GRAVITAS-309: Itacitinib and Corticosteroids as Initial Treatment for Chronic Graft-Versus-Host Disease

An adverse event (AE) was defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. An AE could therefore have been any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of study treatment. A TEAE was defined as any AE either reported for the first time or the worsening of a pre-existing event after the first dose of study drug.

Time frame: until at least 30 days after the last dose of study treatment (up to 1103 days)

Population: Safety Analysis Set

A DLT was defined as the occurrence of any protocol-defined toxicity with onset up to and including Day 28, except those with a clear alternative explanation. Participants who received at least 21 of 28 doses of study drug at the level assigned or had a DLT were considered evaluable for determining tolerability of the dose. Participants who did not achieve this duration of exposure and did not have a DLT were to be replaced for purposes of toxicity identification.

Time frame: up to Day 28

Population: Safety Analysis Set: all enrolled/randomized participants who received at least 1 dose of study drug and/or reference therapy. Treatment groups for this population were determined according to the actual treatment the participant received regardless of assigned study drug treatment.

Response rate was defined as the percentage of participants that had complete response (CR) or partial response (PR), per National Institutes of Health (NIH) Consensus Criteria, as determined by the investigator, within 14 days of the post-Baseline visit date until new anti-GVHD therapy or overall response-progression or relapse/progression of underlying disease. CR was defined as the complete resolution of all signs and symptoms of cGvHD in all evaluable organs. PR was defined as an improvement in at least one organ without progression in other organs.

Time frame: Month 6

Population: Part 2 was not enrolled because the benefit:risk ratio did not support moving the combination of itacitinib with CS to a later phase of development in first-line cGVHD.

Duration to response was defined as the interval between the first response and cGVHD progression, death, or the initiation of a new systemic cGVHD therapy.

Time frame: up to 24 months

Population: Safety Analysis Set. Participants with a first response of CR or PR up to 12 months, until initiation of new anti-GVHD therapy, relapse of underlying malignancy, or overall response of progression or death were analyzed. The 95% confidence interval was calculated using the Brookmeyer and Crowley's method and Klein and Moeschberger's method with log-log transformation.

NRM was defined as the percentage of participants who died due to causes other than a relapse of their primary hematologic disease.

Time frame: up to 24 months

Population: Safety Analysis Set. Participants who did not die due to malignancy relapse were analyzed. The 95% confidence interval was calculated based on the exact method for binomial distributions.

Overall survival was defined as the interval between the date of randomization and the date of death due to any cause.

Time frame: up to 36 months

Population: Safety Analysis Set. The 95% confidence interval was calculated using the Brookmeyer and Crowley's method and Klein and Moeschberger's method with log-log transformation.

The percentage of participants who were not taking any corticosteroids at Day 180 was assessed.

Time frame: Day 180

Population: Safety Analysis Set. Only those participants ongoing in the study at Day 180 were analyzed.

The corticosteroid dose at Day 180 was compared to the corticosteroid dose on Day 1 to assess reduction.

Time frame: Day 1; Day 180

Population: Safety Analysis Set. Only those participants ongoing in the study at Day 180 were analyzed.

The relapse rate was defined as the percentage of participants whose underlying disease relapsed at any time during the course of the study.

Time frame: up to 1073 days

Population: Safety Analysis Set. The 95% confidence interval was calculated based on the exact method for binomial distributions.

Response rate was defined as the percentage of participants that had CR or PR, per NIH Consensus Criteria, as determined by the investigator, within 14 days of the post-Baseline visit date until new anti-GVHD therapy or overall response-progression or relapse/progression of underlying disease. CR was defined as the complete resolution of all signs and symptoms of cGvHD in all evaluable organs. PR was defined as an improvement in at least one organ without progression in other organs.

Time frame: Month 12

Population: Safety Analysis Set. Confidence intervals were calculated based on the exact method for binomial distributions.

