Phase 2 Study of Ruxolitinib with Brentuximab Vedotin or Pembrolizumab in Relapsed/Refractory Classical Hodgkin Lymphoma
- Trial ID
- 2024-520123-83-01
- Protocol
- cHL-PG01
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this phase-2 academic trial is to determine the rate of **complete response (CR)** in patients with relapsed or refractory classical Hodgkin lymphoma (cHL) when treated with a combination of **ruxolitinib** and either **brentuximab** (Cohort-1) or **pembrolizumab** (Cohort-2). This objective is clinically relevant as achieving a complete response is a critical indicator of treatment efficacy in managing cHL, particularly in cases where the disease has not responded to or has progressed after previous treatments.
Secondary objectives include:
- Assessing the safety of ruxolitinib in combination with brentuximab or pembrolizumab.
- Determining the rates of partial response (PR) and stable disease (SD) during and after ruxolitinib treatment.
- Evaluating the rates of CR, PR, and SD while patients are off ruxolitinib but may continue with brentuximab or pembrolizumab.
- Assessing the rate of successful hematopoietic stem cell harvesting and bridging to transplantation.
- Evaluating the efficacy of subsequent treatments post-study.
- Assessing patient survival.
- Identifying biomarkers of response.
Participants
The clinical trial involves **adult patients** diagnosed with relapsed or refractory classical Hodgkin lymphoma (cHL) who have not responded to or have progressed after previous treatments. The study population includes both **male and female** participants aged 18 years and older. Participants are required to have an **ECOG performance status** of 0-1 for Cohort-1 and 0-2 for Cohort-2, with a life expectancy of at least 5 months. The trial does not include a vulnerable population. The selection criteria necessitate that participants have completed any prior anti-lymphoma treatment at least four weeks before the initiation of the study medication, unless progression is evident earlier. The trial population was selected based on specific inclusion criteria, such as having a measurable tumor lesion on PET-CT and the availability of certain biological samples for centralized assessment. The sponsor has not provided information regarding the total number of participants in the study.
Plans and Procedures
The clinical trial is a **phase-2** study designed to evaluate the efficacy of combining **ruxolitinib** with either **brentuximab vedotin** or **pembrolizumab** in patients with relapsed or refractory classical Hodgkin lymphoma (cHL). The trial is structured into two parallel non-randomized cohorts, each focusing on a different combination therapy. The primary objective is to determine the rate of complete response (CR) achieved during or at the end of ruxolitinib treatment. The trial is expected to run until August 2026, with recruitment having commenced in February 2020.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a confirmed diagnosis of cHL, measurable tumor lesions, and a life expectancy of at least five months. Following the screening, participants will be assigned to either Cohort-1 (ruxolitinib + brentuximab) or Cohort-2 (ruxolitinib + pembrolizumab) based on their treatment history and eligibility. The trial will include regular follow-up visits to monitor treatment response and adverse events, with assessments conducted through imaging and biomarker analysis. The end-of-study visit will evaluate the overall treatment outcomes and any long-term effects.
Participant involvement is anticipated to last up to 24 months, corresponding to the maximum treatment period. Conditions that may lead to early termination from the study include significant adverse events, disease progression, or withdrawal of consent. The trial aims to improve historical CR rates, with a target CR rate set at 40% for both cohorts. Secondary endpoints include the assessment of partial response (PR), stable disease (SD), and the incidence and severity of adverse events. The study will also explore potential biomarkers of response through centralized analysis of genetic and protein studies.
Treatment
The clinical trial involves the administration of **pembrolizumab**, marketed under the name Keytruda, which is provided as a 25 mg/mL concentrate for solution for infusion. This pharmaceutical form is intended for **intravenous infusion**. The maximum daily dose is 200 mg, with a total maximum dose of 1600 mg over a treatment period of up to 24 weeks. Pembrolizumab is a protein-based therapeutic agent, specifically a monoclonal antibody, and is utilized in the study to evaluate its efficacy in combination with other treatments for relapsed or refractory classical Hodgkin lymphoma (cHL).
**Ruxolitinib**, marketed as Jakavi, is administered in the form of 20 mg tablets. The route of administration is **oral**, with a maximum daily dose of 40 mg and a total maximum dose of 5040 mg over a 24-week treatment period. Ruxolitinib is a chemical-based therapeutic agent, classified as a JAK1/2 inhibitor. In this trial, ruxolitinib is encapsulated at a 5 mg dose to facilitate administration at specified dosages of 10 mg twice daily (b.i.d.) for 12 weeks and 20 mg b.i.d. for another 12 weeks, with potential dosage reductions to 15 mg b.i.d. or 5 mg b.i.d. for toxicity management.
