Ignite Creation Date:
2024-05-06 @ 3:12 PM
Last Modification Date:
2024-10-26 @ 1:44 PM
Study NCT ID:
NCT04551131
Status:
ACTIVE_NOT_RECRUITING
Last Update Posted:
2024-03-12
First Post:
2020-09-02
Brief Title:
Use Of A Response-Adapted Ruxolitinib-Containing Regimen For The Treatment Of Hemophagocytic Lymphohistiocytosis
Sponsor:
St Jude Childrens Research Hospital
Organization:
St Jude Childrens Research Hospital
Study Overview
Official Title:
Use Of A Response-Adapted Ruxolitinib-Containing Regimen For The Treatment Of Hemophagocytic Lymphohistiocytosis
Status:
ACTIVE_NOT_RECRUITING
Status Verified Date:
2024-08
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
No
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
This study is a multi-site Phase IbII 2-arm non-randomized clinical trial to determine the efficacy and tolerability of a response-adapted regimen combining ruxolitinib dexamethasone and etoposide as Frontline therapy for patients with newly diagnosed hemophagocytic lymphohistiocytosis HLH or as Salvage therapy for patients with relapsedrefractory HLH
Primary Objective
To determine the efficacy and tolerability of a response-adapted ruxolitinib-containing regimen for patients with newly diagnosed HLH
Secondary Objectives
To describe the efficacy and tolerability of a response-adapted ruxolitinib-containing regimen for patients with relapsedrefractory HLH
To describe the overall response and outcome for patients with newly diagnosed or relapsedrefractory HLH who are treated with this response-adapted ruxolitinib-containing regimen
Exploratory Objectives
To estimate the pharmacokinetic PK parameters of ruxolitinib assess covariates of ruxolitinib pharmacokinetics and test whether the drugs effectiveness is correlated with systemic drug exposure
To query specific immunologic biomarkers and determine whether the levels of these biomarkers correlate with disease response and outcome
Primary Objective
To determine the efficacy and tolerability of a response-adapted ruxolitinib-containing regimen for patients with newly diagnosed HLH
Secondary Objectives
To describe the efficacy and tolerability of a response-adapted ruxolitinib-containing regimen for patients with relapsedrefractory HLH
To describe the overall response and outcome for patients with newly diagnosed or relapsedrefractory HLH who are treated with this response-adapted ruxolitinib-containing regimen
Exploratory Objectives
To estimate the pharmacokinetic PK parameters of ruxolitinib assess covariates of ruxolitinib pharmacokinetics and test whether the drugs effectiveness is correlated with systemic drug exposure
To query specific immunologic biomarkers and determine whether the levels of these biomarkers correlate with disease response and outcome
Detailed Description:
Frontline Arm Safety Phase and Expansion Phase
Safety Phase The Frontline Arm will begin with a Safety Phase to identify a feasible and safe dose of ruxolitinib to be given in combination with the gold standard HLH-directed agents dexamethasone and etoposide using a response-adapted approach For this part of the trial a minimum of 6 newly diagnosed HLH patients will be included These patients will first receive ruxolitinib 25 mgm2dose by mouth BID twice a day and dexamethasone 5 mgm2dose PO or IV BID For patients whose HLH responds favorably as outlined in the protocol ruxolitinib will be continued for 8 weeks if it is tolerated Dexamethasone will be weaned as tolerated over 8 weeks and then discontinued For patients whose HLH does not respond favorably as outlined in the protocol etoposide 150 mgm2 IV weekly will be added The dose of ruxolitinib may be escalated or de-escalated as needed based on observed toxicities and surrogates of disease response
Expansion Phase When a dose of ruxolitinib deemed feasible and safe is identified the Expansion Phase of the Frontline Arm will begin Patients with newly diagnosed HLH in the Expansion Phase will receive ruxolitinib at the maximally tolerated dose MTD established in the Safety Phase and dexamethasone 5 mgm2dose by mouth or IV BID For patients whose HLH responds favorably as outlined in the protocol ruxolitinib will be continued for 8 weeks if it is tolerated Dexamethasone will be weaned as tolerated over 8 weeks and then discontinued For patients whose HLH does not respond favorably as outlined in the protocol etoposide 150 mgm2 IV weekly will be added The first dose of dexamethasone will be given at least 8 hours after the first dose of ruxolitinib for PK testing purposes but patients will not be excluded if dexamethasone has already been started before initiating of ruxolitinib Disease response evaluations will be completed at 1 2 4 6 and 8 weeks Treatment will be individualized based on response
