Administration of Tadalafil in Conjunction With Lenalidomide and Dexamethasone in Patients With Multiple Myeloma

• Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins (Other)
• Overall Status: Terminated
• CT.gov ID: NCT01374217
• Collaborator: (none)
• Enrollment: 14
• Location: 1
• Arm: 1
• Actual Duration (Months): 21
• Patients Per Site Per Month: 0.7

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Multiple Myeloma	Drug: Tadalafil; Drug: Lenalidomide; Drug: Dexamethasone; Drug: Clarithromycin	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 14 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Administration of an Oral PDE5 Inhibitor, Tadalafil in Conjunction With Lenalidomide and Dexamethasone in Patients With Multiple Myeloma
• Actual Study Start Date: Apr 1, 2012
• Actual Primary Completion Date: Jan 1, 2014
• Actual Study Completion Date: Jan 1, 2014

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Tadalafil Subject will take tadalafil in combination with with Lenalidomide and dexamethasone (Rd) or Clarithromycin/Lenalidomide/ dexamethasone (BiRd)

Drug: 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; Other Names: Cialis ; Drug: Lenalidomide; Lenalidomide will be administered as it was prior to study entry.; Other Names: Revlimid ; Drug: Dexamethasone; Dexamethasone will be administered as it was prior to study entry.; Other Names: Decadron ; Drug: Clarithromycin; Clarithromycin will be administered as it was prior to study entry.; Other Names: Biaxin

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. Duration of Response [Up to 6 months]

   Median length of response in months.

2. Time to Progression [Up to 71 days]

   Median time to progression of disease in days.

3. 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.

4. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts 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:

1. Angina requiring treatment with long-acting nitrates. II. Angina requiring treatment with short-acting nitrates within 90 days of planned tadalafil administration.

1. 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:

1. Myocardial Infarction.

1. Coronary artery bypass graft surgery.

2. Percutaneous coronary intervention (for example, angioplasty or stent placement).

3. 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Sidney Kimmel Comprehensive Cancer Center	Baltimore	Maryland	United States	21287

Sponsors and Collaborators

• Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Investigators

• Principal Investigator: Nilanjan Ghosh, M.D., Ph.D., Johns Hopkins University

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• ClinicalTrials.gov Identifier: NCT01374217
• Other Study ID Numbers: J1167; NA_00049238
• First Posted: Jun 15, 2011
• Last Update Posted: Dec 10, 2018
• Last Verified: Nov 1, 2018

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Additional relevant MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell; Clarithromycin; Dexamethasone; Lenalidomide; Tadalafil

Study Results

Participant Flow

Pre-assignment Detail	One participant was a screen failure.

Arm/Group Title	Tadalafil
Arm/Group Description	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.
Period Title: Overall Study
STARTED	13
COMPLETED	0
NOT COMPLETED	13

Baseline Characteristics

Arm/Group Title	Tadalafil
Arm/Group Description	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.
Overall Participants	13
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	8 61.5%
>=65 years	5 38.5%
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	63
Sex: Female, Male (Count of Participants)
Female	6 46.2%
Male	7 53.8%

Outcome Measures

1. Primary Outcome

Title	Response Rate
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Tadalafil
Arm/Group Description	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.
Measure Participants	11
Count of Participants [Participants]	5 38.5%

2. Secondary Outcome

Title	Duration of Response
Description	Median length of response in months.
Time Frame	Up to 6 months

Outcome Measure Data

Analysis Population Description

This analysis only includes the 5 participants who had a clinical response.

