This is a phase 1, multicenter, open-label study evaluating the safety and efficacy of ruxolitinib, steroids and lenalidomide among multiple myeloma patients who currently show progressive disease.
This trial is currently open and accepting patients.
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.
The following criteria is a partial list of reasons why patients may be eligible to participate in this clinical trial. Further evaluation with a medical professional is required.
Inclusion Criteria:
Subjects must meet all of the following inclusion criteria to be eligible to enroll in this study.
Major criteria:
Minor criteria:
Any of the following sets of criteria will confirm the diagnosis of multiple myeloma:
2. Currently has MM with measurable disease, defined as:
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 2 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:
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:
Impaired cardiac function or clinically significant cardiac diseases, including any one of the following:
Received the following prior therapy:
Phase 1
Enrollment: 134 patients (estimated)
View MoreNovember 23, 2021
As of July 15, 2021, 27 patients were enrolled. The median age was 64 years (range, 46-85), and 17 (63%) were male. Patients received a median of 4 (range, 3-11) prior treatments including LEN and steroid-containing regimens to which they were all refractory. Twenty-six patients have completed at least 1 full cycle of therapy; and, thus, were evaluable for efficacy.
The ORR and CBR were 35% (n=9) and 39% (n=10), respectively. Notably, all 10 responding patients were refractory to LEN (i.e., progressed while on or within 8 weeks of last dosage). The remaining patients showed stable disease (n=12) or PD (n=4). The median follow-up was 13 months. The median progression-free survival was 4 months (range, 1-21). The median duration of response was 11 months (range, 1-20). Of 13 patients who progressed on the two-drug combination and had LEN added to their regimen, 6 patients responded (3 MR and 3 PR).
Nine patients experienced SAEs including sepsis (12%), sepsis with neutropenic fever (4%), thrombocytopenia (4%), hyperglycemia (4%), neutropenia (4%), anemia (4%), acute heart failure (4%), rotator cuff tear (4%), osteomyelitis (4%), aspiration pneumonia (4%), pneumonia and pneumothorax (4%), and deep venous thrombosis (4%). Two patients died (one each from pneumonia and PD).
June 03, 2018
The JAK 1/2 inhibitor ruxolitinib (Jakafi), in combination with lenalidomide and methylprednisolone, overcame resistance to lenalidomide in about half of 28 heavily pre-treated patients with relapsed/refractory multiple myeloma, based on phase I trial results presented at the annual meeting of the American Society of Clinical Oncology (ASCO).
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The overall response rate was 39% (10 of 26 evaluable patients), Dr. Berenson reported. The clinical benefit rate was 50% (13 of 26 patients), with a median duration of response of 5.6 months in that group.
There were no dose-limiting toxicities. Grade 3 toxicities reported included thrombocytopenia in 11% (3 patients, gastrointestinal bleeding in 11% (3 patients), and anemia in 7% (2 patients).
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Encinitas, CA
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