Evaluation of RLS-0071 in Hospitalized Patients with Steroid-Refractory Acute Graft-versus-Host Disease: A Phase 2 Dose-Ranging Study

Trial ID: 2024-510582-42-00
Protocol: RLS-0071-203
Sponsor: Realta Life Sciences Inc.

Trial statistics

science

test molecule

location_city

research sites

public

countries

medical_information

disease

person_search

investigators

handshake

vendors

Diseases & Conditions

Acute graft versus host disease

Objectives

The primary objective of this clinical trial is to **demonstrate safety and tolerability** of RLS-0071 in the treatment of **acute graft versus host disease (aGvHD)**. Additionally, the trial aims to determine the **Overall Response Rate (ORR)** of RLS-0071 at 28 days. These objectives are clinically relevant as they address the need for effective and safe treatment options for patients with steroid-refractory aGvHD, a condition that can significantly impact patient outcomes and quality of life.

Secondary objectives include: - Determining Complete Response (CR) Rate, Very Good Partial Response (VGPR) Rate, and Partial Response (PR) Rate at various time points (7, 14, 28, 56, and 180 days). - Assessing refractoriness to RLS-0071 with or without ruxolitinib. - Evaluating the need for additional or alternative treatments for aGvHD. - Evaluating changes in Stage and attainment of Stage 0 or 1 for different manifestations of aGvHD. - Assessing loss of response or occurrence of flare in participants with an initial response. - Evaluating dose response for efficacy endpoints. - Characterizing overall survival, failure-free survival, and non-relapse mortality. - Characterizing pharmacokinetics of RLS-0071. - Evaluating aGvHD patient outcomes, including FACT-BMT, abdominal pain, diarrhea, food tolerance, TPN use, and hospital stay duration. - Evaluating changes in MAGIC biomarkers (ST2 and REG3a) at specified days.

Participants

The clinical trial involves a total of **44 participants** diagnosed with **acute graft versus host disease (aGvHD)**. The study population includes both male and female subjects, comprising adults and adolescents over the age of 12. Participants were selected based on specific criteria, including neutrophil recovery following stem-cell transplantation and a weight range between 40 kg and 140 kg. The trial population is characterized by individuals who have been hospitalized or are being admitted to the hospital with aGvHD, and who are either initiating or have recently initiated secondary treatment with ruxolitinib. The study includes a vulnerable population, and participants are required to provide informed consent, with additional assent for minors. Lifestyle considerations such as diet and physical activity are not specified, but participants must comply with the study requirements and use highly effective contraception if applicable. The trial aims to assess the safety and tolerability of RLS-0071, as well as determine the overall response rate at 28 days.

Plans and Procedures

The clinical trial is designed to evaluate the **safety** and **tolerability** of RLS-0071 in the treatment of **acute graft versus host disease (aGvHD)**. This is a Phase 2, open-label, prospective, dose-ranging study with escalation and expansion cohorts. The trial aims to determine the overall response rate (ORR) of RLS-0071 at 28 days. The study is not categorized as low intervention and involves hospitalized patients with steroid-refractory aGvHD. The trial is expected to commence recruitment on July 31, 2024, and conclude by January 31, 2026.

Participants will be randomly assigned to receive RLS-0071, administered as an **infusion**. The trial will follow a structured sequence of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, neutrophil recovery, and weight. Participants must provide written informed consent and demonstrate the ability to comply with study requirements. The study includes follow-up visits at 7, 14, 28, 56, and 180 days to monitor primary and secondary endpoints, including complete response (CR), very good partial response (VGPR), and partial response (PR) rates, as well as pharmacokinetics and patient outcomes.

The expected length of participant involvement is up to 180 days, with the possibility of early termination if participants experience treatment failure, defined as the addition of any acute GvHD therapy or an increase in steroid dose. Participants may also be withdrawn if they are unable to comply with study procedures or if the investigator deems it necessary for safety reasons. The trial's primary endpoints focus on the safety and tolerability of RLS-0071, while secondary endpoints include various response rates and overall survival metrics. The study will also assess changes in MAGIC biomarkers and other patient outcomes related to aGvHD.

