A Study to Assess the Safety and Pharmacokinetics of GDC-8264 in Combination With Standard of Care in Participants With Acute Graft-Versus-Host Disease (aGVHD)

Genentech, Inc.7 enrolled

Overview

The primary purpose of the study is to assess the safety and pharmacokinetics (PK) of GDC-8264 in participants with acute graft-versus-host disease (aGVHD).

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Acute Graft-versus-host Disease

Interventions

GDC-8264DRUG

GDC-8264 tablets will be administered as per the schedule specified in the respective arms.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Diagnosis of post-allogeneic hematopoietic stem cell transplantation (HSCT) aGVHD at screening * Evidence of engraftment post-transplant * Diagnosis of high-risk aGVHD, per refined Minnesota high-risk aGVHD criteria during screening * Initiation of treatment with systemic corticosteroids for aGVHD at a dose of prednisone ≥2 milligrams per kilograms per day (mg/kg/day) by orally (PO) or methylprednisolone ≥2 mg/kg/day intravenously (or equivalent) in divided doses at diagnosis and up to 3 days prior to or on the same day as initiation of GDC-8264 (Day 1), with no taper planned prior to Day 3 Exclusion Criteria: * Evidence of relapsed, progressing, or persistent malignancy, or treatment for relapse after transplant, or requirement for rapid immune suppression withdrawal as pre-emergent treatment of early malignancy relapse * Prior receipt of more than one allogeneic HSCT * Prior receipt of solid organ transplantation that are target organs for aGVHD (e.g., liver transplant) * Prior systemic treatment for aGVHD, except for the standard of care corticosteroid treatment initiated as part of this trial * Diagnosis of chronic GVHD or overlap syndrome * Uncontrolled active infection (i.e., progressive symptoms related to infection despite treatment, or persistently positive blood cultures despite treatment, or any other evidence of severe sepsis) * Severe organ dysfunction (e.g., acute liver failure, renal failure requiring dialysis, ventilator support, or vasopressor therapy) * Initiation or planned use of a marketed small molecule (excluding corticosteroids) or biologic therapy as treatment for aGVHD from the start of screening through the treatment period

Locations (4)

City of Hope National Medical Center

Duarte, California, United States

Massachusetts General Hospital

Boston, Massachusetts, United States

Icahn School of Medicine at Mount Sinai

New York, New York, United States

Columbia University Irving Medical Center

New York, New York, United States

Outcomes

Primary Outcomes

Number of Participants With Adverse Events (AEs)

An AE is any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product, regardless of causal attribution. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.

Time frame: From signing informed consent form until 28 days after the final dose of GDC-8264 (up to 9 months)

Plasma Concentration of GDC-8264

Plasma concentration of GDC-8264 at specified timepoints was determined.

Time frame: Predose, 1.5, 2, 3, 4, 6, 12, and 24 hours post-dose on Days 1 and 4; Predose on Days 8, 15, 22, 29

Maximum Plasma Concentration (Cmax) of GDC-8264

Steady-state (SS) PK visit was Day 4 if the participant was hospitalized or Day 8 if the participant was an outpatient. If the SS PK visit samples could not be obtained on Day 4/8, the SS PK visit may have occurred on any dosing day between Day 4 and 28.

Time frame: Day 1 and SS visit (any time between Day 4 to Day 28)

Time to Reach Maximum Plasma Concentration (Tmax) of GDC-8264

SS PK visit was Day 4 if the participant was hospitalized or Day 8 if the participant was an outpatient. If the SS PK visit samples could not be obtained on Day 4/8, the SS PK visit may have occurred on any dosing day between Day 4 and 28.

Time frame: Day 1 and SS visit (any time between Day 4 to Day 28)

Area Under the Plasma Concentration-time Curve From 0 to 24 Hours (AUC0-24) of GDC-8264

Time frame: Day 1 and SS visit (any time between Day 4 to Day 28)

Data from ClinicalTrials.gov

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Secondary Outcomes

Overall Response Rate (ORR) on Day 29

ORR=percentage of participants with complete response (CR), very good partial response (VGPR), or partial response (PR) as determined by investigator. CR=all target organs evaluated as Mount Sinai Acute GVHD International Consortium (MAGIC) aGVHD Stage 0 \[Skin- no GVHD rash; Liver - bilirubin \<2 milligrams/decilitres (mg/dL); Upper gastrointestinal (GI) tract - no intermittent nausea, vomiting/anorexia; Lower GI tract - stool output: \< 500 mL/day or \<3 episodes/day (adults), \<10 mL/kilograms (kg)/day or \<4 episodes/day\]. VGPR=resolution of signs \& symptoms i.e. no rash/residual erythematous rash involving \< 25% of body surface, without (w/o) bullae; bilirubin \<2 mg/dL or \<25% of baseline at screening; toleration of food/enteral feeding; predominantly formed stools; no overt GI bleeding/abdominal cramping; no more than occasional nausea/vomiting. PR=improvement in one/more target organs (skin, liver, upper GI tract, lower GI tract) involved with aGVHD symptoms w/o worsening in others.

Time frame: Up to Day 29

Duration of Response (DOR)

DOR was defined astime from response (CR, VGPR or PR) on Day 29 to aGVHD progression from nadir in any organ, new systemic therapy for aGVHD, or death from any cause (whichever occurs first), as determined by the investigator. CR=all target organs evaluated as MAGIC aGVHD Stage 0 \[Skin- no GVHD rash; Liver - bilirubin \<2 mg/dL; Upper GI tract - no intermittent nausea, vomiting/anorexia; Lower GI tract - stool output: \< 500 mL/day or \<3 episodes/day (adults), \<10 mL/kg/day or \<4 episodes/day\]. VGPR=resolution of signs \& symptoms i.e. no rash or residual erythematous rash involving \< 25% of body surface, without bullae; bilirubin \<2 mg/dL or \<25% of baseline at screening; toleration of food/enteral feeding; predominantly formed stools; no overt GI bleeding or abdominal cramping; no more than occasional nausea or vomiting. PR=improvement in one or more target organs (skin, liver, upper GI tract, lower GI tract) involved with aGVHD symptoms without worsening in others.

Time frame: From Day 29 up to end of study (up to 9 months)

Percentage of Participants With aGVHD Flares by Day 56

aGVHD flare was defined as an increase in aGVHD target organ stage by at least one stage for at least 3 days that requires either addition of a new line of systemic treatment or increase in corticosteroid dose \> 0.25 mg/kg/day.

Time frame: Baseline up to Day 56

Percentage of Participants With Non-relapse Mortality (NRM) by Day 180

NRM was defined as any death that occurred after onset of aGVHD that was not attributable to relapse of the underlying primary disease was considered a non-relapse death.

Time frame: Baseline up to Day 180