Proof-of-concept Trial of Apraglutide in Acute Graft Versus Host Disease (aGVHD)

Phase 2

Terminated

Conditions: GVHD

Interventions: Drug: Apraglutide

Registration Number: NCT05415410

Lead Sponsor: VectivBio AG

Brief Summary: The aim of this trial is to assess safety and efficacy of apraglutide in subjects with steroid refractory gastrointestinal aGVHD.

Detailed Description: This is an international, multicenter, randomized proof-of-concept trial to evaluate safety, tolerability, efficacy, durability of response, and clinical outcomes of apraglutide administration to subjects with steroid-refractory (SR) aGVHD of the lower GI tract being treated with systemic steroids (SS) and ruxolitinib (RUX).

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 31

Inclusion Criteria

Able to give informed consent and agree to follow the details of participation as outlined in the protocol
Male or female subjects aged 12 years or above at the time of consent and who weigh a minimum of 40 kg. Only subjects aged 18 years and above will be included in Germany.
Clinically confirmed steroid refractory lower GI-aGVHD (MAGIC stage 1-4) prior to randomization
Have undergone alloSCT from any donor source, any conditioning regimen
Treated with SS plus RUX (RUX starts concomitantly to apraglutide or a maximum of 72 hours before apraglutide initiation)
Women of childbearing potential (WOCBP): highly effective method of contraception and refrain from donating eggs during the trial and for 4 weeks after the End of Trial (EOT) visit
Male subjects with partner WOCBP: contraception and abstention from sperm donation during the trial and for 2 weeks after the EOT visit

Exclusion Criteria

Treatment with any systemic GVHD therapy other than SS and RUX including methotrexate and mycophenolate mofetil at the time of randomization / Day 0
Concomitant treatment with Janus kinase inhibitor other than RUX at the time of randomization
Failed alloSCT due to relapse of underlying malignant disease
Presence of SR GI-aGVHD occurring after donor lymphocyte infusion for pre-emptive treatment of malignancy recurrence
Any use of enteral glutamine or GLP analogs or known ADA, within 6 months prior to randomization / Day 0
Significant organ system failures (respiratory renal hepatic and cardiac)
Presence of relapsed primary malignancy or treatment for relapse after alloHSCT
Presence or history of GI tumors (including the hepatobiliary system and pancreas) within the last five years before randomization
Presence of colonic polyps not removed
Active clinically uncontrolled infection or active tuberculosis
Known chronic GVHD
Known active GI inflammation not related to GI-aGVHD
Major abdominal surgery in the last 6-months prior to randomization or history of clinically significant intestinal adhesions
Abnormal liver function tests

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Apraglutide Low Dose	Apraglutide	Low-dose, weight-based apraglutide subcutaneous (SC) injections (1.4 to 3.5 mg) once weekly for up to 13 weeks (with optional treatment up to an additional 13 weeks), for participants with body weight of more than 50.0 kg.
Apraglutide High Dose	Apraglutide	High-dose, weight-based apraglutide SC injections (3.5 to 7.6 mg) once weekly for up to 13 weeks (with optional treatment up to an additional 13 weeks), for participants with body weight of more than 50.0 kg.
Apraglutide Standard Dose	Apraglutide	Standard-dose apraglutide SC injections (1.4 mg) once weekly for up to 13 weeks (with optional treatment up to an additional 13 weeks), for participants with body weight between 40.0 kg to 49.9 kg.

