Trial of Duvelisib in Combination With Either Romidepsin or Bortezomib in Relapsed/Refractory T-cell Lymphomas

The phase I portion of the study is designed to determine the MTD of duvelisib with
romidepsin and duvelisib with bortezomib. All patients must have a relapsed or refractory
T-cell lymphoma. The design is a standard 3+3 dose escalation of two parallel phase I
studies. Patients will be enrolled in Arms A (Romidepsin + duvelisib) and B (Bortezomib +
duvelisib) of the study starting at dose level 1.

Three to six patients will be initially treated in each dose level until the MTD is
determined. If dose level 3 is achieved without exceeding one dose limiting toxicity (DLT)
after 1 cycle that dose level will be deemed the "optimal dose" and the study will proceed to
the cohort expansion phase. Should patients be found to develop significant toxicity or not
tolerate therapy at the MTD with repeated cycles of therapy, the "optimal dose" may be
determined to be at dose levels less than the MTD. Patients with measurable disease treated
in the phase I at the optimal dose will be counted towards the accrual of the expansion
cohorts by disease subtype and all efficacy and toxicity endpoints.

Cohort Expansion Phase: The expansion cohorts will further assess toxicity and safety and
allow a preliminary assessment of the efficacy of the combination to provide background for a
potential future subtype specific phase II study. The assessment of efficacy will be
descriptive.

Inclusion Criteria:

- Pathologically confirmed T-cell lymphomas at the enrolling institution, including
stage ≥ Ib CTCL, which has relapsed or progressed after at least one systemic therapy.

- Age ≥ 18

- Previous systemic anti-cancer therapy must have been discontinued at least 3 weeks
prior to treatment. For the dose expansion phase, in progressing subjects, a 2 week
washout may be allowed after discussion with the MSK Principal Investigator.

- Previous radiation and/or surgery must have been discontinued or completed at least 2
weeks prior to treatment in this study and adverse effects must have resolved to Grade
1 or baseline. Lymph node or other diagnostic biopsies within 2 weeks are not
considered exclusionary.

° Patients who have received localized RT as part of their immediate prior therapy may
be allowed to enroll with shorter washout period after discussion with the MSK
Principal Investigator.

- ECOG ≤ 2

- Meet the following laboratory criteria without use of growth factor support or
platelet transfusions for 1 week:

i) Absolute neutrophil count ≥ 1.0 K/mcl, ii) Platelet count ≥ 80 K/μl (in the
expansion cohorts, if thrombocytopenia is due to bone marrow involvement platelet
count must be ≥ 50 K/μL), iii) Patients enrolled in the dose escalation phase who are
not enrolled on the expansion cohorts must have calculated creatinine clearance ≥
50ml/min by Cockcroft-Gault formula. Patients enrolled in the Dose Expansion phase
must have calculated creatinine clearance ≥ 40ml/min by Cockcroft-Gault formula.

iv) Total bilirubin ≤ 1.5 x upper limit of normal (ULN) or ≤ 3 x ULN if documented hepatic
involvement with lymphoma, or ≤ 5 x ULN if history of Gilbert's syndrome; AST (SGOT) and
ALT (SGPT) ≤ 3 x ULN; ≤ 5 ULN if due to lymphoma involvement

- Measurable disease for dose expansion and lead in phase only.

Measurable disease defined by:

1. Revised International Working Group (Cheson, 2007) Classification for systemic
lymphoma or

2. Atypical and or malignant lymphocytes quantifiable by flow cytometry or morphology in
blood

3. or bone marrow mSWAT > 0 or Sezary couny >/= 1000 cells/ul

- Short course systemic corticosteroids for disease control, improvement of
performance status or non-cancer indication (< 7 days) must have been
discontinued at least 6 days prior to study treatment. Stable ongoing
corticosteroid use (≥ 30 days) up to an equivalent dose of 20 mg of prednisone is
permissible.

i) Topical steroids that have been used for > 3 weeks may be continued (CTCL
only). All other histologies (not CTCL): Topical steroids use is permissible
without restriction

- Women of reproductive potential† must have a negative serum or urine β human
chorionic gonadotropin (βhCG) pregnancy test. All women of reproductive
potential, all sexually active male patients, and all partners of patients must
agree to use adequate methods of birth control (e.g. latex condoms) throughout
the study and for 30 days after the last dose of study drug.

- A female of reproductive potential is a sexually mature female who: has not
undergone a hysterectomy or bilateral oophorectomy; or has not been
naturally postmenopausal for at least 24 consecutive months (i.e. has had
menses at any time in the preceding 24 consecutive months).

Exclusion Criteria:

- Any serious medical condition, laboratory abnormality, or psychiatric illness that
would prevent the subject from signing the informed consent form.

- Pregnant females. (Lactating females must agree not to breast feed while taking the
study medications).

