Trial Outcomes & Findings for A Multicenter, Open-label, Phase 1b Study of Carfilzomib, Cyclophosphamide and Dexamethasone in Newly Diagnosed Multiple Myeloma Subjects (NCT NCT01980589)

NCT ID: NCT01980589

Last Updated: 2017-05-30

Results Overview

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

Recruitment status

COMPLETED

Study phase

PHASE1

Target enrollment

22 participants

Primary outcome timeframe

First cycle treatment over 28-days

Results posted on

2017-05-30

Participant Flow

This study was conducted at 9 centers in the United States.

Eligible participants were enrolled into sequential dose-escalation cohorts consisting of 3 to 6 participants to establish the maximum tolerated dose (MTD) of carfilzomib when given in combination with cyclophosphamide and dexamethasone. Additional participants were enrolled in an expansion cohort at the established MTD to collect safety data.

Participant milestones

Participant milestones
Measure	Carfilzomib 36 mg/m² Participants received 36 mg/m² carfilzomib IV infusion on days 1, 2, 8, 9,15, and 16 of each 28 day cycle (on days 1 and 2 of cycle 1, all participants received carfilzomib at 20 mg/m²), cyclophosphamide administered orally at 300 mg/m² on days 1, 8, and 15, and 40 mg dexamethasone on days 1, 8, 15, and 22, for up to eight 28 day cycles, or until progressive disease (PD), unacceptable toxicity, withdrawal of consent, or death.	Carfilzomib 45 mg/m² Participants received 45 mg/m² carfilzomib IV infusion on days 1, 2, 8, 9,15, and 16 of each 28 day cycle (on days 1 and 2 of cycle 1, all participants received carfilzomib at 20 mg/m²), cyclophosphamide administered orally at 300 mg/m² on days 1, 8, and 15, and 40 mg dexamethasone on days 1, 8, 15, and 22, for up to eight 28 day cycles, or until progressive disease (PD), unacceptable toxicity, withdrawal of consent, or death.	Carfilzomib 56 mg/m² Participants received 56 mg/m² carfilzomib IV infusion on days 1, 2, 8, 9,15, and 16 of each 28 day cycle (on days 1 and 2 of cycle 1, all participants received carfilzomib at 20 mg/m²), cyclophosphamide administered orally at 300 mg/m² on days 1, 8, and 15, and 40 mg dexamethasone on days 1, 8, 15, and 22, for up to eight 28 day cycles, or until progressive disease (PD), unacceptable toxicity, withdrawal of consent, or death.
Overall Study STARTED	3	3	16
Overall Study COMPLETED	3	3	16
Overall Study NOT COMPLETED	0	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Carfilzomib 36 mg/m² n=3 Participants Participants received 36 mg/m² carfilzomib IV infusion on days 1, 2, 8, 9,15, and 16 of each 28 day cycle (on days 1 and 2 of cycle 1, all participants received carfilzomib at 20 mg/m²), cyclophosphamide administered orally at 300 mg/m² on days 1, 8, and 15, and 40 mg dexamethasone on days 1, 8, 15, and 22, for up to eight 28 day cycles, or until progressive disease (PD), unacceptable toxicity, withdrawal of consent, or death.	Carfilzomib 45 mg/m² n=3 Participants Participants received 45 mg/m² carfilzomib IV infusion on days 1, 2, 8, 9,15, and 16 of each 28 day cycle (on days 1 and 2 of cycle 1, all participants received carfilzomib at 20 mg/m²), cyclophosphamide administered orally at 300 mg/m² on days 1, 8, and 15, and 40 mg dexamethasone on days 1, 8, 15, and 22, for up to eight 28 day cycles, or until progressive disease (PD), unacceptable toxicity, withdrawal of consent, or death.	Carfilzomib 56 mg/m² n=16 Participants Participants received 56 mg/m² carfilzomib IV infusion on days 1, 2, 8, 9,15, and 16 of each 28 day cycle (on days 1 and 2 of cycle 1, all participants received carfilzomib at 20 mg/m²), cyclophosphamide administered orally at 300 mg/m² on days 1, 8, and 15, and 40 mg dexamethasone on days 1, 8, 15, and 22, for up to eight 28 day cycles, or until progressive disease (PD), unacceptable toxicity, withdrawal of consent, or death.	Total n=22 Participants Total of all reporting groups
Age, Continuous	56.0 years n=5 Participants	63.0 years n=7 Participants	65.0 years n=5 Participants	62.5 years n=4 Participants
Sex: Female, Male Female	0 Participants n=5 Participants	2 Participants n=7 Participants	7 Participants n=5 Participants	9 Participants n=4 Participants
Sex: Female, Male Male	3 Participants n=5 Participants	1 Participants n=7 Participants	9 Participants n=5 Participants	13 Participants n=4 Participants
Race Asian	1 participants n=5 Participants	0 participants n=7 Participants	1 participants n=5 Participants	2 participants n=4 Participants
Race Black or African American	1 participants n=5 Participants	1 participants n=7 Participants	3 participants n=5 Participants	5 participants n=4 Participants
Race White	1 participants n=5 Participants	2 participants n=7 Participants	11 participants n=5 Participants	14 participants n=4 Participants
Race Other	0 participants n=5 Participants	0 participants n=7 Participants	1 participants n=5 Participants	1 participants n=4 Participants
European Cooperative Oncology Group (ECOG) Performance Status 0 (Fully active)	1 participants n=5 Participants	1 participants n=7 Participants	7 participants n=5 Participants	9 participants n=4 Participants
European Cooperative Oncology Group (ECOG) Performance Status 1 (Restrictive but ambulatory)	2 participants n=5 Participants	2 participants n=7 Participants	8 participants n=5 Participants	12 participants n=4 Participants
European Cooperative Oncology Group (ECOG) Performance Status 2 (Ambulatory but unable to work)	0 participants n=5 Participants	0 participants n=7 Participants	1 participants n=5 Participants	1 participants n=4 Participants

