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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/ct2/show/NCT02103335




Registration number
NCT02103335
Ethics application status
Date submitted
27/03/2014
Date registered
3/04/2014
Date last updated
22/11/2017

Titles & IDs
Public title
Combination Study of Pomalidomide, Marizomib, and Low-Dose Dexamethasone in Relapsed and Refractory Multiple Myeloma
Scientific title
A Phase 1, Multicenter, Open-label, Dose-Escalation Combination Study of Pomalidomide, Marizomib, and Low-Dose Dexamethasone in Subjects With Relapsed and Refractory Multiple Myeloma
Secondary ID [1] 0 0
NPI-0052-107
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Multiple Myeloma in Relapse 0 0
Refractory Multiple Myeloma 0 0
Multiple Myeloma 0 0
Condition category
Condition code
Cancer 0 0 0 0
Other cancer types

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - pomalidomide
Treatment: Drugs - marizomib
Treatment: Drugs - low-dose dexamethasone

Experimental: Single Group Assignment - Combination Pomalidomide, low-dose Dexamethasone, and Marizomib:


Treatment: Drugs: pomalidomide
Oral Pomalidomide, days 1-21 of 28 day cycle, dose 3 to 4 mg

Treatment: Drugs: marizomib
IV Marizomib, 0.2 to 0.5 mg/m2 on days 1, 4, 8, 11 of 28 day cycle

Treatment: Drugs: low-dose dexamethasone
Oral Dexamethasone, days 1, 2, 4, 5, 8, 9, 11, 12, 15, 16, 22, 23 of 28 day cycle, 5 or 10 mg
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Maximum tolerated dose and/or recommended Phase 2 dose
Timepoint [1] 0 0
Continuous up to one year
Secondary outcome [1] 0 0
Adverse events
Timepoint [1] 0 0
Up to 5 years
Secondary outcome [2] 0 0
Response rate
Timepoint [2] 0 0
Up to 5 years

Eligibility
Key inclusion criteria
Inclusion Criteria

Subjects must meet the following criteria to be eligible for study participation:

1. At least 18 years at the time of signing the informed consent form.

2. Able to understand and voluntarily sign an informed consent form prior to any
study-related assessments/procedures.

3. Able to adhere to the study visit schedule and other protocol requirements.

4. Documented diagnosis of multiple myeloma and measurable disease by serum or urine
protein electrophoresis (SPEP or UPEP): SPEP =0.5 g/dL, UPEP =200 mg/24 hours, or
involved serum free light chain (FLC) level =10 mg/dL provided the serum FLC ratio is
abnormal.

5. Previously received 1 or more lines of anti-myeloma therapy that must have included
both lenalidomide and bortezomib (either separately or in combination).

6. Documented disease progression during or within 60 days after their most recent line
of anti myeloma therapy.

7. Eastern Cooperative Oncology Group (ECOG) performance status score =2.

8. All study participants in the USA must be registered into the mandatory POMALYST REMS™
(Risk Evaluation & Mitigation Strategy) program, and be willing and able to comply
with the requirements of the POMALYST REMS™ program.

9. All study participants in the USA who are females of child-bearing potential (FCBP)
must adhere to the scheduled pregnancy testing as required in the POMALYST REMS™
program.

10. All study participants outside the USA must agree to comply with the POMALYST® PPRMP
requirements.

11. All subjects must be able and agree to take aspirin (81 or 325 mg) daily as
prophylactic anticoagulation (patients intolerant to ASA may use warfarin or low
molecular weight heparin).

12. For females of child bearing potential (FCBP): Agree to use 2 reliable forms of
contraception simultaneously or practice complete abstinence from heterosexual contact
for at least 28 days before starting study treatment, while participating in the study
(including dose interruptions), and for at least 28 days after study treatment
discontinuation; must follow pregnancy testing requirements as outlined in the
POMALYST REMS™ program or the PPRMP.

13. For all females: Agree to abstain from breastfeeding during study participation and
for at least 28 days after study treatment discontinuation.

14. For all males: Agree to use a latex or synthetic condom during any sexual contact with
FCBP while participating in the study and for at least 28 days following
discontinuation from study treatment, even if he has undergone a successful vasectomy.

15. For all males: Agree to refrain from donating semen or sperm while on study and for at
least 28 days after discontinuation from study treatment.

