Phase I/II Study of Carfilzomib, Ruxolitinib and Low-Dose Dexamethasone for Carfilzomib-Refractory Multiple Myeloma (CarJak)

Background:

Multiple myeloma (MM) remains an incurable malignancy; the majority of MM patients suffer relapses with progressively shorter disease-free intervals. Carfilzomib (CFZ) is a second-generation proteasome inhibitor (PI) with potent activity against MM. Even after an initial clinical response, virtually all patients will eventually develop resistance to further PI-based therapy. CFZ refractoriness is, partially, due to the development of bone marrow (BM) stromal cell dependent-resistance (Murnane et al ASH, 2015). Janus Associated Kinases-2 (JAK-2) inhibitors demonstrate stroma-induced lethality in preclinical models of MM. The constitutive activation of the JAK/STAT pathway promotes the recruitment of STATs (signal transducers and activators of transcription) to cytokine receptors, which promote activation and subsequent nuclear translocalization of STATs where they function as transcription factors modulating genes involved in cellular proliferation and inhibition of apoptosis. JAK2 Gene overexpression is showen in around two thirds of MM patients, and approximately one fourth overexpress JAK1. Ruxolitinib (Rux) is a JAK1/2inhibitor with dose-dependent single-agent activity in MM in vitromodels.Rux has previously demonstrated synergistic activity with both bortezomib and lenalidomide (Len) in MM cell lines. In early-phase clinical trials, the addition of Rux to Len in patients with acquired Len resistance resulted in resensitization to Len.

The aim of the current Phase I/II study is to evaluate the efficacy of the combination of Rux, CFZ, and low-dose dexamethasone (dex) in CFZ-resistant relapsed and/or refractory MM (RRMM) patients.

Study Design and Methods:

• Study population: 18-75 years with RRMM who have progressed through > 2 lines of therapy including , refractory to CFZ (at doses ≥ 27 mg/m2).

• Major inclusion criteria:

1. At least one of the following: Serum monoclonal protein ≥0.5 g/dL for IgG, IgA, or IgM, Urinary M-protein of ≥200 mg /24-hours, Involved free light chain (FLC) ≥10 mg/dL, along with an abnormal FLC ratio.

2. Absolute neutrophil count (ANC) ≥ 1000 cells/mm3. Platelet count of ≥75,000 cells/mm3 for BM plasmacytosis of <50%, or ≥50,000 cells/mm3 for BM plasmacytosis of >50%. Within one week of the initiation of treatment.

3. Creatinine clearance ≥30 mL/min.

4. Cardiac ejection fraction ≥ 40%.

5. Eastern Cooperative Oncology Group (ECOG) performance status of ≤2.

• Major exclusion criteria:

1. Non-secretory MM, amyloidosis, or POEMS syndrome.

• Statistical design:(1)Phase I: Up to 18 subjects may be required to evaluate 3 dose levels of Rux in combination with CFZ and dex in a standard 3+3 design. (2)Phase II: Progression-free survival at 4 months (PFS4) is the primary endpoint for this study. Based on reported median time on treatment in MM patients receiving 3+ lines of therapy (approximately 2 months, Ref: Kumar et al. IMWG, Leukemia 2017), it is assumed that if MM subjects who are CFZ-refractory were retreated with CFZ plus low-dose dex, unitl progression, they would experience a median PFS of 2 months (corresponding) to a PFS4 rate of 25%. In this patient population, median PFS of 4 months is considered a significant clinical benefit. A Simon's 2-stage design will be used to test the hypothesis that the PFS4 rate ≤25%. Ten subjects will be enrolled in the first stage, and if at least 3 of the 10 subjects are alive and progression free at 4 months, an additional 20 subjects will be enrolled (a total of 30 subjects). If at least 11 of 30 subjects are alive and progression free at 4 months, the null hypothesis will be rejected (based on binomial probabilities). Assuming a one-sided α= 0.10 significance level, this sample size will provide at least 90% power to reject the null hypothesis, assuming the true PFS4 rate is 50%

• Study endpoints:

- Primary endpoints: For Phase I, dose limiting toxicities during Cycle 1 of Rux treatment administration. For Phase II, PFS4 determined for each subject as a binary variable per IMWG 2016 criteria.

- Secondary endpoints: PFS, time to progression, overall response rate, clinical benefit rate, disease control, duration of response, overall survival, and safety.

-Exploratory endpoints: Correlation of toxicities and disease response with serial serum cytokine profile, peripheral blood mononuclear cells (PBMC) JAK and proteasome inhibition.