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Phase II study of PS-341 alone or in combination with Dexamethasone in patients with Multiple Myeloma who have relapsed following front-line therapy and are refractory to their most recent therapy

 

  1.  Objectives

 

a.       Primary Objectives

1.       To determine the response rate following monotherapy with PS-341 dose in patients with multiple myeloma who relapsed following initial front-line therapy and are refractory to their most recent therapy.

 

c.       Secondary Objectives

1.       To determine the response rate following treatment with PS-341 plus dexamethasone in patients with multiple myeloma who relapsed following initial front-line therapy before study enrollment, and failed to respond to or relapsed following treatment with PS-341 alone.

2.       To assess efficacy, safety and tolerability of with PS-341 plus dexamethasone in patients with multiple myeloma.

3.       To obtain additional pharmacodynamic information for PS – 341 by the proteasome inhibition assay

4.       To obtain additional genomic information on multiple myeloma and its response to drug, via additional assays and markers of the disease.

5.       To pilot a composite quality of life (QOL) instrument and Functional assessment tool during treatment.

  1. Background

 

Proteasome inhibitors act through multiple mechanisms to arrest tumor growth, spread, and angiogenesis.  Only four drugs are currently approved for the use of myeloma per the US Food and Drug Administration (FDA) internet web site, pamidronate (1998), melphalan (1992), carmustine (BCNU, 1977) and Cyclophosphamide (1959). Furthermore, for patients who are refractory to therapy, there is no agreed upon standard treatment. The ubiquitin-proteasome pathway plays an essential role in the degradation of most short-and long-term lived intracellular proteins in eukaryotic cells.  The 26S proteasome, an adenosine triphosphate-dependent multicatalytic protease, is at the heart of this degradative pathway. Proteolytic degradation of damaged, oxidized, or misfolded ubiquitinated proteins is a usual role for the proteasome, which also plays a vital role in apoptosis, cell trafficking, and transcription factor activation. The ubiquitin-proteasome pathway also plays an important role in regulating the cell cycle, neoplastic growth, and metastasis.  A number of key proteins are degraded during the cell cycle by the ubiquitin-proteasome pathway, and the ordered degradation is required for the cell to progress through the mitosis. The pathway is also required for transcriptional regulation, and a key transcription factor is Nuclear factor -kB (NF-kB).   NF-kB is required in a number of cell types to maintain cell viability as an anti-apoptotic controlling factor due to the production of either cell survival proteins such as Bcl-2 or growth factors, such as IL-6. Through inhibition of  NF-kB by stabilizing the inhibitor protein IkBa, cells will be more sensitive to environmental stress, cytotoxic agents, leading to apoptosis. PS-341 is a potent and reversible inhibitor of the proteasome, which is the final degradative enzyme involved in an important catabolic pathway for many intracellular regulatory proteins, including IkB/NF-kB, p53, and the cyclin-dependent kinase inhibitors p21 and p27. PS-341 is expected to be efficacious in multiple myeloma via its inhibition of NF-kB activation and attenuation of IL-6 mediated cell growth, as well as having a direct apoptotic effect, and its overriding of Bcl-2 cytoprotection, and possibly, anti-angiogenic effect.

 

  1. Treatment Plan

  Patients who are eligible will receive a maximum of eight cycles of study drug.  During the first two cycles, all patients will receive PS-341 Patients will be evaluated after cycles 2, 4 and 6 to determine what treatment will be administered during the following two cycles.

After completion of cycles 1 and 2:

Patients who have achieved CR, PR, or MR or experience NC will again receive PS-341 alone in both cycles 3 and 4.

Patients with PD will be discontinued from the study.

After completion of both cycles 3 and 4

  • if on PS-341 alone and have achieved CR, PR, or MR will again receive PS – 341 alone in Cycles 5 and 6. 

  •     Patients with PD or NC as compared with their status at the end of cycle 2 will receive PS-341 plus dexamethasone in cycle 5 and 6.

After the completion of cycles 5 and 6

  • Patients who were on PS alone, and have maintained CR for at least 12 weeks, will be discontinued from study drug. 

  •  Patients on PS alone, who have achieved a new CR, after Cycle 4, will receive cycles 7 and 8.

  •  Patients on PS alone, now have PD or show NC as compared with their status after cycle 4, will receive dexamethasone with cycles 7 and 8.

  •  Patients on PS and decadron, now with CR, PR, MR or NC, will also receive dexamethasone with cycles 7 and 8. 

  • Patients with progressive disease on PS and dexamethasone will be discontinued.

 

Patient selection: 

(Questions 1 –14 must be answered “YES”)

                         YES                 NO

               

 1.  Patient must be > 18 years of age 

 2.  Does the patient have an ECOG/KPS performance status of  0-2               

3.       The patient meets the following pretreatment laboratory criteria at Baseline

(Day 1, Cycle 1, before drug administration):                                                                          ____               

4.       The patient meets the following pretreatment laboratory criteria

At the screening visit conducted within 14 days of random-

ization (Cycle 1, Day 1)                                                                                                                _____       

                                                                                                                                                      

          e) Creatinine calculated or measured clearance

>30 mL/minute.                                                                                                         

                f)  Serum sodium >130 mmol/L                                                                                     

    g) Total bilirubin < 2 times the upper limit of

institutional laboratory normal                                                                                  

                h) AST < 3 times the upper limit of institutional            

                        laboratory normal                                                                                                       

i)ALT  < 3 times the upper limit of institutional

       laboratory normal                                                                                                       

 

5.       Has given voluntary written informed consent, prior to any study-related

 Procedure not part of normal medical care, with the understanding that consent

May be withdrawn by the patient at any time without prejudice to medical care.                    _____               

6.  Hospitalized or non-hospitalized patients will be considered.                                                                    

7.  Female patients must be either post-menopausal or surgically sterilized or be

Willing to use acceptable methods of birth control ( i.e., a hormonal

contraceptive, intra-uterine device, diaphragm with spermicidal, or condom

with spermicide, abstinence) for the duration of the study and be neither

pregnant nor breast feeding.                                                                                                          

     

8.       Men must also agree to use an acceptable method for contraception through-out the study._____          

 

9.  Previously diagnosed with myeloma based on standard criteria as follows:                         

            Major criteria:

            a.  Plasmacytoma on tissue biopsy.                                                                                      

b.       Bone marrow plasmacytosis ( >30% plasma cells).

