Study of Ibrutinib in Patients With Symptomatic, Previously Untreated Waldenstrom's Macroglobulinemia, and Impact on Tumor Genomic Evolution Using Whole Genome Sequencing

• ClinicalTrials.gov Identifier: NCT02604511
• Recruitment Status: Completed
• First Posted: November 13, 2015
• Results First Posted: January 12, 2022
• Last Update Posted: December 7, 2022
• Sponsor: Dana-Farber Cancer Institute
• Collaborator: Pharmacyclics LLC.
• Information provided by (Responsible Party): Steven Treon, MD, PhD, Dana-Farber Cancer Institute

Study Description

Brief Summary:

This research study is studying a drug called ibrutinib as a possible treatment for untreated Waldenstrom's Macroglobulinemia (WM).

Condition or disease	Intervention/treatment	Phase
Waldenstrom's Macroglobulinemia	Drug: Ibrutinib	Phase 2

Detailed Description:

This research study is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of an investigational intervention to learn whether the intervention works in treating a specific disease. "Investigational" means that the intervention is being studied.

The FDA (the U.S. Food and Drug Administration) has approved ibrutinib as a form of treatment for the patient specific disease.

Ibrutinib has been under investigation in research studies in participants with recurrent B-cell lymphoma, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), and prolymphocytic leukemia, and WM. In a study of ibrutinib in relapsed/refractory WM patients, response rates were high and the treatment was well tolerated.

The prior studies suggest that ibrutinib may be a useful treatment strategy for untreated WM patients. This study will test the safety and efficacy of ibrutinib as an option for untreated WM patients. The study will also conduct genomic sequencing of malignant WM cells before the start of treatment, and 6, 12, 24, 36 and 48 months afterwards. Genomic sequencing is the analysis of the entire DNA structure from tumor and normal cells. The purpose of this sequencing is to study which genetic changes effect how ibrutinib works. The results of these studies could also help in better understanding the course of WM disease, and be applicable to the development of other effective drug treatments.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 31 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Study of Ibrutinib in Patients With Symptomatic, Previously Untreated Waldenstrom's Macroglobulinemia, and Impact on Tumor Genomic Evolution Using Whole Genome Sequencing
• Actual Study Start Date: January 2016
• Actual Primary Completion Date: November 1, 2022
• Actual Study Completion Date: November 1, 2022

Arms and Interventions

Arm	Intervention/treatment
Experimental: Ibrutinib; This is single arm, open label, Phase II, single center study designed to evaluate the safety and efficacy of ibrutinib in previously untreated WM patients. Treatment will be administered in 4-week cycles, and participants will receive treatment for up to 48 cycles. Treatment will be comprised of ibrutinib at 420 mg per day by oral administration.	Drug: Ibrutinib; Other Names: Imbruvica; PCI-32765

Outcome Measures

Primary Outcome Measures :

1. Major Response Rate [ Time Frame: 4 years ]
   To asses the percentage of participants with a Partial Response (PR) (50% reduction or more in serum IgM) or better.
2. Best Overall Response Rate [ Time Frame: 4 years ]
   To asses the percentage of participants with an Minor Response (MR) (25% reduction or more in serum IgM) or better.

Secondary Outcome Measures :

1. Duration of Response [ Time Frame: 6 years ]
   The amount of time between attainment of at least a minor response and disease progression.

Other Outcome Measures:

1. Time to Response [ Time Frame: 4 years ]
   The amount of time between starting treatment and attaining at least a minor response to therapy
2. Progression Free Survival [ Time Frame: 6 years ]
   The number of participants who have not experienced disease progression 6 years after therapy initiation
3. Overall Survival [ Time Frame: 6 years ]
   The number of participants who are still living 6 years after initiation of ibrutinib

Eligibility Criteria

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

Criteria

Inclusion Criteria:

• Clinicopathological diagnosis of Waldenstrom's Macroglobulinemia and meeting criteria for treatment using consensus panel criteria from the Second International Workshop on Waldenstrom's macroglobulinemia (Kyle et al, 2003).
• Measurable disease, defined as presence of serum immunoglobulin M (IgM) with a minimum IgM level of ≥ 2 times the upper limit of normal is required.
• Age ≥ 18 years.
• Eastern Cooperative Oncology Group (ECOG) performance status ≤2 (see Appendix A.).

