MTD, Safety, and Efficacy of Pomalidomide (CC-4047) Alone or With Low-dose Dexamethasone in Patients With Relapsed and Refractory Multiple Myeloma

Multiple Myeloma Clinical Trial

Official title:

A Phase I/II Multicenter, Randomized, Open Label, Dose-Escalation Study To Determine The Maximum Tolerated Dose, Safety, And Efficacy Of CC-4047 Alone Or In Combination With Low-Dose Dexamethasone In Patients Wth Relapsed And Refractory Multiple Myeloma Who Have Received Prior Treatment That Includes Lenalidomide And Bortezomib

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00833833
• Other study ID #: CC-4047-MM-002
• Status: Completed
• Phase: Phase 1/Phase 2
• First received: January 30, 2009
• Last updated: January 6, 2016
• Start date: June 2008
• Est. completion date: September 2015

Study information

• Verified date: January 2016
• Source: Celgene
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug AdministrationUnited States: Institutional Review Board
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to determine the maximum tolerated dose and effectiveness of the study drug (CC-4047) Alone Or in Combination With Low-dose Dexamethasone as treatment for patients with relapsed and refractory multiple myeloma

Description:

The Phase 1 segment of the study was designed to determine the maximum tolerated dose (MTD) of single-agent pomalidomide, which was to be determined in the first cycle of treatment. Following completion of the first cycle, participants were allowed to continue the study at their assigned dose of pomalidomide.

Participants who developed progressive disease (PD) at any time, or who had not achieved at least a 25% reduction of serum myeloma (M)-protein levels (if measurable) and a 50% reduction of urine M-protein (if measurable) compared with baseline after completion of 4 cycles of pomalidomide, had the option to receive oral dexamethasone 40 mg on days 1, 8, 15, and 22 of each 28-day treatment cycle in addition to their current dose of pomalidomide. Participants with PD who chose not to add dexamethasone to pomalidomide therapy were to be discontinued from the study. Participants who chose to add dexamethasone were allowed to continue study treatment until PD developed again, unacceptable toxicity or participant withdrew consent, at which time they were to be discontinued.

Based on results from the phase 1 portion, the Data Monitoring Committee confirmed 4 mg/day as MTD of pomalidomide. Therefore, the recommended starting dose of pomalidomide for Phase 2 was 4 mg/day on Days 1-21 of each 28-day cycle. In the combination treatment arm, the starting dose of dexamethasone was 40 mg once per day. For subjects who were > 75 years of age, the starting dose of dexamethasone was 20 mg once per day. To prevent blood clots, all participants were to be given aspirin 81-100 mg daily (commercial supply) unless contraindicated. If contraindicated, another form of anti-thrombotic therapy was provided.

Participants in the Phase II combination treatment arm could continue study treatment until PD developed, at which time they were to be discontinued. Participants in the single agent pomalidomide treatment arm who developed PD, confirmed by the IRAC, at any time had the option to receive oral dexamethasone in addition to their current dose of pomalidomide at the starting dose described above. Participants with PD who chose not to add dexamethasone to pomalidomide therapy were discontinued from study treatment. Participants who chose to add dexamethasone to pomalidomide therapy could continue study treatment until PD developed again, unacceptable toxicity or participant withdrew consent, at which point they were discontinued.

Upon discontinuation from study treatment for PD or any other reason, participants were to be assessed two times per year, up to five years, for survival, second primary malignancy and subsequent anti-myeloma therapies.

Two analyses were planned during the course of the Phase 2 segment: one interim analysis (at 50% information of progression-free survival (PFS) events) and one final analysis. The Data Monitoring Commmittee recommended that Celgene personnel be unblinded based on the strength of the data. Subsequently, Celgene decided to file an application based on more current study data. The product was approved by the FDA in February 2013.

Since no further analyses are required per protocol nor to support the marketing application, the study was amended to remove undue burden from patients who remain on active treatment by ending the treatment segments of this study and transferring all active patients tothe Long-term Follow-up Phase. These patients who continue to be treated with pomalidomide will be provided Pomalyst through the Celgene Patient Support Program (Pomalyst REMSTM) until disease progression, unacceptable toxicity, the investigator decides to change therapy or patient decision. Investigators will treat their patients according to the local standard of care and follow the assessments required for patients in the Long-term Follow-up Phase. These assessments include subsequent myeloma therapies, second primary malignancies and survival.

