Study to Evaluate the Safety and Efficacy of Pomalidomide Monotherapy in Subjects With Refractory or Relapsed Refractory Multiple Myeloma

Multiple Myeloma Clinical Trial

Official title:

Open-label, Multi-center, Single Arm Study For The Safety And Efficacy Of Pomalidomide Monotherapy For Subjects With Refractory Or Relapsed And Refractory Multiple Myeloma. A Companion Study For Clinical Trial CC-4047-MM003

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01324947
• Other study ID #: CC-4047-MM-003/C
• Secondary ID: 2010-023343-16
• Status: Completed
• Phase: Phase 3
• Start date: March 1, 2011
• Est. completion date: July 31, 2014

Study information

• Verified date: November 2019
• Source: Celgene
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to evaluate the efficacy and safety of pomalidomide monotherapy in subjects with refractory or relapsed and refractory multiple myeloma who were enrolled in study CC-4047-MM-003 (NCT01311687) and discontinued treatment with high-dose dexamethasone due to disease progression.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 74
• Est. completion date: July 31, 2014
• Est. primary completion date: July 31, 2014
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Subjects with refractory or relapsed and refractory multiple myeloma who were enrolled in Study CC-4047-MM-003 and discontinued study therapy with dexamethasone alone (Treatment Arm B) after at least starting the second cycle of dexamethasone treatment and due to development of documented disease progression according to the International Myeloma Working Group (IMWG) criteria and as decided by an Independent Review Adjudication Committee (IRAC).

2. Must be = 18 years at the time of signing the informed consent form.

3. The subject must understand and voluntarily sign an informed consent document prior to any study related assessments/procedures being conducted. The only exception is if a skeletal survey was performed within 90 days prior to the start of Cycle 1, then a new survey will not be required.

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

5. Subjects must have documented diagnosis of multiple myeloma and have measurable disease (serum M-protein = 0.5g/dL or urine M-protein = 200 mg/24 hours).

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

7. Females of childbearing potential (FCBP†) must agree to utilize two reliable forms of contraception simultaneously or practice true abstinence [when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post ovulation methods) and withdrawal are not acceptable methods of contraception]from heterosexual contact for at least 28 days before starting study drug, while participating in the study (including dose interruptions), and for at least 28 days after study treatment discontinuation and must agree to regular pregnancy testing during this timeframe.

8. Females must agree to abstain from breastfeeding during study participation and 28 days after study discontinuation.

9. Males must agree to either use a latex condom during any sexual contact with FCBP or practice true abstinence [when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception] while participating in the study and for 28 days following discontinuation from this study, even if he has undergone a successful vasectomy. .

10. Males must also agree to refrain from donating semen or sperm while on pomalidomide and for 28 days after discontinuation from this study treatment.

11. All subjects must agree to refrain from donating blood while on study drug and for 28 days after discontinuation from this study treatment.

12. All subjects must agree not to share study medication

Exclusion Criteria

• The presence of any of the following will exclude a subject from enrollment:

1. Subjects with multiple myeloma who were not treated as a part of Study CC-4047-MM-003 (Arm B).

2. Subjects who received any anti-myeloma or anti-cancer therapies within the last 14 days of wash-out period before initiation of study treatment.

3. Subjects who discontinued CC-4047-MM-003 study =120 days.

4. Subjects who initiate another anti-myeloma therapy from the time of disease progression on study CC-4047-MM-003 to the time of treatment initiation in the companion study.

5. Any of the following laboratory abnormalities:

• Absolute neutrophil count (ANC) < 1,000/µL.

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

• Creatinine Clearance < 45 mL/min according to Cockcroft-Gault formula (If creatinine clearance calculated from the 24-hour urine sample is =45 ml/min, patient will qualify for the trial)

• Corrected serum calcium > 14 mg/dL (> 3.5 mmol/L);

• Hemoglobin < 8 g/dL (< 4.9 mmol/L; prior RBC transfusion or recombinant human erythropoietin use is permitted)

• Serum SGOT/AST or SGPT/ALT > 3.0 x upper limit of normal (ULN)

• Serum total bilirubin > 2.0 mg/dL (34.2 µmol/L); or > 3.0 x ULN for subjects with hereditary benign hyperbilirubinaemia

6. Prior history of malignancies, other than Multiple Myeloma (MM), unless the subject has been free of the disease for = 5 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)

7. Hypersensitivity to thalidomide or lenalidomide. (This includes = Grade 3 rash during prior thalidomide or lenalidomide therapy).

