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ASH 2019 | MANIFEST phase II results: CPI-0610 BETi for refractory/intolerant myelofibrosis

May 12, 2020
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Bromodomain and extraterminal domain proteins (BET) are epigenetic modulators that bind to acetylated histones and non-histone proteins and regulate the production of proinflammatory cytokines in response to Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signalling pathway activation.1 Proinflammatory cytokines have been shown to contribute to myelofibrosis (MF) etiology by supporting the development of bone marrow fibrosis and other symptoms.2 BET inhibitors, like CPI-0610 have shown promising preclinical efficacy for MF as single agents and in combination with JAK inhibitors, like ruxolitinib (rux).2 In an attempt to clinically validate these results the MANIFEST study was established. This ongoing phase II trial investigates the efficacy of CPI-0610 with or without rux in patients with refractory or intolerant MF.

During the 61st American Society of Hematology (ASH) Annual Meeting & Exposition (2019), John Mascarenhas presented an oral abstract1 on the interim results of MANIFEST. This article is based on data presented at ASH and may supersede the data in the published abstract.

Study design

  • Global, multicenter, open label, phase II trial
  • Treatment arms and patient eligibility:
    • CPI-0610 monotherapy arm (n = 36):
      • patients no longer on rux with resistant/refractory or intolerant MF and Dynamic International Prognostic Scoring System (DIPSS) ≥ intermediate
      • CPI-0610 starting dose at 125 mg once daily on days 1-14 (21-day dosing cycles). Dose increase by 25 mg was allowed from Cycle 3 onwards to a maximum dose of 225 mg
    • CPI-0610 + rux arm (n = 54):
      • patients with suboptimal response or MF progression that have received ≥ 6 months of rux and stable dose for at least 8 weeks and DIPSS ≥ intermediate
      • dosing for CPI-0610 same as above. Rux standard licenced dosing with up-titration not allowed
    • In both treatment arms, patients were further stratified as transfusion dependent (TD) or independent (TI). TI was defined as absence of transfusions over a 12-week period
  • Primary endpoints:
    • for TI patients: spleen volume response defined as ≥ 35% reduction after 24weeks (SVR35)
    • for TD patients: conversion from TD to TI
  • Key secondary endpoints: spleen volume response (SVR), patient global impression of change (PGIC), safety and change in total symptom score (TSS) defined as ≥ 50% reduction after 24 weeks
  • Exploratory endpoints: anemic response, transfusion rate, proinflammatory cytokine levels, mutant allele burden, bone marrow morphology

Key findings

  • The majority of patients enrolled had DIPSS ≥ intermediate, anemia, high-risk mutations and high symptom burden. These along with the key baseline characteristics are shown in Table 1

Table 1. Key baseline characteristics from the MANIFEST phase II trial1

ASXL, additional sex comb-like gene; DIPSS, dynamic international prognostic scoring system; ECOG, eastern cooperative oncology group; ET, essential thrombocytopenia; MF, myelofibrosis; PV; polycythemia vera; rux, ruxolitinib; TSS, total symptom score

Characteristics

CPI-0610 monotherapy

(n = 36)

CPI-0610 + rux

(n = 54)

Overall

(n = 90)

Median age (years)

69

69

69

Males

21%

32%

53%

ECOG

    ≤ 1

    > 1

 

91.7%

8.3%

 

92.6%

5.6%

 

92.2%

6.7%

DIPSS

    Intermediate

    High

 

55.6%

30.6%

 

64.8%

22.2%

 

61.1%

25.6%

MF subtype

     Primary MF

     Post-PV MF

     Post-ET MF

 

63.9%

19.4%

11.1%

 

66.7%

16.7%

16.7%

 

65.6%

17.8%

14.4%

Mutations

     ≥ 3 mutations

     High molecular risk

     ASXL

 

38.9%

52.8%

41.7%

 

68.5%

64.8%

55.6%

 

56.7%

60.0%

50.0%

Hemoglobin (g/dl)

     < 10 g/dl

 

72.2%

 

74.1%

 

73.3%

Median TSS (n)

22.0

19.5

21.0

  • The best overall responses are shown in Table 2, in summary:
    • TD patients seemed to benefit more than TI patients from CPI-0610 monotherapy with or without rux
    • CPI-0610 in combination with rux led to the conversion of more patients from TD to TI than CPI-0610 alone

Table 2. Best responses from the MANIFEST phase II trial1

PGIC, patient global impression of change; rux, ruxolitinib; SVR35, spleen volume response of 35% reduction from baseline at 24 weeks; TD, transfusion dependent; TI, transfusion independent; TSS, total symptom score

Best responses

CPI-0610 + rux

 

CPI-0610 monotherapy

 

