Advanced B-cell Lymphoid Malignancies
Conditions
Brief summary
This is a Phase 0/1 open-label, non-randomized, biomarker and pharmacodynamic study in patients with advanced B-cell lymphoid malignancies, including B-cell chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), acute lymphocytic leukemia (ALL), multiple myeloma (MM), Waldenström's macroglobulinemia (WM), mantle cell lymphoma, follicular lymphoma, or diffuse large B-cell lymphoma (DLBCL) who have failed at least one prior therapy and for whom no standard curative therapy exists. Patients with advanced stage disease are those whose disease is resistant or refractory to standard chemotherapy or biological therapies.
Detailed description
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.
Interventions
DRUGPrednisone
Patients may receive additional courses of treatment with prednisone (and roflumilast) at the discretion of the investigator if they did not experience unacceptable toxicity and have stable disease or objectively responding disease.
DRUGRoflumilast
Patients may receive additional courses of treatment with roflumilast (and prednisone) at the discretion of the investigator if they did not experience unacceptable toxicity, and have stable disease or objectively responding disease.
Sponsors
Anand B. Karnad
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 100 Years
Healthy volunteers
No
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 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. * 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 and CLL: The hematological criteria do not apply.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Total Number of Adverse Events. | Average of 21 days. | Adverse events were listed using CTCAE Version 4.03 (Common Terminology Criteria for Adverse Events) toxicity grade. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Roflumilast and Prednisone Roflumilast 500 mcg will be administered orally daily for 21 consecutive days (a 21-day cycle).
In Cycle 1, prednisone 60 mg/m2 up to a maximum of 100 mg oral (PO) daily will be taken on Days 8 through 14 at the same time as roflumilast.
In Cycle 2 and subsequent cycles, prednisone 60 mg/m2 PO up to a maximum of 100 mg daily will be taken on Days 1 through 7 at the same time as roflumilast.
Prednisone: Patients may receive additional courses of treatment with prednisone (and roflumilast) at the discretion of the investigator if they did not experience unacceptable toxicity and have stable disease or objectively responding disease.
Roflumilast: Patients may receive additional courses of treatment with roflumilast (and prednisone) at the discretion of the investigator if they did not experience unacceptable toxicity, and have stable disease or objectively responding disease. | 10 |
| Total | 10 |
Baseline characteristics
| Characteristic | Roflumilast and Prednisone |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 5 Participants |
| Age, Categorical Between 18 and 65 years | 5 Participants |
| Gender Female | 6 Participants |
| Gender Male | 4 Participants |
| Region of Enrollment United States | 10 participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 2 / 10 |
| serious Total, serious adverse events | 0 / 10 |
Outcome results
Primary
Total Number of Adverse Events.
Adverse events were listed using CTCAE Version 4.03 (Common Terminology Criteria for Adverse Events) toxicity grade.
Time frame: Average of 21 days.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Roflumilast and Prednisone | Total Number of Adverse Events. | 2 Adverse events |