16. Refrain from donating blood while on study treatment and for at least 28 days after
discontinuation from study treatment.

17. Agree not to share medication.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Exclusion Criteria

Subjects with any of the following will be excluded from participation in the study:

1. Peripheral neuropathy Grade =2.

2. Non-secretory multiple myeloma.

3. Any of the following laboratory abnormalities:

- ANC <1,000/µL;

- Platelet count <50,000/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 (CrCL) <45 mL/min as measured directly or as calculated
according to Cockcroft Gault formula;

- Corrected serum calcium >13.5 mg/dL (>3.4 mmol/L);

- Hemoglobin <8 g/dL (<4.9 mmol/L; prior red blood cell [RBC] transfusion or
recombinant human erythropoietin use is permitted before study entry);

- Serum aspartate aminotransferase (AST) >3.0 x upper limit of normal (ULN);

- Serum alanine aminotransferase (ALT) >3.0 x ULN;

- Serum total bilirubin >1.5 x ULN (>3.0 x ULN for subjects with known Gilbert's
disease).

4. Prior history of malignancies, other than MM, unless the subject has been free of the
disease for =5 years. Subjects may be entered earlier than 5 years if they have
received curative treatment for the following:

- Basal cell carcinoma of the skin;

- Squamous cell carcinoma of the skin;

- Carcinoma in situ of the cervix;

- Carcinoma in situ of the breast;

Or if they have:

o Incidental histologic finding of prostate cancer (T1a or T1b using the TNM [tumor,
nodes, metastasis] clinical staging system) or non metastatic prostate cancer that is
in complete remission or does not require treatment.

5. Previous therapy with POM and/or MRZ.

6. History of allergic reaction or hypersensitivity to thalidomide, lenalidomide,
bortezomib, carfilzomib, boron, mannitol, or DEX.

7. Grade =3 rash during prior thalidomide or lenalidomide therapy.

8. Gastrointestinal disease that may significantly alter the absorption of POM.

9. History of the following:

- Congestive heart failure of Class III or IV of the New York Heart Association
(NYHA) classification;

- Myocardial infarction within 12 months prior to starting study treatment;

- Unstable or poorly controlled angina pectoris, including Prinzmetal variant
angina pectoris.

10. Any of the following within 14 days prior to initiation of study treatment:

- Plasmapheresis;

- Major surgery (kyphoplasty is not considered major surgery);

- Radiation therapy;

- Anti-myeloma drug therapy.

11. Received any investigational agents within 28 days or 5 half-lives (whichever is
longer) prior to initiation of study treatment.

12. Conditions requiring chronic steroid or immunosuppressive treatment (eg, rheumatoid
arthritis, multiple sclerosis, or lupus), which likely need additional steroid or
immunosuppressive treatments in addition to the study treatment.

13. Subjects may not receive corticosteroids (>10 mg/day of prednisone or equivalent)
within 3 weeks prior to enrollment (use of steroidal inhalation aerosol for asthma is
permitted).

14. Unable or unwilling to undergo antithrombotic prophylactic 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, as determined
by the Investigator.

16. Pregnant and/or breastfeeding females.

17. Known seropositive for or active viral infection with human immunodeficiency virus
(HIV).

18. Known seropositive for or active viral infection with hepatitis B virus (HBV), with
the following exceptions:

- negative are eligible.

- Subjects who had hepatitis B but have received an antiviral treatment and show
non-detectable viral DNA for 6 months are eligible.

- Subjects who are seropositive because of hepatitis B virus vaccine are eligible.

19. Known seropositive for or active viral infection with hepatitis C virus (HCV), with
the following exception: Subjects who had hepatitis C but have received an antiviral
treatment and show no detectable viral ribonucleic acid (RNA) for 6 months are
eligible.

