Clinical Trials

Inclusion Criteria:

• Histologically confirmed diagnosis of: B-cell NHL with histological subtype limited to the following based on criteria established by the World Health Organization (WHO) 2008 classification of tumors of hematopoietic and lymphoid tissues:
  • Follicular Lymphoma (FL) of Grade 1, 2, or 3a;
  • Marginal Zone Lymphoma (MZL) (splenic, nodal, or extranodal); or
  • Mantle Cell Lymphoma (MCL) – with documentation of either overexpression of cyclin D1 or t(11;14);
  • Note: Subjects with Diffuse Large B-Cell Lymphoma (DLBCL) and Small Lymphocytic Lymphoma (SLL) were previously eligible, however new subject enrollment for these subtypes was closed in protocol V5.0;
  • As of protocol V6.0 – Small Lymphocytic Lymphoma (SLL) subjects are eligible for enrollment. 
• Treatment status:
  • As of Protocol V6.0 – FL, SLL and MZL subjects - Treatment naïve or previously treated with a maximum of two prior lines of therapy (excluding antibiotics); FL subjects must have documented evidence for requiring treatment (one or more of the following: bulky disease (>5 cm), high LDH, B symptoms, threatened organ function, splenomegaly, cytopenias due to lymphoma, or effusions;
  • Protocol V3.0 - V5.1 (closed) - FL subjects: relapsed or refractory after ≥ 2 prior lines of systemic therapy. Subjects must have received an anti-CD20 mAb and an alkylating agent, and must have documented evidence for requiring treatment (one or more of the following: bulky disease (> 5 cm), high LDH, B symptoms, threatened organ function, splenomegaly, cytopenias due to lymphoma, or effusions);
  • Protocol V2.0 - V5.1 (closed) - MZL subjects: prior treatment with one or more lines of therapy including at least one CD20-directed regimen (either as monotherapy or as chemoimmunotherapy) with documented failure to achieve at least PR or documented PD after the most recent systemic treatment regimen, and must have documented evidence for requiring treatment (one or more of the following: bulky disease (>5 cm), high LDH, B symptoms, threatened organ function, splenomegaly, cytopenias due to lymphoma, or effusions);
  • Protocol V4.0 – V6.0 - MCL subjects: prior treatment with one or more lines of therapy including at least one BTK inhibitor (either ibrutinib, acalabrutinib or zanibrutinib only) with documented failure to achieve at least PR or documented PD during, or within 6 months of discontinuing, prior BTK therapy.
• Measurable disease, defined as at least 1 measurable disease lesion > 1.5 cm in at least one diameter by CT/CT-PET or magnetic resonance imaging (MRI) in an area of no prior radiation therapy, or in an area that was previously irradiated that has documented progression.
• Adequate organ system function, defined as follows:
  • Absolute neutrophil count (ANC) > 1,000/mm^3 (µL) & platelet count > 50,000/mm^3 (µL);
  • Total bilirubin ≤ 1.5 times the upper limit of normal (ULN);
  • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x ULN if no liver involvement or ≤ 5 x the ULN if known liver involvement;
  • Calculated creatinine clearance ≥ 30 mL/min (as calculated by the Cockcroft-Gault formula).
• ECOG performance status ≤ 2.
• Male or female ≥ 18 years of age.
• Ability to swallow and retain oral medication.
• Female subjects who are not of child-bearing potential (see Appendix B- Contraceptive Guidelines and Pregnancy), and female subjects of child-bearing potential who have a negative serum pregnancy test within 3 days prior to Cycle 1, Day 1. Female subjects of child-bearing potential, and male partners must consent to use a medically acceptable method of contraception throughout the study period and for 4 months after the last dose of either study drug.
• Willingness and ability to comply with trial and follow-up procedures, and give written informed consent.

Exclusion Criteria:

• Subjects receiving cancer therapy (i.e., chemotherapy, radiation therapy, immunotherapy, biologic therapy, hormonal therapy, surgery and/or tumor embolization) or any investigational drug within 21 days of Day 1 of Cycle 1:
  • Corticosteroid therapy started at least 7 days prior to study entry (prednisone ≤ 10 mg daily or equivalent) is allowed as clinically warranted. Topical or inhaled corticosteroids are permitted;
  • Palliative radiation therapy is allowed as clinically warranted.
• Subjects who have received autologous hematologic stem cell transplant within 6 months of study entry. Prior allogeneic hematologic stem cell transplant is excluded.
• Evidence of chronic active Hepatitis B (HBV) as evidenced by a detectable hepatitis B surface antigen (not including subjects with prior hepatitis B vaccination); or positive serum Hepatitis B surface antibody) or chronic active Hepatitis C infection (HCV), cytomegalovirus (CMV), or known history of HIV. If HBc antibody, HCV antibody or CMV IgG or IgM is positive the subject must be evaluated for the presence of HBV DNA, HCV RNA, or CMV DNA by PCR.
• Known history of Central Nervous System (CNS) lymphoma; subjects with symptoms of CNS disease must have a negative MRI scan and negative diagnostic lumbar puncture.
• Known histological transformation from chronic lymphocytic leukemia to large cell lymphoma (i.e., Richter’s transformation). 
• Evidence of ongoing systemic bacterial, fungal or viral infection, except localized fungal infections of skin or nails.
• History of anaphylaxis (excluding infusion related reactions) in association with previous antiCD20 administration (for subjects eligible to enroll to an ublituximab containing regimen only).
• Prior exposure to idelalisib (CAL-101), duvelisib (IPI-145), copanlisib or any other drug that specifically inhibits phosphoinositide-3-kinase (PI3K).
• Any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study such as:
  • Symptomatic, or history of documented congestive heart failure (NY Heart Association functional classification III-IV NYHA Classifications]);
  • Significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of randomization;
  • 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), angioplasty, cardiac/vascular stenting within 6 months of enrollment.
• 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.