• Participants must have normal organ and marrow function as defined below:

  • Absolute neutrophil count ≥ 1,000/μL
  • Platelets ≥ 50,000/μL
  • Hemoglobin ≥ 8 g/dL
  • Total bilirubin ≤ 2.0. mg/dL or < 2.5 mg/dL if attributable to hepatic infiltration by neoplastic disease or Gilbert's syndrome.
  • Aspartate aminotransferase (AST or SGOT) and Alanine aminotransferase (ALT or SGPT) ≤ 2.5 X institutional upper limit of normal
  • Estimated Creatinine Clearance ≥30ml/min
• Not on any active therapy for other malignancies with the exception of topical therapies for basal cell or squamous cell cancers of the skin.
• Females of childbearing potential (FCBP) must agree to use two reliable forms of contraception simultaneously or have or will have complete abstinence from heterosexual intercourse during the following time periods related to this study: 1) while participating in the study; and 2) for at least 28 days after discontinuation from the study. Men must agree to use a latex condom during sexual contact with a FCBP even if they have had a successful vasectomy. FCBP must be referred to a qualified provider of contraceptive methods if needed.
• Able to adhere to the study visit schedule and other protocol requirements.
• Ability to understand and the willingness to sign a written informed consent document.
• Both men and women of all races and ethnic groups are eligible for this trial.

Exclusion Criteria:

• Prior systemic therapy for WM
• Any serious medical condition, laboratory abnormality, uncontrolled intercurrent illness, or psychiatric illness/social condition that would prevent the participant from signing the informed consent form.
• Concurrent use of any other anti-cancer treatments or any other investigational agents.
• Concomitant use of warfarin or other Vitamin K antagonists.
• Concomitant treatment with strong CYP3A4/5 inhibitor.
• Any condition, including the presence of laboratory abnormalities, which places the participant at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study.
• Any life-threatening illness, medical condition, or organ system dysfunction which, in the investigator's opinion could interfere with the absorption or metabolism of ibrutinib.
• Known Central nervous system (CNS) lymphoma.
• Concomitant use of medication known to cause QT prolongation.
• Currently active, clinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, Class 3 or 4 congestive heart failure as defined by the New York Heart Association Functional Classification, or history of myocardial infarction, unstable angina or acute coronary syndrome within 6 months of screening.
• Malabsorption, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel, ulcerative colitis, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction.
• Known history of Human Immunodeficiency Virus (HIV), active infection with Hepatitis B Virus (HBV), and/or Hepatitis C Virus (HCV). Subjects who are positive for hepatitis B core antibody or hepatitis B surface antigen must have a negative polymerase chain reaction (PCR) result before enrollment. Those who are PCR positive will be excluded.
• Lactating or pregnant women.
• Inability to swallow capsules.
• History of non-compliance to medical regimens.
• Unwilling or unable to comply with the protocol.
• Major surgery within 4 weeks of first dose of study drug.
• No active infections requiring systemic therapy.
• Known bleeding disorders with the exception of acquired Von Willebrand Disorder suspected on the basis of WM.
• History of stroke or intracranial hemorrhage within 6 months prior to enrollment.

Contacts and Locations

Locations

United States, Massachusetts

Massacusetts General Hospital

Boston, Massachusetts, United States, 02114

Dana-Farber Cancer Institute

Boston, Massachusetts, United States, 02215

Sponsors and Collaborators

Dana-Farber Cancer Institute

Pharmacyclics LLC.

Investigators

• Principal Investigator: Steven P Treon, MD, PhD; Dana-Farber Cancer Institute

  Study Documents (Full-Text)

Documents provided by Steven Treon, MD, PhD, Dana-Farber Cancer Institute:

Study Protocol and Statistical Analysis Plan  [PDF] April 5, 2021

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Castillo JJ, Meid K, Gustine JN, Leventoff C, White T, Flynn CA, Sarosiek S, Demos MG, Guerrera ML, Kofides A, Liu X, Munshi M, Tsakmaklis N, Xu L, Yang G, Branagan AR, O'Donnell E, Raje N, Yee AJ, Patterson CJ, Hunter ZR, Treon SP. Long-term follow-up of ibrutinib monotherapy in treatment-naive patients with Waldenstrom macroglobulinemia. Leukemia. 2022 Feb;36(2):532-539. doi: 10.1038/s41375-021-01417-9. Epub 2021 Sep 16.

Treon SP, Gustine J, Meid K, Yang G, Xu L, Liu X, Demos M, Kofides A, Tsakmaklis N, Chen JG, Munshi M, Chan G, Dubeau T, Raje N, Yee A, O'Donnell E, Hunter ZR, Castillo JJ. Ibrutinib Monotherapy in Symptomatic, Treatment-Naive Patients With Waldenstrom Macroglobulinemia. J Clin Oncol. 2018 Sep 20;36(27):2755-2761. doi: 10.1200/JCO.2018.78.6426. Epub 2018 Jul 25.

• Responsible Party: Steven Treon, MD, PhD, Steven P. Treon, MD, PhD, Dana-Farber Cancer Institute
• ClinicalTrials.gov Identifier: NCT02604511
• Other Study ID Numbers: 15-359
• First Posted: November 13, 2015
• Results First Posted: January 12, 2022
• Last Update Posted: December 7, 2022
• Last Verified: December 2022

Keywords provided by Steven Treon, MD, PhD, Dana-Farber Cancer Institute:

Waldenstrom's Macroglobulinemia

Additional relevant MeSH terms:

Waldenstrom Macroglobulinemia; Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Neoplasms; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemorrhagic Disorders; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases