VITAS: Atezolizumab in Combination with Chemotherapy for Pediatric Relapsed/refractory Solid Tumors

Inclusion Criteria:

1. Signed informed consent

2. Relapsed or refractory solid tumor after at least one prior course of therapy.

3. Hodgkin lymphoma or non-Hodgkin lymphoma are not permitted.

4. Patients with CNS malignancy or asymptomatic CNS metastases may be enrolled,provided all of the following criteria are met.

• No metastatic or primary disease affecting the brainstem, midbrain, pons,or cerebellum, or within 10 mm of optic nerve
• No history of leptomeningeal disease
• No history of intracranial or spinal cord hemorrhage
• No evidence of progression of neurologic deficit, in the investigator'sjudgment, within 7 days prior to initiation of study medications.

3. Must have histologically confirmed rhabdomyosarcoma (RMS) for RMS efficacycohort.

4. Age ≥ 6 months and ≤ 30 years

5. Lansky Performance Status (patients < 16 years old) or Karnofsky Performance Status (patients ≥ 16 years old) ≥ 50

6. Ability to comply with the study protocol, in the investigator's judgment

7. For RMS efficacy cohort, disease must be measurable as defined by RECIST v1.1.

8. For the feasibility cohort, disease must be evaluable, but patients enrolled inthe feasibility cohort will be prospectively assessed for measurable disease,RMS patients will also be included in the RMS efficacy cohort.

9. Previously irradiated lesions can be considered as measurable disease only ifprogressive disease has been unequivocally documented at that site sinceradiation.

10. Availability of a tumor specimen suitable for determination of PD-L1 status, eitherfrom initial diagnosis or from a recurrence.

11. For PD-L1 staining to be performed at the central site, a formalin-fixedparaffin-embedded (FFPE) tumor specimen in a paraffin block (preferred) or atleast 15 slides containing unstained, freshly cut, serial sections must beavailable along with an associated pathology report prior to study enrollment.

12. Patients for whom the required number of slides are not available may still beeligible to enroll on study with PI approval

13. For the RMS efficacy cohort, it will be required that at least 8 of 17 patients havePD-L1(+) tumor. PD-L1 status will be determined at time of enrollment for allpatients. When the maximum allowable number of PD-L1(-) patients has been enrolledand treated on study, PD-L1 positivity will be required for all further enrolledpatients.

14. Staining will be performed in the central site CAP/CLIA-certified laboratoryusing the 22c3 antibody for immunohistochemical analysis

15. PD-L1(+) status will be defined as staining on ≥1% of tumor cells or ≥1% ofstroma.

16. For the feasibility cohort, PD-L1 positivity is not required but will beperformed centrally in all cases for exploratory biomarker studies.

17. Adequate organ and marrow function as defined by the following laboratory valuesobtained within 21 days prior to initiation of study medication.

18. For patients without known bone marrow involvement:

• Absolute neutrophil count ≥ 1.0 x 10^9 / L (1000/µL) without granulocytecolony-stimulating factor support (≥14 days after the last dose of along-acting growth factor such as pegfilgrastim, or 7 days aftershort-acting growth factor)
• Absolute lymphocyte count ≥ 0.5 x 10^9 / L (500/µL)
• Platelet count ≥ 75 x 10^9 / L (75,000/µL) without transfusion in the last 7 days

2. Patients with known bone marrow metastatic disease will be eligible for thestudy if they meet the following criteria:

• Patients with documented liver metastases: AST and ALT ≤ 5 x ULN
• Patients with documented liver or bone metastases: ALP ≤ 5 x ULN
• Absolute neutrophil count (ANC) ≥ 750/mm^3
• Absolute lymphocyte count ≥ 0.4 x 10^9 / L (400/µL)
• Platelet count ≥ 50,000/mm^3 (may receive transfusions provided they arenot known to be refractory to red cell or platelet transfusions)
• These patients will not be evaluable for hematologic toxicity. At least 4of 6 patients in the feasibility cohort must be evaluable for hematologictoxicity. If dose-limiting hematologic toxicity is observed, allsubsequent patients enrolled must be evaluable for hematologic toxicity.

3. Total bilirubin ≤1.5 x upper limit of normal (ULN) for age (Patients with knownGilbert disease: serum bilirubin ≤ 3 x ULN)

4. AST (SGOT) and ALT (SPGT) ≤ 2.5 x ULN for age

5. Serum albumin ≥ 25 g/L (2.5 g/dL)

6. Creatinine ≤ 1.5 x ULN for age or creatinine clearance (or radioisotopeglomerular filtration rate) ≥ 70 mL/min/1.73 m2

7. Left ventricular ejection fraction ≥ 50% or shortening fraction ≥ 30%

8. Hemoglobin ≥ 90 g/L (9 g/dL)

9. Patients may be transfused to meet this criterion.

10. For patients not receiving therapeutic anticoagulation: INR or aPTT ≤ 1.5 x ULN

11. For patients receiving therapeutic anticoagulation: stable anticoagulantregimen

12. Negative HIV and hepatitis B surface antigen (HBsAg) tests at screening

13. For women of childbearing potential: agreement to remain abstinent (refrain fromheterosexual intercourse) or use contraceptive methods, and agreement to refrainfrom donating eggs, as defined below:

14. Women must remain abstinent or use contraceptive methods with a failure rate of < 1% per year during the treatment period and for 5 months after the finaldoses of atezolizumab, vincristine, and temozolomide. Women must refrain fromdonating eggs during this same period.

