Clinical Trials /

Durvalumab in Pediatric and Adolescent Patients

NCT02793466

Description:

This clinical trial is the first clinical trial to study Durvalumab, a checkpoint inhibitor which stimulates the patient's own immune system to act against cancer cells in children and adolescents. This trial will assess the safety and tolerability of Durvalumab in children and adolescents and also study how Durvalumab is processed in their bodies.

Related Conditions:
  • Central Nervous System Neoplasm
  • Lymphoma
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Durvalumab in Pediatric and Adolescent Patients
  • Official Title: A Phase I, Open-Label, Single Institution Study to Assess the Safety, Tolerability, and Pharmacokinetics of Durvalumab in Pediatric Patients With Relapsed or Refractory Solid Tumors, Lymphoma, and Central Nervous System Tumors

Clinical Trial IDs

  • ORG STUDY ID: ESR-14-10488
  • NCT ID: NCT02793466

Conditions

  • Solid Tumor
  • Lymphoma
  • Central Nervous System Tumors

Interventions

DrugSynonymsArms
Durvalumab; MEDI4736DurvalumabDurvalumab; MEDI4736

Purpose

This clinical trial is the first clinical trial to study Durvalumab, a checkpoint inhibitor which stimulates the patient's own immune system to act against cancer cells in children and adolescents. This trial will assess the safety and tolerability of Durvalumab in children and adolescents and also study how Durvalumab is processed in their bodies.

Detailed Description

      This trial will assess the safety and tolerability of Durvalumab in children and adolescents
      and also study how Durvalumab is processed in their bodies.
    

Trial Arms

NameTypeDescriptionInterventions
Durvalumab; MEDI4736ExperimentalOpen label
  • Durvalumab; MEDI4736

Eligibility Criteria

        Inclusion Criteria:

          1. Age: Patients must be >12 months and <18 years of age at the time of study enrollment.

          2. Diagnosis: Patient must have disease that is either refractory to frontline treatment
             or have relapsed. Patient must have had histologic verification of a solid tumor
             (including lymphoma and CNS tumors) at the time of original diagnosis or relapse with
             the following exceptions:

               1. Patients with germ cell tumors (both CNS and non-CNS) that have elevated tumor
                  markers (e.g. α-fetoprotein, β-human chorionic gonadotropin, inhibin A/B) and
                  radiographic evidence of disease.

               2. Patients with diffuse intrinsic pontine glioma (DIPG) diagnosed by radiographic
                  studies.

          3. Disease Status: Patients must have either measurable or evaluable disease that can be
             accurately assessed at baseline by computerized tomography (CT) or magnetic resonance
             imaging (MRI) and is suitable for repeated assessment with the following exception:

             a. Patients with a third relapse of osteosarcoma and no measurable disease after
             surgical resection will be eligible for this study.

          4. Therapeutic Options: Patient's current disease state must be one for which there is no
             known curative therapy.

          5. Performance Level: Karnofsky ≥ 50 for patients > 16 years of age and Lansky ≥ 50 for
             patients ≤ 16 years of age. Patients who are unable to walk because of paralysis, but
             who can actively sit up in a wheelchair, will be considered ambulatory for the purpose
             of assessing the performance score. See Appendix I for scoring guidelines.

          6. Organ Function Requirements:

             Adequate organ and bone marrow function as defined below:

               1. Absolute neutrophil count ≥ 750/mm3

               2. Platelets ≥ 75,000/mm3 . Patients must be transfusion independent and should not
                  have received a platelet transfusion within 5 days of enrollment.

               3. Hemoglobin ≥8.0 g/dL. Patients may receive PRBC transfusion.

               4. Adequate renal function as defined by: Creatinine clearance or radioisotope GFR >
                  70ml/min/m 2

               5. Total serum bilirubin (conjugated plus unconjugated) ≤1.5 x upper limit of normal
                  (ULN) for age. For patients with Hepatocellular Carcinoma (HCC) or patients with
                  documented/suspected Gilbert's disease, bilirubin ≤3x ULN.

               6. In patients with no liver metastasis: AST and ALT ≤2.5 x ULN

               7. In patients with HCC or liver metastasis: AST or ALT ≤5 x ULN

               8. Adequate cardiac function as indicated by shortening fraction of > 28% by
                  echocardiogram or ejection fraction of ≥ 55% by radionuclide angiogram.

          7. Informed Consent: Provision of signed and dated written informed consent (parent/legal
             guardian if patient <18 years of age) and assent (from patients aged >7 years) prior
             to any study specific procedures, sampling and analyses, including screening
             evaluations.

          8. Female patients must either be of non-reproductive potential or must have a negative
             serum pregnancy test upon study entry.

          9. Subject is willing and able to comply with the protocol for the duration of the study
             including undergoing treatment and scheduled visits as well as follow up examinations.

        Exclusion Criteria:

          1. Prior therapy:

               1. Nitrosourea or mitomycin C within 6 weeks of the first dose of study treatment.

               2. Any investigational agents or study drugs from a previous clinical study within
                  28 days of the first dose of study treatment. Patient may be enrolled in other
                  non-therapeutic studies.

               3. Hematopoietic growth factors: Within 14 days of the last dose of a long acting
                  growth factor (e.g. Neulasta) or within 7 days of receiving a short acting growth
                  factor. This does not apply to erythropoetin.

               4. Monoclonal antibodies: Less than 3 half-lives or 28 days (whichever is shorter)
                  after the last dose of monoclonal antibody, and without resolution of all known
                  toxicity of the antibody .

               5. Any other chemotherapy, immunotherapy or anticancer agents within 4 weeks of the
                  first dose of study treatment. For agents with known adverse events occurring
                  beyond 3 weeks of administration after administration, this period must be
                  extended beyond the time during which adverse events are known to occur.

