Clinical trial NCT01478581: Study of the Bruton's Tyrosine Kinase Inhibitor in Subjects With Relapsed or Relapsed and Refractory Multiple Myeloma
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Multiple Myeloma
Keywords: PCI-32765
Multiple Myeloma
Relapsed Refractory Multiple Myeloma
Bruton's Tyrosine Kinase
Lead sponsor: Pharmacyclics LLC.
Sponsor class: INDUSTRY
First posted: 2011-11-23
Enrollment: 92
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: The Clinical Benefit Response (CBR)
timeFrame: From the date of first study treatment until disease progression per IMWG, up to 60 months
Secondary outcomes:
measure: To Evaluate the Efficacy of PCI-32765 by Assessing ORR
timeFrame: From the date of first study treatment until disease progression per IMWG, up to 60 months
measure: Pharmacokinetics (PK). (Assessed by Sampling and Testing for Drug and Metabolite Levels at Designated Time Points). Mean Maximum Observed Plasma Concentration (Cmax)
timeFrame: Procedure was performed up to 60 weeks.
measure: Pharmacokinetics (PK) (Assessed by Sampling and Testing for Drug and Metabolite Levels at Designated Time Points). Mean Time to Maximum Observed Plasma Concentration (Tmax).
timeFrame: Procedure was performed up to 60 weeks.
measure: 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).
timeFrame: Procedure was performed up to 60 weeks.
measure: Pharmacokinetics (PK) (Assessed by Sampling and Testing for Drug and Metabolite Levels at Designated Time Points). Mean Terminal Elimination Half-life (t1/2,Term).
timeFrame: Procedure was performed up to 60 weeks.
measure: 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)
timeFrame: Procedure was performed up to 60 weeks.
measure: 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)
timeFrame: Procedure was performed up to 60 weeks.
measure: 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)
timeFrame: Procedure was performed up to 60 weeks.
measure: Duration of Clinical Benefit Response (DCB)
timeFrame: From the date of first study treatment until disease progression per IMWG, up to 60 months
measure: Duration of Response (DOR)
timeFrame: up to 3 Years
Other outcomes:
Locations:
city: La Jolla
country: United States
facility: SITE-13
state: California
city: Baltimore
country: United States
facility: SITE-5
state: Maryland
city: Boston
country: United States
facility: SITE-4
state: Massachusetts
city: Ann Arbor
country: United States
facility: SITE-8
state: Michigan
city: Saint Louis
country: United States
facility: SITE-2
state: Missouri
city: Hackensack
country: United States
facility: SITE-6
state: New Jersey
city: New York
country: United States
facility: SITE-10
state: New York
city: New York
country: United States
facility: SITE-3
state: New York
city: Nashville
country: United States
facility: SITE-1
state: Tennessee
city: Dallas
country: United States
facility: SITE-11
state: Texas
city: Seattle
country: United States
facility: SITE-9
state: Washington
Study officials:
References: