Phase 2 Open‑Label Dose‑Ranging Study of RLS‑0071 in Hospitalized Patients with Steroid‑Refractory Acute Graft‑Versus‑Host Disease

Trial ID: 2024-510582-42-02
Protocol: RLS-0071-203
Sponsor: Realta Life Sciences Inc.

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Diseases & Conditions

Acute graft versus host disease

Objectives

The primary objective of this clinical trial is to demonstrate the **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 lead to significant morbidity and mortality.

Secondary objectives include evaluating various response rates and clinical outcomes at multiple time points. These are: - Complete Response (CR) at 7, 14, 28, 56, and 180 days. - Very Good Partial Response (VGPR) Rate at 7, 14, 28, 56, and 180 days. - Partial Response (PR) Rate at 7, 14, 28, 56, and 180 days. - Overall Response Rate (ORR) at 7, 14, 56, and 180 days. - ORR focused on lower gastrointestinal (GI) response criteria at 7, 14, 28, 56, and 180 days for the overall study population and the subset with lower GI aGvHD. - CR, VGPR, and PR Rates focused on lower GI response criteria at 7, 14, 28, 56, and 180 days for the overall study population and the subset with lower GI aGvHD. - Incidence of refractoriness to RLS-0071 +/- ruxolitinib at Days 7, 14, 28, 56, and 180. - Overall corticosteroid use on Days 7, 14, 28, 56, and 180. - Initiation of additional or alternative treatments for aGvHD. - Change or shift in Stage for lower GI, liver, skin, or upper GI aGvHD from baseline to Days 7, 14, 28, 56, and 180. - Attainment of Stage 0 or 1 for lower GI, liver, skin, or upper GI aGvHD at Days 7, 14, 28, 56, and 180. - Change or shift in overall Grade of aGvHD from baseline to Days 7, 14, 28, 56, and 180. - Loss of response, reduction in response, or incidence of flare in participants with an initial response to RLS-0071. - Dose response for the primary and secondary efficacy endpoints. - Overall survival, failure-free survival, and non-relapse mortality. - Pharmacokinetics of RLS-0071. - aGvHD patient outcomes including FACT-BMT, abdominal pain, diarrhea volume/frequency, food tolerance, use of TPN, and duration of hospital stay. - Change in MAGIC biomarkers (ST2 and REG3a) at Days 7, 14, and 28.

Participants

The clinical trial investigating the safety and tolerability of RLS-0071 in the treatment of **acute graft versus host disease (aGvHD)** involves a total of 44 participants. The study population comprises both male and female subjects, including adults and adolescents over the age of 12. Participants have undergone first allogeneic hematopoietic stem cell transplantation for hematologic malignancies and exhibit steroid-refractory aGvHD. The trial includes individuals with a weight range of over 40 kg and up to 140 kg. Participants are required to have a neutrophil count greater than 500/mL at screening, without growth factor supplementation. The selection criteria ensure that participants are able to communicate effectively with the study personnel and comply with study requirements. The trial population is characterized by a vulnerable group, as it includes individuals hospitalized or being admitted to the hospital with aGvHD. Lifestyle considerations such as diet and physical activity are not specified, but participants must agree to use highly effective contraception during and after the study drug treatment period. The trial does not plan to introduce additional GvHD treatment medications during the 7-day RLS-0071 treatment period.

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 Phase 2 trial is open-label and prospective, incorporating dose-ranging with escalation and expansion cohorts. The primary objectives include assessing the overall response rate (ORR) of RLS-0071 at 28 days. The trial is expected to conclude by January 31, 2026, with recruitment starting on December 15, 2024. Participants will be involved for a maximum treatment period of 14 days, with the possibility of early termination if additional acute GvHD therapy is required or if there is a significant increase in steroid dose.

The trial involves a sequence of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, weight, and neutrophil count. Participants must have undergone a first allogeneic hematopoietic stem cell transplantation and exhibit steroid-refractory aGvHD. Follow-up visits will occur 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. The end-of-study visit will assess overall survival, failure-free survival, and non-relapse mortality.

Participants are required to comply with study requirements, including the use of highly effective contraception for specified periods post-treatment. The trial will exclude individuals with plans to alter GvHD treatment medications during the study. The study drug, RLS-0071, will be administered as a solution for infusion, with a maximum daily dose of 120 mg/kg and a total dose not exceeding 840 mg/kg. The trial will also evaluate pharmacokinetics and patient outcomes, such as changes in MAGIC biomarkers and quality of life measures.

