Pomalidomide for Lenalidomide for Relapsed or Refractory Multiple Myeloma Patients

A Phase 2 Study of Pomalidomide as a Replacement for Lenalidomide for Multiple Myeloma Patients Relapsed or Refractory to a Lenalidomide-Containing Combination Regimen

The purpose of this clinical research study is to evaluate the safety and effectiveness (good and bad effects) of pomalidomide given as part of a combination therapy that include more than just steroids to treat subjects with relapsed (subjects whose disease came back) or refractory (subjects whose disease did not respond to past treatment) multiple myeloma (MM).

Pomalidomide (alone or in combination with dexamethasone) has been approved by the United States Food and Drug Administration (FDA) for the treatment of MM patients who have received at least two prior therapies, including lenalidomide and bortezomib, and have demonstrated disease progression on or within 60 days of completion of their last therapy. However, the use of pomalidomide in combination with other drugs used to treat MM, such as chemotherapeutic agents and proteasome inhibitors, is currently being tested and is not approved. Pomalidomide is in the same drug class as thalidomide and lenalidomide. Like lenalidomide, pomalidomide is a drug that alters the immune system and it may also interfere with the development of small blood vessels that help support tumor growth. Therefore, in theory, it may reduce or prevent the growth of cancer cells. The testing done with pomalidomide thus far has shown that it is well-tolerated and effective for subjects with MM both on its own and in combination with dexamethasone. Using another drug class, namely proteasome inhibitors, we have demonstrated that simply replacing a proteasome inhibitor with another in an established anti-myeloma treatment regimen can frequently overcome resistance regardless of the other agents that are part of the anti-myeloma regimen. Importantly, the toxicity profile of the new combinations closely resembled that of the proteasome inhibitor administered as a single agent. Based on this experience, we hypothesize that the replacement of lenalidomide with pomalidomide will yield similar results in a similar relapsed/refractory MM patient population.

This is a phase 2, multicenter, open-label and non-randomized study to evaluate the efficacy and safety of pomalidomide as a replacement for lenalidomide among MM patients who have failed lenalidomide-containing regimens that include more than steroids within 6 months of their last dose of lenalidomide. Pomalidomide will replace lenalidomide in a combination regimen containing an alkylating agent (cyclophosphamide), anthracycline (doxorubicin or PLD), proteasome inhibitor (bortezomib or carfilzomib) and/or a glucocorticosteroid (prednisone, dexamethasone or methylprednisolone). Pomalidomide will be administered on days 1-21 of a 28-day cycle, whereas other drugs (anthracyclines, proteasome inhibitors, steroids or alkylating agents except melphalan) will be administered using the same schedule(s), dose(s) and drug combination as the last lenalidomide-containing regimen that the patient received and failed. This study will enroll patients resistant to a lenalidomide-containing combination regimen as demonstrated by PD while being treated or that has relapsed within 6 months of the last dose of lenalidomide in their last lenalidomide-containing combination regimen or while on lenalidomide or lenalidomide and steroid maintenance therapy. Forty-five patients will be enrolled in the study.

The study consists of: 1) a screening period; 2) up to eight 28-day, treatment cycles; 3) a final assessment to occur 28 days after the end of the last treatment cycle; and 4) a follow-up period.

Subjects eligible for this study will receive treatment with study drug for a maximum of eight 28-day treatment cycles, depending on the schedule of their last lenalidomide-containing regimen. Subjects are to be treated to a maximum response (lowest level of paraprotein) plus 1 additional cycle, without exceeding a total of 8 cycles, or complete 8 cycles of therapy without progressing (PD).

Key Inclusion Criteria:

1. Has a diagnosis of MM based on standard criteria as follows:

   • Major criteria:

     1. plasmacytomas on tissue biopsy
     2. bone marrow plasmacytosis (greater than 30% plasma cells)
     3. monoclonal immunoglobulin (Ig) spike on serum electrophoresis IgG greater than 3.5 g/dL or IgA greater than 2.0 g/dL; kappa or lambda light chain excretion greater than 1 g/day on 24-hour urine protein electrophoresis

   • Minor criteria:

     1. bone marrow plasmacytosis (10% to 30% plasma cells)
     2. monoclonal immunoglobulin present but of lesser magnitude than given under major criteria
     3. lytic bone lesions
     4. normal IgM less than 50 mg/dL, IgA less than 100 mg/dL, or IgG less than 600 mg/dL

