A Multicenter, Open-label, Phase 1b Study of Carfilzomib, Cyclophosphamide and Dexamethasone in Newly Diagnosed Multiple Myeloma Subjects

Phase 1

Completed

• Conditions: Multiple Myeloma
• Interventions: Drug: Carfilzomib; Drug: Cyclophosphamide; Drug: Dexamethasone

• Registration Number: NCT01980589
• Lead Sponsor: Amgen

Brief Summary

The primary objective was to determine the maximum tolerated dose of carfilzomib given twice weekly in combination with cyclophosphamide and dexamethasone for patients with newly diagnosed multiple myeloma.

Detailed Description

Not available

Study Timeline

• Study Start: 2013-08
• Study First Submitted: 2013-10-28
• Study First Submitted QC: 2013-11-04
• Study First Posted: 2013-11-11
• Primary Completion: 2016-03
• Study Completion: 2016-03
• Results First Submitted: 2016-09-07
• Results First Submitted QC: 2016-09-07
• Results First Posted: 2016-10-31
• Status Verified: 2017-04
• Last Update Submitted: 2017-04-28
• Last Update Posted: 2017-05-30

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 22

Inclusion Criteria

1. Newly diagnosed multiple myeloma

2. Measurable disease, as defined by 1 or more of the following

   • Serum M-protein ≥ 0.5 g/dL, or
   • Urine M-protein ≥ 200 mg/24 hours, or
   • In subjects without detectable serum or urine M-protein, serum free light chain (SFLC) > 100 mg/L (involved light chain) and an abnormal kappa lambda ( κ/λ) ratio

3. Males and females ≥ 18 years of age

4. Eastern Cooperative Oncology Group (ECOG) performance status 0-2

5. Adequate hepatic function

6. Left ventricular ejection fraction (LVEF) ≥ 40%

7. Absolute neutrophil count (ANC) ≥ 1.0 × 10^9/L

8. Platelet count ≥ 50 × 10^9/L

9. Calculated or measured creatinine clearance (CrCl) of ≥ 15 mL/min

Exclusion Criteria

1. Planned autologous hematopoietic stem cell transplantation (HSCT) for the initial therapy of newly diagnosed multiple myeloma
2. Multiple myeloma of immunoglobulin M (IgM) subtype
3. Prior systemic treatment for multiple myeloma
4. Glucocorticoid therapy within 14 days prior to enrollment that equals or exceeds the equivalent of dexamethasone 160 mg
5. Known amyloidosis
6. Active congestive heart failure (New York Heart Association [NYHA] Class III to IV), symptomatic ischemia, or conduction abnormalities uncontrolled by conventional intervention. Myocardial infarction within 6 months prior to enrollment.
7. Known human immunodeficiency virus (HIV) seropositive, hepatitis C infection, and/or hepatitis B (subjects with hepatitis B surface antigen [SAg] or core antibody receiving and responding to antiviral therapy directed at hepatitis B are allowed)
8. Significant neuropathy (Grades ≥ 2) within 14 days prior to enrollment
9. Any other 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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Carfilzomib, Cyclophosphamide and Dexamethasone (CCd)	Dexamethasone	Participants received carfilzomib, cyclophosphamide and dexamethasone for up to eight 28-day cycles, or until progressive disease (PD), unacceptable toxicity, withdrawal of consent, or death.
Carfilzomib, Cyclophosphamide and Dexamethasone (CCd)	Carfilzomib	Participants received carfilzomib, cyclophosphamide and dexamethasone for up to eight 28-day cycles, or until progressive disease (PD), unacceptable toxicity, withdrawal of consent, or death.
Carfilzomib, Cyclophosphamide and Dexamethasone (CCd)	Cyclophosphamide	Participants received carfilzomib, cyclophosphamide and dexamethasone for up to eight 28-day cycles, or until progressive disease (PD), unacceptable toxicity, withdrawal of consent, or death.

Primary Outcome Measures

Name	Time	Method
Number of Participants With Dose-limiting Toxicities (DLTs)	First cycle treatment over 28-days	The MTD is defined as the highest carfilzomib dose at which fewer than 33% of participants experience a treatment-related dose-limiting toxicity (DLT) during the first 28-day cycle. The number of participants who experienced a DLT is reported.; Dose-limiting toxicities are defined as any of the following carfilzomib-related adverse events: Nonhematologic: * ≥ Grade 3 non-hematological toxicity; * ≥ Grade 3 acute kidney injury (creatinine \> 3 × baseline or \> 4.0 mg/dL) lasting \> 72 hours; Hematologic: * Grade 4 neutropenia (absolute neutrophil count \[ANC\] \< 0.5 × 10\^9/L) lasting for \> 7 days; * Febrile neutropenia (ANC \< 1.0 × 10\^9/L with a fever ≥ 38.3ºC) of any duration; * Grade 4 thrombocytopenia (\< 25 × 10\^9/L) that persists for \> 14 days, despite holding treatment; * Grade 3 or 4 thrombocytopenia associated with \> Grade 1 bleeding

Secondary Outcome Measures

Name	Time	Method
Overall Response Rate (ORR)	Disease response was assessed at the end of each cycle and 30 days after the last treatment; maximum treatment duration was 32 weeks.	Participants were evaluated for disease response and progression by the investigator according to the International Myeloma Working Group-Uniform Response Criteria (IMWG-URC). Disease response and progression assessments included serum protein electrophoresis (SPEP), urine protein electrophoresis (UPEP), serum immunofixation, serum free light chain (SFLC), bone marrow sample (including fluorescent in situ hybridization \[FISH\]), plasmacytoma evaluation, and skeletal survey. Overall response rate is defined as the percentage of participants with a best response of stringent complete response, complete response, very good partial response (VGPR), or partial response.
Time To Response (TTR)	Disease response was assessed at the end of each cycle and 30 days after the last treatment; maximum treatment duration was 32 weeks.	Time to response is defined as months from treatment start to first documentation of response of partial response or better. Summary of time to response includes confirmed responders of PR or better only.
Number of Participants With Adverse Events	From first dose of study drug until 30 days after last dose; median duration of treatment was 31 weeks.	Adverse events (AEs) were graded according to the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 4.03 and using the following scale: Grade 1 = Mild, Grade 3 = Moderate; Grade 3 = Severe, Grade 4 = Life-threatening; Grade 5 = Fatal.

Trial Locations

Locations (9)

James R. Berenson, MD; 🇺🇸 West Hollywood, California, United States

California Cancer Associates for Research and Excellence; 🇺🇸 Encinitas, California, United States

The Oncology Institute of Hope and Innovation; 🇺🇸 Whittier, California, United States

Clinical Research Alliance; 🇺🇸 New York, New York, United States

Horizon Oncology Research; 🇺🇸 Lafayette, Indiana, United States

Center for Cancer and Blood Disorders; 🇺🇸 Bethesda, Maryland, United States

Tennessee Oncology; 🇺🇸 Nashville, Tennessee, United States

Texas Oncology; 🇺🇸 Austin, Texas, United States

Virginia Oncology Associates; 🇺🇸 Norfolk, Virginia, United States