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.
