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Clinical Trials

The treatment of myelofibrosis (MF) commonly relies on the use of Janus kinase (JAK) inhibitors such as Jakafi® (ruxolitinib), Inrebic® (fedratinib), and Vonjo™ (pacritinib), all of which are approved by regulatory agencies.¹ With the aim of fulfilling unmet needs in the treatment of MF, such as the management of disease refractory to current therapies and ways to delay disease progression, many other drugs are being evaluated in phase 2 and 3 clinical trials as combination therapies. These include CPI-0610 (pelabresib), parsaclisib, and navitoclax.¹

MANIFEST Clinical Trials

Phase 2 and 3 clinical trials sponsored by Constellation Pharmaceuticals (recently acquired by MorphoSys) are currently evaluating CPI-0610 (pelabresib) in patients with MF.^2,3 CPI-0610 is an investigational small molecule that inhibits the function of bromodomain and extraterminal (BET) proteins.^4,5

The MANIFEST (NCT02158858) trial is an open-label phase 2 study of pelabresib with and without Jakafi® (ruxolitinib) in patients with MF.^2,6 The trial design includes 3 arms. In arm 1, pelabresib is being evaluated as a monotherapy in patients resistant to, intolerant of, or not eligible for Jakafi. In arm 2, pelabresib is being evaluated in combination with Jakafi in patients with a suboptimal response to Jakafi or with disease progression.⁵

Patients in these 2 study arms are being stratified according to their transfusion-dependent (TD) status. The primary endpoint for patients who are TD at baseline is transfusion independence for 12 consecutive weeks. For patients who are not TD at baseline, the primary endpoint is a spleen volume reduction of 35% or more from baseline after 24 weeks of treatment.^5,6

Arm 3 of MANIFEST is studying CIP-0610 in combination with Jakafi in patients with MF who are JAK inhibitor-naïve. Similar to arm 2b, the primary endpoint is spleen volume reduction of 35% or more from baseline after 24 weeks of treatment. Thrombocytopenia, depression, and anxiety were the adverse events associated with the study, along with anemia and hematologic toxicities.^5,6

A recent analysis of MANIFEST data has revealed durable spleen volume reduction and symptom score improvement after 24 weeks of treatment with the investigational drug combined with Jakafi in JAK inhibitor-naïve patients. The same analysis has reported data on an association of biomarkers with potential disease-modifying activity of CPI-0610.⁵

The double-blind, placebo-controlled phase 3 MANIFEST-2 (NCT04603495) study is currently recruiting patients for a comparison of the efficacy and safety of CPI-0610 combined with Jakafi vs the efficacy and safety of placebo and Jakafi in JAK inhibitor-naïve patients with MF.⁴ The estimated date for the completion of this clinical trial is April 2027.³

Read more about Jakafi

LIMBER Clinical Trials

The phase 3 LIMBER-304 (NCT04551053) and LIMBER-313 (NCT04551066) clinical trials, sponsored by Incyte, are currently recruiting patients for an evaluation of the safety and efficacy of parsaclisib in patients with MF. The LIMBER-304 date of completion is estimated to be March 2025, and the LIMBER-313 estimated date of completion is March 2026.^7,8

Parsaclisib is a phosphatidylinositol 3-kinase delta (PI3Kδ) inhibitor that was first evaluated in a phase 2 clinical trial of 51 patients with MF and an inadequate response to Jakafi.¹ The median percentage decrease in spleen volume at 24 weeks of treatment was 2.5% in a group that received parsaclisib daily then weekly vs 27.1% in a group that received parsaclisib daily.¹

In the phase 2 LIMBER-304 trial, parsaclisib is being studied in patients who had a suboptimal response while receiving Jakafi monotherapy; the patients in LIMBER-313 have never received a JAK inhibitor but require treatment.^7,8

The primary endpoint of the LIMBER trials is spleen volume reduction at week 24. Key secondary endpoints include reduction in the Total Symptom Score (TSS) at week 24, overall survival, safety, and tolerability.^7,8