Primary Outcome Measures

Name	Time	Method
Number of Participants With Adverse Events (AEs)	Screening (up to 12 weeks) through End of Trial (up to 2 years/104 weeks) for a total of up to 116 weeks	AE=any untoward medical occurrence which does not necessarily have a causal relationship with study drug. Serious AE (SAE)=any AE that: results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect in a neonate/infant born to a mother or father exposed to study drug; is a clinically significant event in the Investigator's judgment. Treatment-emergent AE (TEAE)=AE with a start on or after the first administration of apraglutide (or present prior to the first dose of apraglutide but worsening in severity after starting treatment relative to the pre-treatment state) up to 28 days after the last dose of apraglutide. Pre-treatment AE=occurs after informed consent and before first dose; post-treatment AE=occurs after 28 days from last dose. AE are graded as follows: mild (1), moderate (2), severe (3), life-threatening (4), death (5).
Number of Participants With Treatment-Emergent Adverse Events of Special Interest (AESIs)	From first dose of study drug through End of Trial (up to 2 years/104 weeks) for a total of up to 116 weeks	An AESI (serious or non-serious) is an AE of scientific and medical concern specific to the Sponsor's product or program, for which ongoing monitoring, additional information, and rapid communication by the Investigator to the Sponsor is appropriate. AESIs include: * Injection site reactions * Gastrointestinal obstructions * Gallbladder, biliary, and pancreatic disease * Fluid overload * Colorectal polyps * Newly diagnosed malignancies * Systemic hypersensitivity
Number of Participants With Clinically Significant Changes From Baseline Over Time in Vital Signs	Baseline, Weeks 1, 2, 3, 4, 6, 8, 13, 17, 21, 26, 52, End of Treatment (up to Week 25), Week 104/End of Trial	Systolic Blood Pressure: * High is defined as \>= 160 mmHg AND \>=20 mmHg increase from baseline * Low is defined as \<= 90 mmHg AND \>=20 mmHg decrease from baseline Diastolic Blood Pressure: * High is defined as \>= 100 mmHg AND \>=15 mmHg increase from baseline * Low is defined as \<= 50 mmHg AND \>=15 mmHg decrease from baseline Heart Rate: * High is defined as \>= 120 bpm AND \>= 15 bpm increase from baseline * Low is defined as \<= 50 bpm AND \>= 15 bpm decrease from baseline Baseline is defined as the last measurement prior to the first dose of apraglutide. Minimum post-baseline is defined as the minimum measurement after the first dose of apraglutide. Maximum post-baseline is defined as the maximum measurement after the first dose of apraglutide.
Number of Participants With Potentially Clinically Significant Values Over Time in Liver Function Tests: Potential Hy's Law Cases	Baseline, Weeks 1, 2, 3, 4, 6, 8, 13, 17, 21, 26, 52, End of Treatment (up to Week 25), Week 104/End of Trial	Potential Hy's Law cases were defined as ALT or AST \>= 3 x ULN AND total bilirubin \>= 2 x ULN AND alkaline phosphatase (ALP) \<= 2 x ULN at the same visit. Baseline is defined as the last measurement prior to the first dose of apraglutide.
Number of Participants With Clinically Significant Changes From Baseline Over Time in QT Corrected for Heart Rate Using Fridericia's Formula (QTcF)	Baseline, Weeks 26, 52, 104/End of Trial	Baseline is defined as the last measurement prior to the first dose of apraglutide. Minimum post-baseline is defined as the minimum measurement after the first dose of apraglutide. Maximum post-baseline is defined as the maximum measurement after the first dose of apraglutide.
Number of Participants With Potentially Clinically Significant Values Over Time in Liver Function Tests: Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST)	Baseline, Weeks 1, 2, 3, 4, 6, 8, 13, 17, 21, 26, 52, End of Treatment (up to Week 25), Week 104/End of Trial	Baseline is defined as the last measurement prior to the first dose of apraglutide. Minimum post-baseline is defined as the minimum measurement after the first dose of apraglutide. Maximum post-baseline is defined as the maximum measurement after the first dose of apraglutide.
Number of Participants With Potentially Clinically Significant Values Over Time in Liver Function Tests: Total Bilirubin	Baseline, Weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 52, End of Treatment (up to Week 25), Week 104/End of Trial	Baseline is defined as the last measurement prior to the first dose of apraglutide. Minimum post-baseline is defined as the minimum measurement after the first dose of apraglutide. Maximum post-baseline is defined as the maximum measurement after the first dose of apraglutide.
Number of Participants With Anti-drug Antibodies (ADAs) Over Time	Baseline, Weeks 1, 2, 3, 4, 6, 8, 13, 17, 21, 26, 52, End of Treatment (up to Week 25), Week 104/End of Trial
Shift Table From Baseline to Worst Post-Treatment (WPT) Physical Examinations	Baseline (BL), up to Week 104/End of Treatment

