Study of the Bruton's Tyrosine Kinase Inhibitor in Subjects With Relapsed or Relapsed and Refractory Multiple Myeloma

A Multicenter Phase 2 Study of the Bruton's Tyrosine Kinase (Btk) Inhibitor, PCI-32765, in Subjects With Relapsed or Relapsed and Refractory Multiple Myeloma

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01478581

Enrollment

Registered

2011-11-23

Start date

2012-03-31

Completion date

2018-08-31

Last updated

2020-03-10

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Multiple Myeloma

Keywords

PCI-32765, Multiple Myeloma, Relapsed Refractory Multiple Myeloma, Bruton's Tyrosine Kinase

Brief summary

The primary objective of this study is to determine the efficacy of PCI-32765, both as a single agent and in combination with dexamethasone, in subjects with relapsed or relapsed and refractory Multiple Myeloma (MM)

Detailed description

Bruton's tyrosine kinase (Btk) is an enzyme that is present in hematopoietic cells other than T cells and is necessary for downstream signal transduction from various hematopoietic receptors including the B cell receptor as well as some Fc, chemokine, and adhesion receptors, and is crucial for both B cell development and osteoclastogenesis. Although down-regulated in normal plasma cells, Btk is highly expressed in the malignant cells from many myeloma patients and some cell lines. PCI 32765 is a potent and specific inhibitor of Btk currently in Phase 2 clinical trials. The current study is designed and intended to determine the effects of PCI-32765 in subjects with MM.

Interventions

DRUGPCI-32765

DRUGDexamethasone

Study design

Allocation

NON_RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

Inclusion criteria

* Diagnosis of symptomatic MM with measurable disease, defined here as having at least one of the following: 1. Serum monoclonal protein (M-protein) ≥0.5 g/dL as determined by serum protein electrophoresis (SPEP) 2. Urine M-protein ≥200 mg/24 hrs 3. Serum free light chain (FLC) assay: involved FLC level ≥10 mg/dL (≥100 mg/L) provided serum FLC ratio is abnormal * Relapsed or relapsed and refractory MM after receiving at least 2 but no more than 5 previous lines of therapy, 1 of which must be an immunomodulator. * Refractory myeloma (to most recent treatment) is defined as disease that is nonresponsive while on treatment or progressive disease within 60 days after the completion of preceding treatment. Nonresponsive disease is defined as either failure to achieve minimal response or development of progressive disease while on therapy. * Men and women ≥18 years of age. * ECOG performance status of ≤ 1.

Exclusion criteria

* Subject must not have primary refractory disease defined as disease that is nonresponsive in subjects who have never achieved a minor response (MR) or better with any therapy. * Polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes (POEMS) syndrome, osteosclerotic myeloma, or Crow-Fukase syndrome. * Plasma cell leukemia. * Primary amyloidosis. * Certain exclusions on prior therapy. * ANC \<0.75 x 10\^9/L independent of growth factor support. * Platelets \<50 x 10\^9/L) independent of transfusion support. * AST or ALT ≥3.0 x upper limit of normal (ULN). * Total bilirubin \>2.5 x ULN, unless due to Gilbert's syndrome. * Creatinine \>2.5 mg/dL. * Unable to swallow capsules or disease significantly affecting gastrointestinal function. * Requires anti-coagulation with warfarin or a vitamin K antagonist. Requires treatment with strong CYP3A4/5 inhibitors.

Design outcomes

Primary

Measure	Time frame	Description
The Clinical Benefit Response (CBR)	From the date of first study treatment until disease progression per IMWG, up to 60 months	The clinical benefit response (CBR) rate, defined as the proportion of subjects who achieved stringent complete response (sCR), complete response (CR), very good partial response (VGPR), partial response (PR), or minimal response (MR) as assessed by the modified International Myeloma Working Group (IMWG) response criteria

Secondary

Measure	Time frame	Description
Pharmacokinetics (PK). (Assessed by Sampling and Testing for Drug and Metabolite Levels at Designated Time Points). Mean Maximum Observed Plasma Concentration (Cmax)	Procedure was performed up to 60 weeks.	Ibrutinib and PCI-45227 concentrations were measurable following once-daily dosing of ibrutinib in subjects with MM. The following time-points were included: 0hr, 1hr, 2hr, 7hr, 24hr post-dose. Maximum observed plasma concentration of ibrutinib during the dosing interval on Day 8.
Pharmacokinetics (PK) (Assessed by Sampling and Testing for Drug and Metabolite Levels at Designated Time Points). Mean Time to Maximum Observed Plasma Concentration (Tmax).	Procedure was performed up to 60 weeks.	Ibrutinib and PCI-45227 concentrations were measurable following once-daily dosing of ibrutinib in subjects with MM. The following time-points were included: 0hr, 1hr, 2hr, 7hr, 24hr post-dose. Time to corresponding maximum observed plasma concentration of ibrutinib during the dosing interval on Day 8.
Pharmacokinetics (PK) (Assessed by Sampling and Testing for Drug and Metabolite Levels at Designated Time Points). Mean Area Under the Plasma Concentration-Time Curve From Time 0 to 24 Hours (AUC0-24h).	Procedure was performed up to 60 weeks.	Ibrutinib and PCI-45227 concentrations were measurable following once-daily dosing of ibrutinib in subjects with MM. The following time-points were included: 0hr, 1hr, 2hr, 7hr, 24hr post-dose. Ibrutinib AUC0-24h calculated using linear trapezoidal summation after dosing from time 0 to 24 hours on Day 8.
Pharmacokinetics (PK) (Assessed by Sampling and Testing for Drug and Metabolite Levels at Designated Time Points). Mean Terminal Elimination Half-life (t1/2,Term).	Procedure was performed up to 60 weeks.	Ibrutinib and PCI-45227 concentrations were measurable following once-daily dosing of ibrutinib in subjects with MM. The following time-points were included: 0hr, 1hr, 2hr, 7hr, 24hr post-dose. Ibrutinib terminal elimination half-life associated with the terminal slope (λz) of the semi-logarithmic plasma concentration-time curve, calculated as 0.693/λz on Day 8.
To Evaluate the Efficacy of PCI-32765 by Assessing ORR	From the date of first study treatment until disease progression per IMWG, up to 60 months	The objective response rate, defined as the proportion of subjects who achieved stringent complete response (sCR), complete response (CR), very good partial response (VGPR), or partial response (PR), as assessed by the modified International Myeloma Working Group (IMWG) response criteria.
Pharmacokinetics (PK) (Assessed by Sampling and Testing for Drug and Metabolite Levels at Designated Time Points). Mean Metabolite-to-Parent Ratio for Cmax (M/P Cmax)	Procedure was performed up to 60 weeks.	Ibrutinib and PCI-45227 concentrations were measurable following once-daily dosing of ibrutinib in subjects with MM. The following time-points were included: 0hr, 1hr, 2hr, 7hr, 24hr post-dose. Calculated as (PCI-45227 Cmax/PCI-45227 molecular weight)/(ibrutinib Cmax/ibrutinib molecular weight) on Day 8.
Pharmacokinetics (PK) (Assessed by Sampling and Testing for Drug and Metabolite Levels at Designated Time Points). Mean Metabolite-to-Parent Ratio for AUC0-24h (M/P AUC0-24h)	Procedure was performed up to 60 weeks.	Ibrutinib and PCI-45227 concentrations were measurable following once-daily dosing of ibrutinib in subjects with MM. The following time-points were included: 0hr, 1hr, 2hr, 7hr, 24hr post-dose. Calculated as (PCI-45227 AUC0-24h/PCI-45227 molecular weight)/(ibrutinib AUC0-24h/ibrutinib molecular weight) on Day 8.
Duration of Clinical Benefit Response (DCB)	From the date of first study treatment until disease progression per IMWG, up to 60 months	DCB is defined as the time from first observation of response to the time of disease progression.
Duration of Response (DOR)	up to 3 Years	The time interval between the date of initial documentation of a response and the date of first documented evidence of progressive disease, death, or date of censoring for the subjects not progressed/died. The censoring date is the last adequate tumor assessment date.
Pharmacokinetics (PK) (Assessed by Sampling and Testing for Drug and Metabolite Levels at Designated Time Points). Mean Accumulation Ratio for AUC0-24h (Acc. Ratio AUC0-24h)	Procedure was performed up to 60 weeks.	Ibrutinib and PCI-45227 concentrations were measurable following once-daily dosing of ibrutinib in subjects with MM. The following time-points were included: 0hr, 1hr, 2hr, 7hr, 24hr post-dose. Acc. Ratio calculated as Day 8 ibrutinib AUC0-24h/ Day 1 ibrutinib AUC0-24h.

Countries

United States

Participant flow

Pre-assignment details

Simon 2-stage design . Stage 1 -13 subjects enrolled in cohort 1. For cohort 2,3, and 4, up to 18 subjects were enrolled in Stage 1. Cohort 4 was selected for expansion for enrollment of 43 subjects in Stage 2.

