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

Trial Status: Active

This phase II trial studies how well umbralisib and rituximab work as initial therapy for patients with follicular lymphoma and marginal zone lymphoma. Umbralisib blocks a protein called P13K, that plays a role in the way cells grow. In follicular lymphoma and marginal zone lymphoma, P13K is increased and more active than usual, allowing cancer cells to grow and survive. Umbralisib may kill cancer cells in some patients and cause their tumors to shrink. Monoclonal antibodies, such as rituximab, may interfere with the ability of cancer cells to grow and spread. Umbralisib and rituximab combination may work better than standard initial therapies in patients with follicular lymphoma and marginal zone lymphoma.

Inclusion Criteria

  • Participants must have histologically confirmed follicular lymphoma grade 1-3A or marginal zone lymphoma by World Health Organization (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 >= 3 cm), 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
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 2
  • Total bilirubin < 1.5 x institutional upper limit of normal (ULN) or < 3 x ULN if considered due to Gilbert’s syndrome
  • Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT)(serum glutamic pyruvic transaminase [SGPT]) =< 2.5 x institutional upper limit of normal
  • Creatinine within normal institutional limits OR creatinine clearance >= 30 mL/min for participants with creatinine levels above institutional normal
  • 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 Bacille Calmette-Guerin (BCG) within 6 months, localized prostate cancer and prostate specific antigen (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 human immunodeficiency virus (HIV). If hepatitis B core (HBc) antibody is positive, the patient must be evaluated for the presence of HBV deoxyribonucleic acid (DNA) (by polymerase chain reaction [PCR]). If HCV antibody is positive, the subject must be evaluated for the presence of HCV ribonucleic acid (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) * Significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure (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

Massachusetts

Boston
Beth Israel Deaconess Medical Center
Status: ACTIVE
Contact: Jon E. Arnason
Massachusetts General Hospital Cancer Center
Status: ACTIVE
Contact: Jacob D. Soumerai
Phone: 617-724-4000

PRIMARY OBJECTIVE:

I. To determine the complete response rate of umbralisib and rituximab in previously untreated patients with follicular lymphoma grade 1-3a and marginal zone lymphoma.

SECONDARY OBJECTIVES:

I. To assess safety and tolerability measured by the nature, frequency, severity, and timing of adverse events.

II. To determine the frequency of complete plus partial responses (overall response rate).

III. To determine the durability of clinical benefit as measured by progression-free and overall survival.

CORRELATIVE OBJECTIVE:

I. To evaluate for mechanisms of resistance to PI3Kdelta inhibition in patients with follicular lymphoma.

OUTLINE:

Patients receive umbralisib orally (PO) once daily (QD) on days 1-28 of cycles 1-24. Patients also receive rituximab intravenously (IV) on days 1, 8, 15, and 22 of cycle 1, then IV or subcutaneously (SC) on day 1 of cycles 2-6, 7, 9, 11, 13, 15, 17, 19, 21, and 23. Treatment repeats every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 28 days, then every 12 weeks for 2 years.

Trial Phase Phase II

Trial Type Treatment

Lead Organization
Dana-Farber Harvard Cancer Center

Principal Investigator
Jacob D. Soumerai

  • Primary ID 19-011
  • Secondary IDs NCI-2019-07931
  • Clinicaltrials.gov ID NCT03919175