.
Time Frame	Following the first 4 courses of treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Dose Level -1	Dose Level 0	Dose Level 1	Dose Level 2
Arm/Group Description	Patients receive: Oral 300 mg/m^2 cyclophosphamide on days 1, 8, and 15; Oral 40 mg dexamethasone on days 1, 8, 15, and 22; Oral 100 mg thalidomide on days 1-28. Patients also recieve 15 mg/m^2 carfilzomib IV on days 1, 2, 8, 9, 15, and 16 in cycle 1, and 20 mg/m^2 on days 1, 2, 8, 9, 15, and 16 in subsequent cycles.	Patients receive: Oral 300 mg/m^2 cyclophosphamide on days 1, 8, and 15; Oral 40 mg dexamethasone on days 1, 8, 15, and 22; Oral 100 mg thalidomide on days 1-28. Patients also recieve 20 mg/m^2 carfilzomib IV on days 1, 2, 8, 9, 15, and 16 in cycle 1, and 27 mg/m^2 on days 1, 2, 8, 9, 15, and 16 in subsequent cycles.	Patients receive: Oral 300 mg/m^2 cyclophosphamide on days 1, 8, and 15; Oral 40 mg dexamethasone on days 1, 8, 15, and 22; Oral 100 mg thalidomide on days 1-28. Patients also recieve 20 mg/m^2 carfilzomib IV on days 1, 2, 8, 9, 15, and 16 in cycle 1, and 36 mg/m^2 on days 1, 2, 8, 9, 15, and 16 in subsequent cycles.	Patients receive: Oral 300 mg/m^2 cyclophosphamide on days 1, 8, and 15; Oral 40 mg dexamethasone on days 1, 8, 15, and 22; Oral 100 mg thalidomide on days 1-28. Patients also recieve 20 mg/m^2 carfilzomib IV on days 1, 2, 8, 9, 15, and 16 in cycle 1, and 45 mg/m^2 on days 1, 2, 8, 9, 15, and 16 in subsequent cycles.
Measure Participants	3	25	29	7
Number [participants]	0 0%	2 NaN	3 NaN	0 NaN

7. Secondary Outcome

Title	Survival Time (Phase II)
Description	Survival time is defined as the time from registration to death due to any cause. The distribution of survival time will be estimated using the method of Kaplan-Meier
Time Frame	From baseline to death

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	All Treated Patients
Arm/Group Description	Patients receive carfilzomib IV on days 1, 2, 8, 9, 15, and 16; oral cyclophosphamide on days 1, 8, and 15; oral dexamethasone on days 1, 8, 15, and 22; and oral thalidomide on days 1-28.
Measure Participants	64
Median (95% Confidence Interval) [months]	NA

8. Secondary Outcome

Title	Progression Free Survival (12 Month)
Description	Progression-free survival time is defined as the time from registration to the earliest date of documentation of disease progression. If a patient dies without a documentation of disease progression the patient will be considered to have had disease progression at the time of their death. If the patient is declared to be a major treatment violation, the patient will be censored on the date the treatment violation was declared to have occurred. In the case of a patient starting treatment and then never returning for any evaluations, the patient will be censored for progression 1 day post-registration. This is reported as the percentage of patients alive and progression free at the 12 month mark.
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

All of the 64 participants that were eligible and began treatment were evaluated.

Arm/Group Title	All Treated Patients
Arm/Group Description	Patients receive carfilzomib IV on days 1, 2, 8, 9, 15, and 16; oral cyclophosphamide on days 1, 8, and 15; oral dexamethasone on days 1, 8, 15, and 22; and oral thalidomide on days 1-28.
Measure Participants	64
Number (95% Confidence Interval) [percentage of participants at 12 months]	85 132.8%

9. Secondary Outcome

Title	Progession Free Survival (24 Month)
Description	Progression-free survival time is defined as the time from registration to the earliest date of documentation of disease progression. If a patient dies without a documentation of disease progression the patient will be considered to have had disease progression at the time of their death. If the patient is declared to be a major treatment violation, the patient will be censored on the date the treatment violation was declared to have occurred. In the case of a patient starting treatment and then never returning for any evaluations, the patient will be censored for progression 1 day post-registration. This is reported as the percentage of patients alive and progression free at the 24 month mark.
Time Frame	24 months

Outcome Measure Data

Analysis Population Description

All of the 64 participants that were eligible and began treatment were evaluated.

