Individualized Immunotherapy in Early-Stage Unfavorable Classical Hodgkin Lymphoma

Overview

Sponsor-declared trial summary

Key facts

Sponsor

University Of Cologne

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

15 May 2024 → ongoing

Decision date (initial)

2023-12-18

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

BeiGene Ltd.

External identifiers

EU CT number

2022-500571-32-00

ClinicalTrials.gov

NCT04837859

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy

By implementation of tislelizumab into a PET-guided treatment strategy, the aim of this trial is to establish an individualized first-line treatment incorporating checkpoint inhibition for early-stage unfavorable cHL, which is effective and well tolerated.
The primary objective of this prospective, multicenter phase II trial is to estimate efficacy of the novel regimen in terms of the primary endpoint, the 1-year PFS estimate, in the main cohort of patients aged 18-60 years.

Secondary objectives 1

1. Secondary objectives of this phase II trial are to further describe efficacy, safety and feasibility of the new regimen in the main cohort as well as in the separate, exploratory cohort of patients above the age of 60 years. PFS and OS after three years will serve as measures for efficacy and safety in the long term. Correlative scientific substudies will be performed in participants providing separate informed consent as exploratory analyses.

Conditions and MedDRA coding

Early-Stage Unfavorable Classical Hodgkin Lymphoma

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 12

1. Age ≥ 18 and ≤ 60 years on the day of signing the patient information and informed consent form (ICF)
2. Histologically proven first diagnosis of cHL
3. No prior cHL treatment except corticosteroid pre-phase, if clinically indicated
4. Early-stage unfavorable cHL per GHSG criteria, defined as stage IA, IB or IIA with any risk factor a-d; or stage IIB with c and/or d according to locally assessed PET/CT based staging including all mandatory imaging examinations as outlined in Section 5.1.2.3: a) Large mediastinal mass (≥ 1/3 of the thorax maximum transverse diameter); b) Extranodal lesion(s); c) Elevated erythrocyte sedimentation rate (ESR; ≥ 50 mm/h without B symptoms, ≥ 30 mm/h with B symptoms); d) ≥ 3 nodal areas
5. Able to provide written informed consent and can understand and agree to comply with the requirements of the clinical trial including measures for contraception and schedule of assessments
6. Estimated life expectancy > 3 months
7. Adequate organ function as indicated by the following parameters (except for cHL-related disorders) obtained within 7 days prior to enrollment: a) Patients must not have required a blood transfusion or growth factor support ≤ 14 days before sample collection at screening for the following - Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L - Platelets ≥ 75 x 10^9/L - Hemoglobin ≥ 9.0 g/dL b) Serum creatinine ≤ 1.5 x upper limit of normal (ULN) or estimated GFR ≥ 60 mL/min/1.73 m2 c) Total bilirubin ≤ 1.5 x ULN (total bilirubin < 3 x ULN in patients with Gilberts syndrome). d) AST and ALT ≤ 3 x ULN e) Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1, ECOG = 2 allowed if due to cHL
8. Contraception: a) Females of childbearing potential (WOCBP, defined as any woman who has experienced menarche and who is not postmenopausal with menopause documented by amenorrhea for > 12 months and repeated follicle-stimulating hormone (FSH) levels > 30 mIU/mL or surgical sterilization) must be willing to use a highly effective method of contraception and abstain from breastfeeding children from enrollment to at least 6 months after the last dose of systemic trial treatment, and have a negative urine or serum pregnancy test ≤ 7 days of first dose of trial treatment. b) Non-sterile males who are sexually active with WOCBP must be willing to use barrier methods such as a condom for effective contraception and refrain from sperm-donation from enrollment to at least 6 months after the last dose of systemic trial treatment.
9. Exploratory cohort: Patients are eligible for enrollment into the exploratory cohort for older patients if the inclusion criteria 2.-8. (see above) as well as the following additional criteria are met.
10. Age ≥ 61 years on the day of signing the ICF (exploratory cohort only)
11. Considered eligible for 4 cycles of AVD chemotherapy by the investigator (exploratory cohort only)
12. Total CIRS-G score < 10 and score ≤ 3 for each organ system assessed. Note: The presence of cHL as hematologic malignancy or cHL-associated blood count deviations are not scored as hematopoietic disorder in this context and patients with score 4 for the organ system "Eyes, Ears, Nose and Throat and Larynx" are permitted for trial enrollment (exploratory cohort only)

