An Investigational Drug, Palbociclib (PD-0332991), Is Being Studied In Combination With Velcade And Dexamethasone In Patients With Multiple Myeloma. Patients Must Have Received Prior Treatment For Multiple Myeloma.

Multiple Myeloma Clinical Trial

Official title:

Phase 1/2 Open-label Study Of The Safety And Efficacy Of Pd 0332991 In Combination With Bortezomib And Dexamethasone In Patients With Refractory Multiple Myeloma

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00555906
• Other study ID #: A5481004
• Secondary ID: 2010-022515-20
• Status: Completed
• Phase: Phase 2
• First received: November 8, 2007
• Last updated: March 4, 2015
• Start date: January 2008
• Est. completion date: March 2013

Study information

• Verified date: March 2015
• Source: Pfizer
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

This is a Phase 1/2 study evaluating the safety and anti-tumor activity of PD 0332991 in combination with Velcade® [bortezomib] and dexamethasone in patients who have received at least one previous treatment for multiple myeloma.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 53
• Est. completion date: March 2013
• Est. primary completion date: August 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Diagnosis of symptomatic multiple myeloma as defined by International Myeloma Working Group (IMWGURC).

• Phase 1: Relapsed or relapsed/refractory myeloma after at least 1 previous treatments and with a life expectancy of more than 3 months.

• Phase 2: Measurable (as defined by IMWGURC) disease after at least 1 previous treatment.

Exclusion Criteria:

• History of allogeneic stem cell transplant.

• Phase 2 only: Prior bortezomib therapy will only be allowed if there was a demonstrated positive response, and disease progression occurred off therapy.

• Must have not experienced significant blood level changes, e.g. very low platelets, while on previous bortezomib therapy

• Prior radiation therapy to > 25% of the bone marrow (whole pelvis is 25%).

Study Design

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Multiple Myeloma
• Neoplasms, Plasma Cell

Intervention

Drug:
• Bortezomib
Escalating doses of bortezomib will be administered intravenously on Days 8, 11, 15 and 18 of a 28-day cycle (Schedule A) or of a 21-day cycle (Schedule B). The planned doses to be evaluated are 0.7, 1 and 1.3 mg/m2 in combination with PD 0332991 and dexamethasone.
• Dexamethasone
20 mg, orally on Days 8, 11, 15 and 18 of a 28 day cycle (Schedule A) or of a 21-day cycle (Schedule B) in combination with PD 0332991 and bortezomib.
• PD 0332991
Escalating doses of PD 0332991 will be administered orally on Days 1-21 of a 28-day cycle for Schedule A and on Days 1-12 of a 21-day cycle for Schedule B. The planned doses to be evaluated are 50, 75, 100 mg and 125 mg once daily in combination with bortezomib and dexamethasone.

Locations

Country	Name	City	State
Czech Republic	Vseobecna fakultni nemocnice v Praze	Praha 2
Germany	Universitaetsklinikum Heidelberg	Heidelberg
Germany	Klinikum Johannes-Gutenberg -Universitaet, III. Medizinische Klinik und Poliklinik	Mainz
United States	University of Maryland	Baltimore	Maryland
United States	Roswell Park Cancer Institute	Buffalo	New York
United States	Hollings Cancer Center	Charleston	South Carolina
United States	Medical University of South Carolina	Charleston	South Carolina
United States	Northwestern Medical Faculty Foundation	Chicago	Illinois
United States	Northwestern Memorial Hospital/Main Labs	Chicago	Illinois
United States	Karmanos Cancer Institute	Detroit	Michigan
United States	University of Kansas Medical Center	Kansas City	Kansas
United States	New York Presbyterian, Weill Cornell Medical College	New York	New York
United States	Nebraska Methodist Hospital	Omaha	Nebraska
United States	University of Pennsylvania Abramson Cancer Center	Philadelphia	Pennsylvania
United States	University of Pittsburgh Cancer Institute	Pittsburgh	Pennsylvania
United States	Barnes-Jewish Hospital	St. Louis	Missouri
United States	Washington University School of Medicine	St. Louis	Missouri
United States	Washington University School of Medicine	St. Louis	Missouri
United States	University of Kansas Cancer Center and Medical Pavilion	Westwood	Kansas

Sponsors (1)

