Patients with relapsed or refractory cHL that has not responded to, or has progressed after, the previous treatment MedDRA version: 20.0 Level: LLT Classification code 10020328 Term: Hodgkin's lymphoma System Organ Class: 100000004864
Conditions
Interventions
Trade Name: JAKAVI - 20 MG - COMPRESSA - USO ORALE - BLISTER (PVC/PCTFE/ALU) - 56 COMPRESSE
Product Name: Ruxolitinib
Product Code: [L01XE18]
Pharmaceutical Form: Tablet
INN or Proposed INN: RUXOLITIN
Sponsors
PROF.BRUNANGELO FALINI, DR.ENRICO TIACCI. DIPARTIMENTO DI MEDICINA, UNIVERSITA' DI PERUGIA
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Cohort-1: ruxolitinib + brentuximab 1. Adult patients with CD30+ cHL relapsed or refractory after autologous stem cell transplantation (ASCT), or after at least two previous lines of treatment if ASCT or polichemotherapy do not represent treatment options (as per AIFA label of brentuximab). Patients must also fulfill other specific inclusion and exclusion criteria described below ("Additional inclusion and exclusion criteria"). [2.Even when fulfilling the criteria of point 1 above, patients cannot be enrolled if: i) They had previously received an allotransplant (as they would be blocked by the AIFA registry for brentuximab); ii) or they can receive less than 6 infusions of brentuximab through the AIFA registry (due to previous infusions of the drugs through the registry); iii) or they had progressed on brentuximab after activating the AIFA registry for this drug (because progression on brentuximab recorded in the AIFA registry would block further requests of the drug through this registry). 3. If complying with the criteria of points 1 and 2 above, patients progressing after previous treatment in Cohort-2 may be enrolled in Cohort-1 upon decision of the Sponsor in conjunction with the clinical investigator(s). 4. If complying with the criteria of points 1 and 2 above, patients taken off Cohort-2 due to important toxicity from nivolumab may be enrolled in Cohort-1, upon decision of the Sponsor in conjunction with the clinical investigator(s), as long as they have not responded (i.e., no PR nor CR) to the treatment received in Cohort-2. Cohort 2: ruxolitinib + nivolumab 1. Adult patients with relapsed or refractory cHL previously treated with both ASCT and brentuximab (as per AIFA label of nivolumab). Patients must also fulfill other specific inclusion and exclusion criteria described below (see below section "Additional inclusion and exclusion criteria"). 2. Patients fulfilling the criteria of point 1 above can be enrolled even if: i) They had previously received an allotransplant (which does not block the AIFA registry for nivolumab); ii) They had progressed on nivolumab before activating the AIFA registry for this drug (as they might benefit from combining ruxolitinib to nivolumab). However, even if fulfilling the criteria of point 1 above, patients cannot be enrolled if they progressed on nivolumab after activating the AIFA registry for this drug (because progression on nivolumab recorded in the AIFA registry would block further requests of the drug through this registry). 3. If complying with the criteria of points 1 and 2 above, patients progressing after previous treatment in Cohort-1 may be enrolled in Cohort-2 upon decision of the Sponsor in conjunction with the clinical investigator(s). 4. If complying with the criteria of points 1 and 2 above, patients taken off Cohort-1 due to important toxicity from brentuximab may be enrolled in Cohort-2, upon decision of the Sponsor in conjunction with the clinical investigator(s), as long as they have not responded (i.e., no PR nor CR) to the treatment received in Cohort-1. Additional inclusion criteria (for both cohorts, see the specific section of the protocol) Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 19 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 8
Exclusion criteria
Exclusion criteria: Cohort-1: ruxolitinib + brentuximab 2. Patients cannot be enrolled if: i) They had previously received an allotransplant (as they would be blocked by the AIFA registry for brentuximab); ii) or they can receive less than 6 infusions of brentuximab through the AIFA registry (due to previous infusions of the drugs through the registry); iii) or they had progressed on brentuximab after activating the AIFA registry for this drug (because progression on brentuximab recorded in the AIFA registry would block further requests of the drug through this registry). However, patients fulfilling the criteria of point 1 above can be enrolled if they progressed on brentuximab before activating the AIFA registry (as no record of progression would be present in this registry and the patients might benefit from combining ruxolitinib to brentuximab). Cohort-2: ruxolitinib + nivolumab 2. ii) Patients cannot be enrolled if they progressed on nivolumab after activating the AIFA registry for this drug (because progression on nivolumab recorded in the AIFA registry would block further requests of the drug through this registry). Additional exclusion criteria (for both cohorts, except where noted): 1. Previous treatment of cHL with ruxolitinib or another JAK inhibitor received before enrollment in the trial 2. Refractory nausea and vomiting, malabsorption, external biliary shunt, or significant bowel resection that would preclude adequate absorption. Patients must be able to swallow capsules. 