Acute Graft-versus-host Disease
Conditions
Brief summary
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).
Interventions
DRUGGDC-8264
GDC-8264 tablets will be administered as per the schedule specified in the respective arms.
Sponsors
Genentech, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Apparent Volume of Distribution (Vz/F) of GDC-8264 | Day 1 and SS visit (any time between Day 4 to Day 28) | 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 to Reach Maximum Plasma Concentration (Tmax) of GDC-8264 | Day 1 and SS visit (any time between Day 4 to Day 28) | 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. |
| Area Under the Plasma Concentration-time Curve From 0 to 24 Hours (AUC0-24) of GDC-8264 | Day 1 and SS visit (any time between Day 4 to Day 28) | 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. |
| Terminal Half-life (T1/2) of GDC-8264 | Day 1 and SS visit (any time between Day 4 to Day 28) | 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. |
| Apparent Clearance (CL/F) of GDC-8264 | Day 1 and SS visit (any time between Day 4 to Day 28) | 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. |
| Maximum Plasma Concentration (Cmax) of GDC-8264 | Day 1 and SS visit (any time between Day 4 to Day 28) | 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. |
| Number of Participants With Adverse Events (AEs) | From signing informed consent form until 28 days after the final dose of GDC-8264 (up to 9 months) | 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. |
| Plasma Concentration of GDC-8264 | 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 | Plasma concentration of GDC-8264 at specified timepoints was determined. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Response (DOR) | From Day 29 up to end of study (up to 9 months) | 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. |
| Percentage of Participants With aGVHD Flares by Day 56 | Baseline up to 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. |
| Percentage of Participants With Non-relapse Mortality (NRM) by Day 180 | Baseline up to 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. |
| Overall Response Rate (ORR) on Day 29 | Up to 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. |
Countries
United States
Participant flow
Recruitment details
A total of 7 participants took part in the study across 4 investigative sites in the United States from 06 April 2023 to 15 January 2024.
Pre-assignment details
Participants with acute graft-versus-host disease (aGVHD) were randomized in 1:1 ratio to receive GDC-8264, 35 milligrams (mg) or GDC-8264, 75 mg.
Participants by arm
| Arm | Count |
|---|---|
| GDC-8264 35 mg Participants received GDC-8264, 35 mg tablets, orally, QD in combination with standard-of-care corticosteroid treatment during the 28 day treatment period. | 4 |
| GDC-8264 75 mg Participants received GDC-8264, 75 mg tablets, orally, QD in combination with standard-of-care corticosteroid treatment during the 28 day treatment period. | 3 |
| Total | 7 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 3 | 1 |
| Overall Study | Physician Decision | 0 | 1 |
| Overall Study | Study Terminated by Sponsor | 0 | 1 |
Baseline characteristics
| Characteristic | GDC-8264 75 mg | Total | GDC-8264 35 mg |
|---|---|---|---|
| Age, Continuous | 57.3 years STANDARD_DEVIATION 6.8 | 59.6 years STANDARD_DEVIATION 10 | 61.3 years STANDARD_DEVIATION 12.7 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 3 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 1 Participants | 3 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 3 Participants | 5 Participants | 2 Participants |
| Sex: Female, Male Female | 2 Participants | 4 Participants | 2 Participants |
| Sex: Female, Male Male | 1 Participants | 3 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 3 / 4 | 2 / 3 |
| other Total, other adverse events | 4 / 4 | 3 / 3 |
