INDIE: Phase II Trial of Individualized Immunotherapy in Early-Stage Unfavorable Classical Hodgkin Lymphoma
- Trial ID
- 2022-500571-32-00
- Protocol
- Uni-Koeln-4470
- Sponsor
- University Of Cologne
Trial statistics
Objectives
The primary objective of this phase II trial is to evaluate the efficacy of a novel treatment regimen incorporating **tislelizumab** within a PET-guided strategy for patients with early-stage unfavorable classical Hodgkin lymphoma (cHL). The primary endpoint is the 1-year progression-free survival (PFS) estimate in the main cohort of patients aged 18-60 years. This objective is clinically relevant as it aims to establish an effective and well-tolerated first-line treatment option that includes checkpoint inhibition, potentially improving patient outcomes in this specific lymphoma subset.
Secondary objectives include further assessment of the regimen's efficacy, safety, and feasibility in both the main cohort and an exploratory cohort of patients over 60 years of age. Long-term efficacy and safety will be measured by PFS and overall survival (OS) after three years. Additionally, correlative scientific substudies will be conducted as exploratory analyses for participants who provide separate informed consent.
Participants
The clinical trial focuses on individuals diagnosed with **Early-Stage Unfavorable Classical Hodgkin Lymphoma**. The study population includes both male and female participants, aged between 18 and 60 years, with an exploratory cohort for those aged 61 and above. Participants are required to have a histologically confirmed first diagnosis of classical Hodgkin lymphoma (cHL) and must not have received prior cHL treatment, except for corticosteroid pre-phase if clinically indicated. The trial includes individuals with adequate organ function and an estimated life expectancy of more than three months. Participants must be able to provide written informed consent and comply with trial requirements, including contraception measures. The trial population was selected based on specific inclusion criteria, such as being eligible for AVD chemotherapy and having a total CIRS-G score of less than 10. The sponsor has not provided information regarding the total number of participants. The study considers lifestyle factors such as the ability to comply with contraception requirements and the exclusion of prior cHL treatments, which may influence the participants' health status and trial outcomes.
Plans and Procedures
The clinical trial is designed as a **randomized**, **double-blind**, and controlled study to evaluate the efficacy and safety of an individualized immunotherapy regimen for patients with early-stage unfavorable classical Hodgkin lymphoma. The trial will incorporate the use of **tislelizumab** in a PET-guided treatment strategy, aiming to establish a first-line treatment that is both effective and well-tolerated. The primary endpoint is the 1-year progression-free survival (PFS) estimate, with secondary endpoints including adverse events, 3-year PFS estimate, overall survival estimates, and patient-reported outcomes. The trial is expected to run until December 2027, with recruitment starting in December 2023.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, histologically proven diagnosis of classical Hodgkin lymphoma, and adequate organ function. Following the screening, participants will be randomized to receive the investigational treatment. The treatment period will last up to 33 weeks, during which participants will receive **doxorubicin**, **vinblastine**, **dacarbazine**, and **tislelizumab** via infusion. Follow-up visits will be scheduled to monitor the participants' response to treatment and any adverse events. The end-of-study visit will occur after the completion of the treatment regimen to assess the final outcomes and remission status.
The expected length of participant involvement is approximately 33 weeks, with conditions for early termination including significant adverse events, withdrawal of consent, or any other medical reasons deemed necessary by the investigator. Participants will be closely monitored throughout the trial to ensure safety and adherence to the protocol. The trial aims to provide valuable insights into the potential benefits of incorporating checkpoint inhibition into the treatment of early-stage unfavorable classical Hodgkin lymphoma.
Treatment
The clinical trial involves the administration of several **experimental medications** and auxiliary treatments. **Doxorubicin** is utilized in this study as an auxiliary treatment. It is provided in the form of an **injection** and is administered via **infusion**. The dosing regimen for doxorubicin is set at a maximum daily dose of 25 mg/m², with a total maximum dose of 200 mg/m² over a treatment period of 33 days. The active substance, doxorubicin, is of chemical origin.
**Tislelizumab** serves as the primary experimental medication in this trial. It is supplied as a **solution for infusion** and is administered through infusion. The maximum daily dose for tislelizumab is 300 mg, with a cumulative maximum dose of 1600 mg over the course of 33 days. Tislelizumab is a protein-based substance, specifically categorized as "Protein - Other," and is produced by BeiGene.