Patients whose HLH responds favorably after 1 week SD 8 of therapy eg favorable response FR Week 1 will remain on ruxolitinib and dexamethasone As long as patients show a CR or partial response PR at Week 2 SD15 ruxolitinib and dexamethasone are tolerated and patients are clinically stable they will remain on both agents for the remainder of the 8-week study period Dexamethasone will be weaned every 2 weeks as tolerated In case of disease reactivation therapy will be re-intensified
Patients whose HLH responds unfavorably after 1 week SD8 of therapy eg unfavorable response Week 1 will have etoposide added 150 mgm2dose IV weekly If patient meets CR or PR at Week 2 SD15 then combination treatment with ruxolitinib dexamethasone and etoposide will be continued until Week 4 disease evaluation SD 29 If patients have a CR or PR at the Week 4 disease evaluation SD 29 or later further etoposide doses may be held at site PI discretion Dexamethasone weaning may continue beyond the 8-week study period Patients whose HLH does not respond favorably eg exhibit non-response NR progressive disease PD despite treatment with ruxolitinib dexamethasone and etoposide will be taken off treatment and salvage therapy will be considered and decided by the treating physician
Salvage Arm Patients with relapsedrefractory HLH will be treated on the Salvage Arm They will not be included in the Safety Phase but will use the same response-adapted approach Patients may be enrolled on the Salvage Arm as the Safety Phase is ongoing Patients will receive ruxolitinib 25 mgm2dose by mouth BID and dexamethasone 5 mgm2dose by mouth or IV BID The first dose of dexamethasone will be given at least 8 hours after the first dose of ruxolitinib for PK testing purposes but patients will not be excluded if dexamethasone has already been started before starting ruxolitinib Disease response evaluations will be completed at 1 2 4 6 and 8 weeks Treatment will be individualized based on response as described for the Expansion Phase of the Frontline Arm When the MTD of ruxolitinib has been determined on the Safety Phase of the Frontline Arm it will be the dose used for any additional patients enrolled on the Salvage Arm Any patients already on the Salvage Arm who show no adverse effects or toxicity at an assigned dose of 25 mgm2 BID will be continued on this dose for the 8 week study period
HLH Reactivation For patients who initially respond favorably but then worsen eg reactivate during the later phases of induction when dexamethasone is weaned dexamethasone will be increased back to 5 mgm2dose POIV BID 10 mgm2day If the patient is on a reduced dose of ruxolitinib due to prior toxicityies the ruxolitinib dose may be increased to patients starting dose provided the prior toxicityies has resolved for at least 1 week Patients whose HLH responds favorably will continue to receive ruxolitinib and dexamethasone or ruxolitinib dexamethasone and etoposide Patients receiving ruxolitinib dexamethasone and etoposide whose HLH responds unfavorably will be taken off treatment and be considered for an alternative salvage therapy For patients receiving ruxolitinib and dexamethasone whose HLH responds unfavorably etoposide may be added If the response is favorable the patient will continue on all 3 medications If the response is unfavorable after adding etoposide the patient will be taken off treatment and will be considered for an alternative salvage therapy
All patients with CNS disease will receive intrathecal IT MTX and hydrocortisone HC per age-based dosing once per week for up to 4 weeks
Patients will be followed for one year after starting protocol therapy or 1 year after HSCT for those undergoing HSCT
Safety Phase The Frontline Arm will begin with a Safety Phase to identify a feasible and safe dose of ruxolitinib to be given in combination with the gold standard HLH-directed agents dexamethasone and etoposide using a response-adapted approach For this part of the trial a minimum of 6 newly diagnosed HLH patients will be included These patients will first receive ruxolitinib 25 mgm2dose by mouth BID twice a day and dexamethasone 5 mgm2dose PO or IV BID For patients whose HLH responds favorably as outlined in the protocol ruxolitinib will be continued for 8 weeks if it is tolerated Dexamethasone will be weaned as tolerated over 8 weeks and then discontinued For patients whose HLH does not respond favorably as outlined in the protocol etoposide 150 mgm2 IV weekly will be added The dose of ruxolitinib may be escalated or de-escalated as needed based on observed toxicities and surrogates of disease response