Study design
Purpose of the study
Treatment
Allocation to intervention
N/A
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 1
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
5/06/2014
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
30/11/2016
Sample size
Target
Accrual to date
Final
38
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 0 0
Peter MacCallum Cancer Centre - East Melbourne
Recruitment hospital [2] 0 0
Alfred Hospital - Prahran
Recruitment postcode(s) [1] 0 0
3002 - East Melbourne
Recruitment postcode(s) [2] 0 0
3181 - Prahran
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Illinois
Country [2] 0 0
United States of America
State/province [2] 0 0
Maryland
Country [3] 0 0
United States of America
State/province [3] 0 0
Massachusetts
Country [4] 0 0
United States of America
State/province [4] 0 0
Michigan

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
Celgene
Address
Country
Other collaborator category [1] 0 0
Commercial sector/Industry
Name [1] 0 0
Celgene Corporation
Address [1] 0 0
Country [1] 0 0

Ethics approval
Ethics application status

Summary
Brief summary
This is a Phase 1 clinical trial to evaluate a new combination of drugs for the treatment of
relapsed or refractory (drug-resistant) multiple myeloma. The drugs being studied are:

- Pomalidomide (POMALYST®) is a drug that affects the immune system (an immunomodulatory
drug) that has been approved by the United States (US) Food and Drug Administration
(FDA) for the treatment of multiple myeloma.

- Marizomib is an investigational drug being developed by Triphase that is being studied
for the treatment of multiple myeloma. Investigational drugs are drugs that have not yet
been approved by health authorities, such as the FDA, for general use but have been
approved for use in specific clinical studies. Marizomib inhibits a cellular machine
called the proteasome, which destroys unnecessary or damaged proteins. Other proteasome
inhibitors have been shown to be effective in the treatment of multiple myeloma.

- Dexamethasone is a corticosteroid drug that affects the immune system (an
immunomodulatory drug) that has been approved by the FDA for the treatment of multiple
myeloma.

This is the first study to evaluate the three-drug combination of pomalidomide (POM),
marizomib (MRZ), and dexamethasone (LD-DEX) in humans. Pomalidomide, alone or in combination
with dexamethasone, is approved by the FDA for the treatment of relapsed or refractory
multiple myeloma.