| serious Total, serious adverse events | 4 / 4 | 3 / 3 |
Outcome results
Primary
Apparent Clearance (CL/F) 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)
Population: PK population included participants who received at least one dose of GDC-8264 and had at least one evaluable post-dose PK concentration. Overall number analyzed is the number of participants with data available for analysis. Number analyzed is the number of participants with data available for analysis at the specified timepoint.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| GDC-8264 35 mg | Apparent Clearance (CL/F) of GDC-8264 | Day 1 | 9608.61 millilitres/hours (mL/hr) | — |
| GDC-8264 35 mg | Apparent Clearance (CL/F) of GDC-8264 | SS PK Day | 6871.73 millilitres/hours (mL/hr) | Geometric Coefficient of Variation 32.5 |
| GDC-8264 75 mg | Apparent Clearance (CL/F) of GDC-8264 | Day 1 | 6131.74 millilitres/hours (mL/hr) | Geometric Coefficient of Variation 69.5 |
| GDC-8264 75 mg | Apparent Clearance (CL/F) of GDC-8264 | SS PK Day | 3216.19 millilitres/hours (mL/hr) | — |
Primary
Apparent Volume of Distribution (Vz/F) 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)
Population: PK population included participants who received at least one dose of GDC-8264 and had at least one evaluable post-dose PK concentration. Overall number analyzed is the number of participants with data available for analysis. Number analyzed is the number of participants with data available for analysis at the specified timepoint.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| GDC-8264 35 mg | Apparent Volume of Distribution (Vz/F) of GDC-8264 | Day 1 | 97480.88 millilitres (mL) | — |
| GDC-8264 35 mg | Apparent Volume of Distribution (Vz/F) of GDC-8264 | SS PK Day | 67784.28 millilitres (mL) | Geometric Coefficient of Variation 21 |
| GDC-8264 75 mg | Apparent Volume of Distribution (Vz/F) of GDC-8264 | Day 1 | 69212.58 millilitres (mL) | Geometric Coefficient of Variation 37.3 |
| GDC-8264 75 mg | Apparent Volume of Distribution (Vz/F) of GDC-8264 | SS PK Day | 40355.80 millilitres (mL) | — |
Primary
Area Under the Plasma Concentration-time Curve From 0 to 24 Hours (AUC0-24) 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)
Population: PK population included participants who received at least one dose of GDC-8264 and had at least one evaluable post-dose PK concentration. Overall number analyzed is the number of participants with data available for analysis. Number analyzed is the number of participants with data available for analysis at the specified timepoint.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| GDC-8264 35 mg | Area Under the Plasma Concentration-time Curve From 0 to 24 Hours (AUC0-24) of GDC-8264 | Day 1 | 3250.37 nanograms*hours/millilitres (ng*hr/mL) | — |
| GDC-8264 35 mg | Area Under the Plasma Concentration-time Curve From 0 to 24 Hours (AUC0-24) of GDC-8264 | SS PK Day | 4534.44 nanograms*hours/millilitres (ng*hr/mL) | Geometric Coefficient of Variation 24.4 |
| GDC-8264 75 mg | Area Under the Plasma Concentration-time Curve From 0 to 24 Hours (AUC0-24) of GDC-8264 | Day 1 | 10528.86 nanograms*hours/millilitres (ng*hr/mL) | Geometric Coefficient of Variation 57.8 |
| GDC-8264 75 mg | Area Under the Plasma Concentration-time Curve From 0 to 24 Hours (AUC0-24) of GDC-8264 | SS PK Day | 19405.83 nanograms*hours/millilitres (ng*hr/mL) | — |
Primary
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)
Population: PK population included participants who received at least one dose of GDC-8264 and had at least one evaluable post-dose PK concentration. Overall number analyzed is the number of participants with data available for analysis. Number analyzed is the number of participants with data available for analysis at the specified timepoint.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| GDC-8264 35 mg | Maximum Plasma Concentration (Cmax) of GDC-8264 | Day 1 | 270.00 ng/mL | — |