PRIMARY outcome

Timeframe: First cycle treatment over 28-days

Population: The Safety population is defined as all enrolled participants who received any study treatment.

Outcome measures

Outcome measures
Measure	Carfilzomib 36 mg/m² n=3 Participants Participants received 36 mg/m² carfilzomib IV infusion on days 1, 2, 8, 9,15, and 16 of each 28 day cycle (on days 1 and 2 of cycle 1, all participants received carfilzomib at 20 mg/m²), cyclophosphamide administered orally at 300 mg/m² on days 1, 8, and 15, and 40 mg dexamethasone on days 1, 8, 15, and 22, for up to eight 28 day cycles, or until progressive disease (PD), unacceptable toxicity, withdrawal of consent, or death.	Carfilzomib 45 mg/m² n=3 Participants Participants received 45 mg/m² carfilzomib IV infusion on days 1, 2, 8, 9,15, and 16 of each 28 day cycle (on days 1 and 2 of cycle 1, all participants received carfilzomib at 20 mg/m²), cyclophosphamide administered orally at 300 mg/m² on days 1, 8, and 15, and 40 mg dexamethasone on days 1, 8, 15, and 22, for up to eight 28 day cycles, or until progressive disease (PD), unacceptable toxicity, withdrawal of consent, or death.	Carfilzomib 56 mg/m² n=16 Participants Participants received 56 mg/m² carfilzomib IV infusion on days 1, 2, 8, 9,15, and 16 of each 28 day cycle (on days 1 and 2 of cycle 1, all participants received carfilzomib at 20 mg/m²), cyclophosphamide administered orally at 300 mg/m² on days 1, 8, and 15, and 40 mg dexamethasone on days 1, 8, 15, and 22, for up to eight 28 day cycles, or until progressive disease (PD), unacceptable toxicity, withdrawal of consent, or death.
Number of Participants With Dose-limiting Toxicities (DLTs)	0 participants	0 participants	0 participants

SECONDARY outcome

Timeframe: Disease response was assessed at the end of each cycle and 30 days after the last treatment; maximum treatment duration was 32 weeks.

Population: Safety population

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.

