Spartalizumab and low-dose PAzopanib in Refractory or Relapsed solid TumOrs of pediatric and adults SPARTO

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Centre Hospitalier Universitaire De Bordeaux

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

2 May 2022 → ongoing

Decision date (initial)

2024-10-03

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

INCa 2019 “CLIP2 - Molécules innovantes (Novartis-INCA)” call for project

External identifiers

EU CT number

2024-513535-24-00

EudraCT number

2021-002804-11

ClinicalTrials.gov

NCT05210413

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy

To identify the recommended dose for phase II study (RP2D) of spartalizumab in association with a fixed dose of pazopanib in the pediatric cohort

To estimate the efficacy of the combination of spartlizumab and pazopanib on the 6-month disease control rate in the adult cohort

Secondary objectives 11

1. To describe the safety profile of the combination of spartalizumab and pazopanib in the pediatric cohort
2. To estimate preliminary sign of efficacy on objective response rate in the pediatric cohort
3. To estimate overall survival (OS) and progression-free survival (PFS) in the pediatric cohort
4. To estimate the proportion of long-term responder patients (response duration > 6 months) in the pediatric cohort
5. To describe the safety profile of the combination of spartalizumab and pazopanib in the adult cohort
6. To estimate objective response rate (ORR), OS and PFS in the adult cohort
7. To describe PK parameters of pazopanib with lower dose at D-7C1, D1C1 and D8C1
8. To determine if an early point of PK allows predicting evolution of pazopanib PK
9. To exclude implication of pazopanib in a DLT observation (in case of DLT, pazopanib levels will be determined promptly)
10. To determine if a pazopanib concentration target could be related to higher or lower response of spartalizumab
11. To perform integrative assessment of prognostic factors of ORR, PFR, PFS and OS.

Conditions and MedDRA coding

Refractory or Recurrent Solid Tumor

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 23

1. For pediatric patients, patients should be without standard established therapeutic alternatives at the time 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 high MSI status - a Mismatch repair-deficient syndrome. - tumor, whatever the histology, with proven PDL1 expression (≥1%) or presence of mature tertiary lymphoid structure (TLS).
2. For pediatric patients, Age ≥5 and <18 years at inclusion, patients 18 years and older may be included after discussion with the Sponsor if they have a pediatric recurrent/refacractory malignancy.
3. For pediatric patients, performance status: Karnofsky performance status (for patients >16 years of age) or Lansky Play score (for patients ≤16 years of age) ≥70%. Patients who are unable to walk because of paralysis or stable neurological disability, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.
4. For pediatric patients, able to swallow tablets.
5. For pediatric patients, evaluable or measurable disease as defined by standard imaging criteria for the patient’s tumor type (RECIST v1.1…).
6. For pediatric patients, life expectancy ≥ 3 months.
7. For pediatric patients, 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 ejection fraction (LVEF) ≥ 50% at baseline, as determined by echocardiography (mandatory only for patients who have received cardiotoxic therapy), absence of QTc prolongation (QTc >450 msec on baseline ECG, using the Fridericia correction [QTcF formula]) or other clinically 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; aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase/SGOT ≤ 2.5 x ULN except in patients with documented tumor involvement of the liver who must have AST/SGOT and ALT/SGPT ≤ 5 x ULN.
8. For pediatric patients, Written informed consent from parents/legal representative and age-appropriate assent before any study-specific screening procedures are conducted according to local, regional or national guidelines.
9. For pediatric patients, Patient affiliated to a social security regimen or beneficiary of the same according to local requirements.
10. For adults patients: - Pre-screening phase: adults (≥ 18 years old) with solid tumor (include rhabdomyosarcoma, Ewing’s sarcoma, osteosarcoma and other) and/or tumor with High mutation rate (>10 somatic mutations/Mb) and/or suffering of Mismatch repair-deficient syndrome.
11. For adults patients: - Pre-screening phase: Adult patients with an ECOG score of 0/1. Patients who are unable to walk because of paralysis or stable neurological disability, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.
12. For adults patients: - Pre-screening phase: Evaluable or measurable disease as defined by standard imaging criteria for the patient’s tumor type (RECIST v1.1…).
13. For adults patients: - Pre-screening phase: Written informed consent from patient before any study-specific screening procedures are conducted according to local, regional or national guidelines.
14. For adults patients : - Screening phase (Cohort 2): adults without standard established therapeutic alternatives at the time of enrollment suffering from refractory or recurrent advanced solid tumor characterized by the presence of mature TLS
15. For adults patients : - Screening phase (Cohort 2): Age ≥ 18 years at inclusion
16. For adults patients : - Screening phase (Cohort 2): Adult patients with an ECOG score of 0/1. Patients who are unable to walk because of paralysis or stable neurological disability, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.
17. For adults patients : - Screening phase (Cohort 2): Evaluable or measurable disease as defined by standard imaging criteria for the patient’s tumor type (RECIST v1.1…).
18. For adults patients : - Screening phase (Cohort 2): Life expectancy ≥ 3 months
19. For adults patients : - Screening phase (Cohort 2): 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 ejection fraction (LVEF) ≥50% at baseline, as determined by echocardiography (mandatory only for patients who have received cardiotoxic therapy), absence of QTc prolongation (QTc >450 msec on baseline ECG, using the Fridericia correction [QTcF formula]) or other clinically 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; aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase/SGOT ≤ 2.5 x ULN except in patients with documented tumor involvement of the liver who must have AST/SGOT and ALT/SGPT ≤5 x ULN.
20. For adults patients : - Screening phase (Cohort 2): Able to comply with scheduled follow-up and with management of toxicity.
21. For adults patients : - Screening phase (Cohort 2): Females of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test within 72 hours prior to initiation of treatment. Sexually active women of childbearing potential must agree to use a highly effective contraception during the study and for at least 6 months after the last study treatment administration. Sexually active male patients must agree to use condoms during the study and for at least 6 months after the last study treatment administration.
22. For adults patients : - Screening phase (Cohort 2): Written informed consent from patient before any study-specific screening procedures are conducted according to local, regional or national guidelines.
23. For adults patients : - Screening phase (Cohort 2): Patient affiliated to a social security regimen or beneficiary of the same according to local requirements.

