Phase I-II Study of Brentuximab Vedotin with R-DHAP in CD30+ Diffuse Large B-Cell Lymphoma Refractory or Relapsed Post-First-Line Chemotherapy

Trial ID: 2023-510556-22-00
Protocol: HO136
Sponsor: Hemato-Oncologie voor Volwassenen Nederland (Hovon) Stichting

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Diseases & Conditions

Diffuse large B-cell lymphoma Non-Hodgkin's lymphoma

Objectives

The primary objective of this study is to evaluate the **feasibility** and recommended dose level (RDL) of **brentuximab vedotin** in combination with R-DHAP in patients with CD30 positive diffuse large B-cell lymphoma (DLBCL) who are refractory to first-line chemotherapy or in first relapse. Additionally, the study aims to assess the efficacy of this combination as a salvage treatment in terms of metabolic complete response (CR) rate after the third cycle. The clinical relevance of this objective lies in optimizing treatment regimens for DLBCL patients, potentially improving outcomes for those who are eligible for high-dose treatment followed by autologous stem cell transplantation (ASCT).

Secondary objectives include:

Phase 1: Assessing the toxicity of brentuximab vedotin with R-DHAP and the success rate of autologous peripheral blood stem cell harvest.
Phase 2: Evaluating the overall response rate (ORR) after 3 cycles and post-ASCT, the toxicity profile, hematological recovery after each cycle, and the success rate of harvesting an autologous peripheral blood stem cell graft. Additionally, the study will assess the fraction of patients eligible for ASCT who undergo the procedure, peripheral blood neutrophil and platelet recovery post-ASCT, and survival metrics including progression-free survival (PFS), event-free survival (EFS), and overall survival (OS). An exploratory analysis will identify predictive factors for response, PFS, EFS, and OS.

These secondary objectives aim to provide comprehensive insights into the treatment's safety, efficacy, and potential prognostic indicators, which are crucial for refining therapeutic strategies in DLBCL management.

Participants

The clinical trial involves participants diagnosed with **non-Hodgkin lymphoma (NHL)**, specifically focusing on **Diffuse large B-cell lymphoma (DLBCL)**. The study population includes both male and female subjects, aged 18 years and older, with no upper age limit specified for autologous stem cell transplantation (ASCT) eligibility, which is determined at the discretion of the participating center. Participants are required to have a WHO performance status of 0-2, indicating they are ambulatory and capable of self-care. The trial includes individuals with adequate hepatic, renal, and bone marrow function, and a hemoglobin level of at least 8 g/dL, with transfusions permitted to meet this criterion. The study population is selected based on their primary refractory status to or first relapse after first-line therapy with R-CHOP or R-CHOP-like therapy. Participants must have measurable disease, with at least one lesion/node greater than 1.5 cm on a CT scan and at least one positive lesion on an 18F-FDG PET scan. The trial also requires a life expectancy of more than three months with treatment. Both male and female participants must adhere to strict contraceptive measures throughout the study and for 12 months following the last dose of the study drug. The sponsor has not provided information regarding the total number of participants in the trial.

Plans and Procedures

The clinical trial is designed to evaluate the **efficacy** and safety of **brentuximab vedotin** in combination with R-DHAP chemotherapy in patients with CD30 positive **diffuse large B-cell lymphoma** (DLBCL) who are refractory to first-line chemotherapy or in first relapse. This is a Phase I-II study, structured as a randomized, double-blind, controlled trial. The trial is expected to run from June 2018 to February 2027, with the primary objective of identifying the recommended dose level and assessing the metabolic complete response rate after the third cycle of treatment.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as CD30 positivity, eligibility for high-dose chemotherapy and autologous stem cell transplantation (ASCT), and adequate organ function. The trial includes multiple follow-up visits to monitor treatment response and adverse events, with assessments conducted after each cycle of the combination therapy. The end-of-study visit will evaluate the overall response rate and long-term outcomes such as progression-free survival and overall survival.

The expected length of participant involvement is up to nine months, corresponding to the maximum treatment period. Conditions that may lead to early termination from the study include the occurrence of serious adverse events, failure to achieve hematological recovery, or withdrawal of consent. Participants are required to adhere to specific contraceptive measures throughout the study and for 12 months after the last dose of the study drug. The trial aims to provide valuable insights into the potential benefits and risks of this treatment regimen for patients with relapsed or refractory DLBCL.

Treatment

The clinical trial involves the administration of **brentuximab vedotin**, marketed under the name ADCETRIS, which is provided as a 50 mg powder for concentrate for solution for infusion. This experimental medication is intended for **intravenous use**. The pharmaceutical form is a solution for infusion, and the dosing regimen is based on body weight, with a maximum daily dose of 1.8 mg/kg and a total maximum dose of 113.4 mg. The treatment period is limited to a maximum of 9 cycles. Brentuximab vedotin is a protein-based therapeutic agent, specifically categorized under the ATC code L01XC12. The medication is not formulated for pediatric use and is not classified as an orphan drug. The product is manufactured by Takeda Pharma A/S.

