Umbralisib and Rituximab as Initial Therapy for Patients With Follicular Lymphoma and Marginal Zone Lymphoma

A Phase 2 Study of Umbralisib and Rituximab as Initial Therapy for Patients With Follicular Lymphoma and Marginal Zone Lymphoma

This research is being done to assess Umbralisib and Rituximab as a first line therapy for Follicular Lymphoma or Marginal Zone Lymphoma.

Study Overview

• Status: Active, not recruiting
• Conditions: Lymphoma; Follicular Lymphoma; Marginal Zone Lymphoma; Follicular Lymphoma, Grade 1; Follicular Lymphoma Grade IIIa; Marginal Zone B Cell Lymphoma; Follicular Lymphoma Grade 2
• Intervention / Treatment: Drug: Umbralisib; Drug: Rituximab

Detailed Description

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

The U.S. Food and Drug Administration (FDA) has not approved Umbralisib as a treatment for any disease.

The FDA has approved Rituximab as a treatment option for this disease.

Umbralisib is an investigational drug which blocks a protein called PI3K. PI3K is a protein that plays a role in the way cells grow. In this type of cancer, PI3K is increased and more active than usual. This helps the cancer cells to grow and survive. Early clinical trials have shown that Umbralisib can kill cancer cells in some patients and cause their tumors to shrink.

• Study Type: Interventional
• Enrollment (Estimated): 41
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital Cancer Center
    • Boston, Massachusetts, United States, 02215
      • Beth Israel Deaconness Medical Center

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Participants must have histologically confirmed follicular lymphoma grade 1-3A or marginal zone lymphoma by WHO criteria.
• Participants must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter [LDi] to be recorded for non-nodal lesions and short axis for nodal lesions) as ≥15 mm in LDi for nodal disease or >10 mm in LDi for extranodal lesions.
• Requires therapy based on: symptomatic disease, threatened end-organ dysfunction, compressive disease, cytopenias secondary to lymphoma, bulky disease (defined as any site ≥7 cm, or 3 or more sites ≥3cm), or steady progression.
• For patients with follicular lymphoma: No prior systemic therapy for follicular lymphoma. Prior radiation to a single site of disease is allowed if completed at least 2 weeks prior to initiation of protocol therapy and there are additional sites of measurable disease outside of the radiation field.
• For patients with marginal zone lymphoma: No prior systemic therapy for marginal zone lymphoma. Prior radiation or surgical resection is allowed if there are additional sites of measurable disease outside of the radiation field. Prior radiation must be completed at least 2 weeks prior to initiation of protocol therapy. Prior H. pylori eradication therapy is allowed.
• Age >18 years.
• ECOG performance status ≤2

• Participants must have adequate organ function as defined below:

  • total bilirubin <1.5 x institutional upper limit of normal (ULN) or <3 x ULN if considered due to Gilbert's syndrome
  • AST(SGOT)/ALT(SGPT) ≤2.5 × institutional upper limit of normal
  • creatinine within normal institutional limits OR
  • creatinine clearance ≥30 mL/min for participants with creatinine levels above institutional normal.

• Participants must have adequate marrow function as defined below (unless abnormalities are considered related to marrow involvement by lymphoma):

  • absolute neutrophil count ≥1,000/mcL (500/mcL is acceptable if due to marrow involvement by lymphoma)
  • platelets ≥70,000/mcL(30,000/mcL is acceptable if due to marrow involvement by lymphoma)
• Female participants who are not of child-bearing potential and female participants of child-bearing potential who have a negative serum pregnancy test within 3 days prior to initial trial treatment. Female participants of child-bearing potential and all male partners, and male participants must consent to use a medically acceptable method of contraception throughout the study period and for a minimum of 1 year after the last dose of rituximab and for a minimum of 4 months after the last dose of umbralisib.
• Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

• Participants who require immediate cytoreduction per the treating investigator.
• For patients with H. pylori related gastric extranodal marginal zone lymphoma in the absence of t(11;18): Patient must have relapsed or refractory marginal zone lymphoma despite appropriate H. pylori eradication.
• For patients with hepatitis C virus related marginal zone lymphoma: Patient must have relapsed or refractory marginal zone lymphoma despite appropriate treatment of hepatitis C virus infection.
• Active systemic therapy for another malignancy within 2 years. Local/regional therapy with curative intent such as surgical resection or localized radiation is allowed if patient is deemed at low risk for recurrence by treating physician.
• Malignancy within 3 years of study enrollment except for adequately treated basal, squamous cell carcinoma or non-melanomatous skin cancer, carcinoma in situ of the cervix, superficial bladder cancer not treated with intravesical chemotherapy or BCG within 6 months, localized prostate cancer and PSA <1.0 mg/dL on 2 consecutive measurements at least 3 months apart with the most recent one being within 4 weeks of study entry.
• Corticosteroid therapy (prednisone >10 mg daily or equivalent) is not permitted within 7 days prior to study entry. Topical, or intra-articular or inhaled corticosteroids are permitted.
• Prior allogeneic stem cell transplant.
• Inflammatory bowel disease (such as Crohn's disease or ulcerative colitis)
• Malabsorption syndromes
• Irritable bowel syndrome with greater than 3 loose stools per day as a baseline.
• Known central nervous system involvement by lymphoma.
• Evidence of histological transformation to large cell lymphoma.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to umbralisib or rituximab.
• Evidence of ongoing systemic bacterial, fungal or viral infection, except localized fungal infections of skin or nails.
• Evidence of chronic active Hepatitis B (HBV, not including patients with prior hepatitis B vaccination; or positive serum Hepatitis B antibody) or chronic active Hepatitis C infection (HCV), active cytomegalovirus (CMV), or known history of HIV. If HBc antibody is positive, the patient must be evaluated for the presence of HBV DNA (by PCR). If HCV antibody is positive, the subject must be evaluated for the presence of HCV RNA by PCR. If the patient is CMV IgG or CMV IgM positive, the subject must be evaluated for the presence of CMV DNA by PCR. Patients with positive HBc antibody and negative HBV DNA via PCR are eligible, but prophylaxis with entecavir or lamivudine is recommended. Subjects who are CMV IgG or CMV IgM positive but who are CMV DNA negative by PCR are eligible, but antiviral prophylaxis should be considered per institutional protocol.
• Any severe and/or uncontrolled medical conditions or other conditions that could affect participation in the study such as:
• Symptomatic, or history of documented congestive heart failure (New York Heart Association functional classification III-IV [see Appendix: NYHA Classifications])
• Significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, CHF, or myocardial infarction within 6 months of enrollment.
• Concomitant use of medication known to cause QT prolongation or torsades de pointes should be used with caution and at investigator discretion.
• Poorly controlled or clinically significant atherosclerotic vascular disease including cerebrovascular accident (CVA), transient ischemic attack (TIA), symptomatic peripheral arterial disease, angioplasty, cardiac or vascular stenting within 6 months of enrollment.
• Psychiatric illness/social situations that would limit compliance with study requirements
• Known history of drug-induced liver injury, alcoholic liver disease, non-alcoholic steatohepatitis, primary biliary cirrhosis, ongoing extrahepatic obstruction caused by stones, cirrhosis of the liver.
• Pregnant women are excluded from this study because rituximab is an agent with known potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with rituximab or umbralisib, breastfeeding should be discontinued if the mother is treated with rituximab or umbralisib. These potential risks may also apply to other agents used in this study.