15. A woman is considered to be of childbearing potential if she is postmenarchal,has not reached a postmenopausal state (≥ 12 continuous months of amenorrheawith no identified cause other than menopause), and has not undergone surgicalsterilization (removal of ovaries and/or uterus), regardless of sexualorientation or marital status.

16. Examples of contraceptive methods with a failure rate of &amp;lt; 1% per yearinclude bilateral tubal ligation, male sterilization, hormonal contraceptivesthat inhibit ovulation, hormone-releasing intrauterine devices, and copperintrauterine devices.

17. The reliability of sexual abstinence should be evaluated in relation to theduration of the clinical trial and the preferred and usual lifestyle of thepatient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, orpostovulation methods) and withdrawal are not adequate methods ofcontraception.

18. For men who are not surgically sterile: agreement to remain abstinent (refrain fromheterosexual intercourse) or use contraceptive measures, and agreement to refrainfrom donating sperm, as defined below:

19. With a female partner of childbearing potential who is not pregnant, men mustremain abstinent or use a condom plus an additional contraceptive method thattogether result in a failure rate of less 1% per year during the treatmentperiod and for 5 months after the final doses of atezolizumab, irinotecan, andtemozolomide. Men must refrain from donating sperm during this same period.

20. The reliability of sexual abstinence should be evaluated in relation to theduration of the clinical trial and the preferred and usual lifestyle of thepatient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, orpostovulation methods) and withdrawal are not adequate methods of contraception

Exclusion Criteria:

1. Pregnancy or breast-feeding:

2. Pregnancy or breastfeeding, or intention of becoming pregnant during studytreatment or within 5 months after the final dose of study treatment

3. Women of childbearing potential must have a negative serum pregnancy testresult within 21 days prior to initiation of study treatment.

4. Medical conditions that are excluded:

5. Active or history of autoimmune disease or immune deficiency, including, butnot limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemiclupus erythematosus, rheumatoid arthritis, inflammatory bowel disease,antiphospholipid antibody syndrome, Guillain-Barré syndrome, multiplesclerosis, or Kawasaki syndrome with the following exceptions:

• Patients with a history of autoimmune-related hypothyroidism who are onthyroid-replacement hormone are eligible for the study.
• Patients with controlled Type 1 diabetes mellitus who are on an insulinregimen are eligible for the study.
• Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligowith dermatologic manifestations only (e.g., patients with psoriaticarthritis are excluded) are eligible for the study provided all offollowing conditions are met at study initiation: (1) Rash must cover less 10% of body surface area, (2) Disease is well controlled at baseline andrequires only low-potency topical corticosteroids, (3) No occurrence ofacute exacerbations of the underlying condition requiring psoralen plusultraviolet A radiation, methotrexate, retinoids, biologic agents, oralcalcineurin inhibitors, or high-potency or oral corticosteroids within theprevious 12 months

2. Uncontrolled or symptomatic hypercalcemia (ionized calcium &amp;gt; 1.5 mmol/L,calcium &amp;gt; 12 mg/dL or corrected serum calcium &amp;gt; ULN)

3. Uncontrolled pleural effusion, pericardial effusion, or ascites requiringrecurrent drainage procedures (once monthly or more frequently)

• Patients with indwelling catheters (e.g., PleurX®) are allowed.

4. Uncontrolled tumor-related pain

• Patients requiring pain medication must be on a stable regimen at studyentry for at least 2 weeks. Intermittent use of as-needed medication isallowed during this period.

5. Clinically significant gastrointestinal disorder that may interfere withabsorption of orally administered drugs (at the discretion of the treatingphysician)

6. History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g.,bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis,or evidence of active pneumonitis on screening chest computed tomography (CT)scan

• History of radiation pneumonitis in the radiation field (fibrosis) ispermitted.

7. Significant cardiovascular disease (such as New York Heart Association Class IIor greater cardiac disease, myocardial infarction, or cerebrovascular accident)within 3 months prior to initiation of study treatment, unstable arrhythmia, orunstable angina

8. History of severe asthma or uncontrolled asthma

9. Dyspnea at rest or requirement for supplemental oxygen

10. Uncontrolled seizures. Patients taking a stable dose of anticonvulsants (for 2weeks) are permitted, as long as they are not strong inducers or inhibitors ofCYP3A4.