| GDC-8264 35 mg | Maximum Plasma Concentration (Cmax) of GDC-8264 | SS PK Day | 541.48 ng/mL | Geometric Coefficient of Variation 31.1 |
| GDC-8264 75 mg | Maximum Plasma Concentration (Cmax) of GDC-8264 | Day 1 | 991.21 ng/mL | Geometric Coefficient of Variation 33.7 |
| GDC-8264 75 mg | Maximum Plasma Concentration (Cmax) of GDC-8264 | SS PK Day | 1480.00 ng/mL | — |
Primary
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)
Population: Safety population included participants who received at least one dose of GDC-8264, with participants grouped according to treatment received.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| GDC-8264 35 mg | Number of Participants With Adverse Events (AEs) | 4 Participants |
| GDC-8264 75 mg | Number of Participants With Adverse Events (AEs) | 3 Participants |
Primary
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
Population: Pharmacokinetic (PK) population included participants who received at least one dose of GDC-8264 and had at least one evaluable post-dose PK concentration. Number analyzed is the number of participants with data available for analysis at the specified timepoint.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| GDC-8264 35 mg | Plasma Concentration of GDC-8264 | Predose on Day 1 | NA nanograms/millilitres (ng/mL) | — |
| GDC-8264 35 mg | Plasma Concentration of GDC-8264 | Predose on Day 4 | 58.9 nanograms/millilitres (ng/mL) | Geometric Coefficient of Variation 167.3 |
| GDC-8264 35 mg | Plasma Concentration of GDC-8264 | 24 hours Postdose on Day 4 | 43.2 nanograms/millilitres (ng/mL) | Geometric Coefficient of Variation 143.2 |
| GDC-8264 35 mg | Plasma Concentration of GDC-8264 | Predose on Day 15 | 6.47 nanograms/millilitres (ng/mL) | — |
| GDC-8264 35 mg | Plasma Concentration of GDC-8264 | 4 hours Postdose on Day 1 | 123 nanograms/millilitres (ng/mL) | Geometric Coefficient of Variation 141.1 |
| GDC-8264 35 mg | Plasma Concentration of GDC-8264 | 1.5 hours Postdose on Day 1 | 28.3 nanograms/millilitres (ng/mL) | Geometric Coefficient of Variation 141.5 |
| GDC-8264 35 mg | Plasma Concentration of GDC-8264 | 2 hours Postdose on Day 1 | 151 nanograms/millilitres (ng/mL) | — |
| GDC-8264 35 mg | Plasma Concentration of GDC-8264 | 3 hours Postdose on Day 1 | 89.7 nanograms/millilitres (ng/mL) | Geometric Coefficient of Variation 321.6 |
| GDC-8264 35 mg | Plasma Concentration of GDC-8264 | 6 hours Postdose on Day 1 | 227 nanograms/millilitres (ng/mL) | — |
| GDC-8264 35 mg | Plasma Concentration of GDC-8264 | 12 hours Postdose on Day 1 | 24.0 nanograms/millilitres (ng/mL) | Geometric Coefficient of Variation 28439.7 |
| GDC-8264 35 mg | Plasma Concentration of GDC-8264 | 24 hours Postdose on Day 1 | 12.2 nanograms/millilitres (ng/mL) | Geometric Coefficient of Variation 5241.5 |
| GDC-8264 35 mg | Plasma Concentration of GDC-8264 | 1.5 hours Postdose on Day 4 | 400 nanograms/millilitres (ng/mL) | Geometric Coefficient of Variation 27.2 |
| GDC-8264 35 mg | Plasma Concentration of GDC-8264 | 2 hours Postdose on Day 4 | 529 nanograms/millilitres (ng/mL) | Geometric Coefficient of Variation 31.8 |
| GDC-8264 35 mg | Plasma Concentration of GDC-8264 | 3 hours Postdose on Day 4 | 433 nanograms/millilitres (ng/mL) | Geometric Coefficient of Variation 19.2 |
| GDC-8264 35 mg | Plasma Concentration of GDC-8264 | 4 hours Postdose on Day 4 | 374 nanograms/millilitres (ng/mL) | Geometric Coefficient of Variation 8.8 |
| GDC-8264 35 mg | Plasma Concentration of GDC-8264 | 6 hours Postdose on Day 4 | 274 nanograms/millilitres (ng/mL) | Geometric Coefficient of Variation 6.7 |
| GDC-8264 35 mg | Plasma Concentration of GDC-8264 | 12 hours Postdose on Day 4 | 129 nanograms/millilitres (ng/mL) | Geometric Coefficient of Variation 43.1 |
| GDC-8264 35 mg | Plasma Concentration of GDC-8264 | Predose on Day 8 | 39.5 nanograms/millilitres (ng/mL) | Geometric Coefficient of Variation 138 |
