Clinical Trials /

A Phase 1 Study of Ruxolitinib, Steroids and Lenalidomide for Relapsed/Refractory Multiple Myeloma (RRMM) Patients

NCT03110822

Description:

This is a phase 1, multicenter, open-label study evaluating the safety and efficacy of ruxolitinib, steroids and lenalidomide among MM patients who currently show progressive disease.

Related Conditions:
  • Multiple Myeloma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: A Phase 1 Study of Ruxolitinib, Steroids and Lenalidomide for Relapsed/Refractory Multiple Myeloma (RRMM) Patients
  • Official Title: A Phase 1 Study of Ruxolitinib, Steroids and Lenalidomide for Relapsed/Refractory Multiple Myeloma (RRMM) Patients

Clinical Trial IDs

  • ORG STUDY ID: I-RUX-15-04
  • NCT ID: NCT03110822

Conditions

  • Multiple Myeloma

Interventions

DrugSynonymsArms
Ruxolitinib Oral Tablet [Jakafi]Ruxolitinib, JakaviRux Len and Steroid
LenalidomideRevlimidRux Len and Steroid
MethylprednisoloneDepo-Medrol, Solu-Medrol, Methyl PrednisolonateRux Len and Steroid

Purpose

This is a phase 1, multicenter, open-label study evaluating the safety and efficacy of ruxolitinib, steroids and lenalidomide among MM patients who currently show progressive disease.

Detailed Description

      Multiple myeloma (MM), a plasma cell dyscrasia, is the most common primary malignancy of the
      bone marrow.The etiology of myeloma is largely unknown, although genetic predisposition and
      environmental factors have been speculated. MM arises from malignant plasma cells that
      clonally expand and accumulate in the bone marrow. These clonal plasma cells produce high
      levels of monoclonal immunoglobulins. Plasma cell dyscrasias are classified as monoclonal
      gammopathy of undetermined significance, solitary plasmacytoma, smoldering myeloma, active
      myeloma, extra-skeletal myeloma, or plasma cell leukemia.

      In 2015 an estimated 26,850 adults (14,090 men and 12,760 women) in the United States will be
      diagnosed with multiple myeloma. It is estimated that 11,240 deaths (6,240 men and 5,000
      women) from this disease will occur this year.

      In recent years, new and more effective drugs have become available for the treatment of MM.
      Such drugs have been evaluated together and in combination with older agents, rapidly
      increasing the number of therapeutic options available to MM patients, and resulting in an
      improvement in their overall survival (OS) rates. Among the drugs that have been FDA approved
      specifically for myeloma are the immunomodulatory agents (IMiDs) thalidomide, and its newer
      analogs lenalidomide and pomalidomide.

      IMiDs exert their anti-neoplastic action by affecting various cancer cell functions and the
      microenvironment, including cytokine production, immune cell function, and in some instances,
      inflammation, cell proliferation and cell death. The IMiD thalidomide has been found to be
      effective as an anti-MM agent in one-third of myeloma patients; notably, higher response
      rates have been observed when combined with steroids. Lenalidomide is an analog of
      thalidomide that has shown more potent anti-MM activity than thalidomide in preclinical
      studies, and has been FDA-approved for the treatment of previously untreated as well as
      relapsed or refractory MM (RRMM) in combination with dexamethasone. Recently, an analog of
      thalidomide and lenalidomide, pomalidomide, has also been approved for RRMM patients.

      The 5-year survival rate for MM patients has increased from 25% in 1975 to 34% in 2003 and is
      currently closer to 40% due to these newer and more effective treatment options.
      Unfortunately, even with these newer agents, responses to therapy are transient, and MM
      remains an incurable disorder with an eventual fatal outcome; and, therefore, new therapies
      are urgently needed.

      JAK2 is an intra-cytoplasmic tyrosine kinase that belongs to the Janus kinase family. JAK
      kinases play a major role in the transmission of signals from cytokine and growth factor
      receptors into the nucleus. JAK kinases activate several intracellular signaling proteins,
      among which the STAT transcription factors are well defined. The JAK/STAT pathway mediates
      diverse cellular events that affect cell growth, differentiation and cell survival.

