| Eligibility |
Inclusion Criteria:
1. Men and women 18 years of age or older.
2. Pathologically proven diffuse large B-cell lymphoma.
3. No prior systemic therapy for lymphoma.
4. Patient has provided informed consent.
5. Patient is willing and able to comply with clinic visits and procedure outlined in the
study protocol.
6. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.
7. Life expectancy of =3 months.
8. Ann Arbor stage II-IV
9. NCCN-IPI risk score of = 2
10. Measurable disease, meaning at least 1 lymph node or other lymphomatous lesion with a
long axis of =1.5 cm by CT imaging, and at least one FDG-avid lesion by FDG-PET scan.
11. Left ventricular ejection fraction of at least 45% by either echocardiography or
radionucleotide angiography.
12. Ability to swallow oral tablets without difficulty.
13. All subjects with preserved reproductive potential must agree to practice abstinence
or employ contraceptive measures for the duration of treatment and for 4 weeks
following final dosing. All male subjects are considered to have reproductive
potential. Female subjects of reproductive potential are those who: 1) are not at
least 50 years old and have no menses for 24 consecutive months; or 2) have not been
rendered surgically sterile (having undergone hysterectomy and/or bilateral
salpingo-oophorectomy). Female subjects of reproductive potential must have a negative
serum pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human
chorionic gonadotropin (hCG) within 7 days of first day of drug dosing.
14. Meet the following clinical laboratory requirements:
- Creatinine clearance =30 ml/min by Cockcroft-Gault formula;
- Total bilirubin = 1.5 × upper limit of normal (ULN) (unless indirect bilirubin is
elevated due to Gilbert's syndrome or hemolysis);
- AST and ALT= 3 × ULN;
- Platelet count = 50,000/µL, with or without transfusion support;
- ANC = 1000/µL, with or without chronic granulocyte growth factor support;
- Hemoglobin =8 g/dL, with or without transfusion support.
Exclusion Criteria:
2. Any active malignancy other than DLBCL 3. High grade B Cell Lymphoma with rearrangements
of MYC and BCL2, MYC and BCL6, and /or MYC and BCL2/BCL6 ("double-hit" or "triple-hit"
DLBCL) 4. Current participation in another interventional clinical study 5. Prior
allogeneic bone marrow transplant within 12 months of screening date. 6. Prior autologous
stem cell transplant within 6 months of screening date. 7. Immunotherapy, chemotherapy,
radiotherapy, or investigational therapy within 6 months prior to drug dosing.
8. Active central nervous system (CNS) involvement by lymphoma, including untreated
symptomatic epidural disease 9. Active uncontrolled infection. 10. Poorly controlled
depressive symptoms and/or currently under management for depression that is poorly
controlled.
11. Significant disease or medical conditions, as assessed by the Investigator and Sponsor,
that would substantially increase the risk-benefit ratio of participating in the study.
This includes, but is not limited to, acute myocardial infarction within the last 6 months,
unstable angina, uncontrolled diabetes mellitus, significant active infections, and
congestive heart failure New York Heart Association Class III-IV.
12. Second malignancy, except treated basal cell or localized squamous skin carcinomas,
localized prostate cancer, or other malignancies for which subjects are not on active
anti-cancer therapies and have had no evidence of active malignancy for at least 1 year.
13. History of major surgery within 3 weeks or minor surgery within 1 week of roflumilast
administration. Major surgery includes, for example, any open or laparoscopic entry into a
body cavity, or operative repair of fracture; minor surgery includes, for example, open
surgical biopsy of palpable/superficial lymph node, or placement of vascular access device.
14. Other medical or psychiatric illness or organ dysfunction, which in the opinion of the
investigator, would either compromise the subject's safety or interfere with the evaluation
of the safety of the study agent.
15. Corrected QT interval (QTc) prolongation (defined as a QTc >450 ms for males and >470
ms for females Fridericia's correction) or other clinically significant ECG abnormalities
as assessed by the investigator.
16. Baseline serum troponin above the upper limit of normal. 17. Baseline serum BNP above
the age-adjusted upper limit of normal. 18. Baseline amylase above the upper limit of
normal. 19. Subjects known to be HIV-positive must not have multi-drug resistant HIV
infection, CD4 counts < 150/µl or other concurrent AIDS-defining conditions. Serologic
screening for HIV is required within the 6 months prior to study enrollment.
20. Subjects positive for Hepatitis B surface antigen (HBsAg) or Hepatitis C-virus
ribonucleic acid (HCV RNA), unless both AST and ALT=1.25 x ULN and there is no known
history of chronic active hepatitis. Serologic screening for hepatitis B and C testing is
required within the 6 months prior to study enrollment.
21. Subjects with moderate or severe liver impairment, as defined by a Child-Pugh class of
B or C.
22. Women who are pregnant or breastfeeding. 23. Current use of any of the following
medications: boceprevir, carbamazepine, ciprofloxacin, cobicistat, conivaptan,
enzalutamide, fluvoxamine, itraconazole, ketoconazole, mitotane, phenytoin, posaconazole,
rifampin, ritonavir, St. John's Wort, telaprevir, voriconazole, or zafirlukast.
24. Current use of non-nucleoside reverse transcriptase inhibitors (NNRTI) including
efavirenz, rilpivirine, etravirine, delavirdine, nevirapine, and lersivirine.
|