Response rate was defined as the percentage of participants that had CR or PR, per NIH Consensus Criteria, as determined by the investigator, within 14 days of the post-Baseline visit date until new anti-GVHD therapy or overall response-progression or relapse/progression of underlying disease. CR was defined as the complete resolution of all signs and symptoms of cGvHD in all evaluable organs. PR was defined as an improvement in at least one organ without progression in other organs.

Time frame: Months 3 and 6

Population: Safety Analysis Set. Confidence intervals were calculated based on the exact method for binomial distributions.

Time to primary hematologic disease relapse was defined as the interval between the date of randomization and the date of relapse.

Time frame: up to 24 months

Population: Safety Analysis Set, including censored participants. Censored participants didn't have an event of relapse at any time up to the last assessment date. Participants who didn't have an event of hematologic disease relapse were censored at the time of the last assessment. The 95% confidence interval was calculated using the Brookmeyer and Crowley's method and Klein and Moeschberger's method with log-log transformation.

Time to response was defined as the interval between randomization and the first response (CR or PR) before initiation of new therapy. CR was defined as the complete resolution of all signs and symptoms of cGvHD in all evaluable organs. PR was defined as an improvement in at least one organ without progression in other organs.

Time frame: up to Month 12

Population: Safety Analysis Set. Participants with a first response of CR or PR up to 12 months, until initiation of new anti-GVHD therapy, relapse of underlying malignancy, or overall response of progression or death were analyzed.

Response rate was defined as the percentage of participants that had CR or PR, per NIH Consensus Criteria, as determined by the investigator, within 14 days of the post-Baseline visit date until new anti-GVHD therapy or overall response-progression or relapse/progression of underlying disease. CR was defined as the complete resolution of all signs and symptoms of cGvHD in all evaluable organs. PR was defined as an improvement in at least one organ without progression in other organs.

Time frame: Months 3, 6, and 12

Population: Safety Analysis Set. Confidence intervals were calculated based on the exact method for binomial distributions.

AUC0-t was defined as the area under the plasma or serum concentration-time curve from time = 0 to the last measurable concentration at time = t.

Time frame: Days 1, 7, and 28: predose and 1, 2, and 5 hours post-dose

Population: Part 2 was not enrolled because the benefit:risk ratio did not support moving the combination of itacitinib with CS to a later phase of development in first-line cGVHD.

The EQ-5D-3L is a descriptive classification consisting of 5 dimensions of health: mobility, self-care, usual activities, anxiety/depression, and pain/discomfort. It was to be used to assess patient-reported changes in health status, symptoms, and well being.

Time frame: Baseline; End of Treatment in Phase 2

Population: Part 2 was not enrolled because the benefit:risk ratio did not support moving the combination of itacitinib with CS to a later phase of development in first-line cGVHD.

The LSS consists of 30 items in 7 subscales (skin, eye, mouth, lung, nutrition, energy, and psychological). It was to be used to assess patient-reported changes in health status, symptoms, and well being.

Time frame: Baseline; End of Treatment in Phase 2

Population: Part 2 was not enrolled because the benefit:risk ratio did not support moving the combination of itacitinib with CS to a later phase of development in first-line cGVHD.

The PGIC is 1 question that captures the overall change in symptoms over the course of treatment. It was to be used to assess patient-reported changes in health status, symptoms, and well being.

Time frame: Baseline; End of Treatment in Phase 2

Population: Part 2 was not enrolled because the benefit:risk ratio did not support moving the combination of itacitinib with CS to a later phase of development in first-line cGVHD.

The PGIS is 1 question that captures the overall change in the severity of symptoms over the previous week. It was to be used to assess patient-reported changes in health status, symptoms, and well being.

Time frame: Baseline; End of Treatment in Phase 2

Population: Part 2 was not enrolled because the benefit:risk ratio did not support moving the combination of itacitinib with CS to a later phase of development in first-line cGVHD.

The QOL-SF-36 v2 is 36-item scale that captures changes in health status during the course of treatment. The SF-36 assesses 8 health concepts related to limitations in physical activities, social activities, bodily pain, general mental and physical health, and vitality. It was to be used to assess patient-reported changes in health status, symptoms, and well being.

Time frame: Baseline; End of Treatment in Phase 2

Population: Part 2 was not enrolled because the benefit:risk ratio did not support moving the combination of itacitinib with CS to a later phase of development in first-line cGVHD.

Cl/F was defined as the apparent oral dose clearance of itacitinib.

Time frame: Days 1, 7, and 28: predose and 1, 2, and 5 hours post-dose

Population: Part 2 was not enrolled because the benefit:risk ratio did not support moving the combination of itacitinib with CS to a later phase of development in first-line cGVHD.

Cmax was defined as the maximum observed concentration of itacitinib.

Time frame: Days 1, 7, and 28: predose and 1, 2, and 5 hours post-dose

Population: Part 2 was not enrolled because the benefit:risk ratio did not support moving the combination of itacitinib with CS to a later phase of development in first-line cGVHD.

Cmin was defined as the minimum observed plasma or serum concentration of itacitinib over the dose interval.

Time frame: Days 1, 7, and 28: predose and 1, 2, and 5 hours post-dose

Population: Part 2 was not enrolled because the benefit:risk ratio did not support moving the combination of itacitinib with CS to a later phase of development in first-line cGVHD.

Duration to response was defined as the interval between the first response and cGVHD progression, death, or the initiation of a new systemic cGVHD therapy.

Time frame: up to 24 months

Population: Part 2 was not enrolled because the benefit:risk ratio did not support moving the combination of itacitinib with CS to a later phase of development in first-line cGVHD.

NRM was defined as the percentage of participants who died due to causes other than a relapse of their primary hematologic disease.

Time frame: up to 24 months

Population: Part 2 was not enrolled because the benefit:risk ratio did not support moving the combination of itacitinib with CS to a later phase of development in first-line cGVHD.

An AE was defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. An AE could therefore have been any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of study treatment. A TEAE was defined as any AE either reported for the first time or the worsening of a pre-existing event after the first dose of study drug.

Time frame: up to 30 days after the last dose in Phase 2

Population: Part 2 was not enrolled because the benefit:risk ratio did not support moving the combination of itacitinib with CS to a later phase of development in first-line cGVHD.

Overall survival was defined as the interval between the date of randomization and the date of death due to any cause.

Time frame: up to 36 months

Population: Part 2 was not enrolled because the benefit:risk ratio did not support moving the combination of itacitinib with CS to a later phase of development in first-line cGVHD.

The percentage of participants who were not taking any corticosteroids at Day 180 was assessed.

Time frame: Day 180

Population: Part 2 was not enrolled because the benefit:risk ratio did not support moving the combination of itacitinib with CS to a later phase of development in first-line cGVHD.

The corticosteroid dose at Day 180 was compared to the corticosteroid dose on Day 1 to assess reduction.

Time frame: Day 1; Day 180

Population: Part 2 was not enrolled because the benefit:risk ratio did not support moving the combination of itacitinib with CS to a later phase of development in first-line cGVHD.

The relapse rate was defined as the defined as the percentage of participants whose underlying disease relapsed at any time during the course of the study.

Time frame: up to 24 months

Population: Part 2 was not enrolled because the benefit:risk ratio did not support moving the combination of itacitinib with CS to a later phase of development in first-line cGVHD.

Response rate was defined as the percentage of participants that had CR or PR, per NIH Consensus Criteria, as determined by the investigator, within 14 days of the post-Baseline visit date until new anti-GVHD therapy or overall response-progression or relapse/progression of underlying disease. CR was defined as the complete resolution of all signs and symptoms of cGvHD in all evaluable organs. PR was defined as an improvement in at least one organ without progression in other organs.

Time frame: Months 3 and 12

Population: Part 2 was not enrolled because the benefit:risk ratio did not support moving the combination of itacitinib with CS to a later phase of development in first-line cGVHD.

Time to primary hematologic disease relapse was defined as the interval between the date of randomization and the date of relapse.

Time frame: up to 24 months

Population: Part 2 was not enrolled because the benefit:risk ratio did not support moving the combination of itacitinib with CS to a later phase of development in first-line cGVHD.

tmax was defined as the time to the maximum concentration of itacitinib.

Time frame: Days 1, 7, and 28: predose and 1, 2, and 5 hours post-dose

Population: Part 2 was not enrolled because the benefit:risk ratio did not support moving the combination of itacitinib with CS to a later phase of development in first-line cGVHD.

Cl/F was defined as the apparent oral dose clearance of itacitinib. For pharmacokinetic steady state Day 7 and Day 28, for the calculation of NCA exposure estimates (as more than 3 PK data points are necessary for the estimation beyond Cmax) it was assumed, that PK concentration returns to the predose value (at 12 hours post-dose for BID dosing; at 24 hours post-dose for QD dosing). Predose PK samples were transposed to 24 hours post-dose for QD administration and to 12 hours post-dose for BID administration to allow the steady-state NCA PK estimates on Day 7 and Day 28.

Time frame: Day 1: predose, and 1, 2, and 5 hours post-dose. Days 7 and 28: predose, and 1, 2, 5, 12 (for BID dosing), and 24 hours post-dose (for QD dosing)

Population: PK Evaluable Population. Because Part I and Part I Expansion were both randomized, open label, and had a parallel design with the same participant population criteria, as pre-specified, the PK data for identical doses/frequency of dosing were grouped for analysis (rather than conducting analysis by treatment arm).

Cmax was defined as the maximum observed concentration of itacitinib.

Time frame: Days 1, 7, and 28: predose and 1, 2, and 5 hours post-dose

Population: Pharmacokinetic (PK) Evaluable Population: all participants who received at least 1 dose of study drug and/or reference therapy and provided at least 1 corresponding post-dose plasma sample (1 PK measurement). Because Part I and Part I Expansion were both randomized, open label, and had a parallel design with the same participant population criteria, as pre-specified, the PK data for identical doses/frequency of dosing were grouped for analysis (rather than conducting analysis by treatment arm).

Ctau was defined as the trough concentration of itacitinib over the dose interval. For pharmacokinetic steady state Day 7 and Day 28, for the calculation of NCA exposure estimates (as more than 3 PK data points are necessary for the estimation beyond Cmax) it was assumed, that PK concentration returns to the predose value (at 12 hours post-dose for BID dosing; at 24 hours post-dose for QD dosing). Predose PK samples were transposed to 24 hours post-dose for QD administration and to 12 hours post-dose for BID administration to allow the steady-state NCA PK estimates on Day 7 and Day 28.

Time frame: Day 1: predose, and 1, 2, and 5 hours post-dose. Days 7 and 28: predose, and 1, 2, 5, 12 (for BID dosing), and 24 hours post-dose (for QD dosing)

Population: PK Evaluable Population. Because Part I and Part I Expansion were both randomized, open label, and had a parallel design with the same participant population criteria, as pre-specified, the PK data for identical doses/frequency of dosing were grouped for analysis (rather than conducting analysis by treatment arm).

tmax was defined as the time to the maximum concentration of itacitinib. For pharmacokinetic steady state Day 7 and Day 28, for the calculation of NCA exposure estimates (as more than 3 PK data points are necessary for the estimation beyond Cmax) it was assumed, that PK concentration returns to the predose value (at 12 hours post-dose for BID dosing; at 24 hours post-dose for QD dosing). Predose PK samples were transposed to 24 hours post-dose for QD administration and to 12 hours post-dose for BID administration to allow the steady-state NCA PK estimates on Day 7 and Day 28.

Time frame: Day 1: predose, and 1, 2, and 5 hours post-dose. Days 7 and 28: predose, and 1, 2, 5, 12 (for BID dosing), and 24 hours post-dose (for QD dosing)

Population: PK Evaluable Population. Because Part I and Part I Expansion were both randomized, open label, and had a parallel design with the same participant population criteria, as pre-specified, the PK data for identical doses/frequency of dosing were grouped for analysis (rather than conducting analysis by treatment arm).