Phase 2 Open Label Prospective Dose-Ranging Clinical Trial with Escalation and Expansion Cohorts to Evaluate Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, Dosing, and Efficacy of RLS-0071 for the Treatment of Hospitalized Patients with Steroid -Refractory Acute Graft-versus-Host Disease

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Realta Life Sciences Inc.

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Phenomena and Processes [G] - Immune system processes [G12]

Decision date (initial)

2024-07-08

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Pharmacodynamic, Dose response, Safety, Pharmacokinetic

• Demonstrate safety and tolerability of RLS-0071 in the treatment of acute graft versus host disease (aGvHD).
• Determine Overall Response Rate (ORR) of RLS-0071 at 28 days.

Secondary objectives 12

1. Determine Complete Response (CR) Rate, Very Good Partial Response (VGPR) Rate, and Partial Response (PR) Rate at 7, 14, 28, 56, and 18
2. Determine ORR at 7, 14, 56, and 180 days.
3. Determine ORR, and CR Rate, VGPR Rate, and PR Rate at 7, 14, 28, 56, and 180 days based on lower gastrointestinal (GI) response only (overall study population and for the subset with lower GI aGvHD).
4. Assess refractoriness to RLS-0071 +/- ruxolitinib.
5. Determine need for initiation of additional or alternative treatments for aGvHD.
6. Evaluate change in Stage and attainment of Stage 0 or 1 for lower GI aGvHD, liver aGvHD, skin aGvHD, and upper GI aGvHD, and overall aGvHD Grade from baseline to Days 7, 14, 28, 56, and 180.
7. Assess loss of response, reduction in response, or occurrence of flare in participants who had an initial response to RLS-0071 (with systemic corticosteroids and +/- ruxolitinib).
8. Evaluate dose response (dose and duration) for the primary and secondary efficacy endpoints.
9. Characterize overall survival, failure-free survival, and non-relapse mortality.
10. Characterize Pharmacokinetics (PK) (based on sparse sampling for all participants and intensive sampling for a subset of participants) of RLS-0071.
11. Evaluate aGvHD patient outcomes: FACT-BMT, abdominal pain, volume/frequency of diarrhea, food tolerance and use of total parenteral nutrition (TPN), and duration of hospital stay.
12. Evaluate change in Mount Sinai Acute GVHD International Consortium (MAGIC) biomarkers (ST2 and REG3a) at Days 7, 14, and 28.

Conditions and MedDRA coding

Acute graft versus host disease (aGvHD)

Regulatory references

Scientific advice from competent authorities

U.S. Food And Drug Administration

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 15

1. Male or female adults or adolescents (>12 years old).
2. 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)
3. 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.
4. 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
5. Hospitalized or being admitted to hospital with aGvHD.
6. Anticipated hospital length-of-stay of at least 1 week from the time of RLS-0071 initiation.
7. 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
8. 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).
9. 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.
10. 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).
11. 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.
12. Weight >40 kg and ≤ 140 kg at screening.
13. Participant (or legally authorized representative for minors) provides written informed consent; additionally, informed assent for minors.
14. Able to communicate well with the Investigator and/or study site personnel and to comply with the requirements of the entire study.
15. 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.

Exclusion criteria 20

1. Has received more than 1 allo-HSCT.
2. 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).
3. Previous failure of ruxolitinib treatment.
4. 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.
5. 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.
6. Chronic GvHD (including presence of GVHD overlap syndrome as per National Institutes of Health [NIH] guidelines).
7. RLS-0071Participants with evidence of relapsed primary disease, or participants who have been treated for relapse after the allo-HSCT was performed.
8. 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.
9. Any corticosteroid therapy for indications other than aGvHD at doses of methylprednisolone or equivalent >1 mg/kg per day within 7 days of enrollment.
10. 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.
11. Known hypersensitivity, allergy, or anaphylactic reaction to polyethylene glycol (PEG) or PEG containing material.
12. Significant liver disease that is unrelated to GvHD.
13. Moderate to severe kidney disease, with an estimated glomerular filtration rate (eGFR) < 60 mL/min (chronic kidney disease [CKD] Stages 3-5).
14. 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.
15. Currently breast feeding.
16. 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.
17. Unable or unwilling to cooperate with the site staff for any reason.
18. Known pregnancy, a positive pregnancy test at screening, or lactation for WOCBP.
19. Active hepatitis B virus (HBV) or hepatitis C virus infection that requires treatment or human immunodeficiency virus (HIV)-1 or HIV-2.
20. Active sepsis

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Safety and tolerability of RLS-0071 in the treatment of aGvHD.
2. ORR of RLS-0071 at 28 days (note that addition of any acute GvHD therapy, including an increase in steroid dose >2 mg/kg MPE, will be considered a treatment failure).

Secondary endpoints 18

1. CR at 7, 14, 28, 56, and 180 days.
2. VGPR Rate at 7, 14, 28, 56, and 180 days.
3. PR Rate at 7, 14, 28, 56, and 180 days.
4. ORR at 7, 14, 56, and 180 days.
5. ORR focused on lower GI response criteria only at 7, 14, 28, 56, and 180 days (for the overall study population and for the subset with lower GI aGvHD).
6. CR, VGPR, and PR Rates focused on lower GI response criteria only at 7, 14, 28, 56, and 180 days (for the overall study population and for the subset with lower GI aGvHD).
7. Incidence of refractoriness (to RLS-0071 +/- ruxolitinib) at Days 7, 14, 28, 56, and 180; refractoriness is defined as at least one of the following: aGvHD increasing in Stage in any organ or developing in a new organ after 3 days of RLS-0071; aGvHD that has not improved in Stage in >1 organ after 7 days of RLS-0071; initiation of additional aGvHD treatment (other than RLS-0071 +/- ruxolitinib); or for after Day 7, participants who progress during corticosteroid tapering before a 50% decrease in
8. Overall corticosteroid use on Days 7, 14, 28, 56, and 180.
9. Initiation of additional or alternative treatment(s) for aGvHD (including an increase in steroid dose to >2 mg/kg methylprednisolone equivalent) to treat refractory aGvHD.
10. Change or shift in Stage for lower GI aGvHD, liver aGvHD, skin aGvHD, or upper GI aGvHD from baseline to Days 7, 14, 28, 56, and 180.
11. Attainment of Stage 0 or 1 lower GI aGvHD, liver aGvHD, skin aGvHD, or upper GI aGvHD at Days 7, 14, 28, 56, and 180.
12. Change or shift in overall Grade of aGvHD (Table 10) from baseline to Days 7, 14, 28, 56, and 180.
13. Loss of response, reduction in response, or incidence of flare in participants who had an initial response to RLS-0071 (with systemic corticosteroids and +/- ruxolitinib).
14. Dose response (dose and duration) for the primary and secondary efficacy endpoints (across the dose regimens in the study).
15. Overall survival, failure-free survival, and non-relapse mortality.
16. Pharmacokinetics (based on sparse sampling for all participants and intensive sampling for a subset of participants) of RLS-0071.
17. aGvHD patient outcomes: FACT-BMT, abdominal pain, volume/frequency of diarrhea, food tolerance and use of TPN, and duration of hospital stay.
18. Change in MAGIC biomarkers (ST2 and REG3a) at Days 7, 14, and 28.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Realta Life Sciences Inc.

Sponsor organisation

Realta Life Sciences Inc.

Address

5665 Lowery Road

City

Norfolk

Postcode

23502-2245

Country

United States

Scientific contact point

Organisation

Realta Life Sciences Inc.

Contact name

Kasia Sujkowska

Public contact point

Organisation

Realta Life Sciences Inc.

Contact name

Katy Burdett

Third parties 4

Locations

2 EU/EEA countries · 8 investigational sites

By country

Investigational sites

Application history

1 submissions — initial application plus substantial / non-substantial modifications