The study continues. A final analysis will be performed when the study is completed and results reported as available.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 259
• Est. completion date: September 2015
• Est. primary completion date: April 2011
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Must be greater than or equal to 18 years at the time of signing the informed consent form

• Must be able to adhere to the study visit schedule and other protocol requirements

• Have a documented diagnosis of multiple myeloma and have relapsed and refractory disease. Patients must have received at least 2 prior therapies. Patients must have relapsed after having achieved at least stable disease for at least one cycle of treatment to at least one prior regimen and then developed PD. Patients must also have documented evidence of PD during or within 60 days (measured from the end of the last cycle) of completing treatment with the last anti-myeloma drug regimen used just prior to study entry (refractory disease)

• Patients must have also undergone prior treatment with at least 2 cycles of lenalidomide and at least 2 cycles of bortezomib (either in separate regimens or within the same regimen)

• Measurable levels of myeloma paraprotein in serum (greater than or equal to 0.5 g/dL) or urine (greater than or equal 0.2 g/dL excreted in a 24 hour collection sample)

• Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2

• Females of childbearing potential (FCBP) [An FCBP is a sexually mature woman who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., who has had menses at any time in the preceding 24 consecutive months)] must agree to refrain from becoming pregnant for 28 days prior to initiation of study drug, while on study drug and for 28 days after discontinuation of study drug and must agree to regular pregnancy testing during this timeframe.

• All patients must also agree to refrain from donating blood while on study drug and for 28 days after discontinuation from this study

• Males must agree to use a latex condom during any sexual contact with FCBP while participating in the study and for 28 days following discontinuation from this study even if he has undergone a successful vasectomy. Males must also agree to refrain from donating blood, semen or sperm during the above referenced timeframe.

• All patients must agree not to share medication with another person.

Exclusion Criteria:

• Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the patient from signing the informed consent form.

• Any serious concurrent medical conditions that may make the patient non-evaluable or put the patient's safety at risk.

• Pregnant or lactating females

• Any of the following laboratory abnormalities:

• Absolute neutrophil count (ANC) < 1,000 cells/mm3

• Platelet count < 75,000/mm3 for patients in whom < 50% of bone marrow nucleated cells are plasma cells; or a platelet count < 30,000/mm3 for patients in whom = 50% of bone marrow nucleated cells are plasma cells

• Serum creatinine > 3.0 mg/dL

• Serum glutamic oxaloacetic transaminase/Aspartate transaminase (SGOT/AST) or Serum Glutamic Pyruvate Transaminase/Alanine transaminase (SGPT/ALT) > 3.0 X upper limit of normal (ULN)

• Serum total bilirubin > 2.0 mg/dL

• Prior history of malignancies, other than multiple myeloma, unless the patient has been free of the disease for = 3 years. Exceptions include the following:

• Basal or squamous cell carcinoma of the skin

• Carcinoma in situ of the cervix or breast

• Incidental histologic finding of prostate cancer (TNM stage of T1a or T1b)

• Known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV) and/or Hepatitis C Virus (HCV) infection

• Hypersensitivity to thalidomide, lenalidomide, or dexamethasone

• Peripheral neuropathy = Grade 2

• Use of any anti-myeloma drug therapy within 14 days of the initiation of study drug treatment or use of any experimental non-drug therapy within 28 days of the initiation of study drug treatment

• Radiation therapy within 14 days of initiation of study drug treatment Inability or unwillingness to comply with birth control requirements

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Multiple Myeloma
• Neoplasms, Plasma Cell

Intervention

Drug:
• Pomalidomide
1 mg, 2 mg, and 5 mg capsules for oral administration packaged in bottles containing a 21-day supply
• Dexamethasone
oral dexamethasone
• Aspirin
As prophylactic anti-thrombotic treatment, all participants were given aspirin 81-100 mg daily (commercial supply) unless contraindicated. If aspirin was contraindicated, participants were given another form of anti-thrombotic therapy according to hospital guidelines or physician preference.

Locations

Country	Name	City	State
Canada	Tom Baker Cancer Center	Calgary	Alberta
Canada	Cross Cancer Institute	Edmonton	Alberta
Canada	Royal Victoria Hosptial	Montreal	Quebec
Canada	Princess Margaret Hospital and University of Toronto	Toronto	Ontario
Canada	Vancouver General Hospital	Vancouver	British Columbia
United States	University of Michigan Comprehensive Cancer CenterDivision of Hematology/Oncology	Ann Arbor	Michigan
United States	Winship Cancer Institute of Emory University	Atlanta	Georgia
United States	Dana-Farber Cancer Institute	Boston	Massachusetts
United States	Mass General Hospital	Boston	Massachusetts
United States	Roswell Park Cancer Institute Department of Medicine	Buffalo	New York
United States	Ohio State University Arthur G. James Cancer Hospital	Columbus	Ohio
United States	Colorado Blood Cancer Institute	Denver	Colorado
United States	The Cancer Center at Hackensack University Medical Center	Hackensack	New Jersey
United States	Mt. Sinai Hospital	New York	New York
United States	University of Pittsburgh	Pittsburgh	Pennsylvania
United States	Mayo Clinic - Arizona	Rochester	Minnesota
United States	Mayo Clinic Arizona	Scottsdale	Arizona
United States	Washington University School of Medicine	St. Louis	Missouri
United States	Moffitt Cancer Center	Tampa	Florida

Sponsors (1)

