Study of Pharmacokinetics, Activity and Safety of Ruxolitinib in Pediatric Patients With Grade II-IV Acute Graft vs. Host Disease

NCT03491215 | Completed Phase 1 Results DMC

• 2 other identifiers: CINC424F122012018-000422-55
• Study Type: interventional
• Target: 45
• Locations: 8 countries
• Sites: 19

Brief Summary

The study was an open-label, single-arm, Phase I/II multi-center study to investigate the PK, activity and safety of ruxolitinib added to the patient's immunosuppressive regimen in infants, children, and adolescents ages ≥28 days to \<18 years old with either grade II-IV aGvHD or grade II-IV SR-aGvHD. The trial design included four age groups: Group 1 included patients ≥12y to \<18y, Group 2 included patients ≥6y to \<12y, Group 3 included patients ≥2y to \<6y, and Group 4 included patients ≥28days to \<2y.

Conditions

Acute Graft Versus Host Disease

Keywords

Graft versus host disease; GvHD; acute graft versus host disease; aGvHD; Steroid refractory acute graft versus host disease; SR-aGvHD; Ruxolitinib; INC424; allogeneic stem cell transplantation; treatment naive

Outcome Measures

Primary Outcomes (8)

• Phase I: Measurement of Pharmacokinetic (PK) Parameter, AUClast, in aGvHD and SR-aGvHD Patients

  Measurement in acute GvHD and SR-acute GvHD subjects used extensive PK sampling in Groups 1-3 sparse sampling in Group 4. AUClast: The AUC from time zero to the last measurable concentration sampling time (Tlast).

  Day 1: at predose, 0.5,1,1.5, 2, 4, 6, 9 hours post dose

• Phase I: Measurement of PK Parameter, Cmax, in aGvHD and SR-aGvHD Patients

  Measurement in acute GvHD and SR-acute GvHD subjects used extensive PK sampling in Groups 1-3 and sparse sampling in Group 4. Cmax: The maximum (peak) observed plasma drug concentration

  Day 1: at predose, 0.5,1,1.5, 2, 4, 6, 9 hours post dose

• Phase I: Measurement of PK Parameter, T1/2, in aGvHD and SR-aGvHD Patients

  Measurement in acute GvHD and SR-acute GvHD subjects used extensive PK sampling in Groups 1-3 and sparse sampling in Group 4. T1/2: The elimination half-life associated with the terminal slope (Lambda\_z ) of a semi logarithmic concentration-time curve

  Day 1: at predose, 0.5,1,1.5, 2, 4, 6, 9 hours post dose

• Phase I: Measurement of PK Parameter, Ctrough, in aGvHD and SR-aGvHD Patients

  Measurement in acute GvHD and SR-acute GvHD subjects used extensive PK sampling in Groups 1-3 and sparse sampling in Group 4. Ctrough: The minimum observed plasma concentration at the end of an administration interval (corresponding to the pre-dose concentration prior to the following administration).

  Day 7 at pre-dose

• Phase I: Age-based Determination of Recommended Phase 2 Dose (RP2D) Using AUClast

  Phase I: Age-based determination of RP2D in Groups 2 and 3 and was based on observed PK parameters in Groups 1-3 * Group 2: age ≥ 6 to \< 12 years * Group 3: age ≥ 2 to \< 6 years AUClast: The AUC from time zero to the last measurable concentration sampling time (Tlast).

  Day 1: at predose, 0.5,1,1.5, 2, 4, 6, 9 hours post dose

• Phase I: Age-based Determination of Recommended Phase 2 Dose (RP2D) Using Cmax

  Phase I: Age-based determination of RP2D in Groups 2 and 3 and was based on observed PK parameters in Groups 1-3 * Group 2: age ≥ 6 to \< 12 years * Group 3: age ≥ 2 to \< 6 years Cmax: The maximum (peak) observed plasma drug concentration.