| GDC-8264 35 mg | Plasma Concentration of GDC-8264 | Predose on Day 22 | 6.50 nanograms/millilitres (ng/mL) | — |
| GDC-8264 35 mg | Plasma Concentration of GDC-8264 | Predose on Day 29 | 61.5 nanograms/millilitres (ng/mL) | Geometric Coefficient of Variation 297.2 |
| GDC-8264 75 mg | Plasma Concentration of GDC-8264 | 4 hours Postdose on Day 1 | 781 nanograms/millilitres (ng/mL) | Geometric Coefficient of Variation 33.8 |
| GDC-8264 75 mg | Plasma Concentration of GDC-8264 | 6 hours Postdose on Day 1 | 700 nanograms/millilitres (ng/mL) | Geometric Coefficient of Variation 52.5 |
| GDC-8264 75 mg | Plasma Concentration of GDC-8264 | 24 hours Postdose on Day 1 | 144 nanograms/millilitres (ng/mL) | Geometric Coefficient of Variation 116 |
| GDC-8264 75 mg | Plasma Concentration of GDC-8264 | 2 hours Postdose on Day 4 | 218 nanograms/millilitres (ng/mL) | Geometric Coefficient of Variation 181.5 |
| GDC-8264 75 mg | Plasma Concentration of GDC-8264 | Predose on Day 4 | 167 nanograms/millilitres (ng/mL) | Geometric Coefficient of Variation 78.1 |
| GDC-8264 75 mg | Plasma Concentration of GDC-8264 | 12 hours Postdose on Day 4 | 373 nanograms/millilitres (ng/mL) | Geometric Coefficient of Variation 82.6 |
| GDC-8264 75 mg | Plasma Concentration of GDC-8264 | Predose on Day 8 | 266 nanograms/millilitres (ng/mL) | Geometric Coefficient of Variation 70.1 |
| GDC-8264 75 mg | Plasma Concentration of GDC-8264 | 24 hours Postdose on Day 4 | 140 nanograms/millilitres (ng/mL) | Geometric Coefficient of Variation 79.9 |
| GDC-8264 75 mg | Plasma Concentration of GDC-8264 | 12 hours Postdose on Day 1 | 361 nanograms/millilitres (ng/mL) | Geometric Coefficient of Variation 106.5 |
| GDC-8264 75 mg | Plasma Concentration of GDC-8264 | Predose on Day 15 | 294 nanograms/millilitres (ng/mL) | Geometric Coefficient of Variation 54.6 |
| GDC-8264 75 mg | Plasma Concentration of GDC-8264 | Predose on Day 22 | 276 nanograms/millilitres (ng/mL) | Geometric Coefficient of Variation 180.1 |
| GDC-8264 75 mg | Plasma Concentration of GDC-8264 | Predose on Day 29 | 1.51 nanograms/millilitres (ng/mL) | — |
| GDC-8264 75 mg | Plasma Concentration of GDC-8264 | 3 hours Postdose on Day 4 | 318 nanograms/millilitres (ng/mL) | Geometric Coefficient of Variation 223.3 |
| GDC-8264 75 mg | Plasma Concentration of GDC-8264 | Predose on Day 1 | NA nanograms/millilitres (ng/mL) | — |
| GDC-8264 75 mg | Plasma Concentration of GDC-8264 | 6 hours Postdose on Day 4 | 539 nanograms/millilitres (ng/mL) | Geometric Coefficient of Variation 127.1 |
| GDC-8264 75 mg | Plasma Concentration of GDC-8264 | 1.5 hours Postdose on Day 1 | 698 nanograms/millilitres (ng/mL) | Geometric Coefficient of Variation 17 |
| GDC-8264 75 mg | Plasma Concentration of GDC-8264 | 1.5 hours Postdose on Day 4 | 195 nanograms/millilitres (ng/mL) | Geometric Coefficient of Variation 158.2 |
| GDC-8264 75 mg | Plasma Concentration of GDC-8264 | 2 hours Postdose on Day 1 | 835 nanograms/millilitres (ng/mL) | Geometric Coefficient of Variation 10.3 |
| GDC-8264 75 mg | Plasma Concentration of GDC-8264 | 4 hours Postdose on Day 4 | 393 nanograms/millilitres (ng/mL) | Geometric Coefficient of Variation 175.7 |
| GDC-8264 75 mg | Plasma Concentration of GDC-8264 | 3 hours Postdose on Day 1 | 858 nanograms/millilitres (ng/mL) | Geometric Coefficient of Variation 57.2 |
Primary
Terminal Half-life (T1/2) 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)
Population: PK population included participants who received at least one dose of GDC-8264 and had at least one evaluable post-dose PK concentration. Overall number analyzed is the number of participants with data available for analysis. Number analyzed is the number of participants with data available for analysis at the specified timepoint.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| GDC-8264 35 mg | Terminal Half-life (T1/2) of GDC-8264 | Day 1 | 7.03 hours | — |
