TGR-1202 and Ibrutinib in Treating Patients With Relapsed or Refractory Diffuse Large B-Cell Lymphoma
Condition: Recurrent Diffuse Large B-Cell Lymphoma; Refractory Diffuse Large B-Cell Lymphoma
MeSH terms: Lymphoma; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse
Intervention: Ibrutinib; Laboratory Biomarker Analysis; PI3K-delta Inhibitor TGR-1202
Intervention description: Given PO; Correlative markers; Given PO
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 13.0
Sex: All
Minimum age: 19 Years
Healthy volunteers: No

Summary:

      This phase IIa trial studies the side effects and how well TGR-1202 and ibrutinib work in
      treating patients with diffuse large B-cell lymphoma that has returned after a period of
      improvement or does not respond to treatment. TGR-1202 and ibrutinib may stop the growth of
      cancer cells by blocking some of the enzymes needed for cell growth.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Histologically confirmed diffuse large B-cell lymphoma (DLBCL) or transformed DLBCL

          -  Hematoxylin and eosin (H&E) stain and immunohistochemistry (IHC) slides or a
             representative formalin-fixed, paraffin-embedded (FFPE) tissue block along with the
             pathology report from initial diagnosis, (as well as, an optional 8 unstained slides
             of 4 micron thickness to store for future IHC and DNA specified research use), should
             be sent to be reviewed, and the diagnosis confirmed by University of Nebraska Medical
             Center (UNMC) (retrospective diagnostic review: treatment may commence prior to the
             UNMC review); please NOTE: the diagnostic H&E slide and IHC slides will be returned
             after review; only the optional 8 unstained slides will be retained and stored for
             future unspecified research use

          -  Patients with relapsed or refractory DLBCL that has relapsed post-transplant or that
             has been determined to be ineligible or unsuitable for transplant; patients must have
             to have received at least one prior systemic therapy

          -  Patients must have measurable (>= 1.5 cm) or evaluable disease; baseline measurements
             and evaluations must be obtained within 6 weeks of registration to the study; abnormal
             PET scans will not constitute evaluable disease, unless verified by CT scan or other
             appropriate imaging; measurable disease must have at least one objective measurable
             disease parameter; a clearly defined, bi-dimensionally measurable defect or mass
             measuring at least 1.5 cm in diameter on a CT scan will constitute measurable disease;
             proof of lymphoma in the liver is required by a confirmation biopsy; skin lesions can
             be used as measurable disease provided bi-dimensional measurements are possible

          -  Absolute neutrophil count (ANC) >= 1.0 x 10^9/L

               -  By automated or manual review, whichever is greatest

          -  Platelets >= 100 x 10^9/L:

               -  Unless due to bone marrow infiltration then eligible if platelets > 50 x 10^9/L)

          -  Total bilirubin =< 1.5 x upper normal limit if documented hepatic involvement with
             lymphoma, or =< 5 x upper normal limit if history of Gilbert's disease

          -  Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 x upper
             limit of normal (ULN) if no liver involvement or =< 5 x the ULN if documented liver
             involvement

          -  Creatinine =< 2.0 mg/dL OR calculated creatinine clearance >= 50 mL/min (as calculated
             by the Cockcroft-Gault method)

          -  Eastern Cooperative Oncology Group (ECOG) performance status =< 2 or expected survival
             duration of > 2 months

          -  Ability to swallow and retain oral medication

          -  Women must not be pregnant or breast-feeding

               -  All female patients of child-bearing potential must have a negative serum
                  pregnancy test within 2 weeks prior to treatment to rule out pregnancy

               -  Pregnancy testing is not required for post-menopausal or surgically sterilized
                  women

          -  Male and female patients of reproductive potential must agree to follow accepted birth
             control measures throughout the study period and for 30 days after the last dose of
             either study drug for females and 3 months after the last dose of study drug for males

          -  Patient must be able to adhere to the study visit schedule and other protocol
             requirements

          -  Patient must be aware of the neoplastic nature of his/her disease and willingly sign
             (or their legally-acceptable representatives must sign) an informed consent document
             indicating that they understand the purpose of and procedures required for the study,
             including biomarkers, and are willing to participate in the study

          -  No serious disease or condition that, in the opinion of the investigator, would
             compromise the patient's ability to participate in the study

        Exclusion Criteria:

          -  Currently receiving cancer therapy (i.e., chemotherapy, radiation therapy,
             immunotherapy, biologic therapy, hormonal therapy, and surgery and/or tumor
             embolization) or any investigational drug within 7 days of cycle 1/day 1, 14 days of
             cycle 1/day 1 for limited palliative radiation, and/or five half-live of an oral
             therapy

               -  Corticosteroid therapy started at least 7 days prior to initiation of treatment
                  (prednisone =< 10 mg daily or equivalent) is allowed as clinically warranted);
                  topical or inhaled corticosteroids are permitted

          -  Major surgery or a wound that has not fully healed within 4 weeks of enrollment

          -  History of stroke or intracranial hemorrhage within 6 months prior to enrollment

          -  Requires anticoagulation with warfarin or equivalent vitamin K antagonists (eg,
             phenprocoumon)

          -  Vaccinated with live, attenuated vaccines within 4 weeks of enrollment

          -  Autologous hematologic stem cell transplant within 3 months of study entry

          -  Allogeneic hematologic stem cell transplant within 12 months of study entry

          -  Active graft versus-host disease and must not be on immunosuppression

          -  Wide field radiotherapy within 28 days of cycle 1/day 1 or active side effects of such
             therapy

          -  Active hepatitis B (hepatitis B virus [HBV]) or C (hepatitis C virus [HCV]) infection
             (negative serology required excluding those with are seropositive due to prior
             vaccination) and/or known history of human immunodeficiency virus (HIV)

          -  Primary central nervous system involvement only

          -  Require treatment with strong cytochrome P450 family 3 subfamily A (CYP3A) inhibitors

          -  Known history of drug-induced liver injury, alcoholic liver disease, primary biliary
             cirrhosis, ongoing extra-hepatic obstruction caused by stones, cirrhosis of the liver
             or portal hypertension

          -  Any life-threatening illness, severe and/or uncontrolled medical condition, or organ
             system dysfunction, laboratory abnormality, psychiatric illness or other condition
             which, in the Investigator's opinion, could compromise the subject's safety, interfere
             with the absorption or metabolism of ibrutinib capsules, put the study outcomes at
             undue risk or affect their participation in the study such as

               -  Symptomatic, or history of documented congestive heart failure New York Heart
                  Association (NYHA) functional classification III-IV (NYHA)

               -  Corrected QT interval using Fridericia's formula (QTcF) > 470 msec (unless
                  related to pacemaker) on echocardiogram (EKG) within 7 days of initiation of
                  treatment

               -  Angina not well-controlled by medication

               -  Poorly controlled or clinically significant atherosclerotic vascular disease
                  including cerebrovascular accident (CVA), transient ischemic attack (TIA),
                  angioplasty, cardiac or vascular stenting within 6 months prior to enrollment

          -  Prior malignancies within the past 1 year with exception of adequately treated basal
             cell, squamous cell skin cancer, or thyroid cancer; carcinoma in situ of the cervix or
             breast; prostate cancer of Gleason grade 6 or less with stable prostate specific
             antigen (PSA) levels

          -  Women who are pregnant or breastfeeding; women who agree to stop breastfeeding would
             be eligible

          -  Known hypersensitivity to either study drug (TGR-1202 or ibrutinib)