Arm/Group Title	All Treated Patients
Arm/Group Description	Patients receive carfilzomib IV on days 1, 2, 8, 9, 15, and 16; oral cyclophosphamide on days 1, 8, and 15; oral dexamethasone on days 1, 8, 15, and 22; and oral thalidomide on days 1-28.
Measure Participants	64
Number (95% Confidence Interval) [percentage of participants at 24 months]	76 118.8%

10. Secondary Outcome

Title	Overall Survival (12 Month)
Description	12 Month Overall survival is defined as the proportion of patients to still be alive after 12 months.
Time Frame	From baseline to death

Outcome Measure Data

Analysis Population Description

All of the 64 participants that were eligible and began treatment were evaluated.

Arm/Group Title	All Treated Patients
Arm/Group Description	Patients receive carfilzomib IV on days 1, 2, 8, 9, 15, and 16; oral cyclophosphamide on days 1, 8, and 15; oral dexamethasone on days 1, 8, 15, and 22; and oral thalidomide on days 1-28.
Measure Participants	64
Number (95% Confidence Interval) [percentage of patients]	96

11. Secondary Outcome

Title	Overall Survival (24 Month)
Description	24 Month Overall survival is defined as the proportion of patients to still be alive after 24 months.
Time Frame	From baseline to death

Outcome Measure Data

Analysis Population Description

All of the 64 participants that were eligible and began treatment were evaluated.

Arm/Group Title	All Treated Patients
Arm/Group Description	Patients receive carfilzomib IV on days 1, 2, 8, 9, 15, and 16; oral cyclophosphamide on days 1, 8, and 15; oral dexamethasone on days 1, 8, 15, and 22; and oral thalidomide on days 1-28.
Measure Participants	64
Number (95% Confidence Interval) [percentage of patients]	96

