Exploratory Endpoints. XXX and duration of second response among subjects retreated with anti‑CD19 CAR T cells (Section 7.12.10)
Exploratory Endpoints. PD Endpoints • Change in DENV viral load (as measured by infectious viral titre) from baseline • Area under the log10-transformed viral load curve (AUC) from first dose to the end of treatment or study (as measured by DENV RNA and viral titre) • Time to viral load clearance, which is defined as the first of 2 consecutive undetectable viral load measurements [as measured by DENV RNA and viral titre] • Time to clearance of NS1 protein using a NS1 antigen test. Clearance is defined as time from start of treatment until the first of 2 consecutive plasma samples are NS1- negative. • Change of DENV viral load (as measured by DENV RNA and viral titre) from baseline, viral load AUC, time to viral load or NS1 clearance by DENV serotype • Treatment-emergent amino acid substitutions in DENV NS5 polymerase • Time to resolution or duration of fever • Exploratory biomarkers on immunological response to dengue (See list in Section 8.3.4) • Exploratory analyses may be performed to evaluate exposure-response relationship. The relationship between the exposure of AT-752 (and its metabolites) and DENV viral load may be explored using graphical displays STUDY DRUG, DOSAGE, AND ROUTE OF ADMINISTRATION: Dose levels of AT-752 will be evaluated across 3 sequential cohorts dosed orally: • Cohort 1: 750 mg AT-752/placebo TID for 5 days • Cohort 2: up to 1000 mg AT-752/placebo BID or TID for 5 days • Cohort 3: up to 1500 mg AT-752/placebo BID for 5 days STATISTICAL ANALYSIS PLANS: Sample Size: In Low et al (Low 2014), the observed standard deviations (SD) for VLR, defined as mean change from baseline viral load on days 2, 3, and 4, ranged from 0.75 (N=26) to 1.07 (N=24). Taking into account that the VLR endpoint in that study was based on an average of 3 measurements and assuming that there is some correlation between measurements on days 2 through 4, we consider power to detect a true effect at a single time point using a one-sided
Exploratory Endpoints. PHARMACODYNAMIC ENDPOINTS Change in DENV viral load (as measured by infectious viral titre) from baseline Area under the log10-transformed viral load curve (AUC) from first dose to the end of treatment or study (as measured by DENV RNA and viral titre) Time to viral load clearance, which is defined as the first of 2 consecutive undetectable viral load measurements (as measured by DENV RNA and viral titre) Time to clearance of NS1 protein using NS1 antigen test. Clearance is defined as time from start of treatment until the first of 2 consecutive plasma samples are NS1- negative. Change of DENV viral load (as measured by DENV RNA and viral titre) from baseline, viral load AUC, time to viral load or NS1 clearance by DENV serotype Treatment-emergent amino acid substitutions in DENV NS5 polymerase Time to resolution or duration of fever Exploratory biomarkers on immunological response to dengue (See list in Section 8.3.4) Exploratory analyses may be performed to evaluate exposure-response relationship. The relationship between the exposure of AT-752 (and its metabolites) and DENV viral load may be explored using graphical displays
Exploratory Endpoints. CST area under the curve (AUC) • Percent of eyes with resolution of fluid (sub-retinal fluid and intraretinal cysts) through week 12 on SD-OCT Additional details on endpoints will be included in the statistical analysis plan.
Exploratory Endpoints. Difference in disease progression according to RECIST 1.1 and iRECIST (Appendix 5) criteria • Compliance rate responding to a phone - based application for the assessment of patient defined symptoms • Improvement in symptoms as recorded by the Patient Personalized Clinical Benefit (PPCB) • Differences in tumor and/or tissue texture on CT scan between the two treatment arms • Differences in gut microbial communities within and between fecal samples using alpha and beta diversity metrics based on 16S rRNA sequencing
Exploratory Endpoints. Exploratory endpoints are provided below. The analysis and subsequent results of these assessments may be reported in separate documents and not included in the Statistical Analysis Plan or Clinical Study Report, respectively. • EORTC QLQ-C30/OV-28, EQ5D-5L, and PGIS • PK parameters will not be calculated due to the use of a sparse sampling schedule. Summary statistics of intact ADC, total Ab, DM4 and S-methyl DM4 concentration data by time will be presented • Immunogenicity is defined as the presence of ADA to MIRV. Based on seroconversion status, the impact of ADA on both efficacy and safety will be evaluated • Identification of soluble FRα levels and other biomarkers, such as protein, genetic, and/or gene expression changes, related to solid malignancies and/or MIRV or IC Chemo mechanism of action. Patient samples will only be used for exploratory research related to this trial and the development of MIRV 3. STUDY POPULATION
Exploratory Endpoints. Treatment related mortality rate 100 days post allogeneic stem cell transplant (TRM-Allogeneic SCT 100 day survival)Overall survival from the time of allogeneic stem cell transplant (OS-Allogeneic SCT): OS-Allogeneic SCT is evaluated in subjects who undergo allogeneic SCT and is defined as the time from allogeneic SCT to the date of death. Subjects who have not died by the analysis data cutoff date will be censored at their last contact date. • Complete Remission with partial Hematological Recovery (CRh). The incidence of a CRh (see Appendix 1 for definition). All subjects that do not meet the criteria for CRh by the analysis data cutoff date will not be considered to have CRh. • Blast-free hypoplastic or aplastic bone marrow rate: The incidence of blast-free hypoplastic or aplastic bone marrow (see Appendix 1 for definition). All subjects who do not meet the criteria for blast-free hypoplastic or aplastic bone marrow by the analysis date cutoff date will not be considered to have blast-free hypoplastic or aplastic bone marrow. • Partial remission (PR) rate: The incidence of PR (see Appendix 1 for definition). All subjects that do not meet the criteria for PR by the analysis data cutoff date will not be considered to have PR. • The overall complete remission rate (CR and CRi), MRD-negative rate, and DOR among subjects retreated with KTE-X19 (Section 7.11.10) • Level and activity of CAR+ T cells, as well presence CD19+ cells in blood and bone marrow. • Levels of cytokines in serum and CSF.
Exploratory Endpoints. Additional exploratory analyses will be conducted to evaluate effects of treatment on Impact of Weight on Quality of Life-Kids (IWQOL-Kids) questionnaire scores, changes in various glycemic and lipid markers, and change in BMI Z-score.
Exploratory Endpoints. ● The pharmacokinetics (PK) of LB100 and its metabolite endothall. ● The relative abundance of immune cell populations before, during and after treatment. The signaling states that evolve in immune cells during treatment and that differentiate responders from non-responders.
Exploratory Endpoints. Treatment related mortality rate 100 days post allogeneic stem cell transplant (TRM-Allogeneic SCT 100 day survival)Overall survival from the time of allogeneic stem cell transplant (OS-Allogeneic SCT): OS-Allogeneic SCT is evaluated in subjects who undergo allogeneic SCT and is defined as the time from allogeneic SCT to the date of death. Subjects who have not died by the analysis data cutoff date will be censored at their last contact date.