Arm/Group Title	Tadalafil
Arm/Group Description	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.
Measure Participants	5
Median (Full Range) [months]	2.3

3. Secondary Outcome

Title	Time to Progression
Description	Median time to progression of disease in days.
Time Frame	Up to 71 days

Outcome Measure Data

Analysis Population Description

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/Group Title	Tadalafil
Arm/Group Description	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.
Measure Participants	11
Median (95% Confidence Interval) [days]	48

4. Secondary Outcome

Title	Quality of Life Scores
Description	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)

Outcome Measure Data

Analysis Population Description

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/Group Title	Tadalafil
Arm/Group Description	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.
Measure Participants	8
Symptoms (M3)	0
Past week (M3)	5
Global health status (M3)	-1.5
Symptoms (M6)	1
Past week (M6)	6
Global health status (M6)	-1

5. Secondary Outcome

Title	Effect of PDE5 Inhibition on Immune Function as Assessed by MDSC Quantification
Description	Percentage change in the amount of myeloid derived suppressor cells (MDSCs) in peripheral blood.
Time Frame	Up to 6 months

Outcome Measure Data

Analysis Population Description

Data was not collected to assess this outcome measure.

Arm/Group Title	Tadalafil
Arm/Group Description	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.
Measure Participants	0

Adverse Events

Time Frame	Up to 7 months
Adverse Event Reporting Description	Adverse events were collected monthly.
Arm/Group Title	Tadalafil
Arm/Group Description	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.
All Cause Mortality
	Tadalafil
	Affected / at Risk (%)	# Events
Total	6/13 (46.2%)
Serious Adverse Events
	Tadalafil
	Affected / at Risk (%)	# Events
Total	0/13 (0%)
Other (Not Including Serious) Adverse Events
	Tadalafil
	Affected / at Risk (%)	# Events
Total	13/13 (100%)
Eye disorders
Red eyes	2/13 (15.4%)	2
Gastrointestinal disorders
Anorexia	1/13 (7.7%)	1
Constipation	2/13 (15.4%)	2
Diarrhea	5/13 (38.5%)	6
Dyspepsia	2/13 (15.4%)	2
Flatulence	1/13 (7.7%)	1
GI bleed	3/13 (23.1%)	3
Mucositis	2/13 (15.4%)	2
Nausea	4/13 (30.8%)	4
Vomiting	1/13 (7.7%)	1
General disorders
Cold intolerance	1/13 (7.7%)	1
Fatigue	9/13 (69.2%)	11
Night sweats	2/13 (15.4%)	2
Epistaxis	1/13 (7.7%)	1
Weight gain	1/13 (7.7%)	1
Weight loss	1/13 (7.7%)	1
Infections and infestations
Fever	2/13 (15.4%)	2
Neutropenic fever	1/13 (7.7%)	1
Upper respiratory infection	2/13 (15.4%)	2
Investigations
High creatinine	1/13 (7.7%)	1
Hyperglycemia	8/13 (61.5%)	14
Hypoalbuminemia	2/13 (15.4%)	3
Hypocalcemia	4/13 (30.8%)	9
Hypokalemia	2/13 (15.4%)	2
Lymphopenia	7/13 (53.8%)	22
Neutropenia	10/13 (76.9%)	22
Low carbon dioxide	1/13 (7.7%)	1
Anemia	13/13 (100%)	33
Thrombocytopenia	9/13 (69.2%)	23
Leukopenia	11/13 (84.6%)	25
Musculoskeletal and connective tissue disorders
Arthralgia	1/13 (7.7%)	1
Myalgia	1/13 (7.7%)	1
Osteonecrosis of the jaw	1/13 (7.7%)	1
Pain - back	7/13 (53.8%)	12
Pain - bone	1/13 (7.7%)	1
Pain - hip	2/13 (15.4%)	2
Pain - rib	1/13 (7.7%)	1
Pain - shoulder	1/13 (7.7%)	1
Nervous system disorders
Blurred vision	1/13 (7.7%)	1
Dizziness	1/13 (7.7%)	1
Eye floaters	1/13 (7.7%)	1
Headache	4/13 (30.8%)	4
Insomnia	2/13 (15.4%)	2
Impaired memory	2/13 (15.4%)	2
Neuropathy	6/13 (46.2%)	9
Hallucinations	1/13 (7.7%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnea	2/13 (15.4%)	3
Wheezing	1/13 (7.7%)	1
Skin and subcutaneous tissue disorders
Pain - throat	1/13 (7.7%)	1
Rash	1/13 (7.7%)	1
Xerosis	1/13 (7.7%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.