Trial Title:
Efficacy and Safety of Frontline Tislelizumab in Patients With de Novo Hodgkin Lymphoma Unsuitable for Standard Frontline Chemotherapy
NCT ID:
NCT05977673
Condition:
Hodgkin Lymphoma
Conditions: Official terms:
Lymphoma
Hodgkin Disease
Tislelizumab
Conditions: Keywords:
Lymphoma
Hodgkin
Tislelizumab
PD1
Checkpoint
Inhibitor
De novo
Unsuitable
Chemotherapy
Immune
Study type:
Interventional
Study phase:
Phase 2
Overall status:
Recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Tislelizumab
Description:
Tislelizumab 200mg IV day1
Arm group label:
Tislelizumab
Summary:
This is a multicenter, prospective, non-randomized, open-label, phase 2 clinical study to
evaluate the efficacy and safety of tislelizumab in patients with de novo Hodgkin
Lymphoma deemed ineligible to frontline chemotherapy.
Detailed description:
Approximately two-thirds of patients with Hodgkin lymphoma (HL) can be cured with
standard frontline chemotherapy with doxorubicin, bleomycin, vinblastine and dacarbazine
(ABVD). The majority of new patients present in the second and third decade of life, but
at least 25% of de novo cases are in patients older than 65. Elderly patients with HL
display dismal outcomes for several reasons: the disease is implicitly more aggressive
than in younger adults, with an advanced stage in at least two-thirds of cases and the
presence of multiple risk factors for poor outcome (according to the International
Prognostic Score). Moreover, patients may show impaired organ function that require
chemotherapy dose reductions, treatment delays or drug withdrawal.
Given the difficulty of delivering of full treatment doses to elderly patients and to
those with relevant medical comorbidities, there is a need for new and better tolerated
agents in this context.
Given the difficulty of delivering of full treatment doses to elderly patients and to
those with relevant medical comorbidities, there is a need for new and better tolerated
agents in this context. Importantly, no single agent has received approval for this kind
of patients, and drugs like gemcitabine and bendamustine - both active in relapsed
patients with limited toxicity - have limitations in their prescription. The anti-CD30
immunoconjugate agent brentuximab vedotin (BV) applied in patients older than 60 years
and considered unsuitable for frontline chemotherapy, yielded an overall response of 92%,
with 73% of patients achieving a complete remission and a median duration of response of
9.1 months.
Immune checkpoint inhibitors, namely nivolumab and pembrolizumab, have been largely
tested in patients with relapsed and refractory HL failing both autologous stem cell
transplant and BV. Both agents display efficacy in this context, with significant rates
of objective responses, which appear to be durable. Along with an acceptable safety
profile, both agents have been approved in relapsed and refractory HL, providing a good
treatment option for heavily pretreated patients. Tislelizumab (T, BGB-A317) is a
humanized IgG4 mAb with high affinity and specificity for programmed cell death protein 1
(PD1), showing a superior antitumor activity compared to nivolumab in mice transplanted
with human cancer cells and peripheral blood mononuclear cells. High response rates have
been reported in Chinese HL patients who have failed or were ineligible to autologous
transplantation, including a complete response rate of 61% and a partial response rate of
24%.
Investigators postulate that an induction based on single-agent tislelizumab can be a
feasible chemo-free treatment strategy to be offered to patients with de novo HL who are
unsuitable for a chemotherapy-based frontline approach.
The study also addresses biological evaluation of biomarkers in the tumor clone and in
the microenvironment at baseline and their possible correlation with patients' outcome
and responses.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
- Histologically confirmed diagnosis of de novo classical Hodgkin Lymphoma (cHL).
Note: Availability of either block or unstained slides plus stained slides used by
the local pathologist to make diagnosis, and of all pathology reports is mandatory
for the study to perform central pathology review for confirmation of cHL diagnosis
and for biological biomarkers assessments. Central pathology confirmation is not
required to start treatment;
- Patients >= 65 years ineligible for frontline standard chemotherapy (mainly due to
medical comorbidities);
- Treatment naïve;
- Measurable disease defined as presence of both fluorodeoxyglucose-avid nodal
involvement and at least one nodal target lesion measurable in two diameters (and at
least 1.5 cm in its major diameter); • Indication for systemic treatment, i.e., all
stages except IA without a large tumor burden, as radiotherapy is regarded curative
in those patients;
- Eastern Cooperative Oncology Group (ECOG) performance status (PS) <= 2;
- Adequate organ and marrow function as defined below:
- Absolute neutrophil count (ANC) > 109/L (without growth factor support within 7
days of ANC measurement), unless due to bone marrow involvement by lymphoma
- Platelet > 50 x 109/L (without growth factor support or transfusion within 7
days of platelets measurement) , unless due to bone marrow involvement by
lymphoma
- Hemoglobin > 8 g/dL (prior transfusion is acceptable)
- Creatinine clearance ≥ 30 ml/min (as estimated by the Cockcroft-Gault equation
or as measured by nuclear medicine scan or 24-hour urine collection)
- Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase, and
alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase ≤ 3.0 ×
upper limit of normal (ULN)
- Serum total bilirubin < 1.5 × ULN (or < 3 x ULN in case of documented Gilbert's
syndrome)
- Life expectancy ≥ 6 months;
- Men must agree to use effective contraception if sexually active. This applies for
the time period between signing of the informed consent form and 4 months after last
tislelizumab dose. The investigator or a designated associate is requested to advise
the patient how to achieve highly effective birth control method, e.g. vasectomy,
use of condoms or complete sexual abstinence, when this is in line with the
preferred and usual lifestyle of the subject.The use of condoms by male patients is
required unless the female partner is permanently sterile. Periodic abstinence
(e.g., calendar, ovulation, symptothermal, post ovulation methods for the female
partner) and withdrawal are not acceptable methods of contraception.