The primary objective of this study is to determine the best drug dosing levels for this
three-drug combination, including the highest safe doses and/or the recommended doses for
future clinical studies of this drug combination. The secondary purposes of this study are to
determine the safety of this drug combination and its effectiveness in treating relapsed or
refractory multiple myeloma. The study will include examination of levels of all three drugs
in the blood during various time points during treatment.
Trial website
https://clinicaltrials.gov/ct2/show/NCT02103335
Trial related presentations / publications
Chauhan D, Li G, Shringarpure R, Podar K, Ohtake Y, Hideshima T, Anderson KC. Blockade of Hsp27 overcomes Bortezomib/proteasome inhibitor PS-341 resistance in lymphoma cells. Cancer Res. 2003 Oct 1;63(19):6174-7.
Chauhan D, Singh AV, Ciccarelli B, Richardson PG, Palladino MA, Anderson KC. Combination of novel proteasome inhibitor NPI-0052 and lenalidomide trigger in vitro and in vivo synergistic cytotoxicity in multiple myeloma. Blood. 2010 Jan 28;115(4):834-45. doi: 10.1182/blood-2009-03-213009. Epub 2009 Nov 13.
Child JA, Morgan GJ, Davies FE, Owen RG, Bell SE, Hawkins K, Brown J, Drayson MT, Selby PJ; Medical Research Council Adult Leukaemia Working Party. High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma. N Engl J Med. 2003 May 8;348(19):1875-83. doi: 10.1056/NEJMoa022340.
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16(1):31-41. doi: 10.1159/000180580.
Dexamethasone Prescribing Information. Roxane Laboratories Inc., Columbus, OH; Sep 2007. http://bidocs.boehringer-ingelheim.com/BIWebAccess/ViewServlet.ser?docBase= renetnt&folderPath=/Prescribing+Information/PIs/Roxane/Dexamethasone/Dexamethasone+Tablets+Solution+and+Intensol.pdf. Accessed 20 September 2013.
Dimopoulos M, Spencer A, Attal M, Prince HM, Harousseau JL, Dmoszynska A, San Miguel J, Hellmann A, Facon T, Foa R, Corso A, Masliak Z, Olesnyckyj M, Yu Z, Patin J, Zeldis JB, Knight RD; Multiple Myeloma (010) Study Investigators. Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. N Engl J Med. 2007 Nov 22;357(21):2123-32. doi: 10.1056/NEJMoa070594. Erratum In: N Engl J Med. 2009 Jul 30;361(5):544.
Durie BG, Harousseau JL, Miguel JS, Blade J, Barlogie B, Anderson K, Gertz M, Dimopoulos M, Westin J, Sonneveld P, Ludwig H, Gahrton G, Beksac M, Crowley J, Belch A, Boccadaro M, Cavo M, Turesson I, Joshua D, Vesole D, Kyle R, Alexanian R, Tricot G, Attal M, Merlini G, Powles R, Richardson P, Shimizu K, Tosi P, Morgan G, Rajkumar SV; International Myeloma Working Group. International uniform response criteria for multiple myeloma. Leukemia. 2006 Sep;20(9):1467-73. doi: 10.1038/sj.leu.2404284. Epub 2006 Jul 20. Erratum In: Leukemia. 2006 Dec;20(12):2220. Leukemia. 2007 May;21(5):1134.
Fermand JP, Katsahian S, Divine M, Leblond V, Dreyfus F, Macro M, Arnulf B, Royer B, Mariette X, Pertuiset E, Belanger C, Janvier M, Chevret S, Brouet JC, Ravaud P; Group Myelome-Autogreffe. High-dose therapy and autologous blood stem-cell transplantation compared with conventional treatment in myeloma patients aged 55 to 65 years: long-term results of a randomized control trial from the Group Myelome-Autogreffe. J Clin Oncol. 2005 Dec 20;23(36):9227-33. doi: 10.1200/JCO.2005.03.0551. Epub 2005 Nov 7.
Hideshima T, Chauhan D, Shima Y, Raje N, Davies FE, Tai YT, Treon SP, Lin B, Schlossman RL, Richardson P, Muller G, Stirling DI, Anderson KC. Thalidomide and its analogs overcome drug resistance of human multiple myeloma cells to conventional therapy. Blood. 2000 Nov 1;96(9):2943-50.
Howlader N, Noone AM, Krapcho M, et al. (eds). SEER Cancer Statistics Review, 1975 2009 (Vintage 2009 Populations), National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/csr/1975_2009_pops09/. Accessed 20 September 2013.
Kastritis E, Charidimou A, Varkaris A, Dimopoulos MA. Targeted therapies in multiple myeloma. Target Oncol. 2009 Jan;4(1):23-36. doi: 10.1007/s11523-008-0102-9. Epub 2009 Jan 17.
Kline JA, Wells PS. Methodology for a rapid protocol to rule out pulmonary embolism in the emergency department. Ann Emerg Med. 2003 Aug;42(2):266-75. doi: 10.1067/mem.2003.268. Erratum In: Ann Emerg Med. 2003 Oct;42(4):600.
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.
Mitsiades N, Mitsiades CS, Poulaki V, Chauhan D, Richardson PG, Hideshima T, Munshi NC, Treon SP, Anderson KC. Apoptotic signaling induced by immunomodulatory thalidomide analogs in human multiple myeloma cells: therapeutic implications. Blood. 2002 Jun 15;99(12):4525-30. doi: 10.1182/blood.v99.12.4525.
