Table 2.
Clinical trials of givinostat in MPNs.
| Study Title | ClinicalTrials.gov Identifier | Phase | Study Design |
Population studied | Efficacy† | Toxicity | Ref. |
|---|---|---|---|---|---|---|---|
| Phase IIA study of the HDAC inhibitor ITF2357 in patients with JAK2V617F+ chronic myeloproliferative diseases | NCT00606307 | IIA | Pilot study multicenter, open-label, non-randomized study | 29 patients in total: 16 with MF; 12 with JAK2V617F+ PV and 1 ET, needing cytoreductive therapy, intolerant/refractory to HU, platelet count > 100 x 109/L | At 24 weeks of treatment at a starting dose of 50 mg twice daily: ITT analysis for 13 PV/ET patients: ORR: 54% (1 CR + 6 PR) For evaluable PV patients: Hct < 45% without phlebotomy: 50% (5/10) WBC count < 10 x109/L: 50% (5/10) Platelet count < 400 x109/L: 20% (2/10) no splenomegaly: 70% (7/10) no pruritus: 90% (9/10) |
No grade 4 AE Mostly grade 2 gastrointestinal disorders and one grade 3; ≤ grade 2 anemia (21%) and 1 grade 3, thrombocytopenia (10%), QTc elongation (17%) | [100] |
| Phase II study of the HDAC inhibitor givinostat (ITF2357) in combination with HU in patients with JAK2V617F+ polycythemia vera not responding to HU | NCT00928707 | II | Multicenter, open-label, randomized study between two groups that received 50 or 100 mg givinostat/day in combination with the MTD of HU (A Simon phase-II dose selection design was applied) | 44 patients with JAK2V617F+ PV not responding to the MTD of HU monotherapy§ | Arm A: 50 mg givinostat/day + MTD of HU at 12 weeks (ITT analysis): ORR: 55% (12 PR) Hct < 45% without phlebotomy: 23% (5/22) WBC < 10 x109/L: 21% (3/14) Platelet count < 400 x 109/L: 42% (5/12) No splenomegaly: 5% (1/19) Pruritus resolution: 64% (7/11) Arm B: 100 mg givinostat/day + MTD of HU at 12 weeks (ITT analysis): ORR: 50% (2 CR + 9 PR) Hct < 45% without phlebotomy: 36% (8/22) WBC count < 10 x109/L: 23% (3/13) Platelet count < 400 x 109/L:37% (3/8) No splenomegaly: 11% (2/18) Pruritus resolution: 67% (8/12) |
No grade 4 AE; 5% of the patients had AE, grade 2 thrombocytopenia and gastrointestinal disorders, 1 grade 3 (nausea, anemia) | [101] |
| A two-part (Phase Ib/II) study to assess the safety and preliminary efficacy of givinostat in patients with JAK2V617F+ polycythemia vera | NCT01901432 | Ib/II | Multinational, open-label, non-randomized Part A: MTD¥ Dose was escalated according to a 3+3 design, adopting a modified Fibonacci escalation scheme Part B: efficacy and safety of MTD (Simon’s two-stage design was employed)‡ | Part A: 12 patients (9 completed 6 cycles) Part B: 35 patients (27 completed 6 cycles) Active/uncontrolled JAK2V617F+ PV: hematocrit ≥ 45% or < 45% with phlebotomy, platelet count > 400 x 109/L, and WBC > 10 x 109/L |
Part A (ITT population): ORR: 72.7%; 1 patient achieved CR after 3 and 1 after 6 cycles. Parameters after 3 and 6 cycles (x 4 weeks) respectively: Hct < 45% without phlebotomy: 54.5 and 27.3%; WBC count ≤ 10 x109/L: 54.5 and 18.2%; platelet count ≤ 400 x109/L: 45.5% for both cycles; normal spleen: 54.5% for both cycles; no pruritus, headache, microvascular disturbances: 63.6 and 72.7% Part B (ITT population). ORR: 80.6%; 3 patients achieved CR after 3 cycles and 1 after 6. Parameters after 3 and 6 cycles‡ (x 4 weeks) respectively: Hct < 45% without phlebotomy: 77.4 and 48.4%; WBC count ≤ 10 x109/L: 90.3 and 67.7%; platelet count ≤ 400 x109/L: 74.2 and 71.0%; normal spleen: 16.1% for both cycles; no pruritus, headache, microvascular disturbances: 74.2% and 61.3% |
Part A: 1 case of grade 4 thrombocytopenia and two grade 3 dyspepsia, grade 1 or 2 thrombocytopenia (33.3%) Part B: No grade 4 AE; one grade 3 neutropenia; thrombocytopenia (45.7%), diarrhea (51.4%), and high serum creatinine (37.1%) | [99,102,103] |
| Long-term Phase II study evaluating the effect of givinostat in patients with JAK2V617F+ chronic myeloproliferative neoplasms* | NCT01761968 EudraCT# 2012-003499-37 | II | Multicenter, international, open label core trial that was expanded to long-term Expanded access* | A total of 45 patients with PV were treated for a median of 4 years, # including 32% of patients treated for ≥ 7 years 33 out of 45 PV patients were still on treatment at the cut-off date (July 2017), and all MF patients (3) had dropped out of the study | Interim data on treatment for a median of 4 years: CR: 11%, PR: 89% Hct < 45% without phlebotomy: 56% WBC count ≤ 10 x109/L: 56% Platelet count ≤ 400 x109/L: 78% normal spleen: 56% no pruritus: 89% 22% JAK2V617F+ allele burden decrease overall incidence of thrombosis: 2.3% patients/year |
No grade 4 AE One grade 3 anemia, and two other grade 3 AEs (asthenia, asymptomatic QTc prolongation) | [104] |
*
Patients who tolerated givinostat and had achieved clinical benefit at the end of the core protocols (and/or while participating in a compassionate use program) were given the opportunity to continue treatment in a long-term, multicenter, international study. The most common dose of givinostat was 100 mg twice daily [104].
§
The patients received givinostat 50 or 100 mg/day combined with the MTD of HU for each patient (the median dose of HU was 1 g) [101].
†
According to ELN response criteria [105].
¥
MTD, maximum tolerated dose: 100 mg twice daily.
‡
The median dose of givinostat in Part B of the study was 150 mg/day [99].
#
Interim data at a median of 4 years (range 6 months to 9 years) were reported [104].
Abbreviations: AE: adverse event; CR: complete response; ET: essential thrombocythemia; Hct: hematocrit; HDAC: histone deacetylase; HU: hydroxyurea; ITT: intention-to-treat; MF: myelofibrosis; MTD: maximum tolerated dose; ORR: overall response rate; PR: partial response; PV: polycythemia vera; QTc: QT interval in electrocardiogram; WBC: white blood cell.