- Subject voluntarily signs and dates an informed consent form approved by an National
Ethics Committee (NEC) prior to the initiation of any screening or study-specific
procedures, indicating that they understand the purpose of and procedures required
for the study and are willing to participate in it;
- Subject must be able to adhere to the study visit schedule and other protocol
requirements, and to return to enrolling institution for follow-up (during the
active monitoring phase of the study).
Exclusion Criteria:
- Nodular lymphocyte predominant HL;
- Any previous treatment (including radiation therapy) for HL;
- Any active autoimmune disease requiring systemic treatment (including
disease-modifying agents, corticosteroids, immunosuppressants) in the past 2 years;
Note: Patients with the following diseases are not excluded and may proceed to
further screening: Type I diabetes under control; Hypothyroidism (provided it is
managed with hormone replacement therapy only); Controlled celiac disease;
- Has known history of interstitial lung disease, non-infectious pneumonitis,
pulmonary fibrosis, acute lung diseases or evidence of dyspnea at rest or pulse
oximetry of < 92% while breathing room air;
- A history of previous exposure to anti-PD1, anti-PDL1 or anti-PDL2 or anti-CTLA-4
agents for any disease other than HL;
- Use of systemic treatment with either corticosteroids (> 10 mg daily prednisone
equivalents) or other immunosuppressive medications ≤14 days from registration;
Note: Inhaled or topical steroids and adrenal replacement doses > 10 mg daily
prednisone equivalents are permitted in the absence of active autoimmune disease;
- Known infection with HIV, human T-cell lymphotropic virus-1, -2; • Serologic status
reflecting active hepatitis B defined as presence of hepatitis B surface antigen
(HBsAg) or hepatitis B core antibody (HBcAb) (mandatory testing). Patients with
occult or prior HBV infection (respectively defined as patient with HBsAg-/HBcAb+
and patients HBsAg+ with HBV DNA undetectable) are eligible, provided that they are
willing to undergo prophylactic antiviral medication according to local standard of
care. Patients who have protective titers of hepatitis B surface antibody (HBsAb)
after vaccination are eligible;
- Presence of hepatitis C virus (HCV) antibody (mandatory HCV antibody serology
testing). Patients with presence of HCV antibody are eligible only if PCR is
negative for HCV RNA;
- Hypersensitivity to tislelizumab or any of its excipients;
- Active central nervous system (CNS) involvement or leptomeningeal metastases
involvement;
- Evidence of other clinically significant uncontrolled and/or active systemic
infection (viral, bacterial or fungal), including active ongoing infection from
SARS-CoV-2;
- Co-morbid systemic illnesses or other severe concurrent disease which, in the
judgment of the investigator, would make the patient inappropriate for entry into
this study or interfere significantly with the proper assessment of safety and
toxicity of the prescribed regimens;
- Major surgery within 4 weeks of the first dose of study drug;
- Vaccination with a live vaccine within 4 weeks prior to the first dose of study
drug;
- Clinically significant cardiovascular disease including the following:
- Myocardial infarction within 6 months before screening;
- Unstable angina within 3 months before screening;
- New York Heart Association Classification III or IV congestive heart failure;
- History of clinically significant arrhythmias (e.g., sustained ventricular
tachycardia, ventricular fibrillation, torsade de pointes);
- QTcF > 480 msecs based on Fridericia's formula;
- History of Mobitz II second-degree or third-degree heart block without a
permanent pacemaker in place;
- Uncontrolled hypertension as indicated by a minimum of 2 consecutive blood
pressure measurements showing systolic blood pressure > 170 mm Hg and diastolic
blood pressure > 105 mm Hg at screening;
- Significant history of neurologic, psychiatric, endocrinological, metabolic,
immunologic, or hepatic disease that would preclude participation in the study or
compromise ability to give informed consent;
- Any history of other active malignancies within 3 years prior to study entry, with
the exception of adequately treated in situ carcinoma of the cervix uterine, basal
cell carcinoma of the skin or localized squamous cell carcinoma of the skin,
previous malignancy confined and surgically resected with curative intent;
- History of severe hypersensitivity reactions to other monoclonal antibodies;
- Concurrent participation in another therapeutic clinical trial.