Lead Sponsor	Collaborator
Pfizer

Countries where clinical trial is conducted

United States,  Czech Republic,  Germany, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Maximum Tolerated Dose (MTD) of PD-0332991: Phase 1	MTD=highest dose level for which no more than 1 out of 6 participants experienced dose-limiting toxicity (DLT). DLT=any of the following treatment-related events: Absolute neutrophil count (ANC) less than (<)1000/microliter (mcL) (Grade 3 neutropenia) associated with documented infection/fever >=38.5degrees Celsius (C); Grade >=3 nonhematologic treatment-related toxicity, except those that were not maximally treated or considered tolerable, Grade 3 corrected QT interval (QTc) prolongation (QTc >500 millisecond [msec]) in asymptomatic participants even after repeat testing to exclude confounding factors and correction of reversible causes; Delay in the administration of Cycle 2 for more than 1 week of the planned date due to platelet count <25,000/mcL and/or ANC <500/mcL, or due to prolonged nonhematologic toxicities of Grade >=3; Inability to deliver at least 80 percent (%) of the planned PD 0332991 or bortezomib doses during Cycle 1 due to toxicity.	Day 1 up to Day 28 during Cycle 1 in schedule A, Day 1 up to Day 21 during Cycle 1 in schedule B	Yes
Primary	Recommended Phase II Dose (RP2D) of PD-0332991: Phase 1	RP2D was determined based on the MTD, safety and tolerability profile of the study treatment.	Day 1 up to Day 28 during Cycle 1 in schedule A, Day 1 up to Day 21 during Cycle 1 in schedule B	Yes
Primary	Percentage of Participants With Objective Response (OR): Phase 2	OR: confirmed stringent complete response(sCR),complete response(CR),very good partial response(VGPR) or partial response(PR) as per International Myeloma Working Group Uniform Response Criteria (IMWGURC). sCR: normal serum free light chain (FLC) ratio, absence of clonal cells in bone marrow. CR: disappearance of any soft tissue plasmacytomas, <5 percent (%) plasma cells in bone marrow, negative immunofixation on serum, urine. VGPR: serum, urine M-protein detectable by immunofixation but not on electrophoresis, >= 90% reduction in serum M-protein, <100 mg/24 hour (hr) urine M-protein. PR: >=50% reduction in serum M-protein, reduction in 24-hr urinary M-protein by >=90% or to <200 mg/24 hr, >=50% decrease in difference between involved and uninvolved FLC levels if serum, urine M-protein were unmeasurable, >= 50% reduction in plasma cells, provided baseline bone marrow plasma cell was >=30% if serum, urine M-protein were unmeasurable and serum free light assay was unmeasureable.	Cycle 1 Day 1 (baseline) up to end of study (up to cycle 22 for schedule B)	No
Secondary	Percent Change From Screening in Phosphorylated Retinoblastoma (Rb), Tumor Biomarkers and Soluble Biomarkers Levels: Phase 1		Screening, C1D1(baseline), C1D8, C1D15, C2D1, C3D1, C4D1, C5D1, C6D1, C7D1, C8D1, C9D1, C10D1, C11D1, C12D1, C13D1, C14D1, C15D1, C16D1, C17D1, C18D1, C19D1, C20D1, C21D1, C22D1, End of Treatment (assessment at early withdrawal occurring up to Cycle 22)	No
Secondary	Best Overall Response: Phase 1	Best overall response: best confirmed response on study after first study dose as per IMWGURC. sCR: normal FLC ratio, absence of clonal cells in bone marrow. CR: negative immunofixation on serum and urine, disappearance of any soft tissue plasmacytomas, <5% plasma cells in bone marrow. VGPR: serum and urine M-protein detectable by immunofixation but not on electrophoresis, >=90% reduction in serum M-protein, <100 mg/24 hr urine M-protein. PR: >=50% reduction of serum M-protein, reduction in 24-hr urinary M-protein by >=90% or to <200mg/24 hr. Progressive disease (PD): >=25% increase from lowest response level in serum M-component or urine M-component, >=10% bone marrow plasma cell percentage, definite development of new bone lesions/soft tissue plasmacytomas/definite increase in size of existing bone lesions/soft tissue plasmacytomas, development of hypercalcemia, attributed solely to plasma cell proliferative disorder. Stable disease (SD): criteria for CR, VGPR, PR or PD not met.	Cycle 1 Day 1 (baseline), assessed on Day 1 of every cycle up to end of study (up to Cycle 22 for schedule A and schedule B)	No