Treatment

The clinical trial involves the administration of the experimental medication **RLS-0071**, which is an **IALILEPICCQERAA peptide sequence with a monodisperse polyethylene glycol tail**. This investigational product is provided in the form of a **concentrate for solution for infusion**. The active substance, **ILE-ALA-LEU-ILE-LEU-GLU-PRO-ILE-CYS-CYS-GLN-GLU-ARG-ALA-ALA-(DISCRETE-POLYETHYLENE GLYCOL)24**, is a peptide consisting of natural L-amino acids. The medication is administered intravenously, with a maximum daily dose of 120 mg/kg and a total maximum dose of 840 mg/kg over a treatment period not exceeding 14 days. The product is not formulated for pediatric use and has been designated as an orphan drug under the identifier EU/3/20/2283.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The focus is on evaluating the safety, tolerability, pharmacokinetics, pharmacodynamics, dosing, and efficacy of RLS-0071 in the treatment of hospitalized patients with steroid-refractory acute graft-versus-host disease. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the protocol. The investigational product is manufactured by Realta Life Sciences, Inc., and is identified by the sponsor product code RLS-0071.

Efficacy

The efficacy of RLS-0071 in the treatment of **acute graft-versus-host disease (aGvHD)** will be assessed through a series of primary and secondary endpoints. The primary efficacy endpoint is the Overall Response Rate (ORR) at 28 days, with treatment failure defined as the addition of any acute GvHD therapy, including an increase in steroid dose greater than 2 mg/kg methylprednisolone equivalent. Secondary endpoints include Complete Response (CR), Very Good Partial Response (VGPR), and Partial Response (PR) rates at multiple timepoints: 7, 14, 28, 56, and 180 days. Additionally, ORR focused on lower GI response criteria will be evaluated at these same intervals for both the overall study population and the subset with lower GI aGvHD.

Further secondary endpoints involve the incidence of refractoriness to RLS-0071 with or without ruxolitinib, overall corticosteroid use, initiation of additional or alternative treatments for aGvHD, and changes in the stage or grade of aGvHD from baseline to specified days. The study will also assess the attainment of Stage 0 or 1 for various forms of aGvHD, loss of response, dose response, overall survival, failure-free survival, non-relapse mortality, and pharmacokinetics of RLS-0071. Patient outcomes will be measured using FACT-BMT, abdominal pain assessments, diarrhea volume/frequency, food tolerance, use of TPN, and duration of hospital stay. Changes in MAGIC biomarkers (ST2 and REG3a) will be monitored at Days 7, 14, and 28.

Inclusion and Exclusion Criteria

check_circle

Inclusion Criteria

Male or female adults or adolescents (>12 years old).
Neutrophil recovery following the stem-cell transplantation, defined as blood neutrophil count >500/mL for at least 3 consecutive measurements (use of growth factor supplementation, e.g., filgrastim, at that time is permitted)
Steroid-refractory aGvHD defined by one or more of the following criteria: progressed after 3 days of treatment with methylprednisolone equivalents (MPE) >2 mg/kg/day; did not improve after 7 days of treatment with MPE >2 mg/kg/day; progressed to a new organ after treatment with MPE >1 mg/kg/day for isolated skin and/or upper GI GvHD; or recurred during or after a steroid taper.
Grade II-IV aGvHD as per MAGIC guidelines, defined as: o Grade II: Stage 3 rash and/or Stage 1 liver and/or Stage 1 upper GI and/or Stage 1 lower GI, or Clinical Study Protocol ReAlta Life Sciences, Inc. RLS-0071-203 09 February 2024 Page 12 of 92 o Grade III: Stage 2–3 liver and/or Stage 2–3 lower GI, with Stage 0–3 skin and/or Stage 0-1 upper GI, or o Grade IV: Stage 4 skin, liver, or lower GI involvement, with Stage 0–1 upper GI
Hospitalized or being admitted to hospital with aGvHD.
Anticipated hospital length-of-stay of at least 1 week from the time of RLS-0071 initiation.
Initiating or recently initiated ruxolitinib for secondary treatment of aGvHD; if ruxolitinib is contraindicated or the investigator considers it inadvisable for a specific participant then that participant can be enrolled in Cohort 1b or Cohort 2b and not treated with ruxolitini
Feasibility to initiate RLS-0071 dosing simultaneously to ruxolitinib or within 48 hours before or after initiation of ruxolitinib (note that from a timing perspective the goal is simultaneous initiation of RLS-0071 and ruxolitinib whenever possible).
No plans to add additional GvHD treatment medications or to add, dose-adjust, or discontinue GvHD prophylactic medications during the 7-days of RLS-0071 treatment. Note that participants who require treatments for conditions other than aGvHD should receive those treatments, including standard-of-care antifungal prophylaxis, antibiotics for fever, antivirals for CMV, pain medications, dysmotility agents, and TPN, etc.
Neutrophil recovery following the stem-cell transplantation, defined as blood neutrophil count >500/mL for at least 3 consecutive measurements (use of growth factor supplementation, e.g., filgrastim, at that time is permitted).
Neutrophil count at study screening >500/mL and not supported by growth factor supplementation, e.g., filgrastim at the time of study screening and RLS-0071 initiation.
Weight >40 kg and ≤ 140 kg at screening.
Participant (or legally authorized representative for minors) provides written informed consent; additionally, informed assent for minors.
Able to communicate well with the Investigator and/or study site personnel and to comply with the requirements of the entire study.
Woman of childbearing potential (WOCBP) (not surgically sterile) or male participant with partners of childbearing potential must agree to use highly effective contraception until the completion of participation in the study. Follow manufacture recommendation for other medications.

