Clinical Trials /

A Trial of Radiotherapy and Durvalumab in DLBCL

NCT03610061

Description:

The primary objective for this study is to determine the safety profile of radiotherapy and durvalumab, a PD-L1 inhibitor. Primary endpoint: Toxicity, drug pharmacokinetics (PK), maximum tolerated dose (MTD) and recommended phase two dose (RPTD) of simultaneous radiotherapy plus durvalumab in patients with relapsed or refractory DLBCL. Secondary endpoints: - ORR - Progression-free survival - Overall survival Exploratory endpoints include description of biological effects of combination radiotherapy plus durvalumab (Imaging results, immune function, PK and PD-see 'research methodologies') and in the PET-Sub-Study, biodistribution of 89Zr Durvalumab and 89Zr-IAB22M2C.

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

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: A Trial of Radiotherapy and Durvalumab in DLBCL
  • Official Title: Phase I Dose Escalation Study of Radiotherapy and Durvalumab in Relapsed/Refractory Diffuse Large B-cell Lymphoma (DLBCL): The RaDD Study

Clinical Trial IDs

  • ORG STUDY ID: ONJ2017-003-DV-008259
  • SECONDARY ID: TRP16-006
  • NCT ID: NCT03610061

Conditions

  • Diffuse Large B Cell Lymphoma

Interventions

DrugSynonymsArms
DurvalumabMEDI4736Radiotherapy plus Durvalumab

Purpose

The primary objective for this study is to determine the safety profile of radiotherapy and durvalumab, a PD-L1 inhibitor. Primary endpoint: Toxicity, drug pharmacokinetics (PK), maximum tolerated dose (MTD) and recommended phase two dose (RPTD) of simultaneous radiotherapy plus durvalumab in patients with relapsed or refractory DLBCL. Secondary endpoints: - ORR - Progression-free survival - Overall survival Exploratory endpoints include description of biological effects of combination radiotherapy plus durvalumab (Imaging results, immune function, PK and PD-see 'research methodologies') and in the PET-Sub-Study, biodistribution of 89Zr Durvalumab and 89Zr-IAB22M2C.

Detailed Description

      Diffuse large B cell lymphoma (DLBCL) is the most common non Hodgkin lymphoma. Standard first
      line treatment achieves cure in approximately half of patients. However 30% die from relapsed
      lymphoma.

      Durvalumab (an antibody which blocks programmed cell death ligand 1) and other
      immunotherapies fight cancer by blocking barriers to immune system activity. Immune control
      of lymphoma provides the prospect of cure, even when chemotherapy has failed. Radiotherapy
      has striking effects on the immune system and can boost responses to these immunotherapies.
      The effect of concurrent radiotherapy and durvalumab in DLBCL is unproven.

      This study will evaluate the safety and effect of simultaneous radiotherapy plus durvalumab
      (a PD-L1 inhibitor) in relapsed DLBCL patients.
    

Trial Arms

NameTypeDescriptionInterventions
Radiotherapy plus DurvalumabExperimentalA minimum of 3 patients will initially be enrolled in each cohort of this arm. Patients will be allocated to a radiotherapy dose and site cohort from the schedule at registration. There will be no intra-patient dose or site escalations. Cohorts will escalate in number of anatomical sites of radiotherapy and dose of radiotherapy given subject to safety. Durvalumab will be administered at a fixed dose every 4 weeks IV.
  • Durvalumab

Eligibility Criteria

        Inclusion Criteria:

          1. Male or Female subjects aged 18 years weighing more than 30 kg

          2. Histologically proven CD20-positive relapsed or refractory diffuse large B cell
             non-Hodgkin lymphoma (DLBCL) either de novo or DLBCL transformed from follicular
             lymphoma, according to the current World Health Organization classification26 on
             tissue biopsy. Archived tissue is permitted however must have been obtained after the
             last known therapy. The Trial Management Group retains the option to limit the number
             of participants enrolled with transformed FL.

          3. At least 1 line of previous treatment for lymphoma which must include a CD20
             monoclonal antibody such as rituximab, with no curative option as determined by the
             investigator. Prior radiotherapy is permitted.

          4. Not eligible or not willing to receive high-dose (myeloablative) chemotherapy (HDC)
             and autologous stem cell transplant (ASCT) OR has received prior ASCT.

          5. Eastern Collaborative Oncology Group performance status 0, or 1, unless attributable
             to lymphoma in which case patients of performance status 2 are also eligible.

          6. Patients must have measurable disease (at least one bi-dimensionally measurable site
             of disease that has not been previously irradiated OR has progressed after
             radiotherapy: nodal disease >1.5 cm or an extranodal lesion > 1.0 cm in longest
             perpendicular diameter). At least three disease sites must be FDG-avid on PET imaging
             AND amenable to radiotherapy according to local radiation oncology investigator
             review.

          7. One site of disease must be amenable to biopsy. It is preferable that this is a site
             not planned for radiotherapy, but not mandated. A fresh tumor biopsy collected during
             screening and /or archival tumor tissue collected after the last relapse/disease
             progression (material which has been collected before the last line of treatment is
             not accepted). In addition, a sufficient amount of the material is required for
             acceptance of the archival material. If neither condition occurs, a fresh tumor biopsy
             needs to be performed as stated above.

          8. Adequate bone marrow function with platelets > 50 x109/l; neutrophils > 1.0x109/l at
             the time of study entry unless attributed to bone marrow infiltration by lymphoma.

          9. Adequate renal function defined by an estimated creatinine clearance ≥ 30 mL/min
             according to the Cockcroft-Gault formula (or local institutional standard method).

