Spartalizumab and Low-dose PAzopanib in Refractory or Relapsed Solid TumOrs of Pediatric and Adults

Inclusion Criteria:

1. For pediatric patients (Cohort 1):

2. Patients should be without standard established therapeutic alternatives at thetime of enrollment suffering from the following conditions :

• refractory or recurrent solid tumor, proven histologically,
• any tumor with high mutational load (> 10 somatic mutations/ Mo) or a highMSI status,
• tumor, whatever the histology, with proven PDL1 expression (≥1%) orpresence of mature tertiary lymphoid structure (TLS).

2. Age ≥5 and <18 years at inclusion, patients 18 years and older may be includedafter discussion with the Sponsor if they have a pediatricrecurrent/refacractory malignancy.

3. Performance status: Karnofsky performance status (for patients >16 years ofage) or Lansky Play score (for patients ≤16 years of age) ≥70%. Patients whoare unable to walk because of paralysis or stable neurological disability, butwho are up in a wheelchair, will be considered ambulatory for the purpose ofassessing the performance score.

4. Able to swallow tablets.

5. Evaluable or measurable disease as defined by standard imaging criteria for thepatient's tumor type (RECIST v1.1…).

6. Life expectancy ≥ 3 months.

7. Adequate organ function:

• Hematologic criteria :peripheral absolute neutrophil count (ANC) ≥1000/μL (unsupported), platelet count ≥100,000/μL (unsupported), hemoglobin ≥8.0g/dL (transfusion is allowed)
• Cardiac function: shortening fraction (SF) >29% (>35% for children <3years) and left ventricular ejection fraction (LVEF) ≥50% at baseline, asdetermined by echocardiography (mandatory only for patients who havereceived cardiotoxic therapy), absence of QTc prolongation (QTc >450 msecon baseline ECG, using the Fridericia correction [QTcF formula]) or otherclinically significant ventricular or atrial arrhythmia.
• Renal and hepatic function: serum creatinine ≤1.5 x upper limit of normal (ULN) for age, total bilirubin ≤1.5 x ULN, alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase (SGPT) ≤ 2.5 x ULN; aspartateaminotransferase (AST)/serum glutamic oxaloacetic transaminase/SGOT ≤ 2.5x ULN except in patients with documented tumor involvement of the liverwho must have AST/SGOT and ALT/SGPT ≤ 5 x ULN.

8. Able to comply with scheduled follow-up and with management of toxicity.

9. Females of childbearing potential (WOCBP) must have a negative serum or urinepregnancy test within 72 hours prior to initiation of treatment. Sexuallyactive women of childbearing potential must agree to use a highly effectivecontraception during the study and for at least 6 months after the last studytreatment administration. Sexually active male patients must agree to usecondoms during the study and for at least 6 months after the last studytreatment administration.

10. Written informed consent from parents/legal representative and age-appropriateassent before any study-specific screening procedures are conducted accordingto local, regional or national guidelines.

11. Patient affiliated to a social security regimen or beneficiary of the sameaccording to local requirements.

12. For adults patients:

• Pre-screening phase:

1. adults (≥ 18 years old) with refractory or recurrent solid tumor (includerhabdomyosarcoma, Ewing's sarcoma, osteosarcoma and other) and/or tumorwith High mutation rate (>10 somatic mutations/Mb) and/or suffering ofMismatch repair-deficient syndrome.
2. Adult patients with an ECOG score of 0/1. Patients who are unable to walkbecause of paralysis or stable neurological disability, but who are up ina wheelchair, will be considered ambulatory for the purpose of assessingthe performance score.
3. Evaluable or measurable disease as defined by standard imaging criteriafor the patient's tumor type (RECIST v1.1…).
4. Written informed consent from patient before any study-specific screeningprocedures are conducted according to local, regional or nationalguidelines.

• Screening phase (Cohort 2):

1. adults without standard established therapeutic alternatives at the timeof enrollment suffering from refractory or recurrent advanced solid tumorcharacterized by the presence of mature TLS
2. Age ≥ 18 years at inclusion
3. Adult patients with an ECOG score of 0/1. Patients who are unable to walkbecause of paralysis or stable neurological disability, but who are up ina wheelchair, will be considered ambulatory for the purpose of assessingthe performance score.
4. Evaluable or measurable disease as defined by standard imaging criteriafor the patient's tumor type (RECIST v1.1…).
5. Life expectancy ≥ 3 months
6. Adequate organ function:

• Hematologic criteria :peripheral absolute neutrophil count (ANC) ≥1000/μL (unsupported), platelet count ≥100,000/μL (unsupported), hemoglobin ≥8.0 g/dL (transfusion is allowed)

• Cardiac function: shortening fraction (SF) >29% and left ventricular ejectionfraction (LVEF) ≥50% at baseline, as determined by echocardiography (mandatoryonly for patients who have received cardiotoxic therapy), absence of QTcprolongation (QTc >450 msec on baseline ECG, using the Fridericia correction [QTcF formula]) or other clinically significant ventricular or atrialarrhythmia.