8. Peripheral neuropathy = Grade 2.

9. Subjects who received an allogeneic bone marrow or allogeneic peripheral blood stem cell transplant less than 12 months prior to initiation of study treatment and who have not discontinued immunosuppressive treatment for at least 4 weeks prior to initiation of study treatment and are currently dependent on such treatment.

10. Subjects who are planning for or who are eligible for stem cell transplant.

11. Subjects with any one of the following:

• Congestive heart failure (NY Heart Association Class III or IV)

• Myocardial infarction within 12 months prior to starting study treatment

• Unstable or poorly controlled angina pectoris, including Prinzmetal variant angina pectoris

12. Subjects who received any of the following within the last 14 days of initiation of study treatment:

• Plasmapheresis

• Major surgery (kyphoplasty is not considered major surgery)

• Radiation therapy

13. Use of any investigational agents within 28 days or 5 half lives (whichever is longer) of treatment.

14. Subjects with chronic conditions such as rheumatoid arthritis, multiple sclerosis and lupus, which likely need additional steroid or immunosuppressive treatments in addition to the study treatment.

15. Any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study.

16. Incidence of gastrointestinal disease that may significantly alter the absorption of pomalidomide.

17. Subjects unable or unwilling to undergo antithrombotic prophylactic treatment.

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

19. Pregnant or breastfeeding females.

20. Known human immunodeficiency virus (HIV) positivity or active infectious hepatitis A, B or C.

Related Conditions & MeSH terms

• Multiple Myeloma
• Neoplasms, Plasma Cell

Intervention

Drug:
• pomalidomide
Oral pomalidomide 4 mg on Days 1-21 of 28-day cycle until progressive disease (PD) or unacceptable toxicity