 

c.       Monoclonal immunoglobulin spike on serum electrophoresis IgG

>3.5 g/dL or IgA >2.0 g/dL; kappa or Lambda light chain excretion

>1g/day on 24 hour urine protein electrophoresis.                  

            Minor criteria:

a.       Bone marrow plasmacytosis  (10 to 30% plasma cells).                                 

                                                                     

b.       Monoclonal immunoglobulin present but of lesser magnitude than

Given under “major” criterion.                                                                                             

            c.  Does the patient have lytic bone lesions?                                                                        

            d.  Normal IgM < 50 mg/dL, IgA < 100mg/dL or IgG <600mg/dl     

 

·         Any of the following sets of criteria will confirm the diagnosis of multiple myeloma (according to Durie-Salmon Staging criterion):

·         Any two of the major criteria                                                                                                    

·         Major criterion 1 plus minor criterion b, c or d.                                                                       

·         Major criterion 3 plus minor criterion a or c.                                                                            

·         Minor criteria a, b and c or a, b and d.                                                                                     

 

10.   Multiple myeloma with measurable disease, defined as monoclonal

Immunoglobulin spike on serum electrophoresis of > 1gm/dL and/or urine

monoclonal immunoglobulin spike of > 200mg/dL.                                                                       

 11.   Received previous front line therapy ( including high-dose therapy with stem

Cell support) and have documentation of relapse/failure to that therapy as

Defined as:                                                                                                                                          

 

  1. Failure to achieve a complete response, remission or partial response to

Front-line therapy                                                                                                                           

      b.   Progression during frontline chemotherapy                                                                               

      c.   Relapsed within six months of completing front-line therapy                                                   

 

12.  Does the patient have a life expectancy of greater than 3 months?                                           

13.    No electrocardiographic evidence of acute ischemia or new conduction           

System abnormalities .                                                                                                                     

14. No history of  Myocardial Infarction within the previous six months.                                              

 

 

Exclusion Criteria:  Patients meeting any of the following exclusion criteria

Are not to be randomized to treatment.                                                                                 

 *(Questions 15-27 must be answered “NO”)                                                                                  

 

15.   POEMS syndrome ( plasma cell dyscrasia with polyneuropathy,

Organomegaly, endocrinopathy, monoclonal protein { M protein} and

Skin changes)                                                                                                                                          

16.   Does the patient have plasma cell leukemia                                                                                       

17.   Does the patient have nonsecretory myeloma?                                                                                            

18.   Has the patient had major surgery within 4 weeks of randomization?                                                

19.  Does the patient have active infection?                                                                                                   

20.  Does the patient have severe hypercalcemia (serum calcium > 14 mg/dL                                          

21.  New York Hospital Association (NYHA) Class III or IV  heart failure                                                       

22.  Previous treatment with PS-341.                                                                                                               

23.     Receipt of chemotherapy within 4 weeks of randomization (patients may be

Screened within 2 weeks), with the exception of nitrosoureas, which should

Be discontinued at least six weeks before randomization.  
                                                                     

24.     Receipt of immunotherapy or radiation therapy within four weeks of

Randomization.                                                                                                                                               

 

25.     Other serious medical or psychiatric illness that could potentially interfere with

            The completion of treatment according to this protocol.                                                                         

26.     HIV infection.  Patients should provide consent for HIV testing according to

The institution’s standard practice.                                                                                                                

27.  Known active hepatitis B or C.                                                                                                                       

Study Measurements:

 

Response to therapy will be assessed through monthly laboratory results, such as CBC with Differential, CMP plus LDH, uric acid, and phosphorous, Beta-2 microglobulin, C- reactive protein, IL-6, Monoclonal protein serum and urine, Protein electrophoresis blood and urine, and 24 – hour urine total protein, urinalysis.   Bone marrow aspirate and biopsy to be done prior to therapy, and at the end of therapy, whenever clinically indicated.   Complete skeletal survey once before therapy, repeat if clinically indicated.  B-HCG pregnancy tests will be administered prior to each cycle for women of child bearing potential. 

 

Other:

1.    Allowable concomitant medications or therapies:  Bisphosphonates, Erythropoietin, Granulocyte growth factors, Thrombopoietin, Immunoglobulin infusions, blood products and Plasmapheresis.

2.       Excluded medications:  Corticosteroids (>10 mg prednisone or equivalent), or any investigational agent other than PS-341.

3.      Serious adverse events (SAE) is any adverse event, occurring at any dose, and regardless of causality that results in death, is life threatening, requires inpatient hospitalization, significant disability, congenital anomaly, and is deemed a medically important event.  These events must be reported immediately to the pharmaceutical company, and/or Dr. Hussein, if they are not receiving drug at the Cleveland Clinic Foundation main campus.

 

 
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