  Day 1: at predose, 0.5,1,1.5, 2, 4, 6, 9 hours post dose

• Phase I: Age-based Determination of Recommended Phase 2 Dose (RP2D) Using Ctrough

  Phase I: Age-based determination of RP2D in Groups 2 and 3 and was based on observed PK parameters in Groups 1-3 * Group 2: age ≥ 6 to \< 12 years * Group 3: age ≥ 2 to \< 6 years Ctrough: The minimum observed plasma concentration at the end of an administration interval (corresponding to the pre-dose concentration prior to the following administration).

  Day 7 at pre-dose

• Phase II: Overall Response Rate (ORR)

  Phase II: ORR is defined as the percentage of patients demonstrating a complete response (CR) or partial response (PR) without requirement for additional systemic therapies for an earlier progression, mixed response or non-response. Scoring of response was relative to the organ stage at the start of the study treatment. Complete response (CR) is defined as a score of 0 for the aGvHD grading in all evaluable organs that indicates complete resolution of all signs and symptoms of aGvHD in all evaluable organs without administration of additional systemic therapy for any earlier progression, mixed response or non-response of aGvHD. Partial response (PR) is defined as improvement of 1 stage in 1 or more organs involved with aGvHD signs or symptoms without progression in other organs or sites without administration of additional systemic therapy for an earlier progression, mixed response or non-response of aGvHD.

  Day 28

Secondary Outcomes (24)

• Percentage of All Patients Who Achieved a Complete Response (CR) or Partial Response (PR) (Durable Overall Response Rate (ORR))

  Day 56

• Percentage of Patients Who Achieved OR (CR+PR) at Day 14

  Day 14

• Area Under the Curve (AUClast) Versus Efficacy: Impact of AUClast on Overall Response Rate (ORR) at Day 28

  Day 28

• Area Under the Curve (AUClast) Versus Efficacy: Impact of AUClast on Durable Response Rate (DRR) at Day 56

  Day 56

• Area Under the Curve (AUClast) Versus Safety: Impact of AUClast on Bleeding

  24 weeks

Study Arms (1)

Ruxolitinib

EXPERIMENTAL

All pediatric participants received ruxolitinib twice a day (BID) for a planned duration of 24 weeks in either tablet, capsule or oral solution (liquid), depending on the group they were in.

Drug: Ruxolitinib

Interventions

Ruxolitinib DRUG

All enrolled pediatric participants received ruxolitinib as a 5 mg tablet (adult and adolescent formulation) or an oral pediatric formulation (administered as oral solution or capsule dispersed in liquid).

Also known as: INC424

Ruxolitinib

Eligibility Criteria

• Age: 28 Days - 17 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• Male or female patients age ≥28 days and \<18 years at the time of informed consent.
• Patients who have undergone alloSCT from any donor source (matched unrelated donor, sibling, haplo-identical) using bone marrow, peripheral blood stem cells, or cord blood. Recipients of myeloablative or reduced intensity conditioning are eligible.
• Patients with a clinically confirmed diagnosis of grades II-IV aGvHD within 48 hours prior to study treatment start. Patients may have either: Treatment-naïve aGvHD (criteria per Harris et al. 2016) OR Steroid refractory aGvHD as per institutional criteria, or per physician decision in case institutional criteria are not available, and the patient is currently receiving systemic corticosteroids.
• Evident myeloid engraftment with ANC \> 1,000/µl and platelet count \>20,000/µl. (Use of growth factor supplementation and transfusion support is allowed.)