**Brentuximab vedotin**, marketed as Adcetris, is provided as a 50 mg powder for concentrate for solution for infusion. This formulation is also administered via **intravenous infusion**. The maximum daily dose is 1.8 mg/kg, with a total maximum dose of 14.4 mg/kg over a 24-week treatment period. Brentuximab vedotin is a protein-based therapeutic agent, specifically a monoclonal antibody conjugated to a cytotoxic agent, and is used in the trial to assess its effectiveness in combination with ruxolitinib for the treatment of relapsed or refractory cHL.
Efficacy
The efficacy of the clinical trial will be assessed by evaluating the rate of **complete response (CR)** in patients with relapsed or refractory classical Hodgkin lymphoma (cHL) treated with a combination of ruxolitinib and either brentuximab or pembrolizumab. The primary endpoint is to achieve or exceed a pre-determined CR rate of 40% during or at the end of ruxolitinib treatment, compared to baseline disease status. This assessment will be conducted through a per-protocol analysis.
Secondary endpoints include determining the rates of partial response (PR) and stable disease (SD) during and after ruxolitinib treatment, as well as while patients continue with brentuximab or pembrolizumab. The trial will also describe the type, incidence, grade, and relationship of adverse events to the study drugs. Additional assessments will include the rate of successful hematopoietic stem cell harvesting, bridging to transplantation, and the efficacy and toxicity of subsequent treatments. Survival metrics such as progression-free survival, overall survival, disease-specific survival, and treatment-free survival will be evaluated. Potential biomarkers of response will be identified through centralized analysis of genetic and protein studies on biopsies and liquid biopsies.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Cohort-1: ruxolitinib + brentuximab 1.This cohort is open to 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).
- Cohort-1: ruxolitinib + brentuximab_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 8 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-1: ruxolitinib + brentuximab_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).
- Cohort-1: ruxolitinib + brentuximab_ 4. If complying with the criteria of points 1 and 2 above, patients taken off Cohort-2 due to important toxicity from pembrolizumab 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 or CR) to the treatment received in Cohort- 2.
- Cohort-2: ruxolitinib + pembrolizumab 1. This cohort is open to adult patients with relapsed or refractory cHL previously treated with both ASCT or with at least two prior therapies when ASCT is not a treatment option (as per AIFA label of pembrolizumab).
- Cohort-2: ruxolitinib + pembrolizumab_ 2. Patients fulfilling the criteria of point 1 above can be enrolled even if they had previously received an allotransplant (which does not block the AIFA registry for pembrolizumab), but they cannot be enrolled if they had previously received a PD1 or PDL1 inhibitor (which blocks the AIFA registry)
- Cohort-2: ruxolitinib + pembrolizumab_ 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).
- Cohort-2: ruxolitinib + pembrolizumab_ 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 or CR) to the treatment received in Cohort- 1
- ≥ 18 years of age
- Immuno-histologically proven diagnosis of classical Hodgkin lymphoma
- At least one measurable tumor lesion on PET-CT
- Availability of the whole paraffin block (or, less preferably, at least 30 paraffin sections) of an adequately sized excisional tumor biopsy (archival and/or newly performed) for mandatory centralized assessment of response biomarkers
- Availability of a baseline whole-blood sample of 40 ml for mandatory centralized assessment of response biomarkers
- ECOG performance status: 0-1 for Cohort-1; 0-2 for Cohort-2 (as per AIFA registry)
- Life expectancy ≥ 5 months
- Any prior anti-lymphoma treatment (e.g., chemotherapy, radiotherapy, immunotherapy, investigational agents) must have been completed at least 4 weeks prior to initiation of study medication, except if no response to, or progression on, this treatment is already manifestly evident earlier
- Signed informed consent prior to performing any study-related procedures
Exclusion Criteria
- Previous treatment of cHL with ruxolitinib or another JAK inhibitor received before enrollment in the trial
- Refractory nausea and vomiting, malabsorption, external biliary shunt, or significant bowel resection that would preclude adequate absorption. Patients must be able to swallow capsules.
- CNS involvement by lymphoma
- Currently uncontrolled active infection
- 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
- 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 pembrolizumab
- Inability to comply with other requirements of the protocol
- [for Cohort-2 only] Previous treatment with a PD1/PDL1 inhibitor, as per AIFA registry on pembrolizumab
- [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 treatmentystemic treatment), as per AIFA registry of pembrolizumab; or active graft-versus-host disease after allo-transplantation.
- [for Cohort-2 only] Therapy with systemic immunosuppressive agents (which would be blocked by the AIFA registry of pembrolizumab, except for doses ≤ 10 mg/day of prednisone or equivalent corticosteroids) must have been stopped since at least 2 weeks
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Italy | Not Recruiting | 01 Feb 2020 | 48 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
ADCETRIS 50 mg powder for concentrate for solution for infusion. | Test | POWDER FOR CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENIOUS INFUSION | 1.8 | 24 | PRD2487300 |
Jakavi 20 mg tablets | Test | TABLETS | ORAL | 40 | 24 | PRD3949627 |
KEYTRUDA 25 mg/mL concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENIOUS INFUSION | 200 | 24 | PRD4323105 |