**Vinblastine** is another auxiliary treatment used in the study. It is available as a **solution for injection** and is administered via infusion. The dosing schedule for vinblastine includes a maximum daily dose of 6 mg/m² and a total maximum dose of 48 mg/m² over a 33-day treatment period. The active substance vinblastine is of unspecified origin.
**Dacarbazine** is also employed as an auxiliary treatment in the trial. It is provided as a **powder for solution for injection/infusion** and is administered through infusion. The dosing regimen for dacarbazine includes a maximum daily dose of 375 mg/m², with a total maximum dose of 3000 mg/m² over a 33-day period. The active substance dacarbazine is of chemical origin.
All medications are administered via infusion, and participant compliance is monitored throughout the trial to ensure adherence to the dosing schedules. The trial aims to evaluate the efficacy of the novel regimen, particularly focusing on the primary endpoint of 1-year progression-free survival (PFS) in patients with early-stage unfavorable Hodgkin Lymphoma.
Efficacy
The efficacy of the clinical trial will be assessed primarily through the 1-year **progression-free survival (PFS)** estimate. This primary endpoint is designed to evaluate the effectiveness of the novel treatment regimen incorporating **tislelizumab** in patients with early-stage unfavorable classical Hodgkin Lymphoma (cHL). Secondary endpoints include the assessment of adverse events, 3-year PFS estimate, 1- and 3-year overall survival (OS) estimates, and patient-reported outcomes related to quality of life. Additionally, remission status will be evaluated after two doses of tislelizumab using PET-2 (Deauville Score) and MTV-2, as well as after the completion of (chemo-) immunotherapy using PET-6 (Deauville Score) and MTV-6. Remission status will also be assessed at the end of treatment.
The trial will employ a prospective, multicenter phase II design to estimate the efficacy of the treatment strategy. The schedule for measuring and collecting these efficacy parameters includes specific timepoints for PET scans and patient-reported outcomes, although exact timepoints are not detailed in the provided data. The trial aims to establish an individualized first-line treatment strategy that is both effective and well-tolerated, with a focus on incorporating checkpoint inhibition through the use of tislelizumab. The trial is expected to conclude by December 2027, with recruitment starting in December 2023.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Age ≥ 18 and ≤ 60 years on the day of signing the patient information and informed consent form (ICF)
- Histologically proven first diagnosis of cHL
- No prior cHL treatment except corticosteroid pre-phase, if clinically indicated
- 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
- 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
- Estimated life expectancy > 3 months
- 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
- 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.
- 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.
- Age ≥ 61 years on the day of signing the ICF (exploratory cohort only)
- Considered eligible for 4 cycles of AVD chemotherapy by the investigator (exploratory cohort only)
- 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
- Presence of nodular lymphocyte-predominant Hodgkin lymphoma, grey-zone lymphoma and/or lymphoma involvement of the central nervous system
- 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
- 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)
- 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.
- 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.
- 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)
- Prior allogeneic stem cell transplantation or organ transplantation
- A history of severe hypersensitivity reactions to humanized antibodies
- Pregnancy or breastfeeding
- Committal to an institution on judicial or official order
- Relationship of dependence or employer-employee relationship to the sponsor or the investigator
- Lack of accountability and inability to appreciate the nature, meaning and consequences of the trial and to formulate their own wishes correspondingly
- 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
- Concurrent participation in another therapeutic clinical trial that could interact with the INDIE trial
- The exclusion criteria (see above) also apply for enrollment into the exploratory cohort for older patients.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Germany | Not Recruiting | 01 Dec 2023 | 120 |
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 |
|---|---|---|---|---|---|---|
VINBLASTINE | Other | — | INFUSION | 6 | 33 | SUB00052MIG |
DACARBAZINE | Other | — | INFUSION | 375 | 33 | SUB06882MIG |
DOXORUBICIN | Other | — | INFUSION | 25 | 33 | SUB06391MIG |
Tislelizumab | Test | SOLUTION FOR INFUSION | INFUSION | 300 | 33 | PRD5423108 |