MANIFEST phase II study of ruxolitinib and CPI-0610 in patients with myelofibrosis: An update from Arms 2 and 3

During the 62nd American Society of Hematology (ASH) Annual Meeting and Exposition, the results of the MANIFEST phase II trial were discussed by Srdan Verstovsek¹ and the MPN Hub Steering Committee member John Mascarenhas². The MPN Hub is happy to summarize these presentations here.

CPI-0610 is a first-in-class, small molecule bromodomain and extraterminal domain (BET) inhibitor. BET proteins act by binding to chromatin to modulate gene expression and are associated with the expression of profibrotic genes. The MANIFEST study (NCT02158858) aimed to examine ruxolitinib (rux) in combination with CPI-0610 in patients with myelofibrosis (MF).

Study design

The MANIFEST phase II, multicenter, open-label trial was designed with three treatment arms.

Arm 1 tested CPI-0610 monotherapy in patients who were resistant/intolerant or ineligible for JAK inhibitor (JAKi) treatment. Patients were divided into transfusion dependent (TD) and transfusion independent (TI).

Arm 2 investigated CPI-0610 as an add-on in patients with advanced MF who had a suboptimal response to rux. This arm was split into TD and TI groups.

Arm 3 used CPI-0610 + rux in patients with no previous exposure to JAKi, who were anemic (hemoglobin < 10 g/dL) and with Dynamic International Prognostic Scoring System (DIPSS) of Int-2 or higher.

Further eligibility criteria for Arms 2 and 3 are shown in Table 1. Only the results of Arms 2 and 3 will be discussed in this article.

Table 1. Eligibility criteria for both treatment arms^1,2

 Primary endpoints

Arm 2:

• The TI group: Spleen volume reduction ≥ 35% from baseline (SVR35) after 24 weeks
• The TD group: Conversion from TD to TI, defined as no red blood cell transfusions over any consecutive 12-week period

Arm 3: SVR35 after 24 weeks

Secondary endpoints

Arm 2:

• The TD group: SVR35 and ≥ 50% reduction in total symptom score (TSS50) from baseline after 24 weeks
• The TI group: TSS50

Arm 3: TSS50 after 24 weeks 

Baseline characteristics

Patient baseline characteristics are shown in Table 2 for Arms 2 and 3. The overall cohort was similar between the two arms in terms of patient age and DIPSS. Arm 3 included 72% of men compared with 62% in Arm 2. Primary MF was the most frequent diagnosis with 71% of patients being diagnosed with it in Arm 2 and 54% in Arm 3. The prevalence of high molecular risk mutations was similar between arms: 63% in Arm 2 and 55% in Arm 3.

In Arm 2, 76% of patients had previously been treated with rux for ≥ 6 months, and the median number of lines of therapy was 1 (range 1−5).

International Prognostic Scoring System (IPSS) was recorded in Arm 3, to facilitate the comparison with previous studies, and 83% of patients were classified as Int-2 or high.

Table 2. Baseline characteristics for Arms 2 and 3^1,2

Arm 2¹

Patient disposition

Out of the 78 patients enrolled, 38 discontinued treatment (46% in the TD group and 54% in the TI group). The most common reasons were withdrawal of consent, disease progression, and principal investigator decision. In the TD cohort, two patients died, while no deaths were recorded in the TI group. In addition, four patients in the intention-to-treat (ITT) population discontinued treatment as they became eligible for stem cell transplant. The median duration of treatment was 45 weeks (range 1−166 weeks).

Key efficacy endpoints from Arm 2

For the TD cohort the conversion of TD to TI occurred in 36% of patients and the median duration of conversion to TI was 27 weeks (range 6−136). The intensity of the transfusion required also decreased over time.

SVR35 results:

• TD group: 21% (95% CI, 9–39)
• TI group: 29% (95% CI, 11–52)

The median change in spleen volume was a decrease of 19% in the TD cohort compared with 17% in the TI group.

Regarding TSS50, 46% (95% CI, 28–64) of patients in the TD cohort and 38% (95% CI, 18–62) in the TI cohort achieved this endpoint. The median change in total symptom score was greater in the TD group, with a 58% decrease, compared with only 45% in the TI group.

Bone marrow fibrosis grade improved with the CPI-0610 and rux treatment in 41% of patients. Out of these, 81% showed improvements within 6 months of treatment. Bone marrow fibrosis deteriorated in three cases.

Arm 3²

Patient disposition

Out of the ITT population, 15% discontinued treatment with the most common reasons being withdrawal of consent (4%), primary investigator decision (4%), and an adverse event or lab abnormality (3%). Treatment continued for a median of 40 weeks (range 2−79 weeks). During the study, two patients died.

The initial results from Arm 3 of the MANIFEST study can be found in a previous article on the MPN Hub, here.

Key efficacy endpoints from Arm 3

• Primary endpoint: SVR35 at 24 weeks was achieved in 67% (95% CI, 54–78) of the ITT population. The median spleen volume reduction was −50%.
• SVR35 by subgroup
  • Int-1, DIPSS 72%
  • Int-1, IPSS 73%
  • Int-2, DIPSS 64%
  • Int-2, IPSS 66%

Spleen volume was shown to decrease with time with CPI-0610 + rux and this was maintained during the study course.

An improvement in symptom burden was seen at 24 weeks with 57% (95% CI, 43–69) of patients reaching TSS50. The median decrease in TSS50 was −59%.

At least one grade of bone marrow fibrosis improvement was seen in 33% of patients. Out of these, 88% of improvements were seen within 6 months of rux + CPI-0610 treatment. Bone marrow fibrosis got worse in two patients.

Safety profile in Arms 2 and 3

The treatment-emergent adverse events (TEAEs) experienced during the study are shown in Table 3. In Arm 2, CPI-0610 + rux seemed to be well tolerated overall. A total of 92% of patients reported at least one TEAE with thrombocytopenia being the most frequent hematological adverse event. Grade 3 or higher TEAEs were mostly hematological.

The most common non-hematological TEAEs included diarrhea (51%), respiratory tract infections (35%), nausea (33%), and asthenic conditions (33%). CPI-0610 discontinuation due to TEAEs occurred in 12% of patients, and six Grade 5 TEAEs were recorded.

As in Arm 2, the TEAEs recorded for Arm 3 were generally mild and showed the combination was well tolerated (Table 3). The Grade 3 and 4 TEAEs were mostly hematological with anemia being the most commonly recorded Grade 3 TEAE. Severe non-hematological TEAEs were not reported in Arm 3. A total of two patients stopped treatment with CPI-0610 due to TEAEs, and two Grade 5 TEAEs were reported.

Table 3. TEAEs from both treatment arms^1,2

Conclusion

The results of the MANIFEST phase II study of rux and CPI-0610 are promising with 2/3 of JAKi-naïve patients in Arm 3 achieving a SVR35 and TSS50 of 57% at Week 24.

In addition, encouraging responses were also seen in patients who stopped responding to JAKi treatment (Arm 2), although at lower rates. Also, 29% of patients in the TI group reached SVR35 at Week 24. The TSS50 response at Week 24 was achieved in 46% of the TD cohort and in 38% of the TI cohort. The conversion from TD to TI occurred in 36% of patients. Improvements in bone marrow fibrosis by at least one grade were seen in both arms.

The safety profile of CPI-0610 was similar between monotherapy and combination with rux, showing excellent tolerability with mostly low-grade TEAEs.

To hear more about the MANIFEST trial have a look at this interview with John Mascarenhas, at the 25th European Hematology Association (EHA) Annual Congress, which can be found here.