Adverse Events

Arm/Group Title	All Treated Patients
Arm/Group Description	Patients receive carfilzomib IV on days 1, 2, 8, 9, 15, and 16; oral cyclophosphamide on days 1, 8, and 15; oral dexamethasone on days 1, 8, 15, and 22; and oral thalidomide on days 1-28.
All Cause Mortality
	All Treated Patients
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	All Treated Patients
	Affected / at Risk (%)	# Events
Total	30/64 (46.9%)
Blood and lymphatic system disorders
Anemia	2/64 (3.1%)	2
Febrile neutropenia	1/64 (1.6%)	1
Cardiac disorders
Atrial fibrillation	1/64 (1.6%)	1
Conduction disorder	1/64 (1.6%)	2
Heart failure	3/64 (4.7%)	3
Restrictive cardiomyopathy	1/64 (1.6%)	1
Ventricular tachycardia	1/64 (1.6%)	2
Eye disorders
Eye disorders - Other, specify	1/64 (1.6%)	1
Gastrointestinal disorders
Lower gastrointestinal hemorrhage	1/64 (1.6%)	1
Nausea	1/64 (1.6%)	1
Vomiting	1/64 (1.6%)	1
General disorders
Fatigue	2/64 (3.1%)	2
Infusion related reaction	1/64 (1.6%)	1
Multi-organ failure	1/64 (1.6%)	1
Immune system disorders
Immune system disorders - Other, specify	1/64 (1.6%)	1
Infections and infestations
Infections and infestations - Other, specify	1/64 (1.6%)	1
Lung infection	4/64 (6.3%)	4
Skin infection	1/64 (1.6%)	1
Urinary tract infection	1/64 (1.6%)	1
Wound infection	1/64 (1.6%)	1
Investigations
Alanine aminotransferase increased	4/64 (6.3%)	4
Alkaline phosphatase increased	1/64 (1.6%)	1
Aspartate aminotransferase increased	4/64 (6.3%)	4
Creatinine increased	3/64 (4.7%)	4
Lymphocyte count decreased	2/64 (3.1%)	5
Neutrophil count decreased	3/64 (4.7%)	3
Urine output decreased	1/64 (1.6%)	4
White blood cell decreased	2/64 (3.1%)	2
Metabolism and nutrition disorders
Dehydration	1/64 (1.6%)	1
Hyperglycemia	1/64 (1.6%)	1
Hyperkalemia	1/64 (1.6%)	1
Hyperuricemia	2/64 (3.1%)	2
Hypocalcemia	2/64 (3.1%)	2
Hypokalemia	3/64 (4.7%)	4
Hyponatremia	1/64 (1.6%)	2
Hypophosphatemia	3/64 (4.7%)	5
Tumor lysis syndrome	1/64 (1.6%)	1
Musculoskeletal and connective tissue disorders
Generalized muscle weakness	2/64 (3.1%)	2
Nervous system disorders
Nervous system disorders - Other, specify	1/64 (1.6%)	1
Peripheral sensory neuropathy	1/64 (1.6%)	1
Syncope	2/64 (3.1%)	2
Psychiatric disorders
Agitation	1/64 (1.6%)	1
Renal and urinary disorders
Acute kidney injury	2/64 (3.1%)	2
Renal and urinary disorders - Other, specify	1/64 (1.6%)	1
Respiratory, thoracic and mediastinal disorders
Adult respiratory distress syndrome	1/64 (1.6%)	1
Dyspnea	2/64 (3.1%)	2
Hypoxia	1/64 (1.6%)	1
Pulmonary hypertension	2/64 (3.1%)	2
Respiratory failure	1/64 (1.6%)	1
Wheezing	1/64 (1.6%)	1
Surgical and medical procedures
Surgical and medical procedures - Other, specify	1/64 (1.6%)	1
Vascular disorders
Hypertension	2/64 (3.1%)	2
Hypotension	2/64 (3.1%)	2
Thromboembolic event	4/64 (6.3%)	7
Other (Not Including Serious) Adverse Events
	All Treated Patients
	Affected / at Risk (%)	# Events
Total	64/64 (100%)
Blood and lymphatic system disorders
Anemia	27/64 (42.2%)	74
Leukocytosis	1/64 (1.6%)	1
Cardiac disorders
Chest pain - cardiac	2/64 (3.1%)	2
Heart failure	1/64 (1.6%)	1
Myocardial infarction	1/64 (1.6%)	1
Palpitations	1/64 (1.6%)	1
Paroxysmal atrial tachycardia	1/64 (1.6%)	1
Sinus bradycardia	2/64 (3.1%)	2
Ear and labyrinth disorders
Hearing impaired	1/64 (1.6%)	4
Endocrine disorders
Cushingoid	1/64 (1.6%)	2
Eye disorders
Floaters	1/64 (1.6%)	4
Gastrointestinal disorders
Abdominal distension	2/64 (3.1%)	2
Abdominal pain	3/64 (4.7%)	5
Constipation	35/64 (54.7%)	106
Diarrhea	10/64 (15.6%)	17
Dry mouth	2/64 (3.1%)	5
Dyspepsia	1/64 (1.6%)	1
Esophageal pain	1/64 (1.6%)	1
Flatulence	1/64 (1.6%)	1
Gastroesophageal reflux disease	2/64 (3.1%)	3