Exclusion criteria 20

1. Patients treated with anti-PD1/anti-PDL1 immunotherapy within 6 months prior to starting study treatment; patients treated with anti-PD1/anti-PDL1 for more than 6 months remain eligible for inclusion, 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 significantly alter 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 cardiac arrhythmia, e.g. ventricular, supraventricular, nodal arrhythmias, or conduction abnormality), unstable ischemia, congestive heart failure within 12 months of screening).
4. Uncontrolled hypertension
5. Active viral hepatitis or known human immunodeficiency virus (HIV) infection or any other uncontrolled infection.
6. Presence of any ≥ CTCAE grade 2 treatment-related toxicity with the exception of alopecia, ototoxicity or peripheral neuropathy.
7. Systemic anticancer therapy within 21 days of the first study dose or 5 times its half-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 (or within 6 weeks for therapeutic doses of MIBG)
11. Major surgery within 21 days of the first dose. Gastrostomy, ventriculo-peritoneal shunt, endoscopic ventriculostomy, tumor biopsy and insertion of central venous access devices are not considered major surgery, but for these procedures, a 48-hour interval must be maintained before the first dose of the investigational drug is administered.
12. Currently taking medications with a known risk of prolonging the QT interval or inducing Torsades de Pointes
13. High dose chemotherapy followed by peripheral stem cell transplantation within less than 6 months.
14. Diagnosis of immunodeficiency or receiving systemic steroid therapy or any other form of immunosuppressive therapy within 14 days prior to the first dose of study treatment. The use of physiologic doses of corticosteroids (up to 0.25 mg/kg daily prednisone 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 type 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 of the Public Health Code (pregnant women, parturient and nursing mothers; persons deprived of their liberty by a judicial or administrative decision, persons hospitalized without consent and persons admitted to a health or social establishment for purposes other than that of research; adults subject to a legal protection measure or incapacitated express consent; people in emergency situations who cannot give prior consent)
20. Vaccinated with live, attenuated vaccines within 4 weeks of the first dose of study drug.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. For the pediatric cohort, the primary endpoint will be the Maximum Tolerated Dose (MTD). MTD will be defined as the dose closest to the target toxicity level of 25% of DLTs (Dose Limiting Toxicity) up to cycle 1 (4 weeks of treatment).
2. For the adult cohort, the primary efficacy endpoint will be the 6-month disease control rate, defined as the proportion of participants in complete response (CR), partial response (PR) or stable disease (SD) 6 months after treatment initiation. The subjects will be assigned a response category (CR, PR, SD or PD) according to RECIST 1.1 (Eisenhauer 2009) for solid tumor after every two treatment cycles.

Secondary endpoints 9

1. Incidence of adverse events and serious adverse events, defined according to the NCI CTCAE v5.0 in all cycles of treatment.
2. Overall Response Rate: The best overall response is the best response (CR or PR) recorded from the start of the treatment until patients get off-study or the cut-off date, whichever comes first (taking as reference for PD the smallest measurements recorded since the treatment started).
3. Progression-free survival
4. Overall survival
5. Response duration: will be measured from the time measurement criteria for CR/PR are first met until the first date that recurrent or progressive disease is objectively documented or death, whichever occurs earlier.
6. Pazopanib pharmacocinetic parameters ( including but not limited to plasma concentration time profiles, AUClast, AUCtau, Cmin, Cmax, Tmax, Clearance, Half-life time) will be performed on D-7, D1 and D8 for cycle 1 and on D1 for cycles 2, 3, 6 and 12.
7. Spartalizumab pharmacocinetic parameters ( including but not limited to plasma concentration time profiles, AUClast, AUCtau, Cmin, Cmax, Tmax, Clearance, Half-life time) will be performed on D1, D8 and D15 of cycle 1, on D1 and D15 of cycles 2, on D1 of cycles 3, 6 and 12.
8. Pharmacodynamics parameters including angiogenic cytokines VEGF, soluble VEGFR-1, soluble VEGFR-2, endoglin (ENG), placental growth factor (PlGF) and Lymphocyte immunophenotyping including CD3, CD4, CD8, CXCR5, CXCR3, CCR6, PD1, ICOS, CD45Ra, OX40, CXCL13, IL6 will be obtained on D1 and D15 for cycle 1, on D1 for cycles 2, 3, 6 and 12.
9. Identification of predictive biomarkers of immunotherapy based on genetic, immunological and metabolomic profiling of immune and tumor cells

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Centre Hospitalier Universitaire De Bordeaux

Sponsor organisation

Centre Hospitalier Universitaire De Bordeaux

Address

12 Rue Dubernat, Cs 91286 Cs 91286

City

Talence

Postcode

33400

Country

France

Scientific contact point

Organisation

Centre Hospitalier Universitaire De Bordeaux

Contact name

Coordinating investigator

Public contact point

Organisation

Centre Hospitalier Universitaire De Bordeaux

Contact name

Coordinating investigator

Locations

1 EU/EEA country · 13 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Temporary halts 1 · Art. 38 CTR

Application history

3 submissions — initial application plus substantial / non-substantial modifications