      Abnormal JAK2 activation has been implicated in several hematological disorders and
      malignancies. Mutations, gene translocations or cytokines released by bone marrow stromal
      cells, may all result in aberrant JAK2 activation. The activating JAK2 V617F mutation results
      in uncontrolled cytokine and growth factor signaling, and is believed to play a key role in
      the pathophysiology of myeloproliferative neoplasms. Constitutive JAK2 activation through
      specific chromosomal translocations is thought to contribute to the development of leukemia,
      lymphoma and multiple myeloma. In MM, elevated levels of cytokines and growth factors such as
      interleukin-6 (IL 6), vascular endothelial growth factor, insulin-like growth factor-1, basic
      fibroblast growth factor, IL-1, IL-10, IL-11, IL-15, IL-21, granulocyte macrophage colony
      stimulation factor, interferon-α, and leukemia inhibitory factor may also contribute to
      exacerbated JAK2 activation.11 Among these cytokines, IL-6 has been most widely studied and
      is considered to be a growth and survival factor for myeloma cells. Binding of IL-6 to the
      IL-6 receptor activates JAK2, which in turn can phosphorylate the IL-6 receptor, thereby
      augmenting its downstream signaling effects. Thus, pharmacological inhibition of JAK1/2 may
      be a promising therapeutic strategy for treatment of MM.

      In this context, treatment of MM cell lines and patient derived primary MM cells with various
      JAK1/JAK2, JAK2 and JAK pan specific inhibitors (e.g. INCB16562, CYT387 and TG101209) has
      been shown to inhibit cell proliferation. Furthermore, JAK inhibitors have demonstrated
      synergistic activity with established anti MM therapies such as melphalan and bortezomib
      (CYT387) or melphalan, bortezomib and dexamethasone (INCB16562), in both MM cell lines and
      patient derived primary MM cells. Sensitization of MM cells to dexamethasone in response to
      JAK inhibitors may occur through crosstalk between the JAK/STAT pathway and glucocorticoids.
      In this regard, dexamethasone treatment has been shown to increase STAT3 and the pro survival
      factor phosphatidylinositol-3 kinase (PI3K) levels in melanoma cells; in turn, PI3K was found
      to increase STAT3 levels. Prolonged exposure to dexamethasone results in resistance, which
      could be overcome, at least in part, by JAK/STAT inhibition.

      Ruxolitinib is an oral, selective inhibitor of JAK1 and JAK2, and is the only JAK1/2
      inhibitor approved by the US FDA for the treatment of intermediate and high-risk
      myelofibrosis. Pilot experiments carried out in our research laboratory at the Institute for
      Myeloma and Bone Cancer Research have demonstrated that the JAK2 inhibitor ruxolitinib in
      combination with lenalidomide and dexamethasone inhibited the proliferation of the MM cell
      lines U266 and RPMI8226 and primary tumor cells derived from MM patients, and that this
      inhibition was greater than that achieved with these drugs as single agents. Enhanced
      anti-tumor activity was also observed when these three drugs were administered together to
      severe combined immunodeficient mice bearing LAGκ-1A (bortezomib- and melphalan-sensitive) or
      LAGĸ-2 (bortezomib- and melphalan-resistant) human myeloma tumors, both of which were
      originally derived from fresh bone marrow biopsies from MM patients. In addition, ruxolitinib
      as a single agent showed no anti MM effects whereas the combination of this drug with
      dexamethasone showed enhanced anti-MM effects compared to steroid treatment alone. Finally,
      an elderly heavily pre treated MM patient with polycythemia rubra vera (PRV), who had
      previously received single-agent ruxolitinib while progressing from MGUS to MM and then
      subsequently failed treatment with lenalidomide and methylprednisolone, responded to the
      addition of low dose ruxolitinib twice daily to these two drugs.

      Together, these results suggest that ruxolitinib may overcome lenalidomide and steroid
      resistance for RRMM patients that are failing therapy from steroids alone or in combination
      with lenalidomide. Therefore, in this phase 1 trial, the investigators will evaluate the
      safety and efficacy of ruxolitinib in combination with methylprednisolone and lenalidomide.
    

Trial Arms

NameTypeDescriptionInterventions
Rux Len and SteroidExperimentalRuxolitinib Oral Tablet [Jakafi] at 5mg, 10mg or 15mg BID, Lenalidomide Oral at 5mg or 10mg QD and Methylprednisolone Oral at 40mg QOD. (Dose varies during dose escalation portion of the study)
  • Ruxolitinib Oral Tablet [Jakafi]
  • Lenalidomide
  • Methylprednisolone
Rux and Steroid until progression, then add LenExperimentalSubject will receive Ruxolitinib Oral Tablet [Jakafi] at 15mg BID, and Methylprednisolone at 40mg QOD until disease progression. Lenalidomide at 10mg QD will be added to the treatment (Ruxolitinib, Methylprednisolone) once disease progression was confirmed.
  • Ruxolitinib Oral Tablet [Jakafi]
  • Lenalidomide
  • Methylprednisolone

Eligibility Criteria

        Inclusion Criteria:

        Subjects must meet all of the following inclusion criteria to be eligible to enroll in this
        study.