Outcome measures

Outcome measures
Measure	Carfilzomib 36 mg/m² n=3 Participants Participants received 36 mg/m² carfilzomib IV infusion on days 1, 2, 8, 9,15, and 16 of each 28 day cycle (on days 1 and 2 of cycle 1, all participants received carfilzomib at 20 mg/m²), cyclophosphamide administered orally at 300 mg/m² on days 1, 8, and 15, and 40 mg dexamethasone on days 1, 8, 15, and 22, for up to eight 28 day cycles, or until progressive disease (PD), unacceptable toxicity, withdrawal of consent, or death.	Carfilzomib 45 mg/m² n=3 Participants Participants received 45 mg/m² carfilzomib IV infusion on days 1, 2, 8, 9,15, and 16 of each 28 day cycle (on days 1 and 2 of cycle 1, all participants received carfilzomib at 20 mg/m²), cyclophosphamide administered orally at 300 mg/m² on days 1, 8, and 15, and 40 mg dexamethasone on days 1, 8, 15, and 22, for up to eight 28 day cycles, or until progressive disease (PD), unacceptable toxicity, withdrawal of consent, or death.	Carfilzomib 56 mg/m² n=16 Participants Participants received 56 mg/m² carfilzomib IV infusion on days 1, 2, 8, 9,15, and 16 of each 28 day cycle (on days 1 and 2 of cycle 1, all participants received carfilzomib at 20 mg/m²), cyclophosphamide administered orally at 300 mg/m² on days 1, 8, and 15, and 40 mg dexamethasone on days 1, 8, 15, and 22, for up to eight 28 day cycles, or until progressive disease (PD), unacceptable toxicity, withdrawal of consent, or death.
Overall Response Rate (ORR)	66.7 percentage of participants Interval 9.4 to 99.2	100.0 percentage of participants Interval 29.2 to 100.0	87.5 percentage of participants Interval 61.7 to 98.4

SECONDARY outcome

Timeframe: Disease response was assessed at the end of each cycle and 30 days after the last treatment; maximum treatment duration was 32 weeks.

Population: Participants with an overall response

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.

Outcome measures

Outcome measures
Measure	Carfilzomib 36 mg/m² n=2 Participants Participants received 36 mg/m² carfilzomib IV infusion on days 1, 2, 8, 9,15, and 16 of each 28 day cycle (on days 1 and 2 of cycle 1, all participants received carfilzomib at 20 mg/m²), cyclophosphamide administered orally at 300 mg/m² on days 1, 8, and 15, and 40 mg dexamethasone on days 1, 8, 15, and 22, for up to eight 28 day cycles, or until progressive disease (PD), unacceptable toxicity, withdrawal of consent, or death.	Carfilzomib 45 mg/m² n=3 Participants Participants received 45 mg/m² carfilzomib IV infusion on days 1, 2, 8, 9,15, and 16 of each 28 day cycle (on days 1 and 2 of cycle 1, all participants received carfilzomib at 20 mg/m²), cyclophosphamide administered orally at 300 mg/m² on days 1, 8, and 15, and 40 mg dexamethasone on days 1, 8, 15, and 22, for up to eight 28 day cycles, or until progressive disease (PD), unacceptable toxicity, withdrawal of consent, or death.	Carfilzomib 56 mg/m² n=14 Participants Participants received 56 mg/m² carfilzomib IV infusion on days 1, 2, 8, 9,15, and 16 of each 28 day cycle (on days 1 and 2 of cycle 1, all participants received carfilzomib at 20 mg/m²), cyclophosphamide administered orally at 300 mg/m² on days 1, 8, and 15, and 40 mg dexamethasone on days 1, 8, 15, and 22, for up to eight 28 day cycles, or until progressive disease (PD), unacceptable toxicity, withdrawal of consent, or death.
Time To Response (TTR)	1.3 months Interval 1.0 to 1.6	0.8 months Interval 0.7 to 1.9	1.0 months Interval 0.9 to 2.8

SECONDARY outcome

Timeframe: From first dose of study drug until 30 days after last dose; median duration of treatment was 31 weeks.