Exclusion criteria 15

1. Presence of nodular lymphocyte-predominant Hodgkin lymphoma, grey-zone lymphoma and/or lymphoma involvement of the central nervous system
2. Active autoimmune diseases or history of autoimmune diseases that may relapse Note: Patients with the following diseases are not excluded and may proceed to further screening: a) Controlled Type I diabetes b) Hypothyroidism (provided it is managed with hormone replacement therapy only) c) Controlled celiac disease d) Skin diseases not requiring systemic treatment (e.g. vitiligo, psoriasis, alopecia) e) Any other disease that is not expected to recur in the absence of external triggering factors
3. Any condition that required systemic treatment with either corticosteroids (> 10 mg daily of prednisone-equivalent) or other immunosuppressive medication ≤ 14 days before enrollment Note: Patients who are currently or have previously been on any of the following steroid regimens are not excluded: a) Adrenal replacement steroid (dose ≤ 15 mg daily of prednisone or equivalent) b) Topical, ocular, intra-articular, intranasal, or inhaled corticosteroid with minimal systemic absorption c) Short course (≤ 7 days) of corticosteroid prescribed prophylactically (e.g. for contrast dye allergy) or for the treatment of a non-autoimmune condition (e.g. pre-phase due to cHL symptoms, delayed-type hypersensitivity reaction caused by contact allergen)
4. Any serious or uncontrolled medical disorder that, in the opinion of the local investigator, may increase the risk associated with trial participation or trial treatment administration, impair the ability of the patient to receive trial treatment, or interfere with the interpretation of trial results including, but not limited to, the following: a) Active interstitial lung disease, non-infectious pneumonitis, chronic obstructive pulmonary disease with global respiratory failure or other uncontrolled symptomatic pulmonary diseases with severely impaired lung function as defined by spirometry (forced expiratory volume, FEV1) and/or diffusing capacity of the lung for carbon monoxide (DLCOc_SB) of < 60% of the normal predicted value at enrollment. b) Any of the following cardiovascular risk factors or conditions: - Unstable cardiac chest pain, defined as moderate pain that limits instrumental activities of daily living, ≤ 28 days before enrollment; - Pulmonary artery embolism ≤ 28 days before enrollment; - History of acute myocardial infarction ≤ 6 months before enrollment; - History of heart failure meeting New York Heart Association (NYHA) Classification III or IV ≤ 6 months before enrollment; - Left ventricular ejection fraction < 50% documented ≤ 6 months before enrollment; - Any event of ventricular arrhythmia ≥ grade 2 in severity ≤ 6 months before enrollment; - Any history of cerebrovascular incident ≤ 6 months before enrollment; - Uncontrolled hypertension: systolic pressure ≥ 180 mmHg or diastolic pressure ≥ 100 mmHg despite anti-hypertension medication ≤ 28 days before enrollment; - Any seizure ≤ 28 days before enrollment c) Severe uncontrolled chronic or active infections requiring prolonged systemic antibacterial, antifungal or antiviral therapy. d) Acute or chronic active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. e) Uncontrolled human immundeficiency virus (HIV) infection. Note: Patients on antiretroviral therapy (ART) with controlled HIV infection (defined as sufficient ART compliance, non-measurable HIV and CD4+ T helper cells > 200/microL) may be enrolled, if considered eligible for trial treatment by the investigator.
5. Administration of a live vaccine ≤ 4 weeks before enrollment Note: Seasonal vaccines for influenza are generally inactivated vaccines and are allowed, as are messenger ribonucleic acid (mRNA)-based vaccines for SARS-CoV-2. Intranasal vaccines are usually live vaccines, and are not allowed.
6. Any other active malignancy diagnosed ≤ 3 years before enrollment except any locally recurring cancer that has been treated curatively (e.g. resected basal or squamous cell skin cancer, superficial bladder cancer, carcinoma in situ of prostate, cervix or breast)
7. Prior allogeneic stem cell transplantation or organ transplantation
8. A history of severe hypersensitivity reactions to humanized antibodies
9. Pregnancy or breastfeeding
10. Committal to an institution on judicial or official order
11. Relationship of dependence or employer-employee relationship to the sponsor or the investigator
12. Lack of accountability and inability to appreciate the nature, meaning and consequences of the trial and to formulate their own wishes correspondingly
13. Non-compliance, for reasons including, but not limited to, the following: - Drug dependency or substance abuse that would interfere with cooperation with requirements of the trial - Refusal of blood products during treatment - Any similar circumstances that appear to make compliance with any trial procedures impossible
14. Concurrent participation in another therapeutic clinical trial that could interact with the INDIE trial
15. The exclusion criteria (see above) also apply for enrollment into the exploratory cohort for older patients.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. 1-year progression-free survival (PFS) estimate

Secondary endpoints 8

1. Adverse events
2. 3-year PFS estimate
3. 1- and 3-year overall survival (OS) estimates
4. Patient-reported outcomes (PRO-CTCAE, quality of life)
5. Remission status after 2 doses of tislelizumab as determined by PET-2 (DS) and MTV-2, respectively
6. Remission status after completion of (chemo-) immunotherapy as determined by PET-6 (DS) and MTV-6, respectively
7. Remission status after end of treatment
8. Types of treatment applied in addition to trial treatment

Investigational products

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

Test 1

Auxiliary 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

University Of Cologne

Sponsor organisation

University Of Cologne

Address

Albertus-Magnus-Platz 1

City

Cologne

Postcode

50923

Country

Germany

Scientific contact point

Organisation

University Of Cologne

Contact name

Paul Bröckelmann

Public contact point

Organisation

University Of Cologne

Contact name

Paul Bröckelmann

Locations

1 EU/EEA country · 68 investigational sites

By country

Investigational sites

Country notifications

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

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Serious breaches 2 · Art. 52 CTR

Results and documents

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

Documents 22 files

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

Application history

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