Read more about MF therapies

TRANSFORM Clinical Trials

TRANSFORM-1 (NCT04472598) and TRANSFORM-2 (NCT04468984) are placebo-controlled phase 3 clinical trials of navitoclax in combination with Jakafi and navitoclax in comparison with Jakafi in JAK inhibitor-naïve patients (TRANSFORM-1) and in patients with refractory/relapsed disease after JAK inhibitor treatment (TRANSFORM-2).^9,10 The estimated date of completion of TRANSFORM-1 is October 2032. The TRANSFORM-2 study is currently recruiting and is expected to be completed by January 2031.^9,10

Navitoclax, a BCL-2/BCL-xL inhibitor, was first studied in a phase 2 trial, also in combination with Jakafi. The study included 34 patients who had failed Jakafi treatment and reported a spleen volume reduction of 35% or more in 27% of the patients.¹

Read more about MF experimental therapies

References

1. Tremblay D, Mascarenhas J. Next generation therapeutics for the treatment of myelofibrosis. Cells. 2021;10(5):1034. doi:10.3390/cells10051034

2. A phase 2 study of CPI-0610 with and without ruxolitinib in patients with myelofibrosis. ClinicalTrials.gov. Jun 19, 2014. Updated December 7, 2022. Accessed December 27, 2022.

3. Phase 3 study of pelabresib (CPI-0610) in myelofibrosis (MF) (MANIFEST-2). ClinicalTrials.gov. October 26, 2020. Updated October 12, 2022. Accessed December 27, 2022.

4. Harrison C, Kremyanskaya M, Bose P, et al. Pelabresib (CPI-0610) as add-on to ruxolitinib in myelofibrosis: durability of response and safety beyond week 24 in the phase 2 MANIFEST study. Blood. 2022;140(Suppl 1):9659-9662. doi:10.1182/blood-2022-157735

5. MorphoSys presents new longer-term phase 2 results on pelabresib in myelofibrosis, including potential disease-modifying activity, at ASH 2022. Media release. MorphoSys; December 11, 2022.

6. Mascarenhas J, Kremyanskaya M, Patriarca A, et al. MPN-375 BET inhibitor pelabresib (CPI-0610) combined with ruxolitinib in patients with myelofibrosis – JAK inhibitor-naïe or with suboptimal response to ruxolitinib – preliminary data from the MANIFEST study. Clin Lymphoma Myeloma Leuk. 2022;22(Suppl 2):S335-S336. doi:10.1016/S2152-2650(22)01456-2

7. To evaluate efficacy and safety of parsaclisib and ruxolitinib in participants with myelofibrosis who have suboptimal response to ruxolitinib (LIMBER-304). ClinicalTrials.gov. September 16, 2020. Updated December 5, 2022. Accessed December 27, 2022.

8. To evaluate the efficacy and safety of parsaclisib and ruxolitinib in participants with myelofibrosis (LIMBER-313). ClinicalTrials.gov. September 16, 2020. Updated December 5, 2022. Accessed December 26, 2022.

9. Study of oral navitoclax tablet in combination with oral ruxolitinib tablet when compared with oral ruxolitinib tablet to assess change in spleen volume in adult participants with myelofibrosis (TRANSFORM-1). ClinicalTrials.gov. July 15, 2020. Updated November 15, 2022. Accessed December 27, 2022.

10. Study of oral navitoclax tablet in combination with oral ruxolitinib tablet to assess change in spleen volume in adult participants with relapsed/refractory myelofibrosis (TRANSFORM-2). ClinicalTrials.gov. July 13, 2020. December 14, 2022. Accessed December 26, 2022.

Reviewed by Debjyoti Talukdar, MD, on 12/30/2022.

Diana Diez Gaspar, PharmD, PhD

Diana earned her PhD and PharmD with distinction in the field of Medicinal and Pharmaceutical Chemistry at the Universidade do Porto. She is an accomplished oncology scientist with 10+ years of experience in developing and managing R&D projects and research staff directed to the development of small proteins fit for medical use.

Myelofibrosis (MF)