early stopping rule

The primary objective of this study is to evaluate the anti-tumor efficacy of tadalafil in combination with Lenalidomide/dexamethasone (Rd) in multiple myeloma.

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.

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