Anderson KC, Alsina M, Bensinger W, Biermann JS, Chanan-Khan A, Cohen AD, Devine S, Djulbegovic B, Gasparetto C, Huff CA, Jagasia M, Medeiros BC, Meredith R, Raje N, Schriber J, Singhal S, Somlo G, Stockerl-Goldstein K, Tricot G, Vose JM, Weber D, Yahalom J, Yunus F; National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: multiple myeloma. J Natl Compr Canc Netw. 2009 Oct;7(9):908-42. doi: 10.6004/jnccn.2009.0061. No abstract available.
Orlowski RZ, Nagler A, Sonneveld P, Blade J, Hajek R, Spencer A, San Miguel J, Robak T, Dmoszynska A, Horvath N, Spicka I, Sutherland HJ, Suvorov AN, Zhuang SH, Parekh T, Xiu L, Yuan Z, Rackoff W, Harousseau JL. Randomized phase III study of pegylated liposomal doxorubicin plus bortezomib compared with bortezomib alone in relapsed or refractory multiple myeloma: combination therapy improves time to progression. J Clin Oncol. 2007 Sep 1;25(25):3892-901. doi: 10.1200/JCO.2006.10.5460. Epub 2007 Aug 6.
Rajkumar SV, Harousseau JL, Durie B, Anderson KC, Dimopoulos M, Kyle R, Blade J, Richardson P, Orlowski R, Siegel D, Jagannath S, Facon T, Avet-Loiseau H, Lonial S, Palumbo A, Zonder J, Ludwig H, Vesole D, Sezer O, Munshi NC, San Miguel J; International Myeloma Workshop Consensus Panel 1. Consensus recommendations for the uniform reporting of clinical trials: report of the International Myeloma Workshop Consensus Panel 1. Blood. 2011 May 5;117(18):4691-5. doi: 10.1182/blood-2010-10-299487. Epub 2011 Feb 3.
Richardson PG, Sonneveld P, Schuster MW, Irwin D, Stadtmauer EA, Facon T, Harousseau JL, Ben-Yehuda D, Lonial S, Goldschmidt H, Reece D, San-Miguel JF, Blade J, Boccadoro M, Cavenagh J, Dalton WS, Boral AL, Esseltine DL, Porter JB, Schenkein D, Anderson KC; Assessment of Proteasome Inhibition for Extending Remissions (APEX) Investigators. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med. 2005 Jun 16;352(24):2487-98. doi: 10.1056/NEJMoa043445.
Richardson PG, Weller E, Jagannath S, Avigan DE, Alsina M, Schlossman RL, Mazumder A, Munshi NC, Ghobrial IM, Doss D, Warren DL, Lunde LE, McKenney M, Delaney C, Mitsiades CS, Hideshima T, Dalton W, Knight R, Esseltine DL, Anderson KC. Multicenter, phase I, dose-escalation trial of lenalidomide plus bortezomib for relapsed and relapsed/refractory multiple myeloma. J Clin Oncol. 2009 Dec 1;27(34):5713-9. doi: 10.1200/JCO.2009.22.2679. Epub 2009 Sep 28.
Richardson PG, Weller E, Lonial S, Jakubowiak AJ, Jagannath S, Raje NS, Avigan DE, Xie W, Ghobrial IM, Schlossman RL, Mazumder A, Munshi NC, Vesole DH, Joyce R, Kaufman JL, Doss D, Warren DL, Lunde LE, Kaster S, Delaney C, Hideshima T, Mitsiades CS, Knight R, Esseltine DL, Anderson KC. Lenalidomide, bortezomib, and dexamethasone combination therapy in patients with newly diagnosed multiple myeloma. Blood. 2010 Aug 5;116(5):679-86. doi: 10.1182/blood-2010-02-268862. Epub 2010 Apr 12.
Richardson PG, Jagannath S, Jakubowiak A, et al. Phase II Trial of Lenalidomide, Bortezomib, and Dexamethasone in Patients (pts) with Relapsed and Relapsed/Refractory Multiple Myeloma (MM): Updated Efficacy and Safety Data After > 2 Years of Follow-up. 2010b; ASH Annual Meeting Abstract #3049.
Weber DM, Chen C, Niesvizky R, Wang M, Belch A, Stadtmauer EA, Siegel D, Borrello I, Rajkumar SV, Chanan-Khan AA, Lonial S, Yu Z, Patin J, Olesnyckyj M, Zeldis JB, Knight RD; Multiple Myeloma (009) Study Investigators. Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America. N Engl J Med. 2007 Nov 22;357(21):2133-42. doi: 10.1056/NEJMoa070596.
Wells PS, Anderson DR, Rodger M, Ginsberg JS, Kearon C, Gent M, Turpie AG, Bormanis J, Weitz J, Chamberlain M, Bowie D, Barnes D, Hirsh J. Derivation of a simple clinical model to categorize patients probability of pulmonary embolism: increasing the models utility with the SimpliRED D-dimer. Thromb Haemost. 2000 Mar;83(3):416-20.
Wells PS, Anderson DR, Rodger M, Forgie M, Kearon C, Dreyer J, Kovacs G, Mitchell M, Lewandowski B, Kovacs MJ. Evaluation of D-dimer in the diagnosis of suspected deep-vein thrombosis. N Engl J Med. 2003 Sep 25;349(13):1227-35. doi: 10.1056/NEJMoa023153.
Velcade® (bortezomib) for Injection Prescribing Information. Millennium Pharmaceuticals Inc., Cambridge, MA; V-12-0388 02/13. http://www.velcade-hcp.com/previously-untreated-multiple-myeloma/dosing.aspx?gclid=CPD4lKn2tbsCFcU5Qgod9R0AdA.
Public notes

Contacts
Principal investigator
Name 0 0
Steven D Reich, MD
Address 0 0
Triphase Research and Development I Corp
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/ct2/show/NCT02103335