• Renal and hepatic function: serum creatinine ≤1.5 x upper limit of normal (ULN)for age, total bilirubin ≤1.5 x ULN, alanine aminotransferase (ALT)/serumglutamic pyruvic transaminase (SGPT) ≤ 2.5 x ULN; aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase/SGOT ≤ 2.5 x ULN except inpatients with documented tumor involvement of the liver who must have AST/SGOTand ALT/SGPT ≤5 x ULN. g. Able to comply with scheduled follow-up and with management of toxicity. h.Females of childbearing potential (WOCBP) must have a negative serum or urinepregnancy test within 72 hours prior to initiation of treatment. Sexuallyactive women of childbearing potential must agree to use a highly effectivecontraception during the study and for at least 6 months after the last studytreatment administration. Sexually active male patients must agree to usecondoms during the study and for at least 6 months after the last studytreatment administration. i. Written informed consent from patient before any study-specific screeningprocedures are conducted according to local, regional or national guidelines. j. Patient affiliated to a social security regimen or beneficiary of the sameaccording to local requirements.

Exclusion Criteria:

For pediatric and adult patients (Cohorts 1 and 2):

1. Patients treated with anti-PD1 immunotherapy within 6 months prior to starting studytreatment; patients treated with anti-PD1 for more than 6 months remain eligible forinclusion, provided that this treatment has brought the patient clinical benefit (objective response or stable disease > 4 months).

2. Impairment of gastrointestinal (GI) function or GI disease that may significantlyalter drug absorption of oral drugs (e.g. ulcerative diseases, uncontrolled nausea,vomiting, diarrhea or malabsorption syndrome).

3. Clinically significant, uncontrolled heart disease (including history of any cardiacarrhythmia, e.g. ventricular, supraventricular, nodal arrhythmias, or conductionabnormality), unstable ischemia, congestive heart failure within 12 months ofscreening).

4. Uncontrolled hypertension

5. Active viral hepatitis or known human immunodeficiency virus (HIV) infection or anyother uncontrolled infection.

6. Presence of any ≥ CTCAE grade 2 treatment-related toxicity with the exception ofalopecia, ototoxicity or peripheral neuropathy.

7. Systemic anticancer therapy within 21 days of the first study dose or 5 times itshalf-life, whichever is less.

8. Previous myeloablative therapy with autologous hematopoietic stem cell rescue within 8 weeks of the first study drug dose

9. Allogeneic stem cell transplant within 3 months prior to the first study drug dose.Patients receiving any agent to treat or prevent graft-versus host disease (GVHD)post bone marrow transplant are not eligible for this trial.

10. Radiotherapy (non-palliative) within 21 days prior to the first dose of drug (orwithin 6 weeks for therapeutic doses of MIBG)

11. Major surgery within 21 days of the first dose. Gastrostomy, ventriculo-peritonealshunt, endoscopic ventriculostomy, tumor biopsy and insertion of central venousaccess devices are not considered major surgery, but for these procedures, a 48-hourinterval must be maintained before the first dose of the investigational drug isadministered.

12. Currently taking medications with a known risk of prolonging the QT interval orinducing Torsades de Pointes

13. High dose chemotherapy followed by peripheral stem cell transplantation within lessthan 6 months.

14. Diagnosis of immunodeficiency or receiving systemic steroid therapy or any otherform of immunosuppressive therapy within 14 days prior to the first dose of studytreatment. The use of physiologic doses of corticosteroids (up to 0.25 mg/kg dailyprednisone equivalent) may be approved after consultation with the Sponsor.

15. Diagnosis of prior or active autoimmune disease.

16. Evidence of interstitial lung disease.

17. Unable to taper steroids due to ongoing mass effect; a maximum dexamethasone dose of 0.05 mg/kg/day is allowed, but preferably have been discontinued.

18. Known hypersensitivity to any study drug or component of the formulation.

19. Persons referred to in Articles L. 1121-5, L. 1121-6, L. 1121-8 and L. 11221-1-2 ofthe Public Health Code (pregnant women, parturient and nursing mothers; personsdeprived of their liberty by a judicial or administrative decision, personshospitalized without consent and persons admitted to a health or socialestablishment for purposes other than that of research; adults subject to a legalprotection measure or incapacitated express consent; people in emergency situationswho cannot give prior consent)

20. Vaccinated with live, attenuated vaccines within 4 weeks of the first dose of studydrug.