Population: Safety population

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.

Outcome measures

Outcome measures
Measure	Carfilzomib 36 mg/m² n=3 Participants Participants received 36 mg/m² carfilzomib IV infusion on days 1, 2, 8, 9,15, and 16 of each 28 day cycle (on days 1 and 2 of cycle 1, all participants received carfilzomib at 20 mg/m²), cyclophosphamide administered orally at 300 mg/m² on days 1, 8, and 15, and 40 mg dexamethasone on days 1, 8, 15, and 22, for up to eight 28 day cycles, or until progressive disease (PD), unacceptable toxicity, withdrawal of consent, or death.	Carfilzomib 45 mg/m² n=3 Participants Participants received 45 mg/m² carfilzomib IV infusion on days 1, 2, 8, 9,15, and 16 of each 28 day cycle (on days 1 and 2 of cycle 1, all participants received carfilzomib at 20 mg/m²), cyclophosphamide administered orally at 300 mg/m² on days 1, 8, and 15, and 40 mg dexamethasone on days 1, 8, 15, and 22, for up to eight 28 day cycles, or until progressive disease (PD), unacceptable toxicity, withdrawal of consent, or death.	Carfilzomib 56 mg/m² n=16 Participants Participants received 56 mg/m² carfilzomib IV infusion on days 1, 2, 8, 9,15, and 16 of each 28 day cycle (on days 1 and 2 of cycle 1, all participants received carfilzomib at 20 mg/m²), cyclophosphamide administered orally at 300 mg/m² on days 1, 8, and 15, and 40 mg dexamethasone on days 1, 8, 15, and 22, for up to eight 28 day cycles, or until progressive disease (PD), unacceptable toxicity, withdrawal of consent, or death.
Number of Participants With Adverse Events Any adverse event	3 participants	3 participants	16 participants
Number of Participants With Adverse Events Adverse event ≥ Grade 3	3 participants	3 participants	10 participants
Number of Participants With Adverse Events Serious adverse events	0 participants	1 participants	5 participants
Number of Participants With Adverse Events AE leading to discontinuation of study drug	0 participants	1 participants	4 participants
Number of Participants With Adverse Events Fatal adverse events	0 participants	1 participants	0 participants