Locations

Country	Name	City	State
Australia	Royal Adelaide Hospital - SA Pathology Haematology	Adelaide
Australia	Princess Alexandra Hospital - Haematology	Brisbane
Australia	Royal Prince Alfred Hospital - Institute of Haematology	Camperdown
Australia	Peter McCallum Cancer Institute - Directorate of Cancer Medicine	East Melbourne
Australia	Frankston Hospital-Peninsula Health - Oncology Day Unit	Frankston
Australia	The Alfred Hospital - Malignant Haematology & Stem Cell Transplantation	Melbourne
Australia	Calvary Mater Newcastle - Haematology	Waratah
Australia	Border Medical Oncology	Wodonga
Australia	Wollongong Hospital - Haematology	Wollongong
Belgium	UZ Gent - Hematology	Gent
Belgium	University Hospital Leuven - Hematology	Leuven
Belgium	Cliniques Universitaires ULC de Mont-Godinne - Hematology	Yvoir
Canada	Tom Baker Cancer Center	Calgary	Alberta
Canada	Cross Cancer Institute	Edmonton	Alberta
Canada	Queen Elizabeth II Health Sciences Centre	Halifax	Nova Scotia
Canada	London Health Sciences Centre	London	Ontario
Canada	Maisonneuve-Rosemont Hospital	Montreal	Quebec
Canada	Royal Victoria Hospital	Montreal	Quebec
Canada	Princess Margaret Hospital, University Health Network	Toronto	Ontario
Canada	British Columbia Cancer Agency, Vancouver Centre	Vancouver	British Columbia
Czechia	Charles University Hospital - Internal Medicine	Prague
Denmark	Aalborg Sygemus - Haematology	Aalborg
Denmark	Aarhus University Hospital	Aarhus
Denmark	Odense University Hospital	Odense
Denmark	Vejle Hospital - Hematology	Vejle
France	CHU Angers - Service des maladies du sang	Angers
France	Centre Hospitalier de la côte basque - Hematologie	Bayonne
France	Centre Hospitalier Départemental Vendée - Onco-hematologie	La Roche
France	CHRU de Lille - Service des maladies du sang	Lille
France	Institut Paoli Calmette - Hematology 1	Marseille
France	CHU Hôtel-Dieu - Hematologie	Nantes
France	CHU Saint Antoine - Service des maladies du sang	Paris
France	Hôpital Saint Louis - Immuno-hematologie	Paris
France	CHRU - Hôpital du Haut Lévêque - Centre François Magendie Service des maladies du sang	Pessac
France	Centre Hospitalier Lyon sud - Hematologie	Pierre-Benite
France	CHRU Hôpital Purpan - Hematologie	Toulouse
France	Hôpital Bretonneau - Hématologie & Thérapie cellulaire	Tours
France	CHU Nancy - Hematologie	Vandoeuvre-les-Nancy
Germany	Universitatsklinikum Carl Gustav Carus-Medizinische Klinik und Poliklinik I	Dresden
Germany	Universitätsklinikum Essen, Klinik für Hämatologie Westdeutsches Tumorzentrum	Essen
Germany	Askepios Klinik Altona-Abteilung Hamatologie und Internistische Onkologie	Hamburg
Germany	Universitätsklinikum Heidelberg - Medizinische Klinik und Poliklinik V	Heidelberg
Germany	Universitätsklinikum Jena - Klinik fur Innere Medizin II-Hamatologie/Onkologie	Jena
Germany	Universitätsklinikum Leipzig - Medizinische Klinik und Poliklinik II	Leipzig
Germany	Universitätsklinikum Münster - Medizinische Klinik und Poliklinik A	Münster
Germany	Universitätsklinikum Tübingen - Medizinische Klinik und Poliklinik - Abteilung II	Tübingen
Germany	Universitätsklinikum Ulm - Klinik fur Innere Medizin III	Ulm
Germany	Universitätsklinikum Würzburg - Medizinische Klinik und Poliklinik II	Würzburg
Greece	University of Athens - Alexandra Hospital	Athens
Italy	Università degli Studi di Bologna - Policlinico S. Orsola - Hematology	Bologna
Italy	AO Universitaria San Martino - hematooncology	Genova
Italy	Fondazione "G. Pascale" - Hematology	Napoli
Italy	Ospedale San Luigi AO Luigi Gonzaga - Hematology	Orbassano
Italy	Universita degli Studi di Padova - Clinical & Experimental Medicine	Padova
Italy	Ospedale Guglielmo da Saliceto - hematooncology	Piacenza
Italy	Unità di Ematologia Arcispedale S. Maria Nuova - Haematology	Reggio Emilia
Italy	Policlinico Umberto I, Università "La Sapienza" di Roma - Hematology	Roma
Italy	A.O.U. San Giovanni Battista - Hematology	Torino
Netherlands	VUMC - Hematology	Amsterdam
Netherlands	Erasmus Medical Center - Hematology	Rotterdam
Netherlands	University Medical Center - Hematology	Utrecht
Russian Federation	Hematological Research Center under the Russian Academy of Medical Sciences - Hematology & BMT	Moscow
Russian Federation	Moscow State Medical Institution Municipal Clinical Hospital n.a. S.P. Botkin - Hematology	Moscow
Russian Federation	Russian Research Institute of Hematology and Blood Transfusion - Hematology	St. Petersburg
Russian Federation	State Higher Educational Institution St. Petersburg State Medical University - Onco-hematology	St. Petersburg
Spain	Hospital Germans Trias i Pujol - Hematology	Badalona
Spain	Hospital Clinic i Provincial de Barcelona - Hematology	Barcelona
Spain	Hospital de Donostia - Hematology	Guipúzcoa
Spain	Hospital 12 de Octubre - Hematology	Madrid
Spain	Hospital de La Princesa - Hematology	Madrid
Spain	Hospital de Salamanca - Hematology	Salamanca
Spain	Hospital Universitario Marqués de Valdecilla - Hematology	Santander
Spain	Hospital La Fe - Hematology	Valencia
Sweden	Sahlgrenska Hospital, University of Goteborg - Hematology	Goteborg
Sweden	Karolinska University Hospital Huddinge - Center of hematology	Stockholm
Sweden	Karolinska University Hospital Solna- medicine	Stockholm
Sweden	Karolinska University Hospital-medicine	Stockholm
Sweden	Overlakare Medocomcentrum - Hematology	Uppsala
Switzerland	Inselspital, Institut für Medizinische Onkologie	Bern
Switzerland	Hôpitaux Universitaire de Genève - Oncologie	Genève
Switzerland	Klinik und Poliklinik für Onkologie - UniversitätsSpital Zürich	Zürich
United Kingdom	Royal Bournemouth Hospital - Haematology	Bournemouth
United Kingdom	St James's University Hospital - Haematology	Leeds
United Kingdom	King's College Hospital - Haematology Clinical Trials	London
United Kingdom	St Bartholomew's Hospital - Medical Oncology	London
United Kingdom	Freeman Hospital - Northern Centre for Cancer Care	Newcastle Upon Tyne
United Kingdom	Nottingham City Hospital - Centre for Clinical Haematology	Nottingham
United Kingdom	Derriford Hospital - Haematology	Plymouth
United Kingdom	Royal hallamshire Hospital - Haematology	Sheffield
United Kingdom	Royal Marsden NHS Foundation Trust - Haematology	Surrey
United Kingdom	Royal Wolverhampton Hospitals Trust - Research and Development	Wolverhampton

