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Phase 0/1 Biomarker and Pharmacodynamic Study of Roflumilast in Patients With Advanced B-Cell Hematologic Malignancies (CTRC# 13-0013)

Phase 0
18 Years
Not Enrolling
Advanced B-cell Lymphoid Malignancies

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Trial Information

Phase 0/1 Biomarker and Pharmacodynamic Study of Roflumilast in Patients With Advanced B-Cell Hematologic Malignancies (CTRC# 13-0013)

This pilot study will evaluate whether the administration of roflumilast inhibits the
activity of PDE4 and results in the modulation of AKT/mTOR pathways in patients with B-cell
hematologic malignancies. Peripheral blood samples will be collected for the purpose of
determining the pharmacodynamics of roflumilast on PDE4 activity and on biomarkers as
related to GC resistance. Samples are obtained at baseline prior to starting study
treatment, on Day 8 before the administration of the Day 8 study drugs (prednisone and
roflumilast), and on Day 15. If a bone marrow biopsy is also performed prior to study
treatment or at any time during treatment, a sample will be sent for analysis. Normal PBMC
(and bone marrow when it is obtained) will be examined for changes in key targets related to
the inhibition of PDE4 and potential reversal of glucocorticoid resistance. Biomarker blood
samples will be analyzed in order to characterize the pharmacodynamics of roflumilast alone
and in combination with prednisone on PDE4 activity and on biomarkers, such as phospho-AKT,
phosphorylation levels of mTOR targets.

Inclusion Criteria:

- Signed informed consent.

- Men and women > 18 years of age

- Diagnosed with relapsed or refractory (per investigator assessment) B-cell
hematologic malignancy, including CLL, SLL, ALL, MM, WM, mantle cell lymphoma,
follicular lymphoma, or DLBCL that has progressed or recurred following prior
therapy. Patients must have failed, refused, be ineligible, or not otherwise
appropriate for any potential standard curative treatment. In addition, patients
must be refractory to or intolerant of established therapy known to provide clinical
benefit for their condition. The original diagnostic biopsy and/or other diagnostic
data (e.g., cell marker data) will suffice.

- Has failed ≥ 1 previous treatment for their malignancy, and has relapsed or
refractory disease following most recent prior treatment.

- ECOG performance status of ≤ 2 and a life expectancy of at least 3 months.

- Ability to swallow oral tablets without difficulty.

- 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

- 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.

- Has recovered from adverse, toxic effects of prior therapies to ≤ Grade 1(NCI-CTCAE
v4) except for alopecia and peripheral neuropathy. This requirement will be
subordinate to specific clinical and laboratory criteria that are otherwise
specifically addressed in these inclusion/exclusion criteria. Peripheral neuropathy
must have recovered to ≤ Grade 2 except for patients with WM, who may enroll with
Grade 3 peripheral neuropathy if due to the underlying WM.

- Meet the following clinical laboratory requirements:

All patients, except ALL:

- Creatinine clearance by Cockcroft-Gault formula of ≥30 ml/min

- Total bilirubin ≤ 1.5 × ULN (unless indirect bilirubin is elevated due to Gilbert's
syndrome or hemolysis)

- Aspartate aminotransaminase (AST) and alanine aminotransaminase (ALT) ≤ 3 × ULN

- Platelet count ≥ 50,000/uL, patients may be transfused to this value.

- Absolute neutrophil count (ANC) ≥ 1000/uL, with or without chronic granulocyte growth
factor support

- Hemoglobin ≥8 g/dL, patients may be transfused to this value

For patients with ALL:

The hematological criteria do not apply.

Exclusion Criteria:

- Prior allogeneic bone marrow transplant within 6 months of screening date.

- Prior autologous stem cell transplant within 3 months of screening date.

- Active central nervous system (CNS) involvement by lymphoma, including untreated
symptomatic epidural disease.

- Patients with autoimmune hemolytic anemia or immune thrombocytopenia requiring
on-going active immunotherapy at study entry other than systemic corticosteroids less
than or equal to prednisone equivalent 20 mg/day.

- Allergy or intolerance to roflumilast.

- Immunotherapy, chemotherapy, radiotherapy or investigational therapy within 3 weeks
(within 4 weeks for monoclonal antibodies; within 6 weeks for nitrosoureas; within 12
weeks for iodine-131 tositumomab and ibritumomab tiuxetan) prior to study drug

- Active uncontrolled infection.

- Is receiving concurrent high doses of systemic corticosteroids. High dose is
considered as >20 mg of dexamethasone a day (or equivalent) for >7 consecutive days.

- Uncontrolled illness including but not limited to: symptomatic congestive heart
failure (New York Heart Association [NYHA] Class III or IV heart failure), unstable
angina pectoris, uncontrolled cardiac arrhythmia, and psychiatric illness that would
limit compliance with study requirements.

- History of myocardial infarction, acute coronary syndromes (including unstable
angina), coronary angioplasty and/or stenting within 6 months prior to study drug

- History of another currently active cancer or any other cancer < 2 years prior to
study drug dosing, except for adequately treated basal cell or squamous cell
carcinoma of the skin, cervical cancer in situ or other adequately treated in situ

- Patients with a history of major surgery within 3 weeks or minor surgery within one
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.

- 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.

- Corrected QT interval (QTc) prolongation (defined as a QTc >450 msec for males and
>470 msec for females [Fridericia's correction]) or other clinically significant ECG
abnormalities as assessed by the investigator.

- Patients known to be HIV-positive must not have multi-drug resistant HIV infection,
CD4 counts < 150/mcl or other concurrent AIDS-defining conditions.

- Patients 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 no known history
of chronic active hepatitis.

- Patients with moderate to severe liver impairment (Child-Pugh B or C)

- Women who are pregnant or breastfeeding.

- Patients with a history of depression or other psychiatric illness

- Patients who are taking strong cytochrome P450 enzyme inducers and inhibitors.

Type of Study:


Study Design:

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Safety which will be evaluated by the incidence, severity, relationship and type of adverse events.

Outcome Description:

To evaluate the safety and tolerability of roflumilast when administered orally alone and in combination with prednisone as therapy for patients with a relapsed or refractory B-cell lymphoid malignancies

Outcome Time Frame:

Expected average of 21 days.

Safety Issue:


Principal Investigator

Kevin Kelly, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:



United States: Food and Drug Administration

Study ID:

CTRC 13-0013



Start Date:

July 2013

Completion Date:

July 2015

Related Keywords:

  • Advanced B-cell Lymphoid Malignancies
  • Neoplasms
  • Hematologic Neoplasms



Ctrc @ Uthscsa San Antonio, Texas  78229