Study to Determine the Maximum Tolerated Dose for the Combination of Pomalidomide, Bortezomib and Low-Dose Dexamethasone in Subjects With Relapsed or Refractory Multiple Myeloma

Multiple Myeloma Clinical Trial

Official title:

A Phase 1, Multicenter, Open Label, Dose-escalation Study to Determine the Maximum Tolerated Dose for the Combination of Pomalidomide (POM), Bortezomib (BTZ) and Low-Dose Dexamethasone (LDDEX) in Subjects With Relapsed or Refractory Multiple Myeloma (MM)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01497093
• Other study ID #: CC-4047-MM-005
• Status: Completed
• Phase: Phase 1
• Start date: February 15, 2012
• Est. completion date: July 23, 2019

Study information

• Verified date: April 2020
• Source: Celgene
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to determine the maximum tolerated dose (MTD) of pomalidomide in combination with bortezomib and low-dose dexamethasone in subjects with relapsed or refractory multiple myeloma

Description:

A 3 + 3 design will be utilized to determine the MTD for POM + IV BTZ + LD-DEX combination treatment in a 21-day treatment cycle. DLT will be assessed to determine MTD during the first treatment cycle. Once the MTD is determined or the maximum planned dose (MPD) is reached without reaching MTD for POM + IV BTZ + LD-DEX, a cohort of 6 additional subjects will be treated at this MTD/MPD level to further confirm the safety and assess preliminary efficacy. An additional cohort of subjects will be enrolled to explore the safety for the combination of POM + BTZ + LD-DEX when using SQ BTZ. Subject in this cohort will receive POM + BTZ + LD-DEX at the MTD/MPD level per the MTD determination part of the study, except, the BTZ will be administered subcutaneously (SQ) instead of intravenously (IV). In, Protocol Amendment #4, the number of subject enrolled to be enrolled into the exploratory SQ BTZ cohort was increased from 6 to 12.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 34
• Est. completion date: July 23, 2019
• Est. primary completion date: July 23, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion criteria:

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

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

3. Subjects must have had at least 1 but no greater than 4 prior anti-myeloma therapies.

4. Subjects must have received at least 2 consecutive cycles of prior treatment with lenalidomide and must be refractory to their last lenalidomide-containing regimen (either as a single agent or in combination).

5. Subjects must have received at least 2 consecutive cycles of prior treatment with a proteasome inhibitor-containing regimen, but must not be refractory to bortezomib (either as a single agent or in combination).

6. Subjects must have documented progression during or after their last anti-myeloma therapy.

7. Subjects must have an Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2.

Exclusion criteria:

1. Subjects who are refractory to bortezomib either as single agent or in combination.

2. Subjects with peripheral neuropathy = Grade 2

3. Subjects with non-secretory multiple myeloma

4. Subjects with 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

• 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 glutamic oxaloacetic transaminase (SGOT)/ aspartate aminotransferase (AST) or Transaminase, serum glutamic pyruvic (SGPT)/ alanine aminotransferase (ALT) > 3.0 x upper limit of normal (ULN)

• Serum total bilirubin > 1.5 x ULN

5. Subjects with prior history of malignancies, other than MM, unless the subject has been free of the disease for = 5 years. Except 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, Incidental histologic finding of prostate cancer (T1a or T1b using the TNM [tumor, nodes, metastasis] clinical staging system) or prostate cancer that is curative.

6. Subjects with previous therapy with Pomalidomide

7. Subjects with hypersensitivity to thalidomide, lenalidomide, bortezomib, boron, mannitol, or dexamethasone

8. Subjects with = Grade 3 rash during prior thalidomide or lenalidomide therapy

9. Subjects who had 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, Any anti-myeloma drug therapy

10. Subjects who have received any investigational agents within 28 days or 5 half-lives (whichever is longer) of treatment

11. Pregnant or breastfeeding females

12. Men or women of childbearing potential or their sexual partners who are unwilling to employ adequate contraception.

13. Subjects with 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
Pomalidomide 1, 2, 3, or 4 mg will be taken orally on Days 1-14 of a 21-day cycle
• Bortezomib
Bortezomib 1 or 1.3 mg/m2 will be administered intravenously or subcutaneously on Days 1, 4, 8 and 11 of 21 days for cycles 1 -8 and on days 1, 8 of 21 days for cycle 9 and onward until disease progression
• Dexamethasone
Dexamethasone 20 mg/day [= 75 years old] or 10 mg/day [> 75 years old] will be taken orally on days 1, 2, 4, 5, 8, 9, 11, 12 of 21 days for cycles 1-8 and on days 1, 2, 8, 9 of 21 days for cycles 9 and onward until disease progression

Locations

Country	Name	City	State
United States	Winship Cancer Institute of Emory University	Atlanta	Georgia
United States	Beth Israel Deaconess Medical Center	Boston	Massachusetts
United States	Dana-Farber Cancer Institute	Boston	Massachusetts
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	Ohio State University Medical Center	Columbus	Ohio
United States	Hackensack University Medical Center	Hackensack	New Jersey

Sponsors (2)

Lead Sponsor	Collaborator
Celgene	Multiple Myeloma Research Consortium

Country where clinical trial is conducted

United States, 

References & Publications (3)

Moreau P, Dimopoulos MA, Richardson PG, Siegel DS, Cavo M, Corradini P, Weisel K, Delforge M, O'Gorman P, Song K, Chen C, Bahlis N, Oriol A, Hansson M, Kaiser M, Anttila P, Raymakers R, Joao C, Cook G, Sternas L, Biyukov T, Slaughter A, Hong K, Herring J, Yu X, Zaki M, San-Miguel J. Adverse event management in patients with relapsed and refractory multiple myeloma taking pomalidomide plus low-dose dexamethasone: A pooled analysis. Eur J Haematol. 2017 Sep;99(3):199-206. doi: 10.1111/ejh.12903. Epub 2017 Jun 14. — View Citation

Pelligra CG, Parikh K, Guo S, Chandler C, Mouro J, Abouzaid S, Ailawadhi S. Cost-effectiveness of Pomalidomide, Carfilzomib, and Daratumumab for the Treatment of Patients with Heavily Pretreated Relapsed-refractory Multiple Myeloma in the United States. Clin Ther. 2017 Oct;39(10):1986-2005.e5. doi: 10.1016/j.clinthera.2017.08.010. Epub 2017 Sep 28. — View Citation

Richardson PG, Hofmeister CC, Raje NS, Siegel DS, Lonial S, Laubach J, Efebera YA, Vesole DH, Nooka AK, Rosenblatt J, Doss D, Zaki MH, Bensmaine A, Herring J, Li Y, Watkins L, Chen MS, Anderson KC. Pomalidomide, bortezomib and low-dose dexamethasone in lenalidomide-refractory and proteasome inhibitor-exposed myeloma. Leukemia. 2017 Dec;31(12):2695-2701. doi: 10.1038/leu.2017.173. Epub 2017 Jun 2. Erratum in: Leukemia. 2018 Oct;32(10):2305. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Maximum Tolerated Dose	To determine the maximum tolerated dose (MTD)	Up to 2 years
Secondary	Adverse events	Number of participants with adverse events (AEs)	Up to 7 years
Secondary	Overall Survival	Number of patients alive	Up to 7 years
Secondary	Response Rate	Overall response rate based on the International Myeloma Working Group (IMWG) Uniform response criteria	Up to 7 years
Secondary	Duration of response	Time from the initial documented response to confirmed disease progression	Up to 7 years
Secondary	Time to response	Time from enrollment to the first documented response	Up to 7 years