Registered objective: safety, pharmacokinetics, pharmacodynamics, and efficacy in anemia due to MDS or multiple myeloma

“This Phase 1/2, open-label, dose-finding study is intended to evaluate the safety and tolerability, PK, PD, and efficacy of INCB000928 administered as monotherapy in participants with MDS or MM who are transfusion-dependent or present with symptomatic anemia.” (opens the source at this quote in a new tab)
“A Phase 1/2, Open-Label, Multicenter Study of INCB000928 Administered as a Monotherapy in Participants With Anemia Due to Myelodysplastic Syndromes or Multiple Myeloma” (opens the source at this quote in a new tab)

Study identifiers, dates, and status: registry record

Field	Registry record
Acronym	“LIMBER”
Sponsor protocol number	“INCB 00928-105”
EudraCT number	“2020-002771-35”
Study start (actual)	“2021-08-19”
Primary completion (actual)	“2024-08-15”
Study completion (actual)	“2024-08-15”
Enrollment (actual)	“22”
Overall status	“Terminated”
Reason stopped	“Strategic Business Decision”
Results first posted	“2025-10-22”

Study centers

“This study was conducted at 8 study centers in the United States, France, and Italy.” (opens the source at this quote in a new tab)

Registered design details

Design feature	Registry record
Primary purpose	“Treatment”
Allocation	“N/A”
Interventional model	“Sequential Assignment”
Masking	“None (Open Label)”

Planned dose-escalation and expansion stages

“In the dose-escalation stage, a BOIN design will be used to determine the MTD. In each dose-escalation cohort, data from both participants with MDS and participants with MM will be evaluated together.” (opens the source at this quote in a new tab)
“The study has 2 disease groups:” (opens the source at this quote in a new tab)
“Participants with MDS or MDS/MPN overlap syndromes, collectively referred to as MDS participants.” (opens the source at this quote in a new tab)
“Participants with relapsed/refractory MM.” (opens the source at this quote in a new tab)

Inclusion criteria

“Participants who are transfusion-dependent or present with symptomatic anemia” (opens the source at this quote in a new tab)
“Ineligible to receive or have not responded to available therapies for anemia such as ESAs or lenalidomide.” (opens the source at this quote in a new tab)
“Histologically confirmed diagnosis of the MDS, CMML and unclassifiable MDS/MPN overlap syndromes.” (opens the source at this quote in a new tab)
“After failure of available standard treatments such as alkylating agents, glucocorticoids, immunomodulatory drugs (lenalidomide,pomalidomide, or thalidomide), proteasome inhibitors (bortezomib or carfilzomib), and daratumumab.” (opens the source at this quote in a new tab)

Exclusion criteria relevant to safety interpretation

“Undergoing treatment with a strong or potent inhibitor or inducer of CYP3A4/5 within 28 days or 5 half-lives (whichever is longer) before the first dose of study drug or expected to receive such treatment during the study.” (opens the source at this quote in a new tab)
“History of clinically significant or uncontrolled cardiac disease.” (opens the source at this quote in a new tab)
“Diagnosis of chronic liver disease.” (opens the source at this quote in a new tab)

Age

“18 Years and older” (opens the source at this quote in a new tab)

Dose levels and treatment duration, posted results

“Participants with myelodysplastic syndromes (MDS) or multiple myeloma (MM) who were transfusion dependent or presented with symptomatic anemia received oral zilurgisertib 50 milligrams (mg) once daily (QD) administered as a monotherapy for up to 6 months.” (opens the source at this quote in a new tab)

Group as posted	Registry record
Dose levels	“Zilurgisertib 50 mg QD”; “Zilurgisertib 100 mg QD”; “Zilurgisertib 200 mg QD”; “Zilurgisertib 400 mg QD”; “Zilurgisertib 600 mg QD”