Treatment

The clinical trial involves the administration of an **experimental medication** known as RLS-0071, which is a peptide sequence with a monodisperse polyethylene glycol tail, also referred to as IALILEPICCQERAA. This investigational product is formulated for **infusion** and is administered as a solution for infusion. The active substance in RLS-0071 is a peptide consisting of natural L-amino acids, specifically ILE-ALA-LEU-ILE-LEU-GLU-PRO-ILE-CYS-CYS-GLN-GLU-ARG-ALA-ALA-(DISCRETE-POLYETHYLENE GLYCOL)24. The maximum daily dose of RLS-0071 is 120 mg/kg, with a total maximum dose of 840 mg/kg over a treatment period not exceeding 14 days. The administration of this medication is intended for hospitalized patients with steroid-refractory acute graft-versus-host disease (aGvHD).

In addition to the experimental treatment, the study may involve the use of **non-experimental treatments** such as standard-of-care therapy, placebo, or comparator treatments, although specific details regarding these are not provided in the available data. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the treatment protocol. The trial aims to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, dosing, and efficacy of RLS-0071 in the specified patient population.

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, the ORR will be evaluated at 7, 14, 56, and 180 days, with a specific focus on lower GI response criteria 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 organ-specific aGvHD manifestations, 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, TPN use, and hospital stay duration. Changes in MAGIC biomarkers (ST2 and REG3a) will be evaluated at Days 7, 14, and 28. These efficacy parameters will be collected and analyzed at the specified timepoints to determine the therapeutic impact of RLS-0071 on aGvHD.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Male or female adults or adolescents (>12 years old).
Have undergone first allogeneic hematopoietic stem cell transplantation (allo-HSCT) from any donor source using bone marrow, peripheral blood stem cells, or cord blood for hematologic malignancies. Recipients of nonmyeloablative and myeloablative conditioning regimens are eligible. Any conditioning regimen and any anti-GVHD prophylactic program are 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: a) Grade II: Stage 3 rash and/or Stage 1 liver and/or Stage 1 upper GI and/or Stage 1 lower GI, or b) Grade III: Stage 2 liver and/or Stage 2–3 lower GI, with Stage 0–3 skin and/or Stage 0- 1 upper GI, or c) Grade IV: Stage 4 skin, liver, or lower GI involvement, with Stage 0–1 upper GI
Hospitalized or being admitted to hospital with aGvHD and a Karnofsky Performance Status (KPS) of at least 50. Inclusion of a participant with a KPS lower than 50 requires discussion with the Medical Monitor.
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 ruxolitinib.
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).
At the time of study screening prior to RLS-0071 initiation: a)Neutrophil count >1000/mL (not supported by growth factor supplementation, e.g., filgrastim); b) Platelet count >50,000/ml (not supported by platelet transfusions); c) Aspartame aminotransferase (AST) and alanine aminotransferase (ALT) < 5 times the upper limit of normal (ULN); d) Serum bilirubin < 6mg/dL; and e) Adequate coagulation function (e.g., prothrombin time (PT)/international normalized ratio (INR) and activated partial thromboplastin time (aPPT)/partial thromboplastin time (PTT) <2 X ULN.
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 participants of childbearing potential (WOCBP) (not surgically sterile) must agree to use highly effective contraception during the study drug treatment period and for 6 additional months following treatment. Follow manufacture recommendation for other medications.
Male participant with partners of childbearing potential must agree to use highly effective contraception during the study drug treatment period and for 3 additional months following treatment. Follow manufacture recommendation for other medications.

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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).
RLS0071 Participants 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: a) Cholestatic disorders or unresolved veno-occlusive disease of the liver (defined as persistent bilirubin abnormalities not attributable to GvHD and ongoing organ dysfunction) b) 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. c) Clinically significant respiratory disease that requires mechanical ventilation support or oxygen supplementation.
Known hypersensitivity, allergy, or anaphylactic reaction to polyethylene glycol (PEG) or PEG containing material.
Significant liver disease that is unrelated to GvHD
Severe kidney disease, with an estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73m2 (chronic kidney disease [CKD] Stages 4-5).
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: a) Participation of the study would be unsafe, b) 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.