Gastrointestinal disorders - Other, specify	3/64 (4.7%)	5
Mucositis oral	1/64 (1.6%)	1
Nausea	13/64 (20.3%)	22
Vomiting	3/64 (4.7%)	4
General disorders
Chills	3/64 (4.7%)	3
Edema limbs	15/64 (23.4%)	28
Edema trunk	2/64 (3.1%)	2
Fatigue	51/64 (79.7%)	159
Fever	5/64 (7.8%)	5
Gait disturbance	1/64 (1.6%)	1
General disorders and administration site conditions - Other, specify	1/64 (1.6%)	2
Irritability	2/64 (3.1%)	4
Malaise	11/64 (17.2%)	34
Pain	1/64 (1.6%)	1
Immune system disorders
Allergic reaction	1/64 (1.6%)	1
Infections and infestations
Lung infection	2/64 (3.1%)	2
Upper respiratory infection	3/64 (4.7%)	3
Urinary tract infection	2/64 (3.1%)	2
Investigations
Alanine aminotransferase increased	7/64 (10.9%)	12
Alkaline phosphatase increased	9/64 (14.1%)	12
Aspartate aminotransferase increased	8/64 (12.5%)	13
Blood bilirubin increased	1/64 (1.6%)	2
Creatinine increased	24/64 (37.5%)	54
Investigations - Other, specify	2/64 (3.1%)	5
Lymphocyte count decreased	26/64 (40.6%)	112
Lymphocyte count increased	4/64 (6.3%)	5
Neutrophil count decreased	32/64 (50%)	95
Platelet count decreased	30/64 (46.9%)	74
Weight gain	1/64 (1.6%)	1
White blood cell decreased	27/64 (42.2%)	76
Metabolism and nutrition disorders
Anorexia	6/64 (9.4%)	9
Dehydration	3/64 (4.7%)	3
Glucose intolerance	1/64 (1.6%)	2
Hypercalcemia	1/64 (1.6%)	1
Hyperglycemia	24/64 (37.5%)	79
Hyperkalemia	4/64 (6.3%)	6
Hypermagnesemia	1/64 (1.6%)	1
Hypernatremia	1/64 (1.6%)	2
Hypertriglyceridemia	2/64 (3.1%)	7
Hyperuricemia	5/64 (7.8%)	7
Hypoalbuminemia	4/64 (6.3%)	6
Hypocalcemia	14/64 (21.9%)	30
Hypokalemia	10/64 (15.6%)	22
Hyponatremia	9/64 (14.1%)	12
Hypophosphatemia	9/64 (14.1%)	14
Metabolism and nutrition disorders - Other, specify	1/64 (1.6%)	2
Musculoskeletal and connective tissue disorders
Arthralgia	1/64 (1.6%)	1
Back pain	1/64 (1.6%)	8
Chest wall pain	1/64 (1.6%)	1
Generalized muscle weakness	2/64 (3.1%)	2
Muscle weakness lower limb	1/64 (1.6%)	1
Musculoskeletal and connective tissue disorder - Other, specify	2/64 (3.1%)	5
Myalgia	3/64 (4.7%)	6
Pain in extremity	4/64 (6.3%)	4
Nervous system disorders
Cognitive disturbance	1/64 (1.6%)	1
Depressed level of consciousness	7/64 (10.9%)	8
Dizziness	7/64 (10.9%)	12
Dysgeusia	2/64 (3.1%)	3
Headache	7/64 (10.9%)	13
Lethargy	16/64 (25%)	22
Memory impairment	1/64 (1.6%)	1
Nervous system disorders - Other, specify	1/64 (1.6%)	3
Peripheral motor neuropathy	5/64 (7.8%)	5
Peripheral sensory neuropathy	23/64 (35.9%)	65
Seizure	1/64 (1.6%)	3
Somnolence	13/64 (20.3%)	19
Tremor	4/64 (6.3%)	11
Psychiatric disorders
Anxiety	5/64 (7.8%)	10
Delirium	1/64 (1.6%)	1
Depression	1/64 (1.6%)	4
Insomnia	4/64 (6.3%)	5
Psychiatric disorders - Other, specify	1/64 (1.6%)	1
Renal and urinary disorders
Acute kidney injury	1/64 (1.6%)	1
Bladder spasm	1/64 (1.6%)	4
Cystitis noninfective	1/64 (1.6%)	1
Renal and urinary disorders - Other, specify	2/64 (3.1%)	3
Urinary frequency	1/64 (1.6%)	1
Urinary incontinence	1/64 (1.6%)	1
Reproductive system and breast disorders
Genital edema	1/64 (1.6%)	2
Respiratory, thoracic and mediastinal disorders
Apnea	1/64 (1.6%)	1
Cough	4/64 (6.3%)	4
Dyspnea	13/64 (20.3%)	21
Epistaxis	1/64 (1.6%)	1
Productive cough	1/64 (1.6%)	1
Sore throat	1/64 (1.6%)	1
Wheezing	1/64 (1.6%)	1
Skin and subcutaneous tissue disorders
Alopecia	1/64 (1.6%)	2
Pruritus	1/64 (1.6%)	1
Rash maculo-papular	6/64 (9.4%)	8
Skin and subcutaneous tissue disorders - Other, specify	1/64 (1.6%)	4
Vascular disorders
Hypertension	5/64 (7.8%)	19
Hypotension	1/64 (1.6%)	1
Thromboembolic event	1/64 (1.6%)	1

Limitations/Caveats

[Not Specified]

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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.