Registered primary outcome measures

Outcome measure	Time frame
“Number of Participants With Any Treatment-emergent Adverse Event (TEAE)”	“up to 950 days”
“Number of Participants With Any ≥Grade 3 TEAE”	“up to 950 days”
“Number of Participants With Dose-limiting Toxicities (DLTs)”	“up to Day 28”
“Maximum Tolerated Dose (MTD)”	“up to Day 28”
“Recommended Dose for Expansion (RDE)”	“up to Day 28”

Dose-limiting toxicity and maximum tolerated dose definitions

“A DLT was defined as the occurrence of any protocol-defined toxicities occurring during the first study drug treatment cycle, from C1D1 up to and including Cycle 1 Day 28 (per regimen cycle schedule), except those with a clear alternative explanation (e.g., disease progression) or transient (≤72 hours) abnormal laboratory values without associated clinically significant signs or symptoms based on investigator determination.” (opens the source at this quote in a new tab)
“Bayesian optimal interval (BOIN) design was used to determine the MTD for this study.” (opens the source at this quote in a new tab)
“RDE doses were defined as pharmacodynamically active. RDE doses were not to have exceeded the MTD defined in each treatment group.” (opens the source at this quote in a new tab)

Secondary endpoints: anemia response and transfusion independence

“Participants with anemia response were those with a hemoglobin (Hgb) increase of ≥1.5 grams per deciliter (g/dL) relative to baseline for any 8-week period (with each assessment meeting this requirement) during the first 24 weeks of treatment if transfusion independent at baseline.” (opens the source at this quote in a new tab)
“Participants with RBC-transfusion independence were defined as those who did not require any RBC transfusion for at least 8 consecutive weeks during the first 24 weeks of treatment.” (opens the source at this quote in a new tab)

Planned sample size

“The cohort size will be 3. In each disease group, up to approximately 24 evaluable participants may be treated in the dose-escalation stages, and the dose-escalation procedure may be stopped if the number of evaluable participants treated at any dose level is > 9.” (opens the source at this quote in a new tab)
“Fifteen participants per cohort will provide a > 75% chance of identifying a toxicity with a true event rate of 9%.” (opens the source at this quote in a new tab)
“All statistical analyses are exploratory in nature.” (opens the source at this quote in a new tab)

Participants enrolled and analyzed

Measure	Registry record
Enrollment (actual)	“22”
Overall number of baseline participants	“21”
Participants with multiple myeloma	“No participants with MM were enrolled.”

Full analysis set and DLT-evaluable population

“The FAS includes all participants who received at least 1 dose of INCB000928. The FAS will be used for the summary of demographics, baseline characteristics, participant disposition, and analyses of all safety and efficacy data.” (opens the source at this quote in a new tab)

“Full Analysis Set-MDS: all participants with myelodysplastic syndromes (MDS) or MDS/myeloproliferative neoplasm (MPN) overlap syndromes who received at least 1 dose of zilurgisertib” (opens the source at this quote in a new tab)
“DLT Evaluable Population: all participants in the FAS Population who met the following criteria: observed for at least the first treatment cycle (i.e., 28 days); received ≥75% of doses of study treatment at the level assigned to that cohort (i.e., 21 days of treatment) or had a DLT during the first study treatment cycle; did not receive any strong or potent CYP3A4/5 inhibitor or inducer during the first study drug treatment cycle (DLT assessment period); was not part of a backfill cohort” (opens the source at this quote in a new tab)

Participant flow by dose group, posted results

Group	Started	Completed	Death	Lost to follow-up	Study terminated by sponsor	Physician decision	Withdrawal by subject	Started new therapy
50 mg once daily	“4”	“0”	“1”	“1”	“1”	“0”	“1”	“0”
100 mg once daily	“5”	“0”	“1”	“0”	“3”	“1”	“0”	“0”
200 mg once daily	“4”	“0”	“0”	“0”	“2”	“0”	“2”	“0”
400 mg once daily	“5”	“0”	“1”	“0”	“2”	“0”	“1”	“1”
600 mg once daily	“3”	“0”	“0”	“0”	“3”	“0”	“0”	“0”