cancel

Exclusion Criteria

Has received more than 1 allo-HSCT.
Current, previous, or planned (in the initial 7 days) use of any systemic treatment in addition to or other than corticosteroids or ruxolitinib (unless initiated within 48 hours of enrollment per Section 6.1) for aGvHD (previously initiated aGvHD prophylaxis is permitted to continue).
Previous failure of ruxolitinib treatment.
Uncontrolled GI infection (e.g., CMV, Cdiff); note that participants with controlled GI infections can be enrolled as long as appropriate anti-infective treatment is initiated and administered.
Endoscopic and biopsy testing (if performed) that definitively rules out lower GI aGvHD in those who are clinically suspected of having lower GI aGvHD; those participants should not be enrolled or should be discontinued from the study (and will be replaced) unless they otherwise meet the study entry criteria for skin, liver, and/or upper GI aGvHD.
Chronic GvHD (including presence of GVHD overlap syndrome as per National Institutes of Health [NIH] guidelines).
RLS-0071Participants with evidence of relapsed primary disease, or participants who have been treated for relapse after the allo-HSCT was performed.
Unresolved toxicity or complications (other than aGvHD) due to the allo-HSCT, which in the opinion of the Investigator would pose a safety risk for participation in this trial.
Any corticosteroid therapy for indications other than aGvHD at doses of methylprednisolone or equivalent >1 mg/kg per day within 7 days of enrollment.
Severe organ dysfunction unrelated to underlying aGvHD, including: Cholestatic disorders or unresolved veno-occlusive disease of the liver (defined as persistent bilirubin abnormalities not attributable to GvHD and ongoing organ dysfunction); Clinically significant or uncontrolled cardiac disease including unstable angina, acute myocardial infarction within 6 months from Day 1 of study drug administration, New York Heart Association Class III or IV congestive heart failure, circulatory collapse requiring vasopressor or inotropic support, or arrhythmia that requires therapy; Clinically significant respiratory disease that requires mechanical ventilation support or 50% oxygen.
Known hypersensitivity, allergy, or anaphylactic reaction to polyethylene glycol (PEG) or PEG containing material.
Significant liver disease that is unrelated to GvHD.
Moderate to severe kidney disease, with an estimated glomerular filtration rate (eGFR) < 60 mL/min (chronic kidney disease [CKD] Stages 3-5).
Participation in any clinical research study evaluating an investigational product (IP) or therapy for GvHD prophylaxis or treatment within 1 month and less than 5 half-lives of IP prior to the Screening visit.
Currently breast feeding.
Any medical or psychiatric condition deemed clinically significant by the Investigator or Sponsor such that: Participation of the study would be unsafe; OR the condition would make study results uninterpretable.
Unable or unwilling to cooperate with the site staff for any reason.
Known pregnancy, a positive pregnancy test at screening, or lactation for WOCBP.
Active hepatitis B virus (HBV) or hepatitis C virus infection that requires treatment or human immunodeficiency virus (HIV)-1 or HIV-2.
Active sepsis