Secondary Outcome Measures

Name	Time	Method
Overall Response Rate at Day 56 on the Lower Gastrointestinal (GI) Tract Mount Sinai aGVHD International Consortium (MAGIC) Stage	Day 56	Overall response rate at Day 56 on the lower GI tract MAGIC stage is defined as the percentage of participants with complete response (CR) or partial response (PR) on the lower GI tract MAGIC stage at Day 56. Lower GI (Stool Output/Day) MAGIC Stages are 0: \<500 mL/day or \<3/episodes/day; 1: 500-999 mL/day or 3-4/episodes/day; 2: 1000-1500 mL/day or 5-7/episodes/day; 3: \>1500 mL/day or \>7/episodes/day; 4: Severe abdominal pain with or without ileus or grossly bloody stool (regardless of volume). CR: Score of 0 in lower GI tract MAGIC stage that indicates complete resolution of all signs and symptoms of aGVHD in all evaluable organs without administration of additional systemic therapies for any earlier progression, mixed response or non-response of aGVHD. PR: Improvement of one stage in lower GI tract MAGIC stage without progression in other organs or sites without administration of additional systemic therapies for an earlier progression, mixed response, or non-response of aGVHD.
Overall Response Rate Over Time on the Lower GI Tract MAGIC Stage	Days 14, 28, 56, 91, 119, 147, and 182	Overall response rate on the lower GI tract MAGIC stage is defined as the percentage of participants with CR or PR on the lower GI tract MAGIC stage at given time points. Lower GI (Stool Output/Day) MAGIC Stages are 0: \<500 mL/day or \<3/episodes/day; 1: 500-999 mL/day or 3-4/episodes/day; 2: 1000-1500 mL/day or 5-7/episodes/day; 3: \>1500 mL/day or \>7/episodes/day; 4: Severe abdominal pain with or without ileus or grossly bloody stool (regardless of volume). CR: Score of 0 in lower GI tract MAGIC stage that indicates complete resolution of all signs and symptoms of aGVHD in all evaluable organs without administration of additional systemic therapies for any earlier progression, mixed response or non-response of aGVHD. PR: Improvement of one stage in lower GI tract MAGIC stage without progression in other organs or sites without administration of additional systemic therapies for an earlier progression, mixed response, or non-response of aGVHD.
Overall Response Rate Over Time on the Total MAGIC Stage	Days 14, 28, 56, 91, 119, 147, and 182	Overall response rate on Total MAGIC staging for each of the 4 evaluable organs of skin, lower and upper GI tract, and liver is defined as the percentage of participants with CR or PR on the total MAGIC stage. Staging values range from 0 to 4, with higher number indicating a worse state of disease. (For complete staging criteria, see: Harris AC, et al. Biol Blood Marrow Transplant. 2016;22(1):4-10.) CR: A score of 0 for the aGVHD grading in all evaluable organs that indicates complete resolution of all signs and symptoms of aGVHD in all 4 evaluable organs without administration of additional systemic therapies for any earlier progression, mixed response or non-response of aGVHD. PR: An improvement of one stage in one or more evaluable organs involved with aGVHD signs or symptoms without progression in other organs or sites without administration of additional systemic therapies for an earlier progression, mixed response, or non-response of aGVHD.
Durable Overall Response Rates on the Lower GI and Total MAGIC Score From Day 28 to Day 56	Day 28 to Day 56	Durable overall response rate on the Lower GI MAGIC Score from Day 28 to Day 56 is defined as the percentage of participants who had a response (either CR responder or PR responder, see Outcome Measure 10 description for details) on the lower GI at Day 28 and remain a CR responder or PR responder on the lower GI at Day 56. Durable overall response rate from Day 28 to Day 56 on the Total MAGIC Score is defined as the percentage of participants who had a response (either CR responder or PR responder, see Outcome Measure 12 description for details) on the total MAGIC score at Day 28 and remain a CR responder or PR responder on the total MAGIC score at Day 56. Total MAGIC staging for each of the 4 evaluable organs of skin, lower and upper GI tract, and liver ranges from 0 to 4, with higher number indicating a worse state of disease. (For complete staging criteria, see: Harris AC, et al. Biol Blood Marrow Transplant. 2016;22(1):4-10.)
