AVID200 is Safe and Tolerable in Myelofibrosis


In a phase 1b trial, AVID200 demonstrated limited toxicity and improved symptom benefit when administered at 3 doses levels.

Primary myelofibrosis: © LASZLO - stock.adobe.com

Primary myelofibrosis: © LASZLO - stock.adobe.com

AVID200 was well-tolerated when given to patients with myelofibrosis (MF), and no dose-limiting toxicities (DLTs) were observed at the 3 dose levels tested in an investigator-initiated, phase 1b clinical trial (NCT03895112).1

Across all cycles, adverse events (AEs) that were grade 3 or higher were seen in 16 of the 21 patients enrolled (76.2%). Grade 3 or 4 nonhematologic AEs were noted in 9 (42.9%) patients. One patient each had cases of grade 3 or 4 epistaxis, mucositis, extraocular muscle paresis, fatigue, rash, duodenal hemorrhage, gastric hemorrhage, urinary tract infection, and syncope.

Grade 3 or 4 anemia occurred in 28.6% of patients and thrombocytopenia in 19.0%, respectively. Two patients had a clinical benefit by IWG-MRT criteria after 6 cycles, and there were spleen and symptom benefits observed across treatment cycles.

“The results of this investigator-initiated multicenter phase 1b study of AVID200 in MF demonstrated both safety and tolerability at the 3 doses levels tested. No deaths were attributable to AVID200 therapy. Pharmacodynamic studies indicated that AVID200 was effective in interrupting TGFβ signaling,” wrote study authors in findings published in Clinical Cancer Research.

Twenty-one patients with advanced MF were included in the trial if they had a confirmed diagnosis of primary MF or post-essential thrombocythemia/polycythemia vera MF using WHO criteria. Patients must have intermediate-2, or high-risk disease according to the IWG-MRT Dynamic International Prognostic Scoring System, at least grade 2 bone marrow fibrosis, have not been previously treated with ruxolitinib (Jakafi), and have baseline platelet counts of ≥25 × 109/L.

Using a modified toxicity probability interval dose-escalation design, 3 dose levels were evaluated with a target toxicity rate of 30%. Once the dose-escalation portion was completed, dose levels 2 and 3 were expanded to include 9 patients per dose level. Intravenous AVID200 (lots A and B) was given in dose cohorts of 180 mg (A), 550 mg (A), 180 mg (B) on day 1 of a 21-day cycle. Then, subjects enrolled in the dose-escalation phase received 70 mg (B) and 180 mg (B) for dose levels 2 and 3. AVID200 was given to patients on day 1 of a 21-day cycle.

The primary end point assessed in the study was to estimate the MTD of AVID200 treatment in MF, and secondary end points consisted of safety and change in bone marrow fibrosis after cycles 6 and 12. Additional exploratory end points evaluated quality-of-life and patient-reported symptoms.

A total of 21 patients were enrolled and 9 patients (3 at each dose level) received AVID200 during the dose-escalation phase and 12 during the dose-expansion phase. Once ruxolitinib was discontinued, the median time to start of AVID200 therapy was 6.0 months (range, 0.5-59.9), and 90.5% of patients had previously received ruxolitinib treatment. The median age among all patients was 73 (range, 51-85), 23.8% of patients were female, patients with intermediate-2 risk made up 61.9% of patients, and high-risk disease accounted for 38.1% of patients, respectively.

A total of 81% of patients had severe bone marrow fibrosis, and 50% had abnormal karyotype present. For baseline somatic mutational profiles, 71% of the 21 patients enrolled had JAK2 mutations, 29% had TET2 mutations, 24% had ASXL1 mutations, and 19% had CALR mutations. At baseline, the median tumor symptom score was 14 (range, 3-39).

Additional findings showed that there were increases in platelet counts in 81% of treated patients, and 3 patients achieved normalization. AVID200 led to potent suppression of plasma TGFβ1 levels and pSMAD2 in MF cells. There also were improvements seen across all cycles of treatment, including a reduction in spleen size of at least 50% in 2 patients with large baseline spleen sizes.Based on these data, AVID200 should be further evaluated in patients with thrombocytopenic MF in combination with agents that target aberrant MF intracellular signaling pathways.

“AVID200 monotherapy in a population of patients with an advanced stage of MF resulted in limited toxicity as well as improvements in spleen size, symptom benefit, and platelet counts…The improvement in platelet counts following AVID200 treatment provides a distinct advantage, as the currently approved therapeutic approaches and those undergoing clinical development in MF are universally associated with treatment-related thrombocytopenia,” wrote the study authors.

  1. Mascarenhas J, Migliaccio AR, Kosiorek H, et al. A phase Ib trial of AVID200, a TGFβ 1/3 trap, in patients with myelofibrosis. Clin Cancer Res. 2023;29(18):3622-3632. doi:10.1158/1078-0432.CCR-23-0276
  2. MPN-RC 118 AVID200 in myelofibrosis. ClinicalTrials.gov. Updated February 10, 2023. Accessed October 10, 2023. https://tinyurl.com/bdh3kytr

Related Videos
Related Content