ADAM17 Inhibitor/ Rituximab After Auto HCT for DLBCL
ADAM17 Inhibitor/ Rituximab After Auto HCT for DLBCL
This is a single institution phase I/II study using an ADAM17 inhibitor (INCB7839) with
 rituximab as consolidation therapy after an autologous hematopoietic cell transplant (HCT)
 for patients with diffuse large B cell lymphoma (DLBCL). The study consists of two phases.
 The dose finding phase is a modified version of a phase I trial and the extended phase is a
 modified version of a phase II trial.
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