Demographics of all 21 treated participants, posted results

Characteristic	Total
Age, mean (years)	“74.4”
Age, standard deviation (years)	“5.55”
Female	“10”
Male	“11”
White	“15”
Asian	“2”
Black or African American	“1”
Race unknown or not reported	“3”

Anemia response and transfusion independence, posted results

Group	Anemia response: participants analyzed	Anemia response (%)	Anemia response 95% CI	Transfusion independence: participants analyzed	Transfusion independence (%)	Transfusion independence 95% CI
50 mg once daily	“2”	“0.0”	“(0.0 to 84.2)”	“2”	“0.0”	“(0.0 to 84.2)”
100 mg once daily	“4”	“0.0”	“(0.0 to 60.2)”	“1”	“100.0”	“(2.5 to 100.0)”
200 mg once daily	“2”	“0.0”	“(0.0 to 84.2)”	“2”	“0.0”	“(0.0 to 84.2)”
400 mg once daily	“4”	“0.0”	“(0.0 to 60.2)”	“1”	“0.0”	“(0.0 to 97.5)”
600 mg once daily	“2”	“0.0”	“(0.0 to 84.2)”	“1”	“0.0”	“(0.0 to 97.5)”

Largest increase in hemoglobin over any rolling 8-week period and transfusion rate, posted results

Group	Hemoglobin: participants analyzed	Largest mean hemoglobin increase (g/L)	Standard deviation	Transfusion rate, Weeks 12 to 24 (RBC units per participant-month)	Standard deviation
50 mg once daily	“3”	“2.19”	“2.782”	“2.53”	“1.955”
100 mg once daily	“4”	“9.73”	“2.842”	“1.34”	“0.948”
200 mg once daily	“3”	“2.51”	“3.681”	“3.01”	“2.955”
400 mg once daily	“5”	“4.92”	“10.240”	“2.71”	“2.232”
600 mg once daily	“3”	“6.59”	“4.229”	“1.19”	“2.067”

Disease response, progression, and leukemic transformation in MDS, posted results

Group	Overall response rate in MDS (%)	MDS participants with progression or death (%)	Participants with leukemia or death (%)
50 mg once daily	“0.0”	“25.0”	“25.0”
100 mg once daily	“0.0”	“0.0”	“20.0”
200 mg once daily	“0.0”	“0.0”	“0.0”
400 mg once daily	“0.0”	“20.0”	“20.0”
600 mg once daily	“0.0”	“0.0”	“0.0”

Percentage change in hepcidin and trough concentration, posted results

Group	Hepcidin: participants analyzed	Mean percent change in hepcidin, Cycle 1 Day 15 to Cycle 7 Day 1	Standard deviation	Mean Ctrough (nanomolar)	Standard deviation
50 mg once daily	“4”	“-24.53”	“41.69”	“214”	“91.8”
100 mg once daily	“4”	“-16.25”	“47.06”	“304”	“175”
200 mg once daily	“4”	“-11.25”	“39.97”	“619”	“241”
400 mg once daily	“5”	“-59.02”	“32.35”	“981”	“3130”
600 mg once daily	“3”	“-63.79”	“44.23”	“NA”	“NA”

Pharmacokinetic values not determined at 600 mg

“Two participants had values above the upper limit of quantification, meaning data for PK parameters could not be determined.” (opens the source at this quote in a new tab)

Primary safety outcomes by dose group, posted results

Group	Participants analyzed	Any TEAE	Any grade 3 or higher TEAE	DLT-evaluable participants	Participants with DLTs
50 mg once daily	“4”	“4”	“2”	“4”	“0”
100 mg once daily	“5”	“5”	“3”	“3”	“0”
200 mg once daily	“4”	“4”	“2”	“4”	“0”
400 mg once daily	“5”	“5”	“2”	“3”	“0”
600 mg once daily	“3”	“2”	“2”	“2”	“1”