Secondary	Time to Tumor Progression (TTP): Phase 2	TTP was defined as the time from first dose of study medication to first documentation of objective tumor progression. TTP was calculated as (first event date minus the date of first dose of study medication plus 1) divided by 30.44. Tumor progression was determined from oncologic assessment data (where data meet the criteria for progressive disease [PD] per IMWGURC). PD: >=25% increase from lowest response level in serum M-component or urine M-component, >=10% bone marrow plasma cell percentage, definite development of new bone lesions/soft tissue plasmacytomas/definite increase in size of existing bone lesions/soft tissue plasmacytomas, development of hypercalcemia, attributed solely to plasma cell proliferative disorder.	Cycle 1 Day 1 (baseline) up to 28 days after last dose of palbociclib	No
Secondary	Progression-free Survival (PFS): Phase 2	PFS was the time from start of study treatment to date progressive disease was documented or death due to any cause, whichever occurred first. PFS was calculated as (first event date minus the date of first dose of study medication plus 1) divided by 30.44. Tumor progression was determined from oncologic assessment data (where data meet the criteria for progressive disease [PD]), or from adverse event (AE) data (where the outcome was "Death"). PD: >=25% increase from lowest response level in serum M-component or urine M-component, >=10% bone marrow plasma cell percentage, definite development of new bone lesions/soft tissue plasmacytomas/definite increase in size of existing bone lesions/soft tissue plasmacytomas, development of hypercalcemia, attributed solely to plasma cell proliferative disorder.	Cycle 1 Day 1 (baseline) up to 28 days after last dose of palbociclib	No
Secondary	Duration of Objective Response (DR): Phase 2	DR was defined as time from first documentation of objective tumor response (sCR, CR, VGPR or PR) that was subsequently confirmed to first documentation of objective tumor progression or death due to any cause since treatment started. sCR: normal FLC ratio, absence of clonal cells in bone marrow. CR: disappearance of any soft tissue plasmacytomas, <5% plasma cells in bone marrow, negative immunofixation on serum, urine. VGPR: serum, urine M-protein detectable by immunofixation but not on electrophoresis, >=90% reduction in serum M-protein, <100 mg/24hr urine M-protein. PR:>=50% reduction in serum M-protein, reduction in 24-hr urinary M-protein by >=90% or to <200 mg/24 hr. PD: >=25% increase from lowest response level in serum M-component, urine M-component, >=10% bone marrow plasma cell percentage, development of new bone lesions/soft tissue plasmacytomas/increase in size of existing bone lesions, development of hypercalcemia, attributed solely to plasma cell proliferative disorder.	Cycle 1 Day 1 (baseline) up to 28 days after last dose of palbociclib	No
Secondary	Overall Survival (OS): Phase 2	OS was defined as the time from first dose of study medication to first documentation of death due to any cause. OS was calculated as (the death date or last known alive date [if death date unavailable] minus the date of first dose of study medication plus 1) divided by 30.44.	Cycle 1 Day 1 (baseline) up to end of study (up to Cycle 22 for schedule B), thereafter every 3 months until 1 year after the last dose of palbociclib	No
Secondary	Number of Participants With Adverse Events (AEs) by Severity: Phase 2	An AE was any untoward medical occurrence attributed to study medication in a participant who received study medication. A serious AE (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Adverse events were graded according to the common terminology criteria for adverse events (CTCAE) criteria as 1=mild AE, 2=moderate AE, 3=severe AE, 4=life-threatening or disabling AE, 5=Death related to AE. The most severe grade was used in case of multiple occurrences of the same event.	Cycle 1 Day 1 (baseline) up to 28 days after last dose of palbociclib	Yes
Secondary	Number of Participants With Treatment-Emergent Adverse Events (TEAEs) by Relationship to Study Medication: Phase 2	An AE was any untoward medical occurrence attributed to study medication in a participant who received study medication. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent are events between first dose of study medication until 28 days after the last dose of study medication that were absent before treatment or that worsened relative to pretreatment state. All causality AEs included SAEs as well as non-serious AEs, without regard to relationship to the study medication, which occurred during the trial. Treatment-related were adverse events (serious as well as non-serious adverse events) considered related to study medication by the investigator. Number of participants with treatment related TEAEs and all causality TEAEs were summarized.	Cycle 1 Day 1 (baseline) up to 28 days after last dose of palbociclib	Yes
Secondary	Number of Participants With Laboratory Abnormalities: Phase 2	Laboratory parameters included hematology (hemoglobin, platelets, leukocytes, total neutrophils, eosinophils, basophils, lymphocytes, monocytes); liver function (total bilirubin, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, albumin, total protein); renal function (creatinine, blood urea nitrogen, uric acid); electrolytes (sodium, potassium, chloride, bicarbonate, calcium, magnesium and phosphate); urinalysis (protein and immunology [C reactive protein]), and clinical chemistry (glucose). Total number of participants with laboratory abnormalities was reported.	Cycle 1 Day 1 (baseline) up to 28 days after last dose of palbociclib	Yes
Secondary	European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (EORTC QLQ-C30): Phase 2	EORTC QLQ-C30: included functional scales (physical, role, cognitive, emotional, and social), global health status, symptom scales (fatigue, pain, nausea/vomiting) and single items (dyspnea, appetite loss, insomnia, constipation, diarrhea and financial difficulties). Most questions used 4 point scale (1 'Not at all' to 4 'Very much'); 2 questions used 7-point scale (1 'very poor' to 7 'Excellent'). Scores for functional scales, global health status and symptom scales were calculated as an average of individual items, transformed to 0-100 scale; higher score=better level of functioning, health status or greater degree of symptoms. Score of the single items were transformed to 0-100 scale; higher score=greater degree of symptom/difficulty.	C1D1 (baseline), C1D8, C1D15, C2D1, C3D1, C4D1, C5D1, C6D1, C7D1, C8D1, C9D1, C10D1, C11D1, C12D1, C13D1, C14D1, C15D1, C16D1, C17D1, C18D1, C19D1, C20D1, C21D1, C22D1, End of Treatment (assessment at early withdrawal occurring up to Cycle 22)	No
Secondary	Quality of Life Questionnaire Multiple Myeloma Module (QLQ-MY20): Phase 2	The QLQ-MY20 consisted of 20 items addressing 4 domains of health-related quality of life (HRQoL) important to participants with multiple myeloma: future perspective (2 items), pain/disease symptoms (6 items), social support /body image (2 items), and treatment side-effects (10 items). All items used 4 point scale (1 'Not at all' to 4 'Very much'). Scores for HRQoL domains were calculated as an average of the individual items, transformed to 0 to 100 range. Higher scores on symptom scales (disease symptoms and side effects of treatment) indicated a higher level of symptoms/problems. Higher scores on functional scales (future perspective and body image) indicated a higher level of QoL/functioning.	C1D1 (baseline), C1D8, C1D15, C2D1, C3D1, C4D1, C5D1, C6D1, C7D1, C8D1, C9D1, C10D1, C11D1, C12D1, C13D1, C14D1, C15D1, C16D1, C17D1, C18D1, C19D1, C20D1, C21D1, C22D1, End of Treatment (assessment at early withdrawal occurring up to Cycle 22)	No
Secondary	Modified Version of Brief Pain Inventory - Short Form (m-BPI-sf) Questionnaire: Phase 2	m-BPI-sf was a questionnaire designed to assess the severity of pain and the impact of pain on daily functions. m-BPI-sf contained questions that assessed pain severity (worst, least, average, right now) and pain interference (general activity, mood, walking ability, normal work, relations with other people, sleep, and enjoyment of life). Each question was answered on a scale ranging from 0 "No pain" to 10 "Pain as bad as you can imagine". The 4 pain severity questions were averaged to derive an index of pain severity and the 7 function questions were averaged to derive an index for pain interference. Total score range for pain severity and interference indices: 0 to 10, where higher score indicated higher severity/interference.	C1D1 (baseline), C1D8, C1D15, C2D1, C3D1, C4D1, C5D1, C6D1, C7D1, C8D1, C9D1, C10D1, C11D1, C12D1, C13D1, C14D1, C15D1, C16D1, C17D1, C18D1, C19D1, C20D1, C21D1, C22D1, End of Treatment (assessment at early withdrawal occurring up to Cycle 22)	No

External Links

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