Duration of Response From Day 56 on the Total MAGIC Score	From Day 56 up to 2 years of follow up after the first dose	Duration of response from Day 56 on the total MAGIC score: defined as the interval from the Day 56 response (PR and CR; see definitions descriptions in Outcome Measure 12) to death or new systemic therapy for aGVHD (including an increase in steroids \>2 mg/kg/day methylprednisolone \[MP\] equivalent), whichever occurs first, with at least 182 days of follow-up. Total MAGIC staging for each of the 4 evaluable organs of skin, lower and upper GI tract, and liver range from 0 to 4, with higher number indicating a worse state of disease. (For complete staging criteria, see: Harris AC, et al. Biol Blood Marrow Transplant. 2016;22(1):4-10.) Full range dates are censored. Censored = participants alive and without missing overall response assessment, initiation of additional systemic therapy for aGVHD or increase of \>2 mg/kg/day MP equivalent in steroids. Subjects are right censored at their last follow-up visit.
Duration of Response From Day 28 on the Total MAGIC Score	From Day 28 up to 2 years of follow up after the first dose	Duration of response from Day 28 on the total MAGIC score: defined as the interval from the Day 28 response (PR and CR; see definitions descriptions in Outcome Measure 12) to death or new systemic therapy for aGVHD (including an increase in steroids \>2 mg/kg/day methylprednisolone \[MP\] equivalent), whichever occurs first, with at least 182 days of follow-up. Total MAGIC staging for each of the 4 evaluable organs of skin, lower and upper GI tract, and liver range from 0 to 4, with higher number indicating a worse state of disease. (For complete staging criteria, see: Harris AC, et al. Biol Blood Marrow Transplant. 2016;22(1):4-10.) Full range dates are censored. Censored = participants alive and without missing overall response assessment, initiation of additional systemic therapy for aGVHD or increase of \>2 mg/kg/day MP equivalent in steroids. Subjects are right censored at their last follow-up visit.
Duration of Lower GI Response Per MAGIC Score	Up to Day 147	Individual duration of lower GI response (either CR responder or PR responder, see Outcome Measure 10 description for details) counted from the first response to return to baseline or worse. Duration of lower GI response is defined as the duration from the first date a participant is identified as a Lower GI MAGIC Score CR or PR responder until the next date a subject is Lower GI MAGIC Score stable disease/progressed disease (SD/PD; i.e., return to baseline or worsening), experiences treatment failure, or dies, whichever occurs first.
Duration of Lower GI Response Per MAGIC Score In Retreated Participants	Up to Day 147	Individual duration of lower GI response (either CR responder or PR responder, see Outcome Measure 10 description for details) counted from the first response to return to baseline or worse in participants that were re-treated with apraglutide because of a lower GI-aGVHD flare, counted from the first response after apraglutide restart to return to baseline or worse. Duration of lower GI response is defined as the duration from the first date a participant is identified as a Lower GI MAGIC Score CR or PR responder until the next date a subject is Lower GI MAGIC Score stable disease/progressed disease (SD/PD; i.e., return to baseline or worsening), experiences treatment failure, or dies, whichever occurs first.
Time to Partial or Complete Lower GI Response (PR or CR) Per MAGIC Score	From first injection of apraglutide up to Day 57	Lower GI (Stool Output/Day) MAGIC Stages are 0: \<500 mL/day or \<3/episodes/day; 1: 500-999 mL/day or 3-4/episodes/day; 2: 1000-1500 mL/day or 5-7/episodes/day; 3: \>1500 mL/day or \>7/episodes/day; 4: Severe abdominal pain with or without ileus or grossly bloody stool (regardless of volume). CR: Score of 0 in lower GI tract MAGIC stage that indicates complete resolution of all signs and symptoms of aGVHD in all evaluable organs without administration of additional systemic therapies for any earlier progression, mixed response or non-response of aGVHD. PR: Improvement of one stage in lower GI tract MAGIC stage without progression in other organs or sites without administration of additional systemic therapies for an earlier progression, mixed response, or non-response of aGVHD.