Gender:
All
Minimum age:
65 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
A.O. SS. Antonio e Biagio e Cesare Arrigo, S.C. Ematologia
Address:
City:
Alessandria
Country:
Italy
Status:
Recruiting
Contact:
Last name:
Manuela Zanni, MD
Email:
manuela.zanni@ospedale.al.it
Investigator:
Last name:
Manuela Zanni, MD
Email:
Principal Investigator
Facility:
Name:
Divisione di Oncologia e dei Tumori immuto-correlati, Centro Di Riferimento Oncologico Di Aviano
Address:
City:
Aviano
Country:
Italy
Status:
Recruiting
Contact:
Last name:
Michele Spina, MD
Email:
mspina@cro.it
Investigator:
Last name:
Michele Spina, MD
Email:
Principal Investigator
Facility:
Name:
Istituto di Ematologia L. e A. Seràgnoli, AOU Policlinico S. Orsola-Malpighi
Address:
City:
Bologna
Country:
Italy
Status:
Not yet recruiting
Contact:
Last name:
Pier Luigi Zinzani, MD
Email:
pierluigi.zinzani@unibo.it
Investigator:
Last name:
Pier Luigi Zinzani, MD
Email:
Principal Investigator
Facility:
Name:
SC Ematologia, Azienda Socio Sanitaria Territoriale Degli Spedali Civili Di Brescia
Address:
City:
Brescia
Country:
Italy
Status:
Not yet recruiting
Contact:
Last name:
Alessandra Tucci, MD
Email:
alessandra.tucci@asst-spedalicivili.it
Investigator:
Last name:
Alessandra Tucci, MD
Email:
Principal Investigator
Facility:
Name:
Ematologia, Fondazione IRCCS Istituto Nazionale Dei Tumori
Address:
City:
Milano
Country:
Italy
Status:
Recruiting
Contact:
Last name:
Chiara Rusconi, MD
Email:
chiara.rusconi@istitutotumori.mi.it
Investigator:
Last name:
Chiara Rusconi, MD
Email:
Principal Investigator
Facility:
Name:
Unità di Ematologia e TMO - Unità Linfomi, Ospedale San Raffaele
Address:
City:
Milano
Country:
Italy
Status:
Recruiting
Contact:
Last name:
Andrés J.M. Ferreri, MD
Email:
andres.ferreri@hsr.it
Investigator:
Last name:
Andrés J.M. Ferreri, MD
Email:
Principal Investigator
Facility:
Name:
Oncologia, IRCCS Istituto Nazionale Tumori Fondazione Pascale
Address:
City:
Napoli
Country:
Italy
Status:
Recruiting
Contact:
Last name:
Antonio Pinto, MD
Email:
a.pinto@istitutotumori.na.it
Investigator:
Last name:
Antonio Pinto, MD
Email:
Principal Investigator
Facility:
Name:
Oncoematologia, Azienda Ospedaliera Ospedali Riuniti Villa Sofia Cervello
Address:
City:
Palermo
Country:
Italy
Status:
Not yet recruiting
Contact:
Last name:
Caterina Patti, MD
Email:
k.patti@villasofia.it
Investigator:
Last name:
Caterina Patti, MD
Email:
Principal Investigator
Facility:
Name:
Istituto Ematologia -Dipartimento di Medicina Traslazionale e di Precisione, Azienda Ospealiero Universitaria Policlinico Umberto I
Address:
City:
Roma
Country:
Italy
Status:
Not yet recruiting
Contact:
Last name:
Ilaria Del Giudice, MD
Email:
ilaria.delgiudice@uniroma1.it
Investigator:
Last name:
Ilaria Del Giudice, MD
Email:
Principal Investigator
Facility:
Name:
U.O di Oncologia Medica ed Ematologia, Humanitas Research Hospital
Address:
City:
Rozzano
Country:
Italy
Status:
Recruiting
Contact:
Last name:
Francesca Ricci, MD
Email:
francesca.ricci@humanitas.it
Investigator:
Last name:
Francesca Ricci, MD
Email:
Principal Investigator
Start date:
May 23, 2024
Completion date:
April 2029
Lead sponsor:
Agency:
Fondazione Italiana Linfomi - ETS
Agency class:
Other
Source:
Fondazione Italiana Linfomi - ETS
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05977673