3. CNS involvement by lymphoma 4. Currently uncontrolled active infection 5. Other severe, acute or chronic medical or psychiatric condition or laboratory abnormality that may, in the judgment of the clinical investigator and/or the Sponsor, increase the risk associated with study participation or study drug administration, or may interfere with the interpretation of study results, or may make the patient inappropriate for entry into this study 6. Pregnant or lactating females, or patients who are not willing to use an adequate method of birth control until 6 month after the last dose of brentuximab or nivolumab 7. Inability to comply with other requirements of the protocol 8. [for Cohort-2 only] Symptomatic interstitial lung disease or active autoimmune disease (except for vitiligo, type-1 diabetes, hypothyroidism secondary to autoimmune thyroiditis requiring hormonal replacement therapy, and psoriasis not requiring systemic treatment), as per AIFA registry of nivolumab 9. [for Cohort-2 only] Therapy with systemic immunosuppressive agents (which would be blocked by the AIFA registry of nivolumab, except for doses = 10 mg/day of prednisone or equivalent corticosteroids) must have been stopped since at least 2 weeks
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To determine, in patients with relapsed or refractory cHL, the rate of complete response (CR) to ruxolitinib in combination with brentuximab (Cohort-1) or nivolumab (Cohort-2), reached by the end of treatment with the study drug combination.;Secondary Objective: •To assess the safety of ruxolitinib in combination with brentuximab (Cohort-1) or nivolumab (Cohort-2). •To determine the rates of partial response (PR) and stable disease (SD) observed during ruxolitinib treatment and/or at the end of ruxolitinib treatment. •To determine the rate of CR, PR and SD observed while patients are off-ruxolitinib and may continue brentuximab (Cohort-1) or nivolumab (Cohort-2) on study. •To assess the rate of successful hematopoietic stem cell harvesting and bridging to transplantation in both cohorts. •To assess the efficacy of subsequent treatments that the patients might receive after those planned in the current study. •To assess the survival of patients. •To identify genetic and non-genetic biomarkers of response through centralized analysis (at the Sponsor Institution) of solid and serial liquid biopsies.;Primary end point(s): The primary endpoint in each cohort is to meet or exceed, according to a per-protocol analysis, a pre-determined rate of CR by the end of treatment with the study drug combination (i.e., obtained either at the interim disease evaluation during treatment or at the end of treatment with the study drug combination). The rate of CR has been set at =40% in Cohort-1 and =30% in Cohort-2 (see also "Statistical design and safety measures" below) to improve on the historical CR rates, in relapsed/refractory cHL, of monotherapy with brentuximab (~15-30% depending on the study population) and nivolumab (~10-20%, depending on the study population). The rate of CR will be also assessed according to an intention-to-treat analysis for informative purpose only, because this is a phase-2 non-randomized trial primarily designed to test the anti-lymphoma | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): 1. To describe the type, incidence, grade and relationship to the study drugs of adverse events (AE) occurring in each cohort. 2. To determine the rates of partial response (PR) and stable disease (SD) observed during ruxolitinib treatment and/or at the end of ruxolitinib treatment. 3. To determine the rate of CR, PR and SD observed while patients are off-ruxolitinib and may continue brentuximab (Cohort-1) or nivolumab (Cohort-2) on study. 4. To assess the rate of successful hematopoietic stem cell harvesting and bridging to transplantation in both cohorts. 5. To assess the specific type, efficacy and toxicity of subsequent treatments that the patients might receive after those planned in the current study. 6. To assess the survival of patients: • Progression-free survival, i.e. from start of treatment until date of progression; • Overall survival, i.e. from start of treatment until death from any cause; • Disease-specific survival, i.e. from start of treatment until death due to the disease or to its treatment; • Treatment-free survival, i.e. from the end of study treatment until the beginning of a new treatment other than those planned in this study. 7. To identify potential biomarkers of response through centralized analysis (at the Sponsor institution) of: • Genetic and protein studies on archival and/or newly performed biopsies (e.g., genetic lesions of JAK-STAT pathway members; expression of PDL1, MHC-II, MHC-I and phosphorylated STAT transcription factors) • Genetic and chemokine (e.g., TARC) studies on liquid biopsies taken before, during and after the study treatments.;Timepoint(s) of evaluation of this end point: The timepoints of secondary end points' evaluation for both treatment cohorts will be during the 3-year follow-up after the end of treatment with the study drug combination. | — |
Countries
Italy
Contacts
Public ContactSez. di Ematologia ed Immunologia C
Dip. di Medicina Università di Perugia
Outcome results
None listed