Adverse Events

Carfilzomib 36 mg/m²

Serious events: 0 serious events

Other events: 3 other events

Deaths: 0 deaths

Carfilzomib 45 mg/m²

Serious events: 1 serious events

Other events: 3 other events

Deaths: 0 deaths

Carfilzomib 56 mg/m²

Serious events: 5 serious events

Other events: 16 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Carfilzomib 36 mg/m² n=3 participants at risk Participants received 36 mg/m² carfilzomib IV infusion on days 1, 2, 8, 9,15, and 16 of each 28 day cycle (on days 1 and 2 of cycle 1, all participants received carfilzomib at 20 mg/m²), cyclophosphamide administered orally at 300 mg/m² on days 1, 8, and 15, and 40 mg dexamethasone on days 1, 8, 15, and 22, for up to eight 28 day cycles, or until progressive disease (PD), unacceptable toxicity, withdrawal of consent, or death.	Carfilzomib 45 mg/m² n=3 participants at risk Participants received 45 mg/m² carfilzomib IV infusion on days 1, 2, 8, 9,15, and 16 of each 28 day cycle (on days 1 and 2 of cycle 1, all participants received carfilzomib at 20 mg/m²), cyclophosphamide administered orally at 300 mg/m² on days 1, 8, and 15, and 40 mg dexamethasone on days 1, 8, 15, and 22, for up to eight 28 day cycles, or until progressive disease (PD), unacceptable toxicity, withdrawal of consent, or death.	Carfilzomib 56 mg/m² n=16 participants at risk Participants received 56 mg/m² carfilzomib IV infusion on days 1, 2, 8, 9,15, and 16 of each 28 day cycle (on days 1 and 2 of cycle 1, all participants received carfilzomib at 20 mg/m²), cyclophosphamide administered orally at 300 mg/m² on days 1, 8, and 15, and 40 mg dexamethasone on days 1, 8, 15, and 22, for up to eight 28 day cycles, or until progressive disease (PD), unacceptable toxicity, withdrawal of consent, or death.
Cardiac disorders Coronary artery occlusion	0.00% 0/3 • From the first dose of study medication until 30 days after the last dose; median duration of treatment was 31 weeks. Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.	33.3% 1/3 • From the first dose of study medication until 30 days after the last dose; median duration of treatment was 31 weeks. Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.	0.00% 0/16 • From the first dose of study medication until 30 days after the last dose; median duration of treatment was 31 weeks. Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.
General disorders Pyrexia	0.00% 0/3 • From the first dose of study medication until 30 days after the last dose; median duration of treatment was 31 weeks. Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.	0.00% 0/3 • From the first dose of study medication until 30 days after the last dose; median duration of treatment was 31 weeks. Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.	6.2% 1/16 • From the first dose of study medication until 30 days after the last dose; median duration of treatment was 31 weeks. Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.
Infections and infestations Sepsis	0.00% 0/3 • From the first dose of study medication until 30 days after the last dose; median duration of treatment was 31 weeks. Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.	0.00% 0/3 • From the first dose of study medication until 30 days after the last dose; median duration of treatment was 31 weeks. Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.	6.2% 1/16 • From the first dose of study medication until 30 days after the last dose; median duration of treatment was 31 weeks. Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.
Infections and infestations Urinary tract infection	0.00% 0/3 • From the first dose of study medication until 30 days after the last dose; median duration of treatment was 31 weeks. Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.	0.00% 0/3 • From the first dose of study medication until 30 days after the last dose; median duration of treatment was 31 weeks. Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.	6.2% 1/16 • From the first dose of study medication until 30 days after the last dose; median duration of treatment was 31 weeks. Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.
Metabolism and nutrition disorders Dehydration	0.00% 0/3 • From the first dose of study medication until 30 days after the last dose; median duration of treatment was 31 weeks. Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.	0.00% 0/3 • From the first dose of study medication until 30 days after the last dose; median duration of treatment was 31 weeks. Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.	6.2% 1/16 • From the first dose of study medication until 30 days after the last dose; median duration of treatment was 31 weeks. Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.
Metabolism and nutrition disorders Hypoglycaemia	0.00% 0/3 • From the first dose of study medication until 30 days after the last dose; median duration of treatment was 31 weeks. Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.	0.00% 0/3 • From the first dose of study medication until 30 days after the last dose; median duration of treatment was 31 weeks. Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.	6.2% 1/16 • From the first dose of study medication until 30 days after the last dose; median duration of treatment was 31 weeks. Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.
Renal and urinary disorders Acute kidney injury	0.00% 0/3 • From the first dose of study medication until 30 days after the last dose; median duration of treatment was 31 weeks. Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.	0.00% 0/3 • From the first dose of study medication until 30 days after the last dose; median duration of treatment was 31 weeks. Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.	12.5% 2/16 • From the first dose of study medication until 30 days after the last dose; median duration of treatment was 31 weeks. Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.
Respiratory, thoracic and mediastinal disorders Pneumonia aspiration	0.00% 0/3 • From the first dose of study medication until 30 days after the last dose; median duration of treatment was 31 weeks. Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.	0.00% 0/3 • From the first dose of study medication until 30 days after the last dose; median duration of treatment was 31 weeks. Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.	6.2% 1/16 • From the first dose of study medication until 30 days after the last dose; median duration of treatment was 31 weeks. Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.

Other adverse events

Additional Information

Study Director

Amgen, Inc.

Phone: 866-572-6436

Results disclosure agreements

Principal investigator is a sponsor employee The Clinical Trial Agreement generally does not restrict an investigator's discussion of trial results after completion. The Agreement permits Amgen a limited period of time to review material discussing trial results (typically up to 45 days and possible extension). Amgen may remove confidential information, but authors have final control and approval of publication content. For multicenter studies, the investigator agrees not to publish any results before the first multi-center publication.
Publication restrictions are in place

Restriction type: OTHER