Update from MANIFEST phase II study: CPI-0610 + ruxolitinib in patients with myelofibrosis and naïve to JAK inhibitor treatment

Bromodomain and extraterminal domain (BET) proteins are transcriptional regulators of oncogenic pathways that drive inflammation in myelofibrosis (MF). CPI-0610 is an oral, selective, small molecule BET inhibitor, that is being studied in Arm 3 of the phase II MANIFEST study (NCT02158858) in combination with ruxolitinib in patients with MF and naïve to JAK inhibitor (JAKi) treatment. The updated safety and efficacy data from this cohort were reported by MPN Hub Steering Committee member John Mascarenhas during the 25th European Hematology Association (EHA) Virtual Congress and are discussed below.¹

The MPN Hub’s comprehensive coverage of all three treatment arms of the MANIFEST study can be found here.

Study design

The starting dose at Cycle 1 Day 1 and dose regimen for each 21-day cycle were:

• CPI-0610, 125 mg once per day, 2 weeks on/1 week off
• Ruxolitinib, 10 mg twice per day when platelet count ≥ 100–200 × 10⁹/L
  • If platelet count was > 200 × 10⁹/L, the starting dose was 15 mg twice per day

Upward titration of either treatment per cycle was allowed if dose titration criteria were met, up to a maximum of:

• CPI-0610, 225 mg once per day
• Ruxolitinib, 25 mg twice per day

At the data cut-off, January 9, 2020, 53 patients were treated with the CPI-0610 and ruxolitinib combination. Patient characteristics are outlined in Table 1.

 The key patient eligibility criteria included:

• Patients with myelofibrosis and naïve to JAKi treatment
• Dynamic International Prognostic Scoring System (DIPSS) score: ≥ Intermediate-2
• Platelet count: ≥ 100 × 109/L
• Spleen volume:  ≥ 450 cm³ using CT or MRI
• Total symptom score (TSS): ≥ 10 using the Myelofibrosis Symptom Assessment Form v4.0
• Measurable symptoms: ≥ 2

Primary endpoints: ≥ 35% spleen volume reduction (SVR35), and ≥ 50% TSS improvement (TSS50) at Week 24.

Secondary endpoints: Assess the safety, pharmacodynamics, alteration in proinflammatory cytokines, and bone marrow fibrosis or morphology.

Table 1. Patient characteristics¹

CALR, calreticulin; DIPSS, Dynamic International Prognostic Scoring System; Int-2, Intermediate-2; Hgb, hemoglobin; JAK2, Janus kinase 2; MF, myelofibrosis; MPL, myeloproliferative leukemia virus; TSS, total symptom score *defined as Hgb < 10g/dL
Characteristic	Arm 3, CPI-0610 + ruxolitinib N = 53
Median age, years (range)	69 (37–85)
Male gender, n (%)	39 (73.6)
DIPSS ≥ Int-2, n (%)	39 (73.6)
Primary MF, n (%)	25 (47.2)
Anemic,* n (%)	32 (60.4)
Median platelet count, (range)	345 × 109/L (100–1849)
Median spleen volume, cm3 (range)	1726.5 (457–7842)
Median TSS, n (range)	14 (0–38)
Mutational status
JAK2, n (%)	39 (73.6)
CALR, n (%)	11 (20.8)
MPL, n (%)	2 (3.8)
High molecular risk, n (%)	27 (50.9)

Key findings

Efficacy

SVR35
A total of 30 patients were evaluable for SVR35 at Week 24. Of these, 14 patients continued to receive the CPI-0610 + ruxolitinib combination for more than 24 weeks, and one patient discontinued before Week 24. SVR35 at Week 24 was reported in 63.3% of patients, with a median change of –52.9% (range, –84.4% to 23.7).  The median spleen size was smaller compared to other studies; the baseline spleen size did not have an impact on the degree of spleen size reduction. The baseline platelet count is also lower than in other studies, however, patients with a lower baseline platelet count had at least as meaningful splenic responses as those with higher counts.

TSS50
A total of 29 patients were evaluable for TSS50 at Week 24. TSS50 at Week 24 was observed in 58.6% of patients, with a median change of –64% (range, –100% to 24.2%). Improvements in bone marrow fibrosis by ≥ 1 Grade were reported in 45.5% of patients, following 6 months of CPI-0610 + ruxolitinib treatment. One patient discontinued treatment to undergo bone marrow transplantation following 24 weeks of therapy.

Safety

Sixty-four patients were evaluable for safety. Anemia (23.4%; Grade ≥ 3, 15.6%) and thrombocytopenia (13%; Grade ≥ 3, 1.6%) were the most common hematological treatment-emergent adverse events (TEAEs) of any grade. Cytopenias were manageable with dose modifications. The most common non-hematological TEAEs were diarrhea (26.6%), nausea (18.8%), respiratory infection (18.8%), dysgeusia (14.1%,), and fatigue (12.5%). Grade ≥ 3 TEAEs occurred in 3.1% of patients with respiratory infection. Two patients discontinued treatment due to adverse events (infection), which were considered unrelated to CPI-0610 treatment; both patients died. 

Conclusion

The results of the Arm 3 cohort from the MANIFEST trial indicate that the combination treatment of CPI-0610 + ruxolitinib was generally well tolerated in patients with MF and naïve to JAKi. The data suggests the combination treatment is potentially synergistic and can enhance efficacy by increasing SVR35 and TSS50 rates at 24 weeks, compared with historical data from previous studies. Additionally, improvements in bone marrow fibrosis were seen along with a lower incidence of Grade ≥ 3 anemia. The improvements seen in hemoglobin with the combination were not previously reported with ruxolitinib alone, which has been shown to aggravate anemia. With these promising results the phase III study is anticipated to start later this year. Earlier results from the MANIFEST study can be found here.