Clinical Trials /

Phase I-II Study in CD30 Positive Diffuse Large B-cell Lymphoma Patients Refractory to First Line Chemotherapy or in First Relapse

NCT03356054

Description:

Patients with CD30 positive DLBCL, primary refractory or in first relapse after R-CHOP or R-CHOP-like therapy will receive brentuximab vedotin in combination with R-DHAP, followed in responsive patients by high dose chemotherapy and ASCT.

Related Conditions:
  • Diffuse Large B-Cell Lymphoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Phase I-II Study in CD30 Positive Diffuse Large B-cell Lymphoma Patients Refractory to First Line Chemotherapy or in First Relapse
  • Official Title: Phase I-II Study Combining Brentuximab Vedotin With Second Line Salvage Chemotherapy (R-DHAP) in CD30 Positive Diffuse Large B-cell Lymphoma Patients Refractory to First Line Chemotherapy or in First Relapse Who Are Eligible for High Dose Treatment Followed by Autologous Stem Cell Transplantation

Clinical Trial IDs

  • ORG STUDY ID: HO136
  • SECONDARY ID: 2016-001211-21
  • NCT ID: NCT03356054

Conditions

  • DLBCL

Interventions

DrugSynonymsArms
Brentuximab VedotinAdcetrisBrentuximab vedotin-R-DHAP

Purpose

Patients with CD30 positive DLBCL, primary refractory or in first relapse after R-CHOP or R-CHOP-like therapy will receive brentuximab vedotin in combination with R-DHAP, followed in responsive patients by high dose chemotherapy and ASCT.

Detailed Description

      Patients with primary refractory or relapse diffuse large B cell lymphoma (DLBCL) after
      R-CHOP have a dismal prognosis. Only 25% long term survivors are observed after salvage with
      high-dose chemotherapy followed by autologous stem cell transplantation (ASCT). CD30
      expression is observed in 30% of refractory/relapse DLBCL.

      Monotherapy with brentuximab vedotin is effective in relapse CD30 positive DLBCL. The
      addition of brentuximab vedotin to R-DHAP might improve the prognosis of these patients.

      Treatment will consist of 3 cycles of brentuximab-vedotin in combination with R-DHAP. During
      the phase I part the recommended dose level for this combination will be established. Cycles
      will be given every 3 weeks.

      Responsive patients will be treated with BEAM followed by ASCT. Total treatment duration is
      approximately 16 weeks.

      Subsequently patients will be followed until 5 years after registration.
    

Trial Arms

NameTypeDescriptionInterventions
Brentuximab vedotin-R-DHAPExperimentalBrentuximab vedotin added to R-DHAP
  • Brentuximab Vedotin

Eligibility Criteria

        Inclusion Criteria:

          -  CD30 positive DLBCL, i.e. more than 1% of DLBCL cells CD30 positive(central pathology
             review results not required to enter patient into the study), 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

               -  Relapse is defined as biopsy confirmed CD30 positive DLBCL after a complete
                  response. The relapse must be histologically confirmed. In case a surgical biopsy
                  is not possible, at least confirmation by FNA biopsy is required

               -  Refractory disease is defined as:

                    1. progressive disease during first line therapy, In this case biopsy
                       confirmation of CD30 positive DLBCL is preferred but not required

                    2. stable disease after at least 3 cycles of first line therapy, In this case
                       biopsy confirmation of CD30 positive DLBCL is preferred but not required

                    3. PR after at least 6 cycles of first line therapy, or in the case of stage
                       I-II disease after at least 3 cycles of therapy and definitive involved
                       field radiotherapy. In this case refractory disease must be histologically
                       confirmed

          -  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, status 3 only if disease related (see appendix C)

          -  Adequate hepatic function: total bilirubin ≤ 1.5 times ULN (unless due to lymphoma
             involvement of the liver or a known history of Gilbert's syndrome as defined by > 80%
             unconjugated bilirubin) and ALAT/ASAT ≤ 3 times ULN (unless due to lymphoma
             involvement of the liver; in that case ALAT/ASAT may be elevated up to 5 times ULN)

          -  Adequate renal function: GFR > 60 ml/min as estimated by the Cockroft&Gault formula at
             rehydration: CrCL = (140-age [in years] x weight [kg] (x 0.85 for females) / (0.815 x
             serum creatinine [μmol/L])

          -  Adequate bone marrow function: Absolute neutrophil count (ANC) ≥ 1.5x109/L and
             platelet count ≥ 100 x 109/L, unless caused by diffuse bone marrow infiltration by the
             NHL

          -  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

        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 as defined by positive serology and transaminitis.
             Non-active hepatitis B carriers or anti-HBc positive patients may be included if
             protected with lamuvidine or entecavir (see 9.4)

          -  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 such as:

               -  Known history of symptomatic congestive heart failure (NYHA III, IV, appendix E),
                  myocardial infarction ≤ 6 months prior to first study drug

               -  Evidence of current serious uncontrolled cardiac arrhythmia, angina pectoris,
                  electrocardiographic evidence of acute ischemia or active conduction system
                  abnormalities

               -  Recent evidence (within 6 months before first dose of study drug) of a
                  left-ventricular ejection fraction <45%

               -  Severely impaired pulmonary function as defined as spirometry and DLCO (diffusing
                  capacity of the lung for carbon monoxide) that is 50% or less of the normal
                  predicted value and/or O2 saturation that is 90% or less at rest on room air

          -  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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:The rate of patients with serious toxicity during cycle 1-2 of the combination brentuximab vedotin-R-DHAP
Time Frame:6 weeks
Safety Issue:
Description:Phase I

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Stichting Hemato-Oncologie voor Volwassenen Nederland

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