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

Phase 2TerminatedNCT05415410

VectivBio AG31 enrolled

Overview

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

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).

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

SINGLE

Enrollment

Conditions

GVHD

Interventions

ApraglutideDRUG

Apraglutide is a new, synthetic glucagon-like peptide 2 (GLP-2) receptor agonist which acts as a gut targeted regenerative approach that is intestinotrophic with a mode of action that improves absorption and enhances gut barrier function.

Eligibility

Sex: ALLMin age: 12 Years

Medical Language ↔ Plain English

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

Locations (13)

Stanford Cancer Center

Stanford, California, United States

University of Iowa

Iowa City, Iowa, United States

Massachusetts General Hospital

Boston, Massachusetts, United States

Outcomes

Primary Outcomes

Number of Participants With Adverse Events (AEs)

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).

Time frame: Screening (up to 12 weeks) through End of Trial (up to 2 years/104 weeks) for a total of up to 116 weeks

Number of Participants With Treatment-Emergent Adverse Events of Special Interest (AESIs)

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

Time frame: From first dose of study drug through End of Trial (up to 2 years/104 weeks) for a total of up to 116 weeks

Number of Participants With Clinically Significant Changes From Baseline Over Time in Vital Signs

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.

Data from ClinicalTrials.gov

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Secondary Outcomes

Overall Response Rate at Day 56 on the Lower Gastrointestinal (GI) Tract Mount Sinai aGVHD International Consortium (MAGIC) Stage

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.

Time frame: Day 56

Overall Response Rate Over Time on the Lower GI Tract MAGIC Stage

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.

Time frame: Days 14, 28, 56, 91, 119, 147, and 182

Overall Response Rate Over Time on the Total MAGIC Stage

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.

Time frame: Days 14, 28, 56, 91, 119, 147, and 182

Durable Overall Response Rates on the Lower GI and Total MAGIC Score From 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.)

Time frame: Day 28 to Day 56

Duration of Response From Day 56 on the Total MAGIC Score

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.

Time frame: From Day 56 up to 2 years of follow up after the first dose

Duration of Response From Day 28 on the Total MAGIC Score

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.

Time frame: From Day 28 up to 2 years of follow up after the first dose

Duration of Lower GI Response Per MAGIC Score

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.

Time frame: Up to Day 147

Duration of Lower GI Response Per MAGIC Score In Retreated Participants

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 frame: Up to Day 147

Time to Partial or Complete Lower GI Response (PR or CR) Per MAGIC Score

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.

Time frame: From first injection of apraglutide up to Day 57

Best Overall Lower GI Response and Total Response at Any Time Point Up to and Including 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.)

Time frame: From first injection of apraglutide up to Day 91

Failure-Free Survival Post-First Dose of Apraglutide

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 frame: Baseline up to 2 years

Time to Non-Relapse Mortality up to 2 Years Post Treatment Start

Non-relapse mortality is defined as time from first dose until death without preceding hematologic relapse.

Time frame: From first dose of apraglutide up to 2 years

Overall Survival

Overall survival is calculated as the time from first dose of apgraglutide to death.

Time frame: Baseline up to 2 years post-first dose of apraglutide

Percentage of Participants With Hematologic Malignancy Relapse/Progression

Time frame: Baseline to 2 years

Percentage of Participants With Graft Failure Up to 2 Years Post-first Dose of Apraglutide

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%

Time frame: From first dose of apraglutide up to 2 years post-first dose

Percentage of Participants Who Experienced Lower-GI Flare by Day 182 After Earlier Cessation of Treatment Due to CR

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).

Time frame: From first apraglutide dose up to Day 182

Cumulative Ruxolitinib (RUX) and Systemic Steroid (SS) Doses 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.

Time frame: From start of the RUX treatment up to Day 91 after the first dose of apraglutide

Number of Participants With Treatment-Emergent Infections and Sepsis

Time frame: From baseline to Day 91 and overall (up to 2 years after the first dose of apraglutide)