         10. Adequate hepatic function defined by a total bilirubin level ≤ 2 × the upper limit of
             normal (ULN) range (excluding Gilbert's disease where a level of ≤ 3 ×ULN is
             acceptable) and AST and alanine aminotransferase (ALT) levels ≤ 2.5 × upper limit of
             institutional normal range unless attributed to lymphoma.

         11. No concurrent uncontrolled medical condition as determined by the investigator.

         12. Life expectancy > 3 months.

         13. Negative blood pregnancy test at screening for women of childbearing potential.
             Effective contraception for both male and female subjects if the risk of conception
             exists.

             (Note: The effects of the trial drug on the developing human fetus are unknown; thus,
             women of childbearing potential and men must agree to use effective contraception,
             defined as 2 barrier methods, or 1 barrier method with an intrauterine device, or use
             of oral female contraceptive. Should a woman become pregnant or suspect she is
             pregnant while she or her partner is participating in this trial, the treating
             physician should be informed immediately. Effective contraception at least 30 days
             prior and up to 3 months after treatment is required for all women of childbearing
             potential and male subjects will be advised not to father a child during the 3 months
             after treatment completion. Male subjects will be requested to seek advice on
             conservation of sperm prior to treatment.)

         14. Signed written informed consent before any trial-related procedure is undertaken that
             is not part of the standard patient management.

        Exclusion Criteria:

          1. T-cell lymphoma, grade 3B Follicular lymphoma.

          2. Central nervous system, meningeal or spinal cord involvement by lymphoma.

          3. Prior therapy with any antibody or drug targeting T-cell coregulatory proteins (immune
             checkpoints) such as PD-1, PD-L1, or cytotoxic T-lymphocyte antigen-4 (CTLA-4).

          4. Patients with active autoimmune disease that might deteriorate when receiving an
             immunostimulatory agent:

        i) Subjects with diabetes type I, vitiligo, psoriasis, hypo- or hyperthyroid disease not
        requiring immunosuppressive treatment are eligible ii) Subjects requiring hormone
        replacement with corticosteroids are eligible if the steroids are administered only for the
        purpose of hormonal replacement and at doses ≤ 10 mg or 10 mg equivalent prednisone per day
        iii) Administration of steroids through a route known to result in a minimal systemic
        exposure (topical, intranasal, intro-ocular, or inhalation) is acceptable.

        e) Subjects with a condition requiring systemic treatment with either corticosteroids (> 15
        mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of
        study drug administration. Inhaled or topical steroids, and adrenal replacement doses > 15
        mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.

        f) Known severe hypersensitivity reactions to monoclonal antibodies (Grade ≥ 3 NCI-CTCAE v
        4.03), any history of anaphylaxis, or uncontrolled asthma (that is, 3 or more features of
        partially controlled asthma) g) Past history of interstitial lung disease. h) Prior organ
        transplantation, including allogeneic stem-cell transplantation i) Prior malignancy active
        within the previous 2 years except for locally curable cancers that have been apparently
        cured, such as basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma
        in situ of the prostate, cervix, or breast.

        j) Major surgery for any reason, except diagnostic biopsy, within 4 weeks of enrolment
        and/or if the subject has not fully recovered from the surgery within 4 weeks of enrolment
        k) Any other serious active disease, including but not limited to; i) clinically
        significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke (< 6
        months prior to enrolment), myocardial infarction (< 6 months prior to enrolment), unstable
        angina pectoris, congestive heart failure (New York Heart Association Classification Class
        ≥ II), or serious cardiac arrhythmia requiring medication (including QTc prolongation of >
        470 ms and/or pacemaker) or prior diagnosis of congenital long QT syndrome.

        ii) uncontrolled active infection, iii) uncontrolled diabetes (e.g., haemoglobin A1c ≥
        8.5%) l) Known history of testing positive for human immunodeficiency virus (HIV) or known
        acquired immunodeficiency syndrome (AIDS), Hepatitis B virus (HBV) or hepatitis C virus
        (HCV) infection at screening (positive HBV surface antigen or HCV RNA if anti-HCV antibody
        screening test positive) m) Medical or psychiatric conditions that compromise the patient's
        ability to give informed consent.

        o) Subject is pregnant, lactating or unwilling/unable to use adequate contraception p)
        Subject weighs less than 30kg
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Number of participants treated with radiotherapy and durvalumab with treatment-related adverse events as assessed using CTCAE v4.0. To determine the maximum tolerated dose (MTD).
Time Frame:First 28 days of treatment
Safety Issue:
Description:A minimum of 3 patients will initially be enrolled in each cohort, if none of the first 3 patients experiences a dose limiting toxicity (DLT), the doses in that cohort will be deemed safe and tolerable and escalation may continue. DLTs will be grade 4 neutropenia or thrombocytopenia, grade 3 hemolysis, grade 4 immune related AEs. If 1 of the first 3 evaluable patients in a cohort experiences a DLT, the cohort will be expanded to at least 6 patients. If there are no further DLTs in the first 6 DLT-evaluable patients, the doses in that cohort will be deemed safe and tolerable and escalation may continue. If a DLT is observed in ≥ 33% of patients (e.g., 2 or more of up to 6 patients), the dose combination at which this occurs will be considered intolerable and the MTD will have been exceeded for radiotherapy If the MTD is exceeded in any cohort, the highest dose combination at which fewer than 33% experience a DLT will be declared the combination MTD.

Secondary Outcome Measures

Measure:Response rates (according to the Lugano classification for Response Criteria for Non-Hodgkin Lymphoma)
Time Frame:0-12 months
Safety Issue:
Description:Response rates
Measure:Progression free survival
Time Frame:From ceasing treatment annually up to 5 years
Safety Issue:
Description:Progression free survival in patients who cease treatment due to toxicity.
Measure:Overall survival
Time Frame:Every 6 months from PD up to two years.
Safety Issue:
Description:Overall survival

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Austin Health

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