A phase-2 academic trial testing, in two parallel non-randomized cohorts, the combination of ruxolitinib (JAK1/2 inhibitor) with brentuximab or pembrolizumab in relapsed or refractory classical Hodgkin lymphoma (cHL)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Universita' Degli Studi Di Perugia

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

11 Feb 2020 → ongoing

Decision date (initial)

2025-01-31

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

No

Funding sources

Dipartimento di Medicina e Chirurgia, Università Degli Studi di Perugia

External identifiers

EU CT number

2024-520123-83-01

EudraCT number

2019-003084-21

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Therapy, Efficacy

To determine, in patients with relapsed or refractory cHL, the rate of complete response (CR) to ruxolitinib in combination with brentuximab (Cohort-1) or pembrolizumab (Cohort-2), reached during ruxolitinib treatment or at the end of ruxolitinib treatment.

Secondary objectives 7

1. To assess the safety of ruxolitinib in combination with brentuximab (Cohort-1) or pembrolizumab (Cohort-2).
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 pembrolizumab (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 efficacy of subsequent treatments that the patients might receive after those planned in the current study.
6. To assess the survival of patients.
7. To identify biomarkers of response.

Conditions and MedDRA coding

Patients with relapsed or refractory cHL that has not responded to, or has progressed after, the previous treatment. Neither Cohort-1 nor Cohort-2 are open to patients with a partial response after the immediate prior treatment (including salvage therapy before autologous or allogeneic transplantation); such patients would become eligible only upon subsequent progression.

Regulatory references

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 17

1. 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).
2. 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).
3. 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).
4. 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.
5. 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).
6. 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)
7. 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).
8. 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
9. ≥ 18 years of age
10. Immuno-histologically proven diagnosis of classical Hodgkin lymphoma
11. At least one measurable tumor lesion on PET-CT
12. 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
13. Availability of a baseline whole-blood sample of 40 ml for mandatory centralized assessment of response biomarkers
14. ECOG performance status: 0-1 for Cohort-1; 0-2 for Cohort-2 (as per AIFA registry)
15. Life expectancy ≥ 5 months
16. 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
17. Signed informed consent prior to performing any study-related procedures

Exclusion criteria 10

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 pembrolizumab
7. Inability to comply with other requirements of the protocol
8. [for Cohort-2 only] Previous treatment with a PD1/PDL1 inhibitor, as per AIFA registry on pembrolizumab
9. [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.
10. [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

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The primary endpoint in each cohort is to meet or exceed, according to a perprotocol analysis, a pre-determined rate of CR during, or at the end of, ruxolitinib treatment (i.e., obtained either at the interim disease evaluation during ruxolitinib treatment or at the end of ruxolitinib treatment, in comparison to the baseline disease status). The rate of CR has been set at ≥40% in both Cohorts to improve on the historical CR rates, in rela

Secondary endpoints 7

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 offruxolitinib and may continue brentuximab (Cohort-1) or pembrolizumab (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
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.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Universita' Degli Studi Di Perugia

Sponsor organisation

Universita' Degli Studi Di Perugia

Address

Piazza Dell' Universita' 1

City

Perugia

Postcode

06123

Country

Italy

Scientific contact point

Organisation

Universita' Degli Studi Di Perugia

Contact name

Enrico Tiacci

Public contact point

Organisation

Universita' Degli Studi Di Perugia

Contact name

Enrico Tiacci

Locations

1 EU/EEA country · 12 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 16 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

3 submissions — initial application plus substantial / non-substantial modifications