Leading in MPNs Beyond Ruxolitinib in Combo With T-Regs

Official title

Phase Ib, Open-label Study of Add on Therapy With CK0804 in Participants With Myelofibrosis, With Suboptimal Response to Ruxolitinib

Overview

To assess the safety and tolerability of CK0804 as add-on therapy in participants with myelofibrosis, with suboptimal response to ruxolitinib

Detailed description

1. Safety Run-in

The study will employ a 3+3+3 design to assess the safety and tolerability of the treatment based on treatment-limiting toxicities (TLTs) occurring up to 1 Cycle (28 days) after the first infusion. 2. Expansion

After a total of 9 participants completed 28 days and are evaluated for tolerability in the safety run-in phase, additional participants may be included in the expansion cohort in order to have approximately 24 evaluable myelofibrosis

Interventions

• Drug CK0804
  CK0804 is a cryopreserved, allogeneic T-regulatory cell product that is manipulated to traffic to the bone marrow.

Primary outcome measures

• To determine Treatment limiting toxicity (TLT) as defined below [Time frame: 28 days]

Secondary outcome measures (4)

• Assessment of overall response rate (ORR) (measured as CR or PR) and its duration, using modified International Working Group-Myeloproliferative Neoplasm Research and Treatment (IWG-MRT) and European Leukemia Net (ELN) consensus report. [Time frame: 6 months]
• Rate of anemia response as per modified IWG-MRT ELN response criteria. [Time frame: 6 months]
• Rate of spleen response by imaging at and after 24 weeks as per IWG-MRT ELN response criteria [Time frame: 6 months]
• Percentage of Participants who will Achieve Total Symptom Score Reduction Greater Than or Equal to (≥) 50% (TSS50) as Measured by Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) [Time frame: 6 months]

Eligibility criteria

Inclusion criteria

• Ability to comprehend and willingness to sign a written informed consent form (ICF) for the study.
• Age above 18 years inclusive at the time of signing the ICF.
• Participants who fulfill the diagnostic criteria of myelofibrosis including primary myelofibrosis and myelofibrosis arising from polycythemia vera and essential thrombocythemia
• Life expectancy is greater than 6 months.
• Subject has been receiving ruxolitinib therapy, is unlikely to benefit from further ruxolitinib monotherapy in the opinion of the investigator; AND meeting the following criteria: receiving ruxolitinib >3 months prior to enrollment; AND stable dose for 8 weeks before starting therapy with CK0804
• Subject with evidence of evaluable residual burden of disease following ruxolitinib monotherapy treatment, consisting of:

• presence of grade ≥2 anemia or thrombocytopenia or neutropenia, OR
• presence of disease-related symptoms, as determined by a Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (MPN SAF TSS) score of ≥10 points, OR
• documented splenomegaly of at least 5 cm below the costal margin as measured by physical examination or splenomegaly as documented by ultrasound or MRI.
• Willingness to avoid pregnancy or fathering children based on the criteria below

• Men must agree to take appropriate precautions to avoid fathering children (with at least 99% certainty) from screening through 90 days after the last study treatment dose and must refrain from donating sperm during this period. Permitted methods that are at least 99% effective in preventing should be communicated to the participants and their understanding confirmed.
• Women of childbearing potential must have a negative serum pregnancy test at screening before the first dose (within 3 days of the first study treatment dose) and must agree to take appropriate precautions to avoid pregnancy (with at least 99% certainty) from screening through the safety follow-up visit and must not donate oocytes during this period. Permitted methods that are at least 99% effective in preventing pregnancy should be communicated to the participants and their understanding confirmed,
• Women of nonchildbearing potential (ie, surgically sterile with a hysterectomy and/or bilateral oophorectomy OR ≥ 12 months of amenorrhea and at least 50 years of age) are eligible.
• ECOG performance status of 0 to 2

Exclusion criteria

• Any major surgery within 28 days before the first dose of study treatment.
• Undergone any prior allogenic or autologous stem cell transplantation or a candidate for such transplantation.
• Received chemotherapy, immunomodulatory drug therapy, immunosuppressive therapy, biological therapy, endocrine therapy, targeted therapy, antibody or hypomethylating agent to treat the participant's disease, with the exception of ruxolitinib, within 5 half-lives or 28 days (whichever is shorter) before the first dose of study treatment.
• Participant has received splenic irradiation within the past 6 months.
• Significant concurrent, uncontrolled medical condition or infections, which in the opinion of the principal investigator may interfere in the study participation.
• Inability or unlikeliness of the participant to comply with the dose schedule and study evaluations, in the opinion of the investigator.
• Women who are pregnant or breastfeeding.
• Any condition that would, in the investigator's judgment, interfere with full participation in the study, including administration of study treatment and attending required study visits; pose a significant risk to the participant; or interfere with interpretation of study data.
• Participants with laboratory values at screening as defined

