Glasdegib in Refractory Patients With Sclerotic Chronic Graft-Versus-Host Disease
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|ClinicalTrials.gov Identifier: NCT03415867|
Recruitment Status : Recruiting
First Posted : January 30, 2018
Last Update Posted : January 30, 2018
|Condition or disease||Intervention/treatment||Phase|
|Sclerodermoid Chronic Graft-Versus-Host Disease (Disorder)||Drug: Glasdegib||Phase 1 Phase 2|
Three patients will be initially treated at the corresponding dose level of glasdegib at each dose escalation stage. Dose escalation will be started in a first cohort of 3 patients at a starting dose of 50 mg (Dose Level 1) and will then proceed as follows:
- If no dose-limiting toxicity is observed among the first 3 patients in a cohort, then 3 additional patients will be treated at the next higher dose level.
- If a dose-limiting toxicity is observed in 1 of the initial 3 treated patients, 3 additional patients, resulting in a total of 6 patients, will be enrolled and treated at the same dose level.
- If no further dose-limiting toxicity is observed (1/6 patients), dose escalation will continue to the next dose level in a new cohort of 3 patients.
- If ≥ 2/3 or 2/6 patients experience a dose-limiting toxicity, then MTD has been exceeded and the next lower dose of glasdegib will be expanded until a total number of 6 patients treated at that dose level is reached. If 0 or 1 patient out of 6 experiences a dose-limiting toxicity, this dose level will be declared MTD. If ≥ 2/6 patients experience a dose-limiting toxicity, the next lower dose level will be expanded.
- Prior safety data evaluation and approval by an independent data monitoring committee will be required before escalation at each dose level.
In case that MTD is exceeded within the first cohort, then a -1 Dose Level (25 mg OD) will be tested. If MTD is exceeded at 25 mg OD, the trial will be stopped and no additional testing of glasdegib at lower doses will be allowed.
Dose escalation will continue following the above-specified rules until MTD is declared. Once MTD is defined, dose expansion at MTD in cohorts of 3 patients will proceed until the pre-established sample size (20 patients) is reached. In the event that the highest pre-defined dose (200 mg OD) is tested in two successive cohorts of 3 patients and MTD is not attained, dose expansion at 200 mg OD will precede until a sample size of 20 patients is reached. The administered dose level may be subject to further adjustment (dose reduction only) in the dose expansion phase based on emerging safety, pharmacokinetic or pharmacodynamic data.
Additional dose levels may be explored, if appropriate, based on emerging safety, pharmacokinetic, or pharmacodynamic data, prior safety data evaluation and approval by an external monitoring committee.
Patients who are not evaluable for dose-limiting toxicity (e.g., those not receiving at least 80% of the planned dose of glasdegib in the dose-limiting toxicity monitoring period (first 2 cycles) for reasons other than study treatment-related toxicities) must be replaced.
If the pre-specified sample size is completed before MTD is defined or before the highest pre-defined dose (200 mg OD) is tested in at least 6 patients, additional patients may be recruited into the study (for a total sample size of up to 24 patients) until MTD is defined or two cohorts of 3 patients complete treatment at 200 mg OD.
Glasdegib may be dose reduced or discontinued during any cycle based on the patient's individual tolerability. Intra-patient dose escalation or re-escalation after a toxicity-related dose reduction will not be permitted.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||24 participants|
|Intervention Model:||Sequential Assignment|
|Masking:||None (Open Label)|
|Official Title:||A Phase 1b/ 2a Pilot Trial of the Oral Hedgehog Signalling Inhibitor Glasdegib in Patients With Sclerotic Chronic Graft-Versus-Host Disease Refractory to Second-Line Treatment|
|Actual Study Start Date :||January 9, 2017|
|Estimated Primary Completion Date :||November 2019|
|Estimated Study Completion Date :||November 2019|
Experimental: Dose escalation sequential cohorts
Glasdegib will be self-administered orally once daily in the morning as monotherapy in continuous 28-day treatment cycles for a maximum of 12 cycles.
A dose escalation/de-escalation design will be applied in successive patient cohorts until identification of MTD (dose range: 25-200 mg OD).
- Maximum tolerated dose. [ Time Frame: Up to 48 weeks. ]To determine the maximum tolerated dose (MTD) or maximum administered dose (MAD) and/or the recommended Phase 2 dose (RP2D) of glasdegib in subjects with sclerotic cGVHD.
- Adverse events. [ Time Frame: Adverse events will be assessed from the date the informed consent document is signed until 28 days after the last administered dose of glasdegib. ]
Type, incidence, severity (graded by the National Cancer Institute [NCI] Common.
Terminology Criteria for Adverse Events [CTCAE], Version 4.0), timing, intensity, and relatedness of adverse events.