| GDC-8264 35 mg | Terminal Half-life (T1/2) of GDC-8264 | SS PK Day | 6.84 hours | Geometric Coefficient of Variation 50.2 |
| GDC-8264 75 mg | Terminal Half-life (T1/2) of GDC-8264 | SS PK Day | 8.70 hours | — |
| GDC-8264 75 mg | Terminal Half-life (T1/2) of GDC-8264 | Day 1 | 7.82 hours | Geometric Coefficient of Variation 27.2 |
Primary
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)
Population: PK population included participants who received at least one dose of GDC-8264 and had at least one evaluable post-dose PK concentration. Overall number analyzed is the number of participants with data available for analysis. Number analyzed is the number of participants with data available for analysis at the specified timepoint.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| GDC-8264 35 mg | Time to Reach Maximum Plasma Concentration (Tmax) of GDC-8264 | Day 1 | 3.4 hours |
| GDC-8264 35 mg | Time to Reach Maximum Plasma Concentration (Tmax) of GDC-8264 | SS PK Day | 2.17 hours |
| GDC-8264 75 mg | Time to Reach Maximum Plasma Concentration (Tmax) of GDC-8264 | Day 1 | 2.30 hours |
| GDC-8264 75 mg | Time to Reach Maximum Plasma Concentration (Tmax) of GDC-8264 | SS PK Day | 3.2 hours |
Secondary
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)
Population: mITT included all enrolled participants who received at least one dose of GDC-8264 and did not miss more than four doses of the GDC-8264 within the first 14 days of the treatment period due to participant noncompliance, voluntary withdrawal, or reasons other than safety or (lack of) efficacy. Overall number analyzed is the number of participants with OR i.e. responders.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| GDC-8264 35 mg | Duration of Response (DOR) | 1.00 days |
| GDC-8264 75 mg | Duration of Response (DOR) | 4.00 days |
Secondary
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
Population: Modified intent to treat (mITT) included all enrolled participants who received at least one dose of GDC-8264 and did not miss more than four doses of the GDC-8264 within the first 14 days of the treatment period due to participant noncompliance, voluntary withdrawal, or reasons other than safety or (lack of) efficacy. Percentages have been rounded off.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| GDC-8264 35 mg | Overall Response Rate (ORR) on Day 29 | 100 percentage of participants |
| GDC-8264 75 mg | Overall Response Rate (ORR) on Day 29 | 66.7 percentage of participants |
Secondary
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
Population: mITT included all enrolled participants who received at least one dose of GDC-8264 and did not miss more than four doses of the GDC-8264 within the first 14 days of the treatment period due to participant noncompliance, voluntary withdrawal, or reasons other than safety or (lack of) efficacy. Percentages have been rounded off.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| GDC-8264 35 mg | Percentage of Participants With aGVHD Flares by Day 56 | 50 percentage of participants |
| GDC-8264 75 mg | Percentage of Participants With aGVHD Flares by Day 56 | 0 percentage of participants |
Secondary
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
Population: mITT included all enrolled participants who received at least one dose of GDC-8264 and did not miss more than four doses of the GDC-8264 within the first 14 days of the treatment period due to participant noncompliance, voluntary withdrawal, or reasons other than safety or (lack of) efficacy. Percentages have been rounded off.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| GDC-8264 35 mg | Percentage of Participants With Non-relapse Mortality (NRM) by Day 180 | 0 percentage of participants |
| GDC-8264 75 mg | Percentage of Participants With Non-relapse Mortality (NRM) by Day 180 | 66.7 percentage of participants |