   • Any of the following sets of criteria will confirm the diagnosis of multiple myeloma:

     • any 2 of the major criteria
     • major criterion 1 plus minor criterion 2, 3, or 4
     • major criterion 3 plus minor criterion 1 or 3
     • minor criteria 1, 2, and 3, or 1, 2, and 4

2. Currently has progressive MM that has relapsed while currently receiving or within 6 months of receiving the maximum tolerated dose of lenalidomide at the physician's discretion as part of a combination treatment that includes more than just steroids in a 21-day or a 28-day cycle schedule. MM patients that are relapsed or have refractory disease, as defined below, are both eligible for enrollment provided they fulfill the other eligibility criteria:

   • Patients are refractory to a lenalidomide combination regimen, when they progress while currently receiving the lenalidomide combination treatment or within 8 weeks of its last dose.
   • Patients are considered relapsed, when they progress between 8 and 26- weeks from their last dose of lenalidomide as part of a lenalidomide-combination therapy that includes more than just steroids.
   • Prior treatment with four days or less of a total of 400 mg of prednisone (or an equivalent potency of another steroid) for MM will not be considered a regimen

3. Currently has MM with measurable disease, defined as:

   • a monoclonal immunoglobulin spike on serum electrophoresis of at least 0.5 g/dL and/or
   • urine monoclonal protein levels of at least 200 mg/24 hours
   • for patients without measurable serum and urine M-protein levels, an abnormal free light chain ratio (normal value: 0.26 - 1.65)
   • Serum free light chain (SFLC) > 100 mg/L (involved light chain) and abnormal ƙ/λ ratio

4. Patients with previous clotting or thrombotic events must be able to take aspirin (acetylsalicylic acid, ASA) at 81 or 325 mg /daily as prophylactic anticoagulation (subjects intolerant to ASA may use warfarin or low molecular weight heparin) and/or antithrombotic agents.

Key Exclusion Criteria:

1. Plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein (M-protein) and skin changes (POEMS) syndrome

2. Plasma cell leukemia

3. Primary amyloidosis

4. Non-hematologic malignancy within the past 5 years with the exception of a) adequately treated basal cell carcinoma, squamous cell skin cancer, or thyroid cancer; b) carcinoma in situ of the cervix or breast; c) prostate cancer of Gleason Grade 6 or less with stable prostate-specific antigen levels; or d) cancer considered cured by surgical resection or unlikely to impact survival during the duration of the study, such as localized transitional cell carcinoma of the bladder or benign tumors of the adrenal or pancreas

5. Impaired cardiac function or clinically significant cardiac diseases, including myocardial infarction within 6 months prior to enrollment, New York Heart Association (NYHA) Class II or greater heart failure, uncontrolled angina, clinically significant pericardial disease, severe uncontrolled ventricular arrhythmias, echocardiogram or multigated acquisition scan (MUGA) evidence of left ventricular ejection fraction (LVEF) below institutional normal within 28 days prior to enrollment, electrocardiographic evidence of acute ischemia or active conduction system abnormalities. Prior to study entry, any ECG abnormality at Screening has to be documented by the investigator as not medically relevant.

6. Received the following prior therapy:

   • Pomalidomide
   • Lenalidomide alone or in combination with steroids in their last treatment regimen. Interim therapy not containing lenalidomide between their last lenalidomide-containing regimen and the start of the trial.
   • A melphalan-containing regimen as the immediate prior line of treatment
   • Chemotherapy within 3 weeks of study drugs (6 weeks for nitrosoureas)
   • Corticosteroids (>10 mg /daily prednisone or equivalent) within 3 weeks of study drugs
   • Immunotherapy or antibody therapy as well as thalidomide, lenalidomide, arsenic trioxide or bortezomib within 21 days before study drugs
   • Extensive radiation therapy within 28 days before study drugs. Receipt of localized radiation therapy does not preclude enrollment.
   • Use of any other experimental drug or therapy within 28 days of study drugs

7. Known hypersensitivity to compounds of similar chemical or biological composition to thalidomide and lenalidomide.

8. The development of erythema nodosum if characterized by a desquamating rash while taking thalidomide or similar drugs