A Phase 1 Study of Ruxolitinib, Steroids and Lenalidomide for Relapsed/Refractory Multiple Myeloma (RRMM) Patients
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|ClinicalTrials.gov Identifier: NCT03110822|
Recruitment Status : Recruiting
First Posted : April 12, 2017
Last Update Posted : March 11, 2020
|First Submitted Date ICMJE||February 27, 2017|
|First Posted Date ICMJE||April 12, 2017|
|Last Update Posted Date||March 11, 2020|
|Actual Study Start Date ICMJE||February 1, 2017|
|Estimated Primary Completion Date||March 2022 (Final data collection date for primary outcome measure)|
|Current Primary Outcome Measures ICMJE
|Original Primary Outcome Measures ICMJE
||Determination of maximum tolerated dose (MTD) of ruxolitinib in combination with steroids and lenalidomide [Tolerability]. [ Time Frame: 30 months ]
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.
|Current Secondary Outcome Measures ICMJE
|Original Secondary Outcome Measures ICMJE
|Current Other Pre-specified Outcome Measures||Not Provided|
|Original Other Pre-specified Outcome Measures||Not Provided|
|Brief Title ICMJE||A Phase 1 Study of Ruxolitinib, Steroids and Lenalidomide for Relapsed/Refractory Multiple Myeloma (RRMM) Patients|
|Official Title ICMJE||A Phase 1 Study of Ruxolitinib, Steroids and Lenalidomide for Relapsed/Refractory Multiple Myeloma (RRMM) Patients|
|Brief Summary||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.|
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.
|Study Type ICMJE||Interventional|
|Study Phase ICMJE||Phase 1|
|Study Design ICMJE||Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Intervention Model Description:
Masking: None (Open Label)
There are 3 study parts: Dose escalation and expansion (Study Part 1), Ruxolitinib/Methylprednisolone Arm (Study Part 2), and Expanded Eligibility Criteria (Study Part 3).
The first 49 subjects will be enrolled into the Ruxolitinib, Lenalidomide and Methylprednisolone treatment arm (Study Part 1).
Subjects in Study Part 2 will receive Ruxolitinib and Methylprednisolone until confirmed disease progression. Lenalidomide will be added to the treatment once disease progression is confirmed.
Subjects in Study Part 3 will receive Ruxolitinib, Lenalidomide and Methylprednisolone treatment.
The study will enroll Part 2 and Part 3 simultaneously. If a patient meets eligibility criteria for Part 2 and Part 3, patient will be enrolled in Part 2 until Part 2 enrollment is complete.
Primary Purpose: Treatment
|Condition ICMJE||Multiple Myeloma|
|Study Arms ICMJE||
|Publications *||Berenson JR, To J, Spektor TM, Martinez D, Turner C, Sanchez A, Ghermezi M, Eades BM, Swift RA, Schwartz G, Eshaghian S, Stampleman L, Moss RA, Lim S, Vescio R. A Phase I Study of Ruxolitinib, Lenalidomide, and Steroids for Patients with Relapsed/Refractory Multiple Myeloma. Clin Cancer Res. 2020 May 15;26(10):2346-2353. doi: 10.1158/1078-0432.CCR-19-1899. Epub 2020 Jan 14.|
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Recruiting|
|Estimated Enrollment ICMJE
|Original Estimated Enrollment ICMJE
|Estimated Study Completion Date ICMJE||September 2022|
|Estimated Primary Completion Date||March 2022 (Final data collection date for primary outcome measure)|
|Eligibility Criteria ICMJE||
Subjects must meet all of the following inclusion criteria to be eligible to enroll in this study.
Any of the following sets of criteria will confirm the diagnosis of multiple myeloma:
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.
|Ages ICMJE||18 Years and older (Adult, Older Adult)|
|Accepts Healthy Volunteers ICMJE||No|
|Listed Location Countries ICMJE||United States|
|Removed Location Countries|
|NCT Number ICMJE||NCT03110822|
|Other Study ID Numbers ICMJE||I-RUX-15-04|
|Has Data Monitoring Committee||Yes|
|U.S. FDA-regulated Product||
|IPD Sharing Statement ICMJE||
|Study Sponsor ICMJE||Oncotherapeutics|
|Collaborators ICMJE||Incyte Corporation|
|Verification Date||March 2020|
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP