Clinical trial NCT01497093: 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
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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Multiple Myeloma
Keywords: Myeloma
Multiple Myeloma
Relapsed Multiple Myeloma
Relapsed and Refractory Multiple Myeloma
Refractory Myeloma
Resistant Multiple Myeloma
Treatment-resistant Multiple Myeloma
Pomalidomide
Lenalidomide-resistant
Lead sponsor: Celgene
Sponsor class: INDUSTRY
Collaborators: name: Multiple Myeloma Research Consortium
First posted: 2011-12-22
Enrollment: 34
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief 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

Detailed 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.

Eligibility criteria: 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

Primary outcomes:
measure: Maximum Tolerated Dose
timeFrame: Up to 2 years
Secondary outcomes:
measure: Adverse events
timeFrame: Up to 7 years
measure: Overall Survival
timeFrame: Up to 7 years
measure: Response Rate
timeFrame: Up to 7 years
measure: Duration of response
timeFrame: Up to 7 years
measure: Time to response
timeFrame: Up to 7 years
Other outcomes:
Locations:
city: Atlanta
country: United States
facility: Winship Cancer Institute of Emory University
state: Georgia
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Hackensack
country: United States
facility: Hackensack University Medical Center
state: New Jersey
city: Columbus
country: United States
facility: Ohio State University Medical Center
state: Ohio
Study officials:
affiliation: Celgene
name: Amine Bensmaine, MD
role: STUDY_DIRECTOR
References:
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.
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.
citation: 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.