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

Phase 3TerminatedNCT03584516

Incyte Corporation155 enrolled

Overview

The purpose of this study is to assess the efficacy and safety of itacitinib in combination with corticosteroids as first-line treatment for moderate or severe chronic graft-versus-host disease (cGVHD).

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

DOUBLE

Enrollment

155

Conditions

Chronic Graft-versus-host Disease

Interventions

ItacitinibDRUG

In Part 1dose determination participants will receive itacitinib administered orally once daily at the protocol-defined dose according to cohort enrollment. In Part 1 expansion, participants will receive either itacitinib administered orally either once daily or twice a day or corticosteroid alone based on the assigned treatment regimen according to cohort enrollment. In Part 2, participants will receive the recommended dose from Part 1 expansion.

PlaceboDRUG

In Part 2, participants will receive matching placebo.

MethylprednisoloneDRUG

Administered in Parts 1 and 2 as background reference therapy at a dose level that is commensurate with institutional guidelines based on organ involvement and severity of disease.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Active, clinically diagnosed, moderate or severe cGVHD per NIH Consensus Criteria * Underwent allogeneic stem cell transplantation (allo-HCT) * Karnofsky Performance Status score ≥ 60%. * Evidence of myeloid and platelet engraftment. * Willingness to avoid pregnancy or fathering children based on protocol-defined criteria. Exclusion Criteria: * Has received more than 3 days/72 hours of systemic corticosteroid treatment for cGVHD. * Has received any other systemic treatment for cGVHD, including extracorporeal photopheresis (ECP). * Prior treatment with a Janus kinase (JAK) inhibitor for acute GVHD, unless the participant achieved complete or partial response and has been off JAK inhibitor treatment for at least 8 weeks before randomization. * cGVHD occurring after a nonscheduled donor lymphocyte infusion (DLI) administered for pre-emptive treatment of malignancy recurrence. * Evidence of relapsed primary malignancy.

Locations (133)

Outcomes

Primary Outcomes

Part 1: Number of Participants With Dose-limiting Toxicities (DLTs)

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

Part 1 Expansion: Number of Participants With Any Treatment-emergent Adverse Event (TEAE)

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)

Part 2: Response Rate at Month 6

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

Secondary Outcomes

Part 1 Expansion: Response Rate at Months 3 and 6

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.

Data from ClinicalTrials.gov

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PrednisoneDRUG

Administered in Parts 1 and 2 as background reference therapy at a dose level that is commensurate with institutional guidelines based on organ involvement and severity of disease.

University of Arizona Cancer Center - Out Pt.

Tucson, Arizona, United States

University of Arkansas For Medical Sciences - Winthrop P Rockefeller Cancer Institute

Little Rock, Arkansas, United States

City of Hope National Medical Center

Duarte, California, United States

University of California San Diego Medical Center, Moores Cancer Center

La Jolla, California, United States

University of Miami Sylvester Comprehensive Cancer Center

Miami, Florida, United States

Winship Cancer Institute of Emory University

Atlanta, Georgia, United States

Augusta University - Medical College of Georgia

Augusta, Georgia, United States

Rush University Medical Center

Chicago, Illinois, United States

Illinois Cancer Specialists

Chicago, Illinois, United States

Loyola University Medical Center

Maywood, Illinois, United States

...and 123 more locations

Time frame: Months 3 and 6

Parts 1 and 1 Expansion: Cmax of Itacitinib

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

Parts 1 and 1 Expansion: Ctau of Itacitinib

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)

Parts 1 and 1 Expansion: Tmax of Itacitinib

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)

Parts 1 and 1 Expansion: Cl/F of Itacitinib

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)

Part 2: Cmax of Itacitinib

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

Part 2: Cmin of Itacitinib

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

Part 2: Tmax of Itacitinib

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

Part 2: AUC0-t of Itacitinib

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

Part 2: Cl/F of Itacitinib

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

Part 1: Response Rate at Months 3, 6, and 12

Time frame: Months 3, 6, and 12

Part 1 Expansion: Response Rate at Month 12

Time frame: Month 12

Part 1 Expansion: Time to Response

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

Part 1 Expansion: Duration of Response

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

Part 1 Expansion: Overall Survival

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

Part 1 Expansion: Nonrelapse Mortality (NRM) Rate

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

Part 1 Expansion: Percentage of Participants With a ≥50% Reduction in Daily Corticosteroid Dose at Day 180 From the Corticosteroid Dose on Day 1

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

Time frame: Day 1; Day 180

Part 1 Expansion: Percentage of Participants Successfully Tapered Off All Corticosteroids at Day 180

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

Time frame: Day 180

Part 1 Expansion: Relapse Rate of Malignant and Nonmalignant Hematologic Diseases

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

Part 1 Expansion: Time to Primary Hematologic Disease Relapse

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

Part 2: Change From Baseline in Lee cGVHD Symptom Scale (LLS) Scores

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

Part 2: Change From Baseline in Quality of Life-Short Form-36 Version 2 (QOL-SF-36 v2) Scores

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

Part 2: Change From Baseline in EQ-5D-3L Scores

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

Part 2: Change From Baseline in Patient Global Impression of Change (PGIC) Responses

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

Part 2: Change From Baseline in Patient Global Impression of Severity (PGIS) Responses

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

Part 2: Response Rate at Months 3 and 12

Time frame: Months 3 and 12

Part 2: Duration of Response

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

Part 2: Overall Survival

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

Part 2: NRM Rate

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

Part 2: Percentage of Participants With a ≥50% Reduction in Daily Corticosteroid Dose at Day 180 From the Corticosteroid Dose on Day 1

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

Time frame: Day 1; Day 180

Part 2: Percentage of Participants Successfully Tapered Off All Corticosteroids at Day 180

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

Time frame: Day 180

Part 2: Relapse Rate of Malignant and Nonmalignant Hematologic Diseases

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

Part 2: Time to Primary Hematologic Disease Relapse

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

Part 2: Number of Participants With Any TEAE

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