Table 2.
Clinical trials* of ruxolitinib-based combinations in myelofibrosis
| Clinicaltrials.gov number | Partner drug | Major inclusion criteria | Phase | Comments |
|---|---|---|---|---|
| NCT02718300 | INCB050465 (PI3K delta inhibitor) | PMF or post-PV/ET MF; spleen > 10 cm below LCM or 5–10 cm with MF symptoms | II | |
| NCT02493530 | TGR-1202 (PI3K delta inhibitor) | PMF or post-PV/ET MF, intermediate or high risk, with grade ≥ 1 BM fibrosis; PV pts meeting indications for ruxolitinib | I | Only patients who have had an insufficient response to ≥ 8 weeks of ruxolitinib can enroll in stage 1; only JAK inhibitor-naïve patients in stage 2; no PI3K or mTOR inhibitors in prior 6 months |
| NCT02436135 | Idelalisib (PI3K delta inhibitor) | PMF or post-PV/ET MF, intermediate or high risk, with disease relapse or progression on ruxolitinib after ≥ 4 weeks on stable dose | I | |
| NCT01433445 | Panobinostat (HDAC inhibitor) | PMF or post-PV/ET MF; spleen ≥ 5 cm below LCM, plts > 100 × 109/L, < 10% blasts | I/II | Phase 2 dose 15 mg ruxolitinib bid and 25 mg panobinostat 3 times/week(116) |
| NCT01693601 | Panobinostat (HDAC inhibitor) | PMF or post-PV/ET MF in chronic or accelerated phase; intermediate-2 or high risk; plts ≥ 75 × 109/L, ANC ≥ 0.75 × 109/L | I/II | |
| NCT02267278 | Pracinostat (HDAC inhibitor) | PMF or post-PV/ET MF, intermediate or high risk if newly diagnosed, spleen ≥ 5 cm below LCM ; plts ≥ 50 × 109/L, ANC ≥ 1 × 109/L | II | Prior ruxolitinib allowed only if duration < 3 months; no prior HDAC inhibitor allowed |
| NCT01787552 | Sonidegib (Hedgehog (smoothened) inhibitor) | PMF or post-PV/ET MF, symptomatic, spleen ≥ 5 cm below LCM, intermediate or high risk; plts ≥ 75 × 109/L | I/II | Phase 2 dose ruxolitinib 20 mg bid and 400 mg/d sonidegib;(121) prior JAK or smoothened inhibitors not allowed |
| NCT02593760 | Vismodegib (Hedgehog (smoothened) inhibitor) | PMF or post-PV/ET MF, intermediate or high risk; spleen > 5 cm below LCM; ANC > 1 × 109/L, plts ≥ 100 × 109/L, < 10% peripheral blasts | I/II | Placebo-controlled trial; prior JAK or hedgehog inhibitor not allowed |
| NCT02370706 | PIM447 (PIM kinase inhibitor) and/or LEE011 (CDK4/6 inhibitor) | PMF or post-PV/ET MF, JAK2 V617F+; splenomegaly ≥ 5 cm by MRI; plts ≥ 100 × 109/L, ANC ≥ 1.5 × 109/L; Hgb ≥ 9 g/dL | I | Has dose escalation and expansion phases: only patients with insufficient spleen response after ≥ 6 months of ruxolitinib allowed in dose escalation phase |
| NCT01375140 | Lenalidomide (Imid) | PMF or post-PV/ET MF, intermediate or high risk if newly diagnosed; plts ≥ 100 × 109/L, ANC ≥ 1 × 109/L | II | Excessive myelosuppression limits tolerability of concomitant ruxolitinib and lenalidomide(64) |
| NCT01644110 | Pomalidomide (Imid) | PMF or post-PV/ET MF, splenomegaly > 11 cm (total diameter) and/or leuko-erythroblastosis; Hgb < 10 g/dL or transfusion-dependent; plts ≥ 100 × 109/L, ANC ≥ 0.5 × 109/L | I/II | Although promising in a phase II study as a treatment for anemia of MF,(67) pomalidomide was not superior to placebo in a phase III study in MF(74) |
| NCT01732445 | Danazol | PMF or post-PV/ET MF, intermediate or high risk; Hgb < 10 g/dL or transfusion-dependent; plts ≥ 50 × 109/L, ANC ≥ 1 × 109/L | II (pilot) | Closed early(53) |
| NCT02742324 | Pegylated interferon-α-2a | PMF or post-PV/ET MF, intermediate or high risk, needing active therapy; ANC ≥ 1.5 × 109/L, plts ≥ 150 × 109/L, ≤ 10% peripheral blasts | I/II | Interferon-α alone mostly disappointing in MF,(78, 79) although it may retard the progression of early PMF;(80) prior interferon-α or JAK2 inhibitor not allowed |
| NCT01787487 | Azacitidine (HMA) | PMF or post-PV/ET MF, intermediate or high risk if newly diagnosed; plts ≥ 50 × 109/L, ANC ≥ 1 × 109/L | II | Completed accrual to MF arm(93) |
| NCT02076191 | Decitabine (HMA) | MPN in accelerated phase or post-MPN AML | I/II | |
| NCT02257138 | Decitabine (HMA) | Phase I portion: R/R AML; phase II portion: Post-MPN AML or MDS/MPN with > 20% blasts | I/II |
Does not include trials involving stem cell transplant.
Abbreviations: MF, myelofibrosis; PMF, primary myelofibrosis; PV, polycythemia vera; ET, essential thrombocythemia; HDAC, histone decetylase; HMA, hypomethylating agent; CDK, cyclin-dependent kinase; Imid, immunomodulatory drug; ANC, absolute neutrophil count; plt, platelet; pts, patients; PI3K, phosphatidylinositol-3-kinase; mTOR, mammalian target of rapamycin; JAK, Janus kinase; MDS, myelodysplastic syndrome; MPN, myeloproliferative neoplasm; AML, acute myeloid leukemia; bid, twice daily; Hgb, hemoglobin; R/R, relapsed/refractory; LCM, left costal margin. Modified with permission from JNCCN-Journal of the National Comprehensive Cancer Network [136]: Bose P, Verstovsek S. Drug Development Pipeline for Myeloproliferative Neoplasms (MPN): Potential Future Impact on MPN Guidelines and Management. JNCCN 2016. In press.