Sponsors (1)

Lead Sponsor	Collaborator
Celgene

Countries where clinical trial is conducted

Australia,  Belgium,  Canada,  Czechia,  Denmark,  France,  Germany,  Greece,  Italy,  Netherlands,  Russian Federation,  Spain,  Sweden,  Switzerland,  United Kingdom, 

References & Publications (3)

Miguel JS, Weisel K, Moreau P, Lacy M, Song K, Delforge M, Karlin L, Goldschmidt H, Banos A, Oriol A, Alegre A, Chen C, Cavo M, Garderet L, Ivanova V, Martinez-Lopez J, Belch A, Palumbo A, Schey S, Sonneveld P, Yu X, Sternas L, Jacques C, Zaki M, Dimopoulos M. Pomalidomide plus low-dose dexamethasone versus high-dose dexamethasone alone for patients with relapsed and refractory multiple myeloma (MM-003): a randomised, open-label, phase 3 trial. Lancet Oncol. 2013 Oct;14(11):1055-1066. doi: 10.1016/S1470-2045(13)70380-2. Epub 2013 Sep 3. — View Citation

Moreau P, Weisel KC, Song KW, Gibson CJ, Saunders O, Sternas LA, Hong K, Zaki MH, Dimopoulos MA. Relationship of response and survival in patients with relapsed and refractory multiple myeloma treated with pomalidomide plus low-dose dexamethasone in the MM-003 trial randomized phase III trial (NIMBUS). Leuk Lymphoma. 2016 Dec;57(12):2839-2847. Epub 2016 May 13. — View Citation