Lead Sponsor	Collaborator
Celgene Corporation

Countries where clinical trial is conducted

United States,  Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Phase 1: Participants With Dose-Limiting Toxicities (DLT) in Cycle 1	The maximum tolerated dose was defined as the highest dose level at which no more than 1 of 6 participants experiences a DLT within the first 28-day cycle.; DLTs were defined as: Grade 4 neutropenia or thrombocytopenia; Febrile neutropenia; Grade 3 or 4 nausea, vomiting or diarrhea despite optimal symptomatic treatment; Serum transaminase > 20 * upper limit of normal (ULN); Serum transaminase > 5 * ULN for >= 7 days; Delay of the start of cycle 2 by >7 days due to pomalidomide-related adverse event	Up to Day 28 (Cycle 1)	Yes
Primary	Phase 2: Kaplan-Meier Estimates of Progression-free Survival (PFS) as of the 01 April 2011 Cut-off	Progression free survival (PFS) is the time from randomization to the first documentation of disease progression or death from any cause during study, whichever occurs earlier. Disease progression was assessed by the Independent Response Adjudication Committee (IRAC).; For the primary PFS analysis, participants who withdrew for any reason or received another antimyeloma therapy (except adding dexamethasone to the Phase 2: Pomalidomide arm) without documented PD (as determined by the IRAC review) were censored on the date of their last adequate response assessment, prior to receiving any other anti-myeloma therapy. Subjects who were still active at the time of the data cut-off date without PD (as determined by the IRAC) were censored on the date of their last adequate response assessment.; Data collection is ongoing and future data results will be included as available.	up to 67 weeks	No
Primary	Phase 2: Percentage of Participants With Progression-Free Survival (PFS) Events as of the 01 April 2011 Cut-off	Percentage of participants with the progression-free survival events: disease progression and death. Disease progression was assessed by the Independent Response Adjudication Committee (IRAC).; Data collection is ongoing and future data results will be included as available.	up to 67 weeks	No
Secondary	Phase 1: Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs) While on Single-Agent Pomalidomide as of the 01 April 2011 Cut-off	Relation to study drug was assessed by the Investigator as either suspected or not suspected. Counts represent the suspected relationship. Severity was assessed using National Cancer Institute Common Toxicity Terminology Criteria for Adverse Events version 3.0 (NCI CTCAE v3.0): 1= Mild 2= Moderate 3= Severe 4= Life-threatening and 5= Death related to AE. Serious AEs (SAEs) are those that resulted in death, were life-threatening, required or prolonged inpatient hospitalization, resulted in persistent or significant disability/incapacity, congenital anomaly, or resulted in an important medical event that may have jeopardized the patient or required medical or surgical intervention to prevent one of the outcomes listed above.; Data collection is ongoing and future data results will be included as available.	Up to week 104	Yes
Secondary	Phase 1: Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs) While on Both Pomalidomide and Dexamethasone as of the 01 April 2011 Cut-off	TEAEs that occurred during Phase 1 after dexamethasone was added to pomalidomide treatment.; Relation to study drug was assessed by the Investigator as either suspected or not suspected. Counts represent the suspected relationship. Severity was assessed using National Cancer Institute Common Toxicity Terminology Criteria for Adverse Events version 3.0 (NCI CTCAE v3.0): 1= Mild 2= Moderate 3= Severe 4= Life-threatening and 5= Death related to AE. Serious AEs (SAEs) are those that resulted in death, were life-threatening, required or prolonged inpatient hospitalization, resulted in persistent or significant disability/incapacity, congenital anomaly, or resulted in an important medical event that may have jeopardized the patient or required medical or surgical intervention to prevent one of the outcomes listed above.; Data collection is ongoing and future data results will be included as available.	Up to week 126	Yes
Secondary	Phase 2: Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs) as of the 01 April 2011 Cut-off	Relation to study drug was assessed by the Investigator as either suspected or not suspected. Counts represent the suspected relationship. Severity was assessed using National Cancer Institute Common Toxicity Terminology Criteria for Adverse Events version 3.0 (NCI CTCAE v3.0): 1= Mild 2= Moderate 3= Severe 4= Life-threatening and 5= Death related to AE. Serious AEs (SAEs) are those that resulted in death, were life-threatening, required or prolonged inpatient hospitalization, resulted in persistent or significant disability/incapacity, congenital anomaly, or resulted in an important medical event that may have jeopardized the patient or required medical or surgical intervention to prevent one of the outcomes listed above.; Data collection is ongoing and future data results will be included as available.	Up to week 70	Yes
Secondary	Phase 2: Summary of Best Myeloma Response As Assessed by Independent Response Adjudication Committee (IRAC) Using European Group for Blood and Bone Marrow Transplant (EBMT) Criteria as of the 01 April 2011 Cut-off	IRAC used EBMT criteria to assess myeloma response: Complete Response (CR)-absence of serum and urine monoclonal paraprotein for 6 weeks, plus no increase in size or number of lytic bone lesions, plus other factors); Partial Response (PR)-not all CR criteria, plus >=50% reduction in serum monoclonal paraprotein plus others; Minimal Response (MR)- 25-49% reduction in serum monoclonal paraprotein plus others; Stable Disease (SD)- not MR or progressive disease (PD); Progressive Disease (PD)- reappearance of monoclonal paraprotein, lytic bone lesions, other; Not Evaluable (NE).; Data collection is ongoing and future data results will be included as available.	up to 70 weeks	No
Secondary	Phase 2: Kaplan-Meier Estimates of Duration of Response as of the 01 April 2011 Cut-off	Duration of myeloma response is defined as the time from when the response criteria are first met for partial response (PR) or better, until the first date the response criteria are met for progressive disease (PD) or until the participant dies from any cause, whichever occurs first. Duration of response for participants last known to be alive with no progression after a complete response (CR) or PR was censored at the date of last adequate response assessment. Participants with confirmed responses that occur after receiving any other anti-myeloma therapy (except for adding dexamethasone to the pomalidomide treatment arm), including radiation therapy initiated after baseline, was censored at the last adequate assessment prior to the initiation of such treatment.; Response was assessed by the Independent Response Adjudication Committee (IRAC) using European Group for Blood and Bone Marrow Transplant (EBMT) criteria as described in the previous outcome.	up to 70 weeks	No
Secondary	Phase 2: Time to Response as of the 01 April 2011 Cut-off	Time to myeloma response is defined as the time from randomization to the time the response criteria for complete response (CR) or partial response (PR) are first met.; Response was assessed by the Independent Response Adjudication Committee (IRAC) using European Group for Blood and Bone Marrow Transplant (EBMT) criteria as described previously.; Data collection is ongoing and future data results will be included as available.	up to 70 weeks	No
Secondary	Phase 2: Kaplan-Meier Estimates of Overall Survival as of the 01 April 2011 Cut-off	Overall survival was defined as the time between randomization and death. Participants who die, regardless of the cause of the death, were considered to have had an event. All participants who were lost to follow-up prior to the end of the trial or who were withdrawn from the trial were censored at the time of last contact. Participants who were still being treated were censored at the last available date the subject was known to be alive, or clinical cut-off date if it was earlier.; Data collection is ongoing and future data results will be included as available.	up to 70 weeks	No