Participants by arm

Arm	Count
Cohort 1 PCI-32765 420 mg per day PCI-32765	13
Cohort 2 PCI-32765 560 mg per day, 40 mg dexamethasone (oral) once per week PCI-32765 Dexamethasone	18
Cohort 3 PCI-32765 840 mg per day PCI-32765	18
Cohort 4 PCI-32765 840 mg per day, 40 mg dexamethasone (oral) once per week PCI-32765 Dexamethasone	43
Total	92

Baseline characteristics

Characteristic	Cohort 1	Total	Cohort 4	Cohort 3	Cohort 2
Age, Continuous	62.0 years STANDARD_DEVIATION 7.57	65.0 years STANDARD_DEVIATION 7.63	65.0 years STANDARD_DEVIATION 7.4	65.5 years STANDARD_DEVIATION 7.52	65.5 years STANDARD_DEVIATION 8.44
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants	7 Participants	6 Participants	1 Participants	0 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	13 Participants	82 Participants	34 Participants	17 Participants	18 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants	3 Participants	3 Participants	0 Participants	0 Participants
Race (NIH/OMB) Other Race American Indian or Alaska Native	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Other Race Asian	0 Participants	1 Participants	0 Participants	1 Participants	0 Participants
Race (NIH/OMB) Other Race Black or African American	2 Participants	18 Participants	6 Participants	4 Participants	6 Participants
Race (NIH/OMB) Other Race More than one race	0 Participants	1 Participants	0 Participants	1 Participants	0 Participants
Race (NIH/OMB) Other Race Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Other Race Unknown or Not Reported	1 Participants	5 Participants	4 Participants	0 Participants	0 Participants
Race (NIH/OMB) Other Race White	10 Participants	67 Participants	33 Participants	12 Participants	12 Participants
Region of Enrollment United States	13 participants	92 participants	43 participants	18 participants	18 participants
Sex: Female, Male Female	5 Participants	36 Participants	17 Participants	5 Participants	9 Participants
Sex: Female, Male Male	8 Participants	56 Participants	26 Participants	13 Participants	9 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk
deaths Total, all-cause mortality	2 / 13	1 / 18	1 / 18	1 / 43
other Total, other adverse events	12 / 13	18 / 18	17 / 18	43 / 43
serious Total, serious adverse events	6 / 13	6 / 18	7 / 18	12 / 43

Outcome results

Primary

The Clinical Benefit Response (CBR)

The clinical benefit response (CBR) rate, defined as the proportion of subjects who achieved stringent complete response (sCR), complete response (CR), very good partial response (VGPR), partial response (PR), or minimal response (MR) as assessed by the modified International Myeloma Working Group (IMWG) response criteria

Time frame: From the date of first study treatment until disease progression per IMWG, up to 60 months

Population: All treated population

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
Cohort 1	The Clinical Benefit Response (CBR)	1 Participants
Cohort 2	The Clinical Benefit Response (CBR)	1 Participants
Cohort 3	The Clinical Benefit Response (CBR)	0 Participants
Cohort 4	The Clinical Benefit Response (CBR)	12 Participants

Secondary

Duration of Clinical Benefit Response (DCB)

DCB is defined as the time from first observation of response to the time of disease progression.

Time frame: From the date of first study treatment until disease progression per IMWG, up to 60 months

Population: Clinical benefit responders.

Arm	Measure	Value (MEDIAN)
Cohort 1	Duration of Clinical Benefit Response (DCB)	27.6 Months
Cohort 2	Duration of Clinical Benefit Response (DCB)	3.7 Months
Cohort 4	Duration of Clinical Benefit Response (DCB)	11.5 Months

Secondary

Duration of Response (DOR)

The time interval between the date of initial documentation of a response and the date of first documented evidence of progressive disease, death, or date of censoring for the subjects not progressed/died. The censoring date is the last adequate tumor assessment date.

Time frame: up to 3 Years

Population: Responders

Arm	Measure	Value (MEDIAN)
Cohort 2	Duration of Response (DOR)	3.7 Month
Cohort 4	Duration of Response (DOR)	15.4 Month

Secondary

Pharmacokinetics (PK) (Assessed by Sampling and Testing for Drug and Metabolite Levels at Designated Time Points). Mean Accumulation Ratio for AUC0-24h (Acc. Ratio AUC0-24h)

Ibrutinib and PCI-45227 concentrations were measurable following once-daily dosing of ibrutinib in subjects with MM. The following time-points were included: 0hr, 1hr, 2hr, 7hr, 24hr post-dose. Acc. Ratio calculated as Day 8 ibrutinib AUC0-24h/ Day 1 ibrutinib AUC0-24h.