               6. Any previous systemic exposure to a PD-1 or PD-L1 inhibitor, including
                  Durvalumab.

               7. Major surgery (excluding placement of vascular access and needle biopsies) within
                  2 weeks of the first dose of study treatment.

               8. Radiotherapy within two weeks for local palliative XRT or within 6 weeks if
                  craniospinal XRT or if ≥ 50% radiation of pelvis.

               9. Current or prior use of immunosuppressive medication within 28 days before the
                  first dose of Durvalumab, with the exceptions of intranasal and inhaled
                  corticosteroids or systemic corticosteroids at physiological doses, which are not
                  to exceed 10 mg/day of prednisone, or an equivalent corticosteroid.

              10. Any prior allogeneic BMT/HSCT.

              11. Autologous BMT/HSCT within 90 days.

          2. All prior acute toxicities from medical therapy or radiation therapy should resolve to
             meet the baseline inclusion criteria in regards to organ function requirement. All
             other prior acute toxicities that are not part of the baseline organ function
             requirements must improve to ≤ Grade 1 as defined in Section 5.1.1 and using CTCAE
             Criteria Version 4.03.

          3. Any of the following cardiac criteria:

               1. Mean resting corrected QT interval (QTc) > 470 msec obtained from at least 2
                  electrocardiograms (ECGs).

               2. Any clinically important abnormalities in rhythm, conduction or morphology of
                  resting ECG (e.g., complete left bundle branch block, third degree heart block)

               3. Any factors that increase the risk of QTc prolongation or risk of arrhythmic
                  events such as heart failure, congenital long QT syndrome, family history of long
                  QT syndrome or unexplained sudden death under 40 years of age or any concomitant
                  medication known to prolong the QT interval.

          4. Judgment by the investigator that the patient should not participate in the study if
             the patient is unlikely to comply with study procedures, restrictions and requirements

          5. Any prior Grade ≥3 immune-related adverse event (irAE) while receiving any previous
             immunotherapy agent, or any unresolved irAE >Grade 1.

          6. Active or prior documented autoimmune disease within the past 2 years. NOTE: Patients
             with vitiligo, Grave's disease, or psoriasis not requiring systemic treatment (within
             the past 2 years) are not excluded. Patients with hypothyroidism as a result of
             irradiation or thyroidectomy are also not excluded.

          7. Active or prior documented inflammatory bowel disease (e.g., Crohn's disease,
             ulcerative colitis).

          8. History of primary immunodeficiency.

          9. Any underlying interstitial lung disease.

         10. Brain metastases or spinal cord compression unless asymptomatic, treated and stable
             for at least 1 month prior to entry into the study.

         11. Ongoing or expected need for systemic corticosteroids ≥10mg/day.

         12. Known history orf previous clinical diagnosis of tuberculosis.

         13. Receipt of live attenuated vaccination within 30 days prior to receiving study
             treatment. Inactivated viruses, such as those in the influenza vaccine, are permitted

         14. History of another primary malignancy within 5 years prior to starting study
             treatment, except for adequately treated basal or squamous cell carcinoma of the skin
             or cancer of the cervix in situ and the disease under study.

         15. Pregnancy or Breast-Feeding: Pregnant patients are ineligible for this study due to
             the unknown teratogenic effects of this agent. Pregnancy tests must be obtained in
             females of childbearing potential prior to enrollment.

         16. Post-menarchal females and males who are sexually active with women of childbearing
             potential who are not employing/willing to employ an effective method of birth
             control.

         17. Clinically Significant Unrelated Systemic Illness: Patients with serious infections or
             significant pulmonary, hepatic, renal, or other end-organ dysfunction which in the
             judgment of the Principal or Co-Investigators would compromise the patient's ability
             to tolerate prescribed chemotherapy or are likely to interfere with the study
             procedures or results will not be eligible.

         18. Patient with HIV, Hepatitis B, or Hepatitis C defined by the following serology
             results:

               1. Positive human immunodeficiency virus (HIV) antibody.

               2. Positive hepatitis B surface antigen (HBsAg) and positive hepatitis B core (HBc)
                  antibody or undetectable hepatitis B (HBV) deoxyribonucleic acid (DNA) by
                  quantitative polymerase chain reaction (PCR) testing.

               3. Positive hepatitis C (HCV) antibody or positive HCV ribonucleic acid (RNA) by
                  quantitative PCR.

         19. Any condition that, in the opinion of the investigator, would interfere with
             evaluation of study treatment or interpretation of patient safety or study results.

         20. History of hypersensitivity to Durvalumab or any excipient.
      
Maximum Eligible Age:17 Years
Minimum Eligible Age:1 Year
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum Tolerated Dose (MTD)
Time Frame:28 days
Safety Issue:
Description:Maximum dose of Durvalumab in milligrams per kilogram body weight that can be administered to children between the age of 1 and 18 years that will be used to study the drug further in a Phase 2 clinical trial in a population of the same age distribution

Secondary Outcome Measures

Measure:Response rate
Time Frame:8 weeks
Safety Issue:
Description:Objective response rate of malignancy following two cycles (4 doses) of treatment
Measure:Drug antibody level
Time Frame:18 months
Safety Issue:
Description:Anti- Durvalumab levels in micrograms/mL
Measure:Suppression of free soluble PD-L1 suppression in serum
Time Frame:15 months
Safety Issue:
Description:Individual soluble PDL-1 levels [pg/mL] in blood with durvalumab monotherapy
Measure:Duration of response
Time Frame:up to 2 years
Safety Issue:
Description:Time from first complete or partial response to disease progression

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Children's Hospital Los Angeles

Trial Keywords

  • Durvalumab
  • solid tumors
  • Immunotherapy
  • Check Point Inhibitor
  • pediatrics
  • children

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