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: Umbralisib+Rituximab; A treatment cycle is defined as 28 consecutive days.; Umbralisib will be administered at 800 mg by mouth once daily on days 1-28 of cycles 1-24.; Rituximab will be administered at 375 mg/m2 by intravenous infusion on Cycle 1 Day 1 and may be administered at 375 mg/m2 by intravenous infusion or at 1400 mg by subcutaneous injection on days 8, 15, 22 of cycle 1, day 1 of cycles 2 to 6, then every 8 weeks starting on day 1 of cycle 7 until completion of 24 cycles of umbralisib (i.e. every other cycle for 18 cycles or 9 doses, for a total of 15 doses of rituximab), or until progression or intolerance.

Drug: Umbralisib; Umbralisib is an investigational drug which blocks a protein called PI3K. PI3K is a protein that plays a role in the way cells grow. In this type of cancer, PI3K is increased and more active than usual. This helps the cancer cells to grow and survive.; Other Names: TGR-1202; Drug: Rituximab; Rituximab works by targeting the CD20 antigen on normal and malignant B-cells. Then the body's natural immune defenses are recruited to attack and kill the marked B-cells; Other Names: MabThera

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Complete Response Rate	The frequency of patients who achieve a complete response	2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Response Rate	The frequency of patients who achieve a complete or partial response	2 years
Progression Free Survival	The median progression-free survival using Kaplan-Meier method with time of registration as time origin.	2 years
Overall Survival Rate	The median overall survival using Kaplan-Meier method with time of registration as time origin.	2 Years
Safety and Adverse Events: frequency, severity, and timing of adverse events	The nature, frequency, severity, and timing of adverse events	2 years

Collaborators and Investigators

• Sponsor: Massachusetts General Hospital
• Collaborators: TG Therapeutics
• Investigators: Principal Investigator: Jacob D. Soumerai, MD, Massachusetts General Hospital

Publications and helpful links

Helpful Links

• Link to MGH Center for Lymphoma

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2019
• Primary Completion (Estimated): November 30, 2023
• Study Completion (Estimated): November 30, 2024

Study Registration Dates

• First Submitted: April 15, 2019
• First Submitted That Met QC Criteria: April 17, 2019
• First Posted (Actual): April 18, 2019

Study Record Updates

• Last Update Posted (Actual): July 7, 2023
• Last Update Submitted That Met QC Criteria: July 5, 2023
• Last Verified: July 1, 2023

More Information

Terms related to this study

• Keywords: Lymphoma; Follicular Lymphoma; Marginal Zone Lymphoma
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma, Non-Hodgkin; Lymphoma, B-Cell; Lymphoma; Lymphoma, Follicular; Lymphoma, B-Cell, Marginal Zone; Physiological Effects of Drugs; Antirheumatic Agents; Antineoplastic Agents; Immunologic Factors; Antineoplastic Agents, Immunological; Rituximab
• Other Study ID Numbers: 19-011

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: The Dana-Farber / Harvard Cancer Center encourages and supports the responsible and ethical sharing of data from clinical trials. De-identified participant data from the final research dataset used in the published manuscript may only be shared under the terms of a Data Use Agreement. Requests may be directed to: [contact information for Sponsor Investigator or designee]. The protocol and statistical analysis plan will be made available on Clinicaltrials.gov only as required by federal regulation or as a condition of awards and agreements supporting the research
• IPD Sharing Time Frame: Data can be shared no earlier than 1 year following the date of publication
• IPD Sharing Access Criteria: BCH - Contact the Technology & Innovation Development Office at www.childrensinnovations.org or email TIDO@childrens.harvard.edu BIDMC - Contact the Beth Israel Deaconess Medical Center Technology Ventures Office at tvo@bidmc.harvard.edu BWH - Contact the Partners Innovations team at http://www.partners.org/innovation DFCI - Contact the Belfer Office for Dana-Farber Innovations (BODFI) at innovation@dfci.harvard.edu MGH - Contact the Partners Innovations team at http://www.partners.org/innovation
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No