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

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ClinicalTrials.gov Identifier: NCT01478581
Recruitment Status : Active, not recruiting
First Posted : November 23, 2011
Results First Posted : June 25, 2018
Last Update Posted : June 25, 2018
Sponsor:
Information provided by (Responsible Party):
Pharmacyclics LLC.

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)

Condition or disease Intervention/treatment Phase
Multiple Myeloma Drug: PCI-32765 Drug: Dexamethasone Phase 2

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.

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 92 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : March 2012
Actual Primary Completion Date : January 2017
Estimated Study Completion Date : August 2018

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Multiple Myeloma

Arm Intervention/treatment
Experimental: Cohort 1
PCI-32765 420 mg per day
Drug: PCI-32765
Other Name: Ibrutinib

Experimental: Cohort 2
PCI-32765 560 mg per day, 40 mg dexamethasone (oral) once per week
Drug: PCI-32765
Other Name: Ibrutinib

Drug: Dexamethasone
Experimental: Cohort 3
PCI-32765 840 mg per day
Drug: PCI-32765
Other Name: Ibrutinib

Experimental: Cohort 4
PCI-32765 840 mg per day, 40 mg dexamethasone (oral) once per week
Drug: PCI-32765
Other Name: Ibrutinib

Drug: Dexamethasone



Primary Outcome Measures :
  1. The Clinical Benefit Response (CBR) [ Time Frame: 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 Outcome Measures :
  1. To Evaluate the Efficacy of PCI-32765 by Assessing ORR [ Time Frame: 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.

  2. Pharmacokinetics (PK). (Assessed by Sampling and Testing for Drug and Metabolite Levels at Designated Time Points). Mean Maximum Observed Plasma Concentration (Cmax) [ Time Frame: 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.

  3. Pharmacokinetics (PK) (Assessed by Sampling and Testing for Drug and Metabolite Levels at Designated Time Points). Mean Time to Maximum Observed Plasma Concentration (Tmax). [ Time Frame: 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.

  4. 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). [ Time Frame: 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.

  5. Pharmacokinetics (PK) (Assessed by Sampling and Testing for Drug and Metabolite Levels at Designated Time Points). Mean Terminal Elimination Half-life (t1/2,Term). [ Time Frame: 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.

  6. 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) [ Time Frame: 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.

  7. 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) [ Time Frame: 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.

  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) [ Time Frame: 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.

  9. Duration of Clinical Benefit Response (DCB) [ Time Frame: 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.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01478581


Locations
United States, California
SITE-13
La Jolla, California, United States, 92093
United States, Maryland
SITE-5
Baltimore, Maryland, United States, 21287
United States, Massachusetts
SITE-4
Boston, Massachusetts, United States, 02215
United States, Michigan
SITE-8
Ann Arbor, Michigan, United States, 48109
United States, Missouri
SITE-2
Saint Louis, Missouri, United States, 63110
United States, New Jersey
SITE-6
Hackensack, New Jersey, United States, 07601
United States, New York
SITE-10
New York, New York, United States, 10029
SITE-3
New York, New York, United States, 10065
United States, Tennessee
SITE-1
Nashville, Tennessee, United States, 37203
United States, Texas
SITE-11
Dallas, Texas, United States, 75390
United States, Washington
SITE-9
Seattle, Washington, United States, 98109
Sponsors and Collaborators
Pharmacyclics LLC.

Responsible Party: Pharmacyclics LLC.
ClinicalTrials.gov Identifier: NCT01478581     History of Changes
Other Study ID Numbers: PCYC-1111-CA
PCI-32765 ( Other Identifier: Sponsor )
First Posted: November 23, 2011    Key Record Dates
Results First Posted: June 25, 2018
Last Update Posted: June 25, 2018
Last Verified: May 2018

Keywords provided by Pharmacyclics LLC.:
PCI-32765
Multiple Myeloma
Relapsed Refractory Multiple Myeloma
Bruton's Tyrosine Kinase

Additional relevant MeSH terms:
Multiple Myeloma
Neoplasms, Plasma Cell
Neoplasms by Histologic Type
Neoplasms
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Lymphoproliferative Disorders
Immunoproliferative Disorders
Immune System Diseases
Dexamethasone acetate
Dexamethasone
BB 1101
Anti-Inflammatory Agents
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Protease Inhibitors
Enzyme Inhibitors