You may not qualify if:

• Has received the following systemic therapy for aGvHD: a) Treatment-naïve aGvHD patients have received any prior systemic treatment of aGvHD except for a maximum 72h of prior systemic corticosteroid therapy of methylprednisolone or equivalent after the onset of acute GvHD. Patients are allowed to have received prior GvHD prophylaxis which is not counted as systemic treatment (as long as the prophylaxis was started prior to the diagnosis of aGvHD); OR b) SR-aGvHD patients have received two or more prior systemic treatments for aGvHD in addition to corticosteroids
• Clinical presentation resembling de novo chronic GvHD or GvHD overlap syndrome with both acute and chronic GvHD features (as defined by Jagasia et al 2015).
• Failed prior alloSCT within the past 6 months.
• Presence of relapsed primary malignancy, or who have been treated for relapse after the alloSCT was performed, or who may require rapid immune suppression withdrawal of immune suppression as pre-emergent treatment of early malignancy relapse.
• Acute GvHD occurring after non-scheduled donor leukocyte infusion (DLI) administered for pre-emptive treatment of malignancy recurrence. Note: Patients who have received a scheduled DLI as part of their transplant procedure and not for management of malignancy relapse are eligible.
• Any corticosteroid therapy for indications other than aGvHD at doses \> 1 mg/kg/day methylprednisolone (or equivalent prednisone dose 1.25 mg/kg/day) within 7 days of Screening. Routine corticosteroids administered during conditioning or cell infusion is allowed.
• Patients who received JAK inhibitor therapy for any indication after initiation of current alloSCT conditioning.

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (19)

Novartis Investigative Site

Ghent, 9000, Belgium

Location

Novartis Investigative Site

Laken, 1020, Belgium

Location

Novartis Investigative Site

Montreal, Quebec, H3T 1C5, Canada

Location

Novartis Investigative Site

Copenhagen, DK-2100, Denmark

Location

Novartis Investigative Site

Lille, 59000, France

Location

Novartis Investigative Site

Nantes, 44093, France

Location

Novartis Investigative Site

Paris, 75015, France

Location

Novartis Investigative Site

Paris, 75019, France

Location

Novartis Investigative Site

Rennes, 35022, France

Location

Novartis Investigative Site

Vandœuvre-lès-Nancy, 54511, France

Location

Novartis Investigative Site

Genova, GE, 16147, Italy

Location

Novartis Investigative Site

Roma, RM, 00165, Italy

Location

Novartis Investigative Site

Nagoya, Aichi-ken, 466 8560, Japan

Location

Novartis Investigative Site

Saitama, 330 8777, Japan

Location

Novartis Investigative Site

Seoul, 03080, South Korea

Location

Novartis Investigative Site

Barcelona, Catalonia, 08035, Spain

Location

Novartis Investigative Site

Barcelona, 08041, Spain

Location

Novartis Investigative Site

Madrid, 28009, Spain

Location

Novartis Investigative Site

Madrid, 28046, Spain

Location

Related Publications (1)

• Locatelli F, Kang HJ, Bruno B, Gandemer V, Rialland F, Faraci M, Takahashi Y, Koh K, Bittencourt H, Cleary G, Rosko C, Li X, St Pierre A, Prahallad A, Diaz-de-Heredia C. Ruxolitinib for pediatric patients with treatment-naive and steroid-refractory acute graft-versus-host disease: the REACH4 study. Blood. 2024 Nov 14;144(20):2095-2106. doi: 10.1182/blood.2023022565.

  PMID: 39046767 DERIVED

Related Links

• A Plain Language Trial Summary is available on www.novctrd.com

MeSH Terms

Conditions

Graft vs Host Disease

Interventions

ruxolitinib

Condition Hierarchy (Ancestors)

Immune System Diseases

Results Point of Contact

• Title: Clinical Disclosure Office
• Organization: Novartis Pharmaceuticals

novatis.email@novartis.com

862-778-8300

Study Officials

• Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 20, 2018
• First Posted: April 9, 2018
• Study Start: February 21, 2019
• Primary Completion: March 11, 2021
• Study Completion: February 2, 2023
• Last Updated: May 4, 2025
• Results First Posted: November 8, 2024

Record last verified: 2025-05

Data Sharing

• IPD Sharing: Will share

Locations

CA (1); JP (2); KR (1); BE (2); DK (1); FR (6); IT (2); ES (4)