• Platelets < 50 × 10\^9/L without the assistance of growth factors, thrombopoietic factors, or platelet transfusions
• ANC < 0.5 × 10\^9/L
• ALT ≥ 2.5 × ULN
• AST ≥ 2.5 × ULN
• Direct Bilirubin > 2.0 × ULN
• ALP ≥ 3 × ULN
• Creatinine clearance < 50 mL/min according to Cockcroft-Gault formula.
• Unwillingness to be transfused with blood components including RBC and platelet transfusions.
• Inability of the participant (or parent, guardian, or legally authorized representative) to comprehend the ICF or unwillingness to sign the ICF.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 4 centers

• UC Davis Health — Sacramento
• Columbia University — New York
• Montefiore Einstein Cancer Center — The Bronx
• The University of Texas MD Anderson Cancer Center — Houston

Publications

• Abdelouahab H, Zhang Y, Wittner M, Oishi S, Fujii N, Besancenot R, Plo I, Ribrag V, Solary E, Vainchenker W, Barosi G, Louache F. CXCL12/CXCR4 pathway is activated by oncogenic JAK2 in a PI3K-dependent manner. Oncotarget. 2016 Jul 22;8(33):54082-54095. doi: 10.18632/oncotarget.10789. eCollection 2017 Aug 15. PMID 28903325
• Barbui T, Thiele J, Gisslinger H, Finazzi G, Vannucchi AM, Tefferi A. The 2016 revision of WHO classification of myeloproliferative neoplasms: Clinical and molecular advances. Blood Rev. 2016 Nov;30(6):453-459. doi: 10.1016/j.blre.2016.06.001. Epub 2016 Jun 11. PMID 27341755
• Barbui T, Thiele J, Gisslinger H, Kvasnicka HM, Vannucchi AM, Guglielmelli P, Orazi A, Tefferi A. The 2016 WHO classification and diagnostic criteria for myeloproliferative neoplasms: document summary and in-depth discussion. Blood Cancer J. 2018 Feb 9;8(2):15. doi: 10.1038/s41408-018-0054-y. PMID 29426921
• Barosi G, Mesa RA, Thiele J, Cervantes F, Campbell PJ, Verstovsek S, Dupriez B, Levine RL, Passamonti F, Gotlib J, Reilly JT, Vannucchi AM, Hanson CA, Solberg LA, Orazi A, Tefferi A; International Working Group for Myelofibrosis Research and Treatment (IWG-MRT). Proposed criteria for the diagnosis of post-polycythemia vera and post-essential thrombocythemia myelofibrosis: a consensus statement fro PMID 17728787
• Bogani C, Ponziani V, Guglielmelli P, Desterke C, Rosti V, Bosi A, Le Bousse-Kerdiles MC, Barosi G, Vannucchi AM; Myeloproliferative Disorders Research Consortium. Hypermethylation of CXCR4 promoter in CD34+ cells from patients with primary myelofibrosis. Stem Cells. 2008 Aug;26(8):1920-30. doi: 10.1634/stemcells.2008-0377. Epub 2008 May 29. PMID 18511598
• Brunstein CG, Miller JS, Cao Q, McKenna DH, Hippen KL, Curtsinger J, Defor T, Levine BL, June CH, Rubinstein P, McGlave PB, Blazar BR, Wagner JE. Infusion of ex vivo expanded T regulatory cells in adults transplanted with umbilical cord blood: safety profile and detection kinetics. Blood. 2011 Jan 20;117(3):1061-70. doi: 10.1182/blood-2010-07-293795. Epub 2010 Oct 15. PMID 20952687
• Brunstein CG, Miller JS, McKenna DH, Hippen KL, DeFor TE, Sumstad D, Curtsinger J, Verneris MR, MacMillan ML, Levine BL, Riley JL, June CH, Le C, Weisdorf DJ, McGlave PB, Blazar BR, Wagner JE. Umbilical cord blood-derived T regulatory cells to prevent GVHD: kinetics, toxicity profile, and clinical effect. Blood. 2016 Feb 25;127(8):1044-51. doi: 10.1182/blood-2015-06-653667. Epub 2015 Nov 12. PMID 26563133
• Cho SY, Xu M, Roboz J, Lu M, Mascarenhas J, Hoffman R. The effect of CXCL12 processing on CD34+ cell migration in myeloproliferative neoplasms. Cancer Res. 2010 Apr 15;70(8):3402-10. doi: 10.1158/0008-5472.CAN-09-3977. Epub 2010 Apr 13. PMID 20388788

Identifiers

NCT: NCT05423691 · CK0804.101.1

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