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

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)

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

Study Overview

• Status: Completed
• Conditions: Multiple Myeloma
• Intervention / Treatment: Drug: Pomalidomide; Drug: Bortezomib; Drug: Dexamethasone

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.

• Study Type: Interventional
• Enrollment (Actual): 34
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Winship Cancer Institute of Emory University
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Beth Israel Deaconess Medical Center
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
    • Boston, Massachusetts, United States, 02115-6084
      • Dana-Farber Cancer Institute
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • Hackensack University Medical Center
  • Ohio
    • Columbus, Ohio, United States, 43210
      • Ohio State University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Pomalidomide/Bortezomib/Dexamethasone; 1, 2, 3 or 4 mg of pomalidomide will be taken orally on Days 1-14 of a 21-day cycle along with 1 or 1.3 mg/m2 of bortezomib 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, and dexamethasone 20 mg/day [≤ 75 years old] or 10 mg/day [> 75 years old] 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

Drug: Pomalidomide; Pomalidomide 1, 2, 3, or 4 mg will be taken orally on Days 1-14 of a 21-day cycle; Other Names: CC-4047; Oral Pomalidomide; Drug: 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; Other Names: Velcade; Drug: 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum Tolerated Dose	To determine the maximum tolerated dose (MTD)	Up to 2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adverse events	Number of participants with adverse events (AEs)	Up to 7 years
Overall Survival	Number of patients alive	Up to 7 years
Response Rate	Overall response rate based on the International Myeloma Working Group (IMWG) Uniform response criteria	Up to 7 years
Duration of response	Time from the initial documented response to confirmed disease progression	Up to 7 years
Time to response	Time from enrollment to the first documented response	Up to 7 years

Collaborators and Investigators

• Sponsor: Celgene
• Collaborators: Multiple Myeloma Research Consortium
• Investigators: Study Director: Amine Bensmaine, MD, Celgene

Publications and helpful links

General Publications

• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): February 15, 2012
• Primary Completion (Actual): July 23, 2019
• Study Completion (Actual): July 23, 2019

Study Registration Dates

• First Submitted: December 20, 2011
• First Submitted That Met QC Criteria: December 21, 2011
• First Posted (Estimate): December 22, 2011

Study Record Updates

• Last Update Posted (Actual): April 7, 2020
• Last Update Submitted That Met QC Criteria: April 3, 2020
• Last Verified: April 1, 2020

More Information

Terms related to this study

• Keywords: Pomalidomide; Multiple Myeloma; Myeloma; Relapsed Multiple Myeloma; Refractory Myeloma; Relapsed and Refractory Multiple Myeloma; Resistant Multiple Myeloma; Treatment-resistant Multiple Myeloma; Lenalidomide-resistant
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Immunoproliferative Disorders; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Multiple Myeloma; Neoplasms, Plasma Cell; Physiological Effects of Drugs; Anti-Infective Agents; Autonomic Agents; Peripheral Nervous System Agents; Anti-Inflammatory Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Anti-Bacterial Agents; Leprostatic Agents; Dexamethasone; Thalidomide; Pomalidomide; Bortezomib
• Other Study ID Numbers: CC-4047-MM-005