11. Any other disease, metabolic dysfunction, physical examination finding, orclinical laboratory finding that contraindicates the use of an investigationaldrug, may affect the interpretation of the results, or may render the patientat high risk from treatment complications in the opinion of the treatinginvestigator

12. Washout periods from prior therapies:

13. Myelosuppressive chemotherapy or radiotherapy within 21 days prior to startingstudy treatment.

• Subjects must have recovered from all acute prior treatment-relatedtoxicities to grade 1 or baseline (excluding alopecia and clinicallystable toxicities requiring ongoing medical management, such ashypothyroidism).

2. Non-myelosuppressive cancer therapy, such as kinase inhibitors, within 7 daysprior to study treatment.

3. Treatment with monoclonal antibodies with long half-lives, within 3 half-livesprior to study treatment.

4. Treatment with targeted cellular therapies within 28 days prior to startingstudy treatment.

5. Major surgical procedure, other than for diagnosis, within 30 days prior toinitiation of study treatment, or anticipation of the need for a major surgicalprocedure during the first four cycles of the study.

• Biopsy tissue collection or placement of a vascular access device ispermitted if the site has healed prior to initiation of study medications.
• For patients with CNS disease, no neurosurgical resection, brain biopsy,or stereotactic/whole-brain radiation within 30 days prior to Cycle 1, Day 1

6. Treatment with a live, attenuated vaccine within 30 days prior to initiation ofstudy treatment, or anticipation of the need for such a vaccine duringatezolizumab treatment or within 5 months after the final dose of atezolizumab

7. Treatment with investigational therapy within 21 days prior to initiation ofstudy treatment or concurrent participation with another investigational agent

8. Treatment with systemic immunostimulatory agents (including, but not limitedto, interferon and interleukin 2 [IL-2]) within 4 weeks or 5 half-lives of thedrug (whichever is longer) prior to initiation of study treatment

9. Treatment with systemic immunosuppressive medication (including, but notlimited to, corticosteroids, cyclophosphamide, azathioprine, methotrexate,thalidomide, and anti-TNF-agents) within 2 weeks prior to initiation of studytreatment, or anticipation of the need for systemic immunosuppressivemedication during study treatment, with the following exceptions:

• Patients who received acute, low-dose systemic immunosuppressantmedication or a one-time pulse dose of systemic immunosuppressantmedication (e.g., 48 hours of corticosteroids for a contrast allergy) areeligible for the study after Principal Investigator confirmation has beenobtained.
• Patients who received mineralocorticoids (e.g., fludrocortisone),corticosteroids for chronic obstructive pulmonary disease (COPD) orasthma, or low-dose corticosteroids for orthostatic hypotension or adrenalinsufficiency are eligible for the study.
• Patients with CNS disease can be receiving concurrent treatment withcorticosteroids with approval from the Principal Investigator. Patientsmust be receiving a stable or decreasing dose for ≥ 5 days prior to thebaseline MRI scan and at the time of drug initiation. The PrincipalInvestigator should be informed when steroid doses are increased becauseof declining patient status.

10. Use of strong CYP3A4 inhibitors or inducers or strong UGT1A1 inhibitors within 12 days of Cycle 1, Day 1.

11. Treatment with high-dose chemotherapy and hematopoietic stem-cell rescue within 3 months prior to initiation of study drug

12. Treatment with herbal cancer therapy within 1 week prior to initiation of studymedications.

13. Treatment with a long-acting hematopoietic growth factor (such aspegfilgrastim) within 2 weeks prior to initiation of study medications, or ashort-acting hematopoietic growth factor (such as G-CSF) within 1 week prior toinitiation of study medications.

14. Prior treatments:

15. Prior allogeneic stem cell or solid organ transplantation

16. Prior treatment with CD137 agonists or immune checkpoint blockade therapies toinclude all anti-PD-1, and anti-PD-L1 therapeutic antibodies

17. Treatment with systemic immunostimulatory agents (including, but not limitedto, interferon and interleukin 2 [IL-2] within 4 weeks or 5 half-lives of thedrug (whichever is longer) prior to initiation of study treatment

18. Subjects must not have previously progressed while receiving regimens thatinclude irinotecan or temozolomide. Patients who have received irinotecan ortemozolomide and did not progress while on these medications are eligible.

19. Known ongoing or untreated infection, including, but not limited to bacteremia,active tuberculosis, or severe pneumonia

20. Active tuberculosis

21. Current treatment with anti-viral therapy for HBV

22. Active hepatitis C

23. Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tractinfection or chronic obstructive pulmonary disease exacerbation) are eligiblefor the study

24. Known allergy or hypersensitivity to any component of the study medications

25. History of severe allergic anaphylactic reactions to chimeric or humanizedantibodies or fusion proteins

26. Known hypersensitivity to Chinese hamster ovary cell products or to anycomponent of the atezolizumab formulation