- Prior use of duvelisib if discontinued due to toxicity.

- For the romidepsin arm of the study, prior therapy with romidepsin if discontinued due
to toxicity.

- For the bortezomib arm of the study, prior therapy with a proteasome inhibitor if
discontinued due to toxicity.

- For the bortezomib arm of the study, patients with grade ≥2 peripheral neuropathy.

- History of chronic liver disease, veno-occlusive disease, or current alcohol abuse.

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

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

- Known seropositive and requiring anti-viral therapy for human immunodeficiency virus
(HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV). Subjects with chronic
hepatitis B or C as defined as test .

- Subjects with positive Hep B serology. Subjects with a negative HBsAg and a positive
HBcAb require an undetectable/negative hepatitis B DNA test (e.g., polymerase chain
reaction [PCR] test) to be enrolled, and will require prophylactic antiviral treatment
(e.g., F) initiated prior to the first dose of study drug, an continued until
approximately 6 to 12 months after completion of study drug(s).

- Patients with positive hepatitis C virus Ab

- Subjects with active EBV unrelated to underlying lymphoma (positive serology for
anti-EBV VCA IgM antibody and negative for anti-EBV EBNA IgG antibody, or clinical
manifestations and positive EBV PCR consistent with active EBV infection.

- Subject with active CMV (positive serology for anti-CMV IgM antibody and negative for
anti-CMV IgG antibody and positive CMV PCR with clinical manifestations consistent
with active CMV infection) and requiring therapy will be excluded from participation
in the study. Carriers will be monitored per institutional guidelines.

- Receiving systemic therapy for another primary malignancy (other than T-cell lymphoma)

- Patients with more than one type of lymphoma may be enrolled after discussion with the
MSK Principal Investigator.

- Adjuvant or maintenance therapy to reduce the risk of recurrence of other malignancy
(other than T-call lymphoma) is permissible after discussion with the MSK Principal
Investigator.

- Known central nervous system or meningeal involvement (in the absence of symptoms,
investigation into central nervous system involvement is not required).

- The following known cardiac abnormalities:

1. Congenital long QT syndrome.

2. QTc/QTf interval ≥ 480 milliseconds; unless secondary to pacemaker or bundle
branch block.

3. Myocardial infarction within 6 months. (Subjects with a history of myocardial
infarction within the last 6 to12 months who are asymptomatic and have had a
negative cardiac risk assessment (treadmill stress test, nuclear medicine stress
test, or stress echocardiogram) since the event may participate.)

4. Other significant ECG abnormalities including 2nd degree atrio- ventricular (AV)
block (AV) block type II, 3rd degree AV block.

5. Symptomatic coronary artery disease (CAD), e.g., angina Canadian Class II-IV (see
Appendix B). In any patient in whom there is doubt, the patient should have a
stress imaging study and, if abnormal, angiography to define whether or not CAD
is present.

II-IV (see Appendix B). In any patient in whom there is doubt, the patient should
have a stress imaging study and, if abnormal, angiography to define whether or
not CAD is present.

6. An ECG recorded at screening showing evidence of cardiac ischemia (ST depression
of ≥2 mm, measured from isoelectric line to the ST segment). If in any doubt, the
patient should have a stress imaging study and, if abnormal, angiography to
define whether or not CAD is present.

7. Congestive heart failure (CHF) that meets New York Heart Association (NYHA) Class
II to IV definitions (see Appendix C) and/or ejection fraction <45% by MUGA,
echocardiogram, or cardiac MRI.

8. A known history of sustained ventricular tachycardia (VT), ventricular
fibrillation (VF), Torsade de Pointes, or cardiac arrest unless currently
addressed with an automatic implantable cardioverter defibrillator (AICD).

9. Hypertrophic cardiomegaly or restrictive cardiomyopathy from prior treatment or
other causes.

10. Uncontrolled hypertension, i.e., blood pressure (BP) of ≥170/95; patients who
have a history of hypertension controlled by medication must be on a stable dose
(for at least one month prior to study registration) and meet all other inclusion
criteria.

11. Any cardiac arrhythmia requiring an anti-arrhythmic medication (excluding stable
doses of beta-blockers)

12. For patients enrolling on the Romidepsin arm; taking drugs associated with
significant QTc/QTf prolongation, unless able to be switched to non-QTc/QTf
prolonging medication or on a stable dose without significant QT prolongation
(>470 msec). Caution should be used when administering study drugs to patients
taking medications significantly metabolized by these enzymes refer to
(http://medicine.iupui.edu/clinpharm/ddis/clinical-table/) for clinically
relevant medications. Particular attention should be paid to patients receiving
warfarin. Patient should have coagulation parameters monitored regularly, and
warfarin dose adjusted accordingly. If these drugs cannot be discontinued or
replaced enrollment may be allowed after discussion with MSK PI.