Carfilzomib and TGR-1202 in Treatment of R/R Lymphoma

Dysregulated c-Myc is associated with resistance to chemotherapy and poor survival in
aggressive lymphomas. Novel strategies that target this biology could markedly improve the
outcome of these participants. To date no drugs that directly target Myc have been approved
for cancer treatment. Recent results by Deng et al. (Blood. 2017 Jan 5. PMID: 27784673)
described a highly synergistic regimen discovered in preclinical models, through combining
TGR-1202, an investigational drug that inhibits PI3K delta, and carfilzomib, a drug approved
by the FDA for multiple myeloma. Importantly, the combination of TGR-1202 and carfilzomib
acts by potently silencing the translation of c-Myc and inducing apoptosis in many cell
lines and primary lymphoma cells representing broad histological subtypes of lymphoma. These
results suggest that TGR-1202 and carfilzomib may be highly effective in relapsed and
refractory lymphoma where c-Myc plays a key pathological role.

Target Population Phase I: Patients with relapsed or refractory NHL and HL Phase II:
Patients with relapsed or refractory NHL

Inclusion Criteria:

- Phase I: Patients must have histologically confirmed R/R NHL or HL (defined by WHO
criteria). Patients with chronic lymphocytic leukemia (CLL) and small lymphocytic
lymphoma (SLL) are eligible. In addition, patients with NHL other than diffuse large
B cell lymphomas (DLBCL) must have received at least 2 prior therapies. Patients with
DLBCL and HL will be eligible if there is no available standard therapy.

- Phase II: Patients must have histologically confirmed R/R NHL (as defined by WHO
criteria). Patients with NHL other than diffuse large B cell lymphomas (DLBCL) must
have received at least 2 prior therapies. Patients with DLBCL will be eligible if
there is no available standard therapy.

- Must have received front line chemotherapy. No upper limit for the number of prior
therapies

- Evaluable Disease in the Phase I, and measurable disease in the Phase II

- Age > 18 years

- ECOG performance status < 2

- Patients must have adequate organ and marrow function

- Adequate Contraception

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

Exclusion Criteria:

1. Prior Therapy Exposure to chemotherapy or radiotherapy within 2 weeks prior to
entering the study or those who have not recovered from adverse events due to agents
administered more than 2 weeks earlier. Systemic steroids that have not been
stabilized (≥ 5 days) to the equivalent of ≤10 mg/day prednisone prior to the start
of the study drugs. No other investigational agents are allowed.

2. History of allergic reactions to TGR-1202 or carfilzomib

3. Uncontrolled inter-current illness

4. Pregnant women

5. Nursing women

6. Current malignancy or history of a prior malignancy

7. Patient known to be Human Immunodeficiency Virus (HIV)-positive

8. Active Hepatitis A, Hepatitis B, or Hepatitis C infection