Maximum tolerated dose and recommended dose for expansion not determined

“The maximum sample size for each dose level was 9. Given that there were 2 DLT-evaluable participants at the 600 mg QD dose level and 1 DLT was observed, the dose should have been de-escalated. As a result, the dose escalation was incomplete at the time of study termination, and the MTD could not be determined since the stopping rule had not been met.” (opens the source at this quote in a new tab)
“The RDE was not established because, at the time of early study termination, dose escalation was ongoing and the dose that had evidence of the best pharmacologic activity while being below the MTD had not yet been identified.” (opens the source at this quote in a new tab)

Serious adverse events and all-cause mortality by dose group, posted results

Group	Serious adverse events, affected/at risk (%)	All-cause mortality, affected/at risk (%)
50 mg once daily	“2/4 (50.00%)”	“1/4 (25.00%)”
100 mg once daily	“1/5 (20.00%)”	“1/5 (20.00%)”
200 mg once daily	“2/4 (50.00%)”	“0/4 (0.00%)”
400 mg once daily	“2/5 (40.00%)”	“1/5 (20.00%)”
600 mg once daily	“0/3 (0.00%)”	“0/3 (0.00%)”
Total	“7/21 (33.33%)”	“3/21 (14.29%)”

Serious adverse events in more than 1 participant

Serious adverse event	Affected/at risk (%)
Anaemia	“2/21 (9.52%)”
COVID-19	“2/21 (9.52%)”

Nonserious adverse events in 3 or more of 21 participants, and events listed in the FOP label

Adverse event	Affected/at risk (%)
Oedema peripheral	“6/21 (28.57%)”
Fatigue	“4/21 (19.05%)”
Nausea	“4/21 (19.05%)”
Urinary tract infection	“4/21 (19.05%)”
Abdominal pain	“3/21 (14.29%)”
Alopecia	“3/21 (14.29%)”
Amylase increased	“3/21 (14.29%)”
Constipation	“3/21 (14.29%)”
Diarrhoea	“3/21 (14.29%)”
Dizziness	“3/21 (14.29%)”
Dyspnoea	“3/21 (14.29%)”
Electrocardiogram QT prolonged	“3/21 (14.29%)”
Hyperphosphataemia	“3/21 (14.29%)”
Pruritus	“3/21 (14.29%)”
Epistaxis	“1/21 (4.76%)”
Arthralgia	“1/21 (4.76%)”
Serum ferritin increased	“1/21 (4.76%)”

Adverse event collection period and population

“Analysis was conducted in the Full Analysis Set-MDS, comprised of all participants with myelodysplastic syndromes (MDS) or MDS/myeloproliferative neoplasm (MPN) overlap syndromes who received at least 1 dose of zilurgisertib.” (opens the source at this quote in a new tab)

Summary: limitations for a formulary review of zilurgisertib in fibrodysplasia ossificans progressiva

LIMBER-105 was terminated for a strategic business decision after enrolling 22 participants, of whom 21 were treated and analyzed. No participants with multiple myeloma were enrolled, so all results come from participants with MDS or MDS/MPN overlap syndromes, with a mean age of 74.4 years. The study was open-label, single-arm, and without a control group, with 2 to 5 participants per dose level (50 mg to 600 mg once daily for up to 6 months). The expansion stage enrolled no participants, the maximum tolerated dose could not be determined because the stopping rule was not met, and the recommended dose for expansion was not established. The SAP defines all analyses as exploratory. No peer-reviewed publication or congress abstract of the results was identified, and no health-related quality of life or patient-reported outcome results were reported.

Registry statement on termination

“The sponsor terminated study enrollment as a strategic decision. Due to early study termination, no participants were enrolled in the expansion stage of the study.” (opens the source at this quote in a new tab)