Morgan G, Palumbo A, Dhanasiri S, Lee D, Weisel K, Facon T, Delforge M, Oriol A, Zaki M, Yu X, Sternas L, Jacques C, Akehurst R, Offner F, Dimopoulos MA. Overall survival of relapsed and refractory multiple myeloma patients after adjusting for crossover in the MM-003 trial for pomalidomide plus low-dose dexamethasone. Br J Haematol. 2015 Mar;168(6):820-3. doi: 10.1111/bjh.13227. Epub 2014 Nov 18. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of Participants With an Objective Response According to International Myeloma Working Group (IMWG) Uniform Response Criteria Based on Investigator Assessment	Objective response defined as a best overall response of stringent complete response (SCR), complete response (CR), very good partial response (VGPR) or partial response (PR) based on Investigator Assessment.; SCR: CR and normal free light chain (FLC) ratio and no clonal cells in bone marrow; CR: Negative serum and urine on immunofixation, disappearance of any soft tissue plasmacytomas and =5% plasma cells in bone marrow; VGPR: Serum and urine M-protein detectable by immunofixation but not on electrophoresis or =90% reduction in serum M-protein and urine M-protein level <100 mg/24 hours; PR: =50% reduction of serum M-Protein and reduction in urinary M-protein by =90% or to <200 mg/24 hours. A =50% decrease in the difference between involved and uninvolved FLC levels in place of the M-protein criteria or a =50% reduction in plasma cells in place of M-protein if baseline was =30%. If present at baseline a =50% reduction in size of soft tissue plasmacytomas.	From randomization through the study follow-up phase; up to the data cut-off of 31 July 2014; Maximum time on follow-up was 141.1 weeks.
Secondary	Percentage of Participants With Objective Response According to European Group for Blood and Marrow Transplantation (EBMT) Criteria Based on Investigator Assessment	Objective response defined as a best overall response of complete response (CR) or partial response (PR) based on the CR and requires all of the following: Absence of original monoclonal paraprotein in serum and urine by immunofixation maintained at least 42 days.; <5% plasma cell in bone marrow aspirate and on bone marrow biopsy, if performed.; No increase in size or number of lytic bone lesions.; Disappearance of soft tissue plasmacytomas.; PR requires all of the following: =50% reduction in level of serum monoclonal paraprotein, maintained at least 42 days.; Reduction in 24-hour urinary light chain extraction by =90% or to <200 mg, maintained at least 42 days.; For patients with non-secretory myeloma, =50% reduction in plasma cells in bone marrow aspirate and on biopsy, if performed, for at least 42 days.	From randomization through the study follow-up phase; up to the data cut-off of 31 July 2014; Maximum time on follow-up was 141.1 weeks.
Secondary	Number of Participants With Adverse Events and Type of Adverse Events	An adverse event is any noxious, unintended, or untoward medical occurrence that may appear or worsen in a participant during the course of a study. A serious AE is any AE occurring at any dose that: Results in death; Is life-threatening; Requires or prolongs existing inpatient hospitalization; Results in persistent or significant disability/incapacity; Is a congenital anomaly/birth defect; Constitutes an important medical event.; The Investigator assessed the relationship of each AE to study drug and graded the severity according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE, Version 4.0): Grade 1 = Mild (no limitation in activity or intervention required); Grade 2 = Moderate (some limitation in activity; no/minimal medical intervention required);-Grade 3 = Severe (marked limitation in activity; medical intervention required, hospitalization possible); Grade 4 = Life-threatening; Grade 5 = Death	From first dose of study drug through to 30 days after the last dose, until the data cut-off date of 31 July 2014. Maximum time on treatment was 94.1 weeks.
Secondary	Kaplan Meier Estimates for Progression Free Survival (PFS) by Investigator Based on IMWG	Progression-free survival was calculated as the time from randomization to disease progression as determined by the Investigator based on the International Myeloma Working Group Uniform Response criteria (IMWG), or death on study, whichever occurred earlier.; Progressive disease requires 1 of the following: Increase of = 25% from nadir in: Serum M-component (absolute increase = 0.5 g/dl); Urine M-component (absolute increase = 200 mg/24 hours); In patients without measurable serum and urine M-protein levels the difference between involved and uninvolved free light chain (FLC) levels (absolute increase > 100 mg/dl); Bone marrow plasma cell percentage (absolute % = 10%); Development of new or increase in the size of existing bone lesions or soft tissue plasmacytomas.	From randomization through the follow-up phase; Maximum duration of follow-up for PFS was 90.3 weeks.
Secondary	Kaplan-Meier Estimate for Time to Progression (TTP) Based on Investigator Assessment Using IMWG Criteria	Time to progression (TTP) was calculated as the time from randomization to the first documented progression confirmed by the investigator and based on the International Myeloma Working Group Uniform Response criteria (IMWG).; Progressive disease requires 1 of the following: Increase of = 25% from nadir in: Serum M-component (absolute increase = 0.5 g/dl); Urine M-component (absolute increase = 200 mg/24 hours); In patients without measurable serum and urine M-protein levels the difference between involved and uninvolved free light chain (FLC) levels (absolute increase > 100 mg/dl); Bone marrow plasma cell percentage (absolute % = 10%); Development of new or increase in the size of existing bone lesions or soft tissue plasmacytomas.; Development of hypercalcemia (corrected serum calcium > 11.5 mg/dl) attributed solely to plasma cell proliferative disease.	From randomization through the follow-up phase; up to the data-cut off of 31 July 2014; Maximum time to progression follow-up was 90.3 weeks.
Secondary	Kaplan-Meier Estimate Duration of Response Based on Investigator Assessment Using IMWG Criteria	Duration of Response (calculated for responders only) is defined as the time from the initial documented response (partial response or better) to confirmed disease progression by the investigator based on IMWG criteria.	From randomization through the study follow-up phase; up to the data cut-off of 31 July 2014; Maximum duration of response follow-up was 90.3 weeks.
Secondary	Kaplan-Meier Estimate for Overall Survival	Overall survival was calculated as the time from randomization to death from any cause. Overall survival was censored at the last date that the participant was known to be alive for participants who were alive at the time of analysis and for participants who were lost to follow-up before death was documented.	From randomization through the follow-up phase; Maximum time on follow-up was 141.1 weeks.
Secondary	Time to Response Based on IMWG and Assessed by the Investigator	Time to Response was calculated as the time from enrollment to the initial response (PR or better) based on IMWG and assessed by the investigator.	From randomization through the follow-up phase; up to the data-cut off of 31 July 2014; Maximum time to response was 23.1 weeks