Best Overall Lower GI Response and Total Response at Any Time Point Up to and Including Day 91	From first injection of apraglutide up to Day 91	Overall response rate on the Lower GI MAGIC Score is defined as the percentage of participants who had a response (either CR responder or PR responder, see Outcome Measure 10 description for details) on the lower GI score. Overall response rate on the Total MAGIC Score is defined as the percentage of participants who had a response (either CR responder or PR responder, see Outcome Measure 12 description for details) on the total MAGIC score. Best overall lower GI response and total response is defined as overall response (PR or CR) at any time point up to and including Day 91 and before the start of additional systemic therapy for lower GI aGVHD. MAGIC staging for each of the 4 evaluable organs of skin, lower and upper GI tract, and liver ranges from 0 to 4, with higher number indicating a worse state of disease. (For complete staging criteria, see: Harris AC, et al. Biol Blood Marrow Transplant. 2016;22(1):4-10.)
Failure-Free Survival Post-First Dose of Apraglutide	Baseline up to 2 years	Failure free survival is defined as time from first dose until death, hematologic malignancy relapse/progression, or treatment failure, whichever comes first. Treatment failure is reported when additional systemic therapies are used for any earlier progression, mixed response or stable aGVHD.
Time to Non-Relapse Mortality up to 2 Years Post Treatment Start	From first dose of apraglutide up to 2 years	Non-relapse mortality is defined as time from first dose until death without preceding hematologic relapse.
Overall Survival	Baseline up to 2 years post-first dose of apraglutide	Overall survival is calculated as the time from first dose of apgraglutide to death.
Percentage of Participants With Hematologic Malignancy Relapse/Progression	Baseline to 2 years
Percentage of Participants With Graft Failure Up to 2 Years Post-first Dose of Apraglutide	From first dose of apraglutide up to 2 years post-first dose	Primary graft failure: Absolute neutrophil count \< 0.5 × 10\^9/L by Day 28 Hemoglobin \<80 g/L and platelets \< 20 × 10\^9/L Reduced intensity conditioning: Confirmation of donor cell origin is required Cord blood transplant: Up to Day +42 Secondary graft failure: Absolute neutrophil count \< 0.5 × 10\^9/L after initial engraftment not related to relapse, infection, or drug toxicity Reduced intensity conditioning: Loss of donor hematopoiesis to \< 5%
Percentage of Participants Who Experienced Lower-GI Flare by Day 182 After Earlier Cessation of Treatment Due to CR	From first apraglutide dose up to Day 182	Incidence of lower GI-aGVHD flare up to Day 182 after the first apraglutide dose following earlier cessation due to complete lower GI-aGVHD response. A lower GI-aGVHD flare is defined as any increase in signs or symptoms of lower GI-aGVHD that is sustained for \>24 hours after apraglutide treatment completion following a CR or PR in the lower GI (see Outcome Measure 10 description for details) and requires re-escalation of immunosuppressive therapy (e.g., corticosteroid, calcineurin inhibitors and/or ruxolitinib dosing).
Cumulative Ruxolitinib (RUX) and Systemic Steroid (SS) Doses From Start of the RUX Treatment up to Day 91 After the First Dose of Apraglutide	From start of the RUX treatment up to Day 91 after the first dose of apraglutide	Concomitant treatment with any systemic GVHD therapy other than SS and RUX was prohibited. The exact dose of SS and RUX taken throughout the trial was recorded in the case report form, including any dose adjustments. Systemic steroid dose was computed using the converted systemic methylprednisolone equivalent dose.
Number of Participants With Treatment-Emergent Infections and Sepsis	From baseline to Day 91 and overall (up to 2 years after the first dose of apraglutide)

Trial Locations

Locations (13): Stanford Cancer Center
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Stanford, California, United States
University of Iowa
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Iowa City, Iowa, United States
Massachusetts General Hospital
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Boston, Massachusetts, United States
The Ohio State University
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Columbus, Ohio, United States
South Austin Medical Center
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Austin, Texas, United States
Universitätsklinikum Köln (AoeR)
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Cologne, Germany
Universitaetsklinikum Duesseldorf
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Düsseldorf, Germany
Universitätsklinikum Freiburg
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Freiburg im Breisgau, Germany
Martin Luther Universität Halle-Wittenberg
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Halle, Germany
Universitätsklinikum Hamburg-Eppendorf
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Hamburg, Germany
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Stanford Cancer Center
🇺🇸Stanford, California, United States