Multiple Myeloma
Conditions
Brief summary
The primary objective of this study is to evaluate the anti-tumor efficacy of tadalafil in combination with Lenalidomide/dexamethasone (Rd) in multiple myeloma.
Detailed description
This is an early phase study to evaluate the safety and efficacy of the combination of tadalafil with lenalidomide and dexamethasone (Rd) or BiRd. 19 patients on Rd or BiRd will be treated with tadalafil for a minimum of 6 months. The investigational drug will be discontinued if there is evidence of disease progression as defined by the International Uniform Response criteria \[1\]. For responding patients (patients who have a CR, VGPR, PR or SD), the therapy will be continued until progression or intolerable adverse effects. Blood and bone marrow will be collected for various studies as detailed in section 14.10. Clinical response will be monitored every month during the study.
Interventions
DRUGTadalafil
Tadalafil will be administered at a dose of 20 mg orally daily starting with day 1 of the first cycle. Each cycle will last for 28 days
DRUGLenalidomide
Lenalidomide will be administered as it was prior to study entry.
DRUGDexamethasone
Dexamethasone will be administered as it was prior to study entry.
DRUGClarithromycin
Clarithromycin will be administered as it was prior to study entry.
Sponsors
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Progressive myeloma as defined by the International Uniform Criteria. * Currently on Lenalidomide and dexamethasone for the treatment of myeloma * Age \> 18 years. * Measurable paraprotein in serum or urine or detectable free light chains in the serum. * ECOG performance status of 0 - 2.
Exclusion criteria
* Hypersensitivity to PDE5 inhibitors such as tadalafil, sildenafil or vardenafil. * History of malignancy other than multiple myeloma in the last five years of, except adequately treated basal or squamous cell skin cancer. * Participation in any clinical trial which involved an investigational drug or device four weeks prior. * Infection requiring treatment with antibiotics, antifungal, or antiviral agents in the last seven days * Any evidence of severe or uncontrolled systemic disease (e.g., unstable or uncompensated respiratory, cardiac, hepatic, or renal disease). * History of significant hypotensive episode requiring hospitalization. * Acute myocardial infarction within prior 3 months, uncontrolled angina * Uncontrolled arrhythmia, or uncontrolled congestive heart failure * History of any of the following cardiac conditions: I. Angina requiring treatment with long-acting nitrates. II. Angina requiring treatment with short-acting nitrates within 90 days of planned tadalafil administration. III. Unstable angina within 90 days of visit 1. IV. Positive cardiac stress test without documented evidence of subsequent, effective cardiac intervention. \- History of any of the following coronary conditions within 90 days of planned tadalafil administration: i. Myocardial Infarction. ii. Coronary artery bypass graft surgery. iii. Percutaneous coronary intervention (for example, angioplasty or stent placement). iv. Any evidence of heart disease (NYHA≥Class III) within 6 months of planned tadalafil administration. * Current treatment with nitrates. * Current systemic treatment with a potent cytochrome P450 3A4 (CYP3A4) inhibitors such as ketoconazole or ritonavir. * Prior chronic immune suppressive state (AIDS, immunosuppressive therapy). * History of hypotension and/or blindness or sudden decrease/loss of hearing during prior treatment with PDE-5 inhibitors. * Prior history of non-arterial ischemic optic retinopathy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Response Rate | Up to 6 months | Percentage of participants who responded to the addition of tadalafil. Response is defined as a complete remission (CR), very good partial remission (VGPR), partial remission (PR), or stable disease (SD) by International Uniform Response criteria. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Response | Up to 6 months | Median length of response in months. |
| Time to Progression | Up to 71 days | Median time to progression of disease in days. |
| Quality of Life Scores | 3 months (M3) and 6 months (M6) | Median change in symptom scores. Scale is the EORTC QLQ-C30. There are three domains: symptom scale (score range 7-14); past week (score range 21-82); and global health status (score range 2-14). Higher or increasing scores mean worse outcomes; lower or decreasing scores mean better outcomes. |
| Effect of PDE5 Inhibition on Immune Function as Assessed by MDSC Quantification | Up to 6 months | Percentage change in the amount of myeloid derived suppressor cells (MDSCs) in peripheral blood. |
Countries
United States
Participant flow
Pre-assignment details
One participant was a screen failure.
Participants by arm
| Arm | Count |
|---|---|
| Tadalafil Subject will take tadalafil in combination with with Lenalidomide and dexamethasone (Rd) or Clarithromycin/Lenalidomide/ dexamethasone (BiRd)
Tadalafil: Tadalafil will be administered at a dose of 20 mg orally daily starting with day 1 of the first cycle. Each cycle will last for 28 days
Lenalidomide: Lenalidomide will be administered as it was prior to study entry.
Dexamethasone: Dexamethasone will be administered as it was prior to study entry.
Clarithromycin: Clarithromycin will be administered as it was prior to study entry. | 13 |
| Total | 13 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Lack of Efficacy | 13 |
Baseline characteristics
| Characteristic | Tadalafil |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 5 Participants |
| Age, Categorical Between 18 and 65 years | 8 Participants |
| Age, Continuous | 63 years |
| Sex: Female, Male Female | 6 Participants |
| Sex: Female, Male Male | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 6 / 13 |
| other Total, other adverse events | 13 / 13 |
| serious Total, serious adverse events | 0 / 13 |
Outcome results
Primary
Response Rate
Percentage of participants who responded to the addition of tadalafil. Response is defined as a complete remission (CR), very good partial remission (VGPR), partial remission (PR), or stable disease (SD) by International Uniform Response criteria.
Time frame: Up to 6 months
Population: One participant was not analyzed because he only received eight days of study drug prior to progression and removal from study. One participant was retrospectively ineligible and was therefore not analyzed.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Tadalafil | Response Rate | 5 Participants |
Secondary
Duration of Response
Median length of response in months.
Time frame: Up to 6 months
Population: This analysis only includes the 5 participants who had a clinical response.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Tadalafil | Duration of Response | 2.3 months |
Secondary
Effect of PDE5 Inhibition on Immune Function as Assessed by MDSC Quantification
Percentage change in the amount of myeloid derived suppressor cells (MDSCs) in peripheral blood.
Time frame: Up to 6 months
Population: Data was not collected to assess this outcome measure.
Secondary
Quality of Life Scores
Median change in symptom scores. Scale is the EORTC QLQ-C30. There are three domains: symptom scale (score range 7-14); past week (score range 21-82); and global health status (score range 2-14). Higher or increasing scores mean worse outcomes; lower or decreasing scores mean better outcomes.
Time frame: 3 months (M3) and 6 months (M6)
Population: Two participants returned the Month 3 survey and seven participants returned the Month 6 survey (there is some overlap). The remaining participants cannot be analyzed as there is no follow-up data.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Tadalafil | Quality of Life Scores | Symptoms (M3) | 0 change in score on a scale |
| Tadalafil | Quality of Life Scores | Past week (M3) | 5 change in score on a scale |
| Tadalafil | Quality of Life Scores | Global health status (M3) | -1.5 change in score on a scale |
| Tadalafil | Quality of Life Scores | Symptoms (M6) | 1 change in score on a scale |
| Tadalafil | Quality of Life Scores | Past week (M6) | 6 change in score on a scale |
| Tadalafil | Quality of Life Scores | Global health status (M6) | -1 change in score on a scale |
Secondary
Time to Progression
Median time to progression of disease in days.
Time frame: Up to 71 days
Population: One participant was not analyzed because he only received eight days of study drug prior to progression and removal from study. One participant was retrospectively ineligible and was therefore not analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Tadalafil | Time to Progression | 48 days |