          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 spike on serum electrophoresis IgG greater than 3.5 g/dL or
             IgA greater than 2.0 g/dL or 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 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 200mg/24 hours

          -  for patients without measurable serum and urine M-protein levels, an involved SFLC >
             100 mg/L or abnormal SFLC ratio

             3. Currently has progressive MM

        MM patients that are relapsed or have refractory disease from at least 3 regimens or lines
        of therapy including an IMID and a proteasome inhibitor, are eligible for enrollment
        provided they fulfill the other eligibility criteria:

        • Patients are considered relapsed, when they progress greater than 8 weeks from their last
        dose of treatment.

          -  Patients are refractory when they progress while currently receiving the treatment or
             within 8 weeks of its last dose.

             4. Previous exposure to lenalidomide independent of the response

             5. The patient is not a candidate for a transplant

             6. Understand and voluntarily sign an informed consent form before receiving any
             study-related procedure that is not part of normal medical care, with the
             understanding that consent may be withdrawn at any time without prejudice to their
             future medical care.

             7. Able to adhere to the study visit schedule and other protocol requirements

             8. ECOG performance status of ≤ 2 at study entry

             9. Life-expectancy of greater than 3 months

             10. Laboratory test results within these ranges at Screening and confirmed at
             enrollment prior to drug dosing on Cycle 1, Day 1:

          -  Absolute neutrophil count ≥ 1.5 x 10E9/L; if the bone marrow is extensively
             infiltrated ( ≥ 70% plasma cells) then ≥ 1.0 x 10E9/L

          -  Platelet count ≥ 75 x 10E9/L; if the bone marrow is extensively infiltrated ( ≥ 70%
             plasma cells) then ≥ 50 x 10E9/L patients must not have received platelet transfusion
             for at least 7 days prior to receiving screening platelet count

          -  Hemoglobin ≥ 8.0 g/dL within 21 days prior to enrollment. Use of erythropoietic
             stimulating factors and red blood cell (RBC) transfusions per institutional guidelines
             is allowed; however, most recent RBC transfusion must have been at least 7 days prior
             to obtaining screening hemoglobin.

          -  Calculated or measured creatinine clearance (CrCl) of ≥ 60 mL/minute as calculated by
             Cockcroft-Gault method (Appendix 3).

          -  Total bilirubin levels ≤ 2.0 mg/dL (normal levels)

          -  AST (SGOT) and ALT (SGPT) ≤ 2 x ULN

          -  Serum potassium 3.0 - 5.5 mEq/L

             11. Patients must be registered into the mandatory REVLIMID REMS™ program, and be
             willing and able to comply with the requirements of the REVLIMID REMS™ program

             12. FCBP† must have a negative serum or urine pregnancy test with a sensitivity of at
             least 25 mIU/mL within 10 - 14 days prior to and again within 24 hours of starting
             ruxolitinib and must either commit to continued abstinence from heterosexual
             intercourse or use acceptable methods of birth control, one highly effective method
             and one additional effective method AT THE SAME TIME, and at least 28 days before she
             starts taking ruxolitinib with or without lenalidomide. FCBP must also agree to
             ongoing pregnancy testing. Men must agree to use a latex condom during sexual contact
             with a FCBP even if they have had a vasectomy. All subjects must be counseled at a
             minimum of every 28 days about pregnancy precautions and risks of fetal exposure.

             † A FCBP (female of childbearing potential) is a sexually mature woman who: 1) has not
             undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally
             postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in
             the preceding 24 consecutive months)

             13. Able to take aspirin (acetylsalicylic acid, ASA) at 81 or 325 mg/daily as
             antiplatelet therapy if platelet count is above 30 x 10E9/L (subjects intolerant to
             ASA may use warfarin or low molecular weight heparin)

        Exclusion Criteria:

          -  Subjects meeting any of the following exclusion criteria are not to be enrolled in the
             study:

               1. POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein,
                  and skin changes)

               2. Plasma cell leukemia (> 2.0 × 10E9/L circulating plasma cells by standard
                  differential)

               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
                  any one of the following:

                    -  Myocardial infarction within 6 months prior to enrollment

                    -  New York Heart Association (NYHA) Class II or greater heart failure or
                       uncontrolled angina

                    -  Clinically significant pericardial disease

                    -  Severe uncontrolled ventricular arrhythmias

                    -  Echocardiogram or MUGA evidence of 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. Severe hypercalcemia, i.e., serum calcium ≥ 12 mg/dL (3.0 mmol/L) corrected for
                  albumin

               7. Any serious medical condition, laboratory abnormality, or psychiatric illness
                  that would prevent the subject from signing the informed consent form

               8. Any condition, including the presence of laboratory abnormalities, which places
                  the subject at unacceptable risk if he/she were to participate in the study or
                  confounds the ability to interpret data from the study

               9. Undergone major surgery within 28 days prior enrollment or has not recovered from
                  side effects of such therapy (vertebroplasty or kyphoplasty is not considered to
                  be a major surgery; however, the investigator is to discuss enrollment of a
                  subject with a recent history of kyphoplasty with the medical monitor).

              10. Pregnant or breast feeding females (lactating females must agree not to breast
                  feed while taking lenalidomide)

              11. Received the following prior therapy:

                    -  Chemotherapy within 3 weeks of study drugs

                    -  Corticosteroids (>20 mg/daily prednisone or equivalent) within 3 weeks of
                       study drugs to ensure that steroid dose intensity at the beginning of the
                       treatment is not altered by administration of steroids prior to the study.
                       Consumption of steroids within 3 weeks of the treatment may interfere with
                       efficacy and side effects due to differences of steroid intensity.

                    -  Immunotherapy or antibody therapy as well as thalidomide, arsenic trioxide,
                       or bortezomib within 21 days before study drugs

                    -  Lenalidomide within 7 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

                    -  Strong or moderate CYP3A4 inhibitors, strong or moderate CYP3A4 inducers and
                       fluconazole doses >200 mg daily within 5 half-lives before study drugs. (For
                       example, clarithromycin has half-life of 4 hours so washout period for
                       clarithromycin is 20 hours.)

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

              13. Concurrent use of other anti-cancer agents or treatments

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

              15. Known positivity for human immunodeficiency virus (HIV), hepatitis B or C, and
                  /or active tuberculosis (TB) including subjects with latent TB or with the risk
                  factor for activation of latent TB.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Determination of maximum tolerated dose (MTD) of ruxolitinib in combination with steroids and lenalidomide [Tolerability].
Time Frame:30 months
Safety Issue:
Description:MTD will be determined by measuring incidence of the dose-limiting toxicities (DLTs) per dose level, of ruxolitinib in combination with steroids and lenalidomide for MM patients currently with progressive disease.

Secondary Outcome Measures

Measure:Overall response rate (ORR) as a measure of efficacy
Time Frame:54 months
Safety Issue:
Description:Overall response rate (ORR) is defined as CR + VGPR + PR
Measure:Clinical benefit rate (CBR) as a measure of efficacy
Time Frame:54 months
Safety Issue:
Description:Clinical benefit rate is defined as ORR + MR
Measure:Progression Free Survival (PFS)
Time Frame:54 months
Safety Issue:
Description:Progression-free survival will be measured in months as the time from initiation of therapy to progressive disease or death from any cause, whichever occurs first
Measure:Assessment of the time to response as a measure of efficacy
Time Frame:54 months
Safety Issue:
Description:Time to response, defined as the time from the initiation of therapy to the first evidence of confirmed clinical benefit defined as > minimal response (MR, including patients who achieved a complete response (CR), very good partial response (VGPR), partial response (PR), or MR
Measure:Assessment of the duration of response as a measure of efficacy
Time Frame:54 months
Safety Issue:
Description:Duration of response, defined as the time (in months) from the first response to progressive disease
Measure:Assessment of the overall survival (OR) as a measure of efficacy
Time Frame:54 months
Safety Issue:
Description:Overall survival, defined as the time (in months) from initiation of therapy to death from any cause or last follow-up visit
Measure:Assessment of response in additional cohort
Time Frame:54 months
Safety Issue:
Description:Response to initial therapy (ruxolitinib and methylprednisolone alone) will be compared to the response to therapy with addition of lenalidomide (ruxolitinib, lenalidomide, methylprednisolone)

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Oncotherapeutics

Trial Keywords

  • Ruxolitinib
  • Steroids
  • Lenalidomide
  • Relapsed/Refractory Multiple Myeloma

Last Updated

April 30, 2019