Expansion Phase When a dose of ruxolitinib deemed feasible and safe is identified the Expansion Phase of the Frontline Arm will begin Patients with newly diagnosed HLH in the Expansion Phase will receive ruxolitinib at the maximally tolerated dose MTD established in the Safety Phase and dexamethasone 5 mgm2dose by mouth or IV BID For patients whose HLH responds favorably as outlined in the protocol ruxolitinib will be continued for 8 weeks if it is tolerated Dexamethasone will be weaned as tolerated over 8 weeks and then discontinued For patients whose HLH does not respond favorably as outlined in the protocol etoposide 150 mgm2 IV weekly will be added The first dose of dexamethasone will be given at least 8 hours after the first dose of ruxolitinib for PK testing purposes but patients will not be excluded if dexamethasone has already been started before initiating of ruxolitinib Disease response evaluations will be completed at 1 2 4 6 and 8 weeks Treatment will be individualized based on response
Patients whose HLH responds favorably after 1 week SD 8 of therapy eg favorable response FR Week 1 will remain on ruxolitinib and dexamethasone As long as patients show a CR or partial response PR at Week 2 SD15 ruxolitinib and dexamethasone are tolerated and patients are clinically stable they will remain on both agents for the remainder of the 8-week study period Dexamethasone will be weaned every 2 weeks as tolerated In case of disease reactivation therapy will be re-intensified
Patients whose HLH responds unfavorably after 1 week SD8 of therapy eg unfavorable response Week 1 will have etoposide added 150 mgm2dose IV weekly If patient meets CR or PR at Week 2 SD15 then combination treatment with ruxolitinib dexamethasone and etoposide will be continued until Week 4 disease evaluation SD 29 If patients have a CR or PR at the Week 4 disease evaluation SD 29 or later further etoposide doses may be held at site PI discretion Dexamethasone weaning may continue beyond the 8-week study period Patients whose HLH does not respond favorably eg exhibit non-response NR progressive disease PD despite treatment with ruxolitinib dexamethasone and etoposide will be taken off treatment and salvage therapy will be considered and decided by the treating physician
Salvage Arm Patients with relapsedrefractory HLH will be treated on the Salvage Arm They will not be included in the Safety Phase but will use the same response-adapted approach Patients may be enrolled on the Salvage Arm as the Safety Phase is ongoing Patients will receive ruxolitinib 25 mgm2dose by mouth BID and dexamethasone 5 mgm2dose by mouth or IV BID The first dose of dexamethasone will be given at least 8 hours after the first dose of ruxolitinib for PK testing purposes but patients will not be excluded if dexamethasone has already been started before starting ruxolitinib Disease response evaluations will be completed at 1 2 4 6 and 8 weeks Treatment will be individualized based on response as described for the Expansion Phase of the Frontline Arm When the MTD of ruxolitinib has been determined on the Safety Phase of the Frontline Arm it will be the dose used for any additional patients enrolled on the Salvage Arm Any patients already on the Salvage Arm who show no adverse effects or toxicity at an assigned dose of 25 mgm2 BID will be continued on this dose for the 8 week study period
HLH Reactivation For patients who initially respond favorably but then worsen eg reactivate during the later phases of induction when dexamethasone is weaned dexamethasone will be increased back to 5 mgm2dose POIV BID 10 mgm2day If the patient is on a reduced dose of ruxolitinib due to prior toxicityies the ruxolitinib dose may be increased to patients starting dose provided the prior toxicityies has resolved for at least 1 week Patients whose HLH responds favorably will continue to receive ruxolitinib and dexamethasone or ruxolitinib dexamethasone and etoposide Patients receiving ruxolitinib dexamethasone and etoposide whose HLH responds unfavorably will be taken off treatment and be considered for an alternative salvage therapy For patients receiving ruxolitinib and dexamethasone whose HLH responds unfavorably etoposide may be added If the response is favorable the patient will continue on all 3 medications If the response is unfavorable after adding etoposide the patient will be taken off treatment and will be considered for an alternative salvage therapy
All patients with CNS disease will receive intrathecal IT MTX and hydrocortisone HC per age-based dosing once per week for up to 4 weeks
Patients will be followed for one year after starting protocol therapy or 1 year after HSCT for those undergoing HSCT
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
True
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| NCI-2020-08320 | REGISTRY | NCI Clinical Trial Registration | None |