In addition to the experimental treatment, the study protocol includes the use of a standard-of-care therapy, R-DHAP, which is a combination chemotherapy regimen. R-DHAP consists of rituximab, dexamethasone, cytarabine, and cisplatin, and is used as a salvage treatment for patients with CD30 positive diffuse large B-cell lymphoma who are refractory to first-line chemotherapy or in first relapse. The combination of brentuximab vedotin with R-DHAP aims to evaluate the efficacy and safety of this regimen, particularly focusing on the metabolic complete response rate and the incidence of CTCAE grade 3/4 non-hematological toxicity, including neurotoxicity, after each cycle.

Efficacy

The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints. The primary efficacy endpoint for the Phase 2 part of the trial is the **metabolic complete response (CR) rate** after the third cycle of Brentuximab Vedotin (BV) combined with R-DHAP salvage therapy, as determined by PET-diagnostic CT scans. Additionally, the primary feasibility and toxicity endpoints include the rate of grade 3/4 non-hematological toxicity, with a focus on neurotoxicity, after each cycle of the BV-R-DHAP combination.

Secondary endpoints for the Phase 2 part include the overall response rate (partial response + complete response) after the third cycle of BV-R-DHAP salvage therapy and after autologous stem cell transplantation (ASCT), based on FDG-PET/CT scan results. Other secondary endpoints involve the metabolic CR rate after ASCT, the fraction of patients eligible for ASCT who actually undergo the procedure, and survival metrics such as progression-free survival (PFS), event-free survival (EFS), and overall survival (OS). The trial will also monitor serious adverse events during the combination treatment and after ASCT, time to hematological recovery after each cycle and after ASCT, and the rate of successful peripheral blood stem cell (PBSC) collection after the second or third cycle of BV-R-DHAP.

Inclusion and Exclusion Criteria

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Inclusion Criteria

CD30 positive DLBCL, i.e. more than 1% of DLBCL cells CD30 positive according to the WHO classification 2008: CD30 positive DLBCL, including EBV positive DLBCL. CD30 positive primary mediastinal B-cell lymphoma
Primary refractory to or in first relapse after first line therapy with R-CHOP or R-CHOP-like therapy
Age ≥ 18 years (upper age limit for ASCT at the discretion of the participating center)
Measurable disease: on CT scan at least 1 lesion/node with a long axis of > 1.5 cm and at least one positive lesion on 18F-FDG PET scan
WHO performance status 0-2
Adequate hepatic function
Adequate renal function
Adequate bone marrow function
Hemoglobin must be ≥ 8 g/dL (5.0 mmol/L), transfusion is allowed
Eligible for high-dose chemotherapy and ASCT
Resolution of relevant toxicities from first-line therapy
Life expectancy of > 3 months with treatment
Negative pregnancy test at study entry, if applicable
Female patient is either post-menopausal for at least 1 year before screening visit or surgically sterile or if of childbearing potential, agrees to practice 2 effective methods of contraception, at the same time, or agrees to completely abstain from heterosexual intercourse, from the time of signing the informed consent through 12 months after the last dose of study drug
Male patients, even if surgically sterilized, (i.e. status post vasectomy) agree to practice effective barrier contraception, or agrees to completely abstain from heterosexual intercourse, during the entire study period and through 12 months after the last dose of study drug
Written informed consent
Patient is capable of giving informed consent

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Exclusion Criteria

Peripheral sensory or motor neuropathy grade ≥ 2
Known cerebral or meningeal disease (NHL or any other etiology), including signs and symptoms of progressive multifocal leukoencephalopathy (PML)
Symptomatic neurological disease compromising normal activities of daily living or requiring medications
Transformed lymphoma
DLBCL after organ transplantation
Immunodeficiency-associated B-cell lymphoproliferative disease
Use of other investigational agents within at least 5 half-lives of the most recent agent used prior to study entry
Treatment with myelosuppressive chemotherapy or biological therapy ≤ 4 weeks before study entry
Female patients who are breast feeding
History of another malignancy less than 3 years before study inclusion, or previously diagnosed with another malignancy and have evidence of residual disease, with the exception of non-melanoma skin cancer, completely resected melanoma TNMpT1 and carcinoma in situ of the uterine cervix
Known hypersensitivity to recombinant proteins, murine proteins, or to any excipient contained in the drug formulation of brentuximab vedotin
Active hepatitis B or C infection
HIV positivity
Radiation therapy within 8 weeks prior to start of protocol treatment. Emergency radiation therapy is allowed, as long as measurable disease (at non-irradiated sites) persists
Patients with a serious psychiatric disorder that could, in the investigator's opinion, potentially interfere with the completion of treatment according to protocol
Major organ dysfunction, unless NHL-related
Patients who have any severe and/or uncontrolled medical condition or other conditions that could affect their participation in the study
Thyroid abnormalities when thyroid function cannot be maintained in the normal range by medication
Current participation in another clinical trial interfering with this trial
Any psychological, familial, sociological and geographical condition potentially hampering compliance with the study protocol and follow-up schedule
Claustrophobia to the extent that PET-CT is impossible