TD patients

TI patients

TD patients

TI patients

SVR35 response (%, n/N)

29% (5/17)

0% (0/15)

25% (1/4)

0% (0/9)

TD to TI conversion (n/N)

6/14

-

0/4

-

TSS 50% response (%, n/N)

76.5% (13/17)

43% (6/14)

50% (1/2)

62.5% (5/8)

PGIC (%, n/N)

89% (16/18)

93.3% (14/15)

100% (4/4)

91% (10/11)

  • Hemoglobin and bone marrow fibrosis (BMF) improvements in the two treatment arms are shown in Table 3
    • At least one grade improvement in BMF was seen in 38% of all patients and 83% of all improvements occurred within the first 6 months of treatment

Table 3. Hemoglobin and bone marrow fibrosis improvements in the MANIFEST trial1

BMF, bone marrow fibrosis; Hgb, hemoglobin; rux, ruxolitinib; TD, transfusion dependent; TI, transfusion independent

 

CPI-0610 + rux

 

CPI-0610 monotherapy

 

BMF improvement (%, n/N)

43.5% (10/23)

22.2% (2/9)

BMF improvement

1.5 g/dl increase of Hgb (%, n/N)

17.4% (4/23)

22.2% (2/9)

BMF improvement

TD to TI conversion (%, n/N)

36.4% (4/11)

0% (0/2)

Hgb increase by 1.5 g/dl (%, n/N)

13% (2/15)

55% (6/11)

Safety

  • CPI-0610 with or without rux was generally tolerable with thrombocytopenia being the most common hematological adverse event (AE) in both treatment groups, followed by anemia
    • thrombocytopenia: 23.3% (all grades), 10% (grade ≥ 3)
    • anemia: 8.0% (all grades), 5.7% (grade ≥ 3)
    • grade ≥ 3 thrombocytopenia occurred in nine patients (none were serious)
  • The most common non-hematological AEs in both groups were fatigue, diarrhea, nausea, cough, vomiting and upper respiratory tract infections, with only few cases of grade ≥ 3 AEs
  • Grade 4 AEs were reported in 8.9% of patients (n/N: 8/90) and all were resolved
  • Three deaths occurred (3.3%), which were considered unrelated to CPI-0610 treatment (acute kidney injury, traumatic subdural hemorrhage due to tripping and brainstem hemorrhage without concurrent thrombocytopenia)
  • A summary of the key AEs combined from both treatment arms are shown below in Table 4

Table 4. Key adverse events combined from both treatment arms of the MANIFEST trial1

         AEs, adverse events; URT, upper respiratory tract

Adverse events

All grade

(n = 90)

 

Grade 3

(n = 90)

Hematological AEs (%, n/N)

 

 

Thrombocytopenia

Anemia

23.3%

8.9%

10.0%

6.7%

Non-hematological AEs (%, n/N)

 

 

Diarrhea

Nausea

Vomiting

Cough

Fatigue

URT infection

32.2%

22.2%

14.4%

16.7%

14.4%

14.4%

4.4%

1.1%

1.1%

-

3.3%

-

Conclusions

The interim results of the MANIFEST phase II trial indicate that the BET inhibitor CPI-0610 both with and without rux has antitumor activity in patients with refractory or intolerant advanced MF. Improvements in hemoglobin levels and BMF were observed with both treatments with a trend for better efficacy when rux and CPI-0610 were used in combination. TD patients seem to benefit the most from the combination treatment with CPI-0610 and rux leading to both objective and subjective patient-reported responses. Moreover, the combination treatment seemed more effective in converting patients with TD to TI. Both treatments were well tolerated with asymptomatic thrombocytopenia being the most common hematological side effect. Building upon these promising early data, the trial has now increased its sample size to further validate the synergistic efficacy of CPI-0610 with rux in TD patients and is also investigating a separate cohort of rux naïve MF patients (Arm 3). Preliminary data from Arm 3 of this trial were presented by Prof Harrison at ASH 2019 here.

  1. Mascarenhas J, Kremyanskaya M, Hoffman R, et al. MANIFEST, a Phase 2 study of CPI-0610, a bromodomain and extraterminal domain inhibitor (BETi), as monotherapy or "add-on" to ruxolitinib, in patients with refractory or intolerant advanced myelofibrosis. Oral Abstract Session #634. 61st American Society of Hematology Annual Meeting & Exposition; Nov 13, 2019; Orlando, US.
  2. Eran Z, Zingariello M, Bochicchio MT, et al. Novel strategies for the treatment of myelofibrosis driven by recent advances in understanding the role of the microenvironment in its etiology. F1000Res. 2019;8:1662. DOI: 12688/f1000research.18581.1

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