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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03919175
Recruitment Status : Recruiting
First Posted : April 18, 2019
Last Update Posted : September 2, 2020
Sponsor:
Collaborator:
TG Therapeutics
Information provided by (Responsible Party):
Jacob Soumerai, MD, Massachusetts General Hospital

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

Condition or disease Intervention/treatment Phase
Lymphoma Follicular Lymphoma Follicular Lymphoma, Grade 1 Follicular Lymphoma Grade 2 Follicular Lymphoma Grade IIIa Marginal Zone Lymphoma Marginal Zone B Cell Lymphoma Drug: Umbralisib Drug: Rituximab 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 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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 41 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 2 Study of Umbralisib and Rituximab as Initial Therapy for Patients With Follicular Lymphoma and Marginal Zone Lymphoma
Actual Study Start Date : September 1, 2019
Estimated Primary Completion Date : November 30, 2022
Estimated Study Completion Date : November 30, 2024


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 Name: 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 Name: MabThera




Primary Outcome Measures :
  1. Complete Response Rate [ Time Frame: 2 years ]
    The frequency of patients who achieve a complete response


Secondary Outcome Measures :
  1. Overall Response Rate [ Time Frame: 2 years ]
    The frequency of patients who achieve a complete or partial response

  2. Progression Free Survival [ Time Frame: 2 years ]
    The median progression-free survival using Kaplan-Meier method with time of registration as time origin.

  3. Overall Survival Rate [ Time Frame: 2 Years ]
    The median overall survival using Kaplan-Meier method with time of registration as time origin.

  4. Safety and Adverse Events: frequency, severity, and timing of adverse events [ Time Frame: 2 years ]
    The nature, frequency, severity, and timing of adverse events



Information from the National Library of Medicine

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

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03919175


Contacts
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Contact: Jacob D. Soumerai, MD 617-724-4000 jsoumerai@mgh.harvard.edu

Locations
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United States, Massachusetts
Massachusetts General Hospital Cancer Center Recruiting
Boston, Massachusetts, United States, 02114
Contact: Jacob D. Soumerai, MD    617-724-4000    jsoumerai@mgh.harvard.edu   
Principal Investigator: Jacob D. Soumerai, MD         
Beth Israel Deaconness Medical Center Recruiting
Boston, Massachusetts, United States, 02215
Contact: Jon Arnason, MD         
Principal Investigator: Jon Arnason, MD         
Sponsors and Collaborators
Massachusetts General Hospital
TG Therapeutics
Investigators
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Principal Investigator: Jacob D. Soumerai, MD Massachusetts General Hospital
Additional Information:
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Responsible Party: Jacob Soumerai, MD, Principal Investigator, Massachusetts General Hospital
ClinicalTrials.gov Identifier: NCT03919175    
Other Study ID Numbers: 19-011
First Posted: April 18, 2019    Key Record Dates
Last Update Posted: September 2, 2020
Last Verified: August 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
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
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Time Frame: Data can be shared no earlier than 1 year following the date of publication
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

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Jacob Soumerai, MD, Massachusetts General Hospital:
Lymphoma
Follicular Lymphoma
Marginal Zone Lymphoma
Additional relevant MeSH terms:
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Lymphoma
Lymphoma, Follicular
Lymphoma, B-Cell, Marginal Zone
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Lymphoma, Non-Hodgkin
Lymphoma, B-Cell
Rituximab
Antineoplastic Agents, Immunological
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents