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.

• ClinicalTrials.gov Identifier: NCT00555906
• Recruitment Status: Completed
• First Posted: November 9, 2007
• Results First Posted: March 19, 2015
• Last Update Posted: March 19, 2015
• Sponsor: Pfizer
• Information provided by (Responsible Party): Pfizer

Tracking Information

• First Submitted Date: November 8, 2007
• First Posted Date: November 9, 2007
• Results First Submitted Date: March 4, 2015
• Results First Posted Date: March 19, 2015
• Last Update Posted Date: March 19, 2015
• Study Start Date: January 2008
• Actual Primary Completion Date: August 2012 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 4, 2015)

• Maximum Tolerated Dose (MTD) of PD-0332991: Phase 1 [ Time Frame: Day 1 up to Day 28 during Cycle 1 in schedule A, Day 1 up to Day 21 during Cycle 1 in schedule B ]
  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.
• Recommended Phase II Dose (RP2D) of PD-0332991: Phase 1 [ Time Frame: Day 1 up to Day 28 during Cycle 1 in schedule A, Day 1 up to Day 21 during Cycle 1 in schedule B ]
  RP2D was determined based on the MTD, safety and tolerability profile of the study treatment.
• Percentage of Participants With Objective Response (OR): Phase 2 [ Time Frame: Cycle 1 Day 1 (baseline) up to end of study (up to cycle 22 for schedule B) ]
  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.

Original Primary Outcome Measures (submitted: November 8, 2007)

• Phase 1 - determine the maximum tolerated dose and recommended Phase 2 dose for PD 0332991 in combination with bortezomib and dexamethasone [ Time Frame: 9 mo ]
• Phase 2 - determine the objective response rate of PD 0332991 in combination with bortezomib and dexamethasone [ Time Frame: 1.5 yr ]

• Change History: Complete list of historical versions of study NCT00555906 on ClinicalTrials.gov Archive Site

Current Secondary Outcome Measures (submitted: March 4, 2015)

• Percent Change From Screening in Phosphorylated Retinoblastoma (Rb), Tumor Biomarkers and Soluble Biomarkers Levels: Phase 1 [ Time Frame: 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) ]
• Best Overall Response: Phase 1 [ Time Frame: 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) ]
  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.
• Time to Tumor Progression (TTP): Phase 2 [ Time Frame: Cycle 1 Day 1 (baseline) up to 28 days after last dose of palbociclib ]
  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.
• Progression-free Survival (PFS): Phase 2 [ Time Frame: Cycle 1 Day 1 (baseline) up to 28 days after last dose of palbociclib ]
  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.
• Duration of Objective Response (DR): Phase 2 [ Time Frame: Cycle 1 Day 1 (baseline) up to 28 days after last dose of palbociclib ]
  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.
• Overall Survival (OS): Phase 2 [ Time Frame: 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 ]
  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.
• Number of Participants With Adverse Events (AEs) by Severity: Phase 2 [ Time Frame: Cycle 1 Day 1 (baseline) up to 28 days after last dose of palbociclib ]
  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.
• Number of Participants With Treatment-Emergent Adverse Events (TEAEs) by Relationship to Study Medication: Phase 2 [ Time Frame: Cycle 1 Day 1 (baseline) up to 28 days after last dose of palbociclib ]
  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.
• Number of Participants With Laboratory Abnormalities: Phase 2 [ Time Frame: Cycle 1 Day 1 (baseline) up to 28 days after last dose of palbociclib ]
  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.
• European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (EORTC QLQ-C30): Phase 2 [ Time Frame: 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) ]
  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.
• Quality of Life Questionnaire Multiple Myeloma Module (QLQ-MY20): Phase 2 [ Time Frame: 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) ]
  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.
• Modified Version of Brief Pain Inventory - Short Form (m-BPI-sf) Questionnaire: Phase 2 [ Time Frame: 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) ]
  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.

Original Secondary Outcome Measures (submitted: November 8, 2007)

• Phase 1 - changes in the phosphorylation status of the Rb protein in myeloma cells [ Time Frame: 9 mo ]
• Phase 2 - determine the time to progression, progression-free survival, duration of response and overall survival of PD 0332991 in combination with bortezomib and dexamethasone [ Time Frame: 1.5 yr ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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.
• 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
• Brief 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.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Multiple Myeloma

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.
  Other Name: Velcade
• Drug: 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.
• Drug: 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.

Study Arms

Experimental: 1

Interventions:

• Drug: Bortezomib
• Drug: Dexamethasone
• Drug: PD 0332991

• Publications *: Niesvizky R, Badros AZ, Costa LJ, Ely SA, Singhal SB, Stadtmauer EA, Haideri NA, Yacoub A, Hess G, Lentzsch S, Spicka I, Chanan-Khan AA, Raab MS, Tarantolo S, Vij R, Zonder JA, Huang X, Jayabalan D, Di Liberto M, Huang X, Jiang Y, Kim ST, Randolph S, Chen-Kiang S. Phase 1/2 study of cyclin-dependent kinase (CDK)4/6 inhibitor palbociclib (PD-0332991) with bortezomib and dexamethasone in relapsed/refractory multiple myeloma. Leuk Lymphoma. 2015;56(12):3320-8. doi: 10.3109/10428194.2015.1030641. Epub 2015 May 15.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: March 14, 2012): 53
• Original Estimated Enrollment (submitted: November 8, 2007): 62
• Actual Study Completion Date: March 2013
• Actual Primary Completion Date: August 2012 (Final data collection date for primary outcome measure)

Eligibility Criteria

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%).

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Czech Republic, Germany, United States

Administrative Information

• NCT Number: NCT00555906
• Other Study ID Numbers: A5481004; 2010-022515-20 ( EudraCT Number )
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Pfizer
• Study Sponsor: Pfizer
• Collaborators: Not Provided

Investigators

• Study Director: Pfizer CT.gov Call Center; Pfizer

• PRS Account: Pfizer
• Verification Date: March 2015