ADAM17 Inhibitor/ Rituximab After Auto HCT for DLBCL

The primary goal of the dose finding phase is to determine the maximum tolerated dose (MTD)
of INCB7839. Up to three dose levels will be tested (100 mg bid, 200 mg bid, and 300 mg bid).
As the 300 mg bid has been proven safe in the non-transplant setting, dose escalation follows
a Fast-Track Design with 1 patient enrolled per dose level unless a grade 2 or greater
treatment emergent event occurs within the 1st 14 days of INCB7839. At that point, dose
escalation converts to a standard 3+3 design and two additional patients are enrolled at the
current dose level. If dose level 3 is completed without dose limiting toxicity (DLT) in the
1st 3 patients, an additional 3 patients will be enrolled at this level (without the
staggering required by the DLT rules) prior to moving to the phase II component.

Once the phase I dose escalation is completed, an additional 12 patients will be enrolled at
the MTD (or dose level 3, if no DLT) to obtain a more detailed toxicity profile as well as a
preliminary estimate of progression free survival at 6 months post-transplant.

Inclusion Criteria:

- Patients 18 years or older who have undergone an autologous HCT for the treatment of
DLBCL and are in a complete remission (CR), partial remission (PR) or have stable
disease (SD) at the day 28 post-transplant reassessment

- Karnofsky Score of ≥ 70% (appendix II)

- Able to start the protocol therapy (1st dose of rituximab) between day 28-75
post-transplant

- Adequate organ function defined as:

- Hematologic: platelets ≥ 50,000 x 109/L; ANC ≥ 1000 x 109/L unsupported by G-CSF
or GM-CSF for 3 days

- Renal: creatinine < 1.5 mg/dl or glomerular filtration rate > 50 ml/min

- Hepatic: Alanine transaminase (ALT, SGPT) and aspartate aminotransferase (SGOT,
AST) < 3 x upper limit of institutional normal and total bilirubin < 3.0 mg/dl
(if total bilirubin is ≥ 3.0 patient is eligible if direct bilirubin is within
normal limits)

- Pulmonary: clinically no evidence of pulmonary disease

- Cardiac: no symptoms of uncontrolled cardiac disease

- If post-transplant consolidation radiation therapy is given, the patient must be at
least 14 days between last radiation treatment and 1st dose of rituximab

- Able to take daily aspirin (325 mg) for the duration of INCB7839 treatment and 1 week
after the last dose to reduce the risk of thrombosis (not applicable if on other
anti-coagulant therapy at time of study enrollment)

- Females are either postmenopausal for at least 1 year, are surgically sterile for at
least 3 months, or must agree to take appropriate precautions to avoid pregnancy (with
at least 99% certainty) from screening through 12 months after the last dose of
rituximab if of childbearing potential. (Note: Permitted methods that are at least 99%
effective in preventing pregnancy should be communicated to the participants and their
understanding confirmed).

- Males must agree to take appropriate precautions to avoid fathering a child (with at
least 99% certainty) from screening through 12 months after the last dose of
rituximab. (Note: Permitted methods that are at least 99% effective in preventing
pregnancy should be communicated to the participants and their understanding
confirmed).

- Voluntary written consent signed before performance of any study-related procedure not
part of normal medical care

Exclusion Criteria:

- Pregnant or lactating - Studies to evaluate the potential for embryo toxicity and
teratogenicity have not been performed for INCB7839. Until additional information is
available, women of childbearing potential should use appropriate precautions to avoid
becoming pregnant. Rituximab is Pregnancy Category C: There are no adequate and
well-controlled studies of rituximab in pregnant women. Females of childbearing
potential must have a negative urine or serum pregnancy test within 14 days of study
treatment start

- Recent venous thrombosis within 4 weeks prior to study enrollment. Patients at high
risk for thrombotic events due to inherited risk factors (i.e. factor V Leiden) or
DVT/PE in the past 12 months should be on secondary prophylaxis with anti-coagulant
therapy (i.e. warfarin or low molecular weight heparin) prior to enrollment

- Active uncontrolled infection

- Active CNS disease

- Previous severe or life-threatening allergic reaction with rituximab or known allergy
to the compounds found in INCB7839

- Any gastrointestinal condition causing malabsorption or obstruction (eg, celiac sprue,
gastric bypass surgery, strictures, adhesions, history of small bowel resection, blind
loop syndrome)

- Unwilling or unable to swallow tablets BID

- Serologic or clinical evidence of current active hepatitis B or C infection, defined
as elevated levels of Hep B antigen or Hep C antibody (unless active infection is
ruled out by nucleic acid tests)

- Known HIV infection