PI left institution

The primary objective is to determine the overall response rate (ORR) of TGR-1202 in R/R FL.

Secondary Objectives

• Determine the genetic and other novel biological markers that may be predictive of response or resistance to TGR-1202 in patients with relapsed or refractory FL.
• Describe the Progression Free Survival (PFS), Duration of Response (DoR) after treatment with TGR-1202.
• Describe the number of dose delays and dose reductions and other safety profile.

This is an open label, phase II study of TGR-1202 in patients with relapsed or refractory (R/R) Grade 1, 2, or 3A follicular lymphoma (FL). FL is the most common subtype of indolent lymphoma. The prognosis of FL depends on the histologic grade, stage, treatment and age of the patient. More recently, efforts have been made to find novel regimens for the treatment of relapsed FL that do not contain non-specific cytotoxic agents.

One of the important goals of this phase II study is to discover novel genetic, biochemical, and immunological markers that are associated with the response and safety of TGR-1202 in patients with FL. TGR-1202 blocks PI3K, a signal that is required for cancer to grow.

Inclusion Criteria:

• Histologically proven diagnosis of grade 1, 2, or 3A FL.

• Relapse following first line immunotherapy or chemoimmunotherapy. There is no upper limit to the number of therapies received prior to study entry. Prior therapies may include high-dose therapy with autologous stem cell rescue.

• Measurable Disease according to the Lugano classification.

• Lymphoma that is amenable to safe pre-treatment and post-treatment biopsy. The safety of the procedures will be determined by the treating physician and the surgeon in consultation with the PI, and in accordance with standard clinical practice. Acceptable sites of disease include, for example: (1) palpable tumor mass that is accessible under direct visualization or sonogram, (2) non-palpable tumor tissue that is accessible for biopsy under computed tomography (CT) or sonogram guidance, (3) bone marrow.

• Age >18 years

• Eastern Cooperative Oncology Group (ECOG) performance status <2

• Patients must have adequate organ and marrow function as defined below:

  1. absolute neutrophil count >1,000/microliter
  2. platelet count ≥50,000/microliter
  3. bilirubin <1.5 x institutional upper limit of normal
  4. aspartate transaminase (AST, SGOT)/alanine transaminase (ALT, SGPT) <3.0 x institutional upper limit of normal
  5. Serum creatinine <2.0 x institutional upper limit of normal or creatinine clearance >50 mL/min (according to the Cockcroft and Gault equation).

• Negative serum pregnancy test within 7 days prior to Cycle 1/Day 1 for women of childbearing potential.

• All women of childbearing potential must agree to use an effective barrier method of contraception, as described in Appendix 4, during the treatment period and for at least 1 month after discontinuation of the study drug. Male subjects should use effective barrier method of contraception during the treatment period and for at least 1 month after discontinuation of the study drug

• Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

• Grade 3B FL or evidence of transformation to a more aggressive lymphoma

• Prior and concomitant therapy:

  1. Prior exposure to any PI3 Kinase inhibitor
  2. Exposure to chemotherapy, radiotherapy, or immunotherapy within 3 weeks prior to entering the study or lack of recovery from adverse events (AE) due to previously administered treatments.
  3. Ongoing chronic immunosuppressants (e.g. cyclosporine) or systemic steroids that have not been stabilized to the equivalent of ≤10 mg/day prednisone prior to the start of the study drug.
  4. Other concurrent investigational agents during the study period.

• Prior allogeneic stem cell transplant

• Central nervous system lymphoma, including lymphomatous meningitis

• Acute intercurrent illness including, but not limited to, active infection, unstable congestive heart failure, unstable angina pectoris, psychiatric illness or any social situation that would limit compliance with study participation requirements in the judgement of the investigator.

• Major surgery performed within 4 weeks of study entry

• Pregnant or nursing women

• Active concurrent malignancy (except non-invasive non-melanoma skin cancer, carcinoma in situ of the cervix, or prostate intraepithelial neoplasia). If there is a history of prior malignancy, the patient must be disease-free for ≥ 3-years at the time of study entry.

• Documented Human Immunodeficiency Virus (HIV)-infection

• Active hepatitis A, hepatitis B, or hepatitis C infection

• History of tuberculosis treatment within 2 years of study entry

• Administration of a live vaccine within 6 weeks of first dose of study drug

• Unable to receive prophylactic treatment for pneumocystis, herpes simplex virus (HSV), or herpes zoster (VZV) at screening

• Prior surgery or gastrointestinal dysfunction that may affect drug absorption (e.g., gastric bypass surgery, gastrectomy)

• Lymphoma that is not amenable for mandatory pre- and post-treatment biopsy as described in the inclusion criteria.

• Unstable or severe uncontrolled medical condition (e.g. unstable cardiac function, unstable pulmonary condition, uncontrolled diabetes) or any important medical illness or abnormal laboratory finding that would, in the investigator's judgment, increase the risk to the patient associated with his or her participation in the study

• Clinically significant cardiovascular abnormalities such as:

  1. QTc ≥ 470 msec.
  2. Angina not well-controlled by medication
  3. 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
  4. Symptomatic or documented congestive heart failure that meets New York Heart Association (NYHA) Class III to IV definitions;
  5. History of stroke within the last 6 months prior to screening

Up to 1 year post treatment