- Overall response rate (ORR). [ Time Frame: Response to treatment will be evaluated on Day 1 of Cycles 1, 2, 4, 7, 10 (each cycle is 28 days) and day 28 of Cycle 12. ]ORR as assessed by the NIH cGVHD Response Criteria.
- Immunosuppression requirements. [ Time Frame: Modifications to the immunosuppressive regimen will be assessed from date of study entry to study withdrawal or end of treatment (up to 48 weeks). ]Dose reduction and/or withdrawal of concomitantly administered immunosuppressive drugs.
- Duration of clinical response. [ Time Frame: Response to treatment will be evaluated on Day 1 of Cycles 1, 2, 4, 7, 10 (each cycle is 28 days) and day 28 of Cycle 12 ]Duration of clinical response as assessed by the NIH cGVHD Response Criteria.
- Survival outcomes: overall survival. [ Time Frame: Survival status of participants will be followed from inclusion to end of trial (once every recruited patient has completed 12 cycles of treatment or withdrawn from the study). ]Overall survival (OS).
- Survival outcomes: progression-free survival. [ Time Frame: Progression-free survival status of participants will be followed from inclusion to end of trial (once every recruited patient has completed 12 cycles of treatment or withdrawn from the study). ]Progression-free survival (PFS).
- Pharmacokinetics: elimination half-life. [ Time Frame: Day 1 of Cycles 1, 2 and 4 (each cycle is 28 days). ]Elimination half-life of glasdegib.
- Pharmacokinetics: AUC. [ Time Frame: Day 1 of Cycles 1, 2 and 4 (each cycle is 28 days). ]Area under the plasma concentration versus time curve (AUC) for each dose group.
- Pharmacokinetics: Cmax. [ Time Frame: Day 1 of Cycles 1, 2 and 4 (each cycle is 28 days). ]Maximum plasma concentration (Cmax) for each dose group.
- Pharmacodynamics: Gli1 expression. [ Time Frame: Day 1 of Cycle 1 and Cycle 2 (each cycle is 28 days). ]To explore the relationship of glasdegib plasma levels and Gli1 expression in peripheral blood mononuclear cells.
- Pharmacodynamics: Gli2 expression [ Time Frame: Day 1 of Cycle 1 and Cycle 2 (each cycle is 28 days). ]To explore the relationship of glasdegib plasma levels and Gli2 expression in peripheral blood mononuclear cells.
- Pharmacodynamics: Shh expression. [ Time Frame: Day 1 of Cycle 1 and Cycle 2 (each cycle is 28 days). ]To explore the relationship of glasdegib plasma levels and Shh expression in peripheral blood mononuclear cells.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03415867
|Contact: José Antonio Pérez-Simón, M.D. Ph.D.||955013414 ext email@example.com|
|Contact: Clara M. Rosso, M.D. Ph.D.||955013414 ext firstname.lastname@example.org|
|Hospital Clinic de Barcelona||Not yet recruiting|
|Contact: Carmen Martínez-Muñoz, M.D. Ph.D. email@example.com|
|Principal Investigator: Carmen Martínez-Muñoz, M.D. Ph.D.|
|Hospital General Universitario Morales Meseguer||Active, not recruiting|
|Hospital Universitario Son Espases||Not yet recruiting|
|Palma de Mallorca, Spain|
|Contact: Antonia Sampol-Mayol, M.D. Ph.D. Antonia.firstname.lastname@example.org|
|Principal Investigator: Antonia Sampol-Mayol, M.D. Ph.D.|
|Hospital Universitario de Salamanca||Not yet recruiting|
|Contact: Lucía López-Corral, M.D. Ph.D. email@example.com|
|Principal Investigator: Lucía López-Corral, M.D. Ph.D.|
|Hospital Universitario Marqués de Valdecilla||Not yet recruiting|
|Contact: Aranzazu Bermúdez-Rodríguez, M.D. firstname.lastname@example.org|
|Principal Investigator: Aranzazu Bermúdez-Rodríguez, M.D.|
|Hospital Universitario Virgen del Rocío||Recruiting|
|Contact: José Antonio Pérez-Simón, M.D. Ph.D. 955013260 ext 0034 email@example.com|
|Contact: Clara M. Rosso, M.D. Ph.D. 955013414 ext 0034 firstname.lastname@example.org|
|Sub-Investigator: Eduardo Rodríguez-Arbolí, M.D. M.Phil.|
|Study Chair:||José Antonio Pérez-Simón, M.D. Ph.D.||Department of Hematology, Hospital Universitario Virgen del Rocío, Sevilla. Instituto de Biomedicina de Sevilla (IBIS)/CSIC/Universidad de Sevilla, Spain|