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

Phase 1/2

Recruiting

• Conditions: Refractory or Recurrent Solid Tumor

• Registration Number: 2024-513535-24-00
• Lead Sponsor: Centre Hospitalier Universitaire De Bordeaux

Brief Summary

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

Detailed Description

Immunotherapies have revolutionized medical oncology following the remarkable and, in some cases, unprecedented outcomes observed in certain groups of patients with cancer. However results in adults and mainly in pediatric cancer are still disappointing. One hypothesis is that the tumor micro-environment (TME) - characterized by hypoxia, a low pH, and a high interstitial fluid pressure - can reduce the effectiveness of virtually all types of anticancer therapies, including immunotherapy. In adults, combination with other therapeutic modalities, including anti-angiogenic agents, is one of the many strategies currently under investigation to improve the response rates and duration of immunotherapies.

Modulators of angiogenesis, such as VEGF, have a broad range of diverse effects on the immune system and the tumor micro-environment that are mainly immunosuppressive. In patients with early-stage disease, anti-VEGF therapy can lead to antitumor effects by modulating immune mechanisms - provided that therapy is maintained for an adequate length and tumors are sufficiently immunogenic. Nevertheless, blocking angiogenic molecules using a strategy based on a single therapeutic approach is likely insufficient to generate a complete or robust immune response against cancer, especially in patients with advanced-stage disease. Therefore, such anti-angiogenic agents will likely need to be used in combination with various immunotherapeutic strategies that boost adaptive immune responses, such as those described in the next sections. For these reasons, the investigators proposed to combine immunotherapy and low dose of pazopanib to enhance the efficacy of immunotherapy in some selected pediatric patients and adults.

PDR001 (also referred to as spartalizumab) is a humanized monoclonal antibody (mAb) directed against human programmed death-1 (PD-1) that blocks the interaction between PD-1 and its ligands (PD-L1 and PD-L2).

Pazopanib is a potent, selective, oral, ATP competitive multitargeted receptor tyrosine kinase inhibitor of vascular endothelial growth factor receptors (VEGFR) -1, -2, and -3, c-kit, and platelet-derived growth factor receptors. It is approved by the US Food and Drug Administration for the treatment of advanced renal cell carcinoma and soft tissue sarcoma (STS) in adults. Based on the results of previous studies which evaluated the safety profile of spartalizumab, of pazopanib and the combination of antiangiogenic agents with checkpoint inhibitors, a study combining spartalizumab and low-dose pazopanib in refractory or relapsed solid tumors of pediatric and adults is proposed. This study will include 2 separate cohorts:

* the pediatric cohort will consist of a phase I study (dose-finding and expansion phases) combining pazopanib at a fixed dose of 225 mg/m2 and spartalizumab with four potential candidate doses (2, 3, 4 and 6 mg/kg).

* the adult cohort will consist of a phase II study combining pazopanib at a fixed dose of 400 mg and spartalizumab at the RP2D of 400 mg every 4 weeks.

Study Timeline

• Study First Posted: 2024-10-03
• Last Update Posted: 2025-02-12

Recruitment & Eligibility

• Status: Ongoing, recruiting
• Sex: Not specified
• Target Recruitment: 74

Inclusion Criteria

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).

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.

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.

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…).

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.

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

For adults patients : - Screening phase (Cohort 2): Age ≥ 18 years at inclusion

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.

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…).

For adults patients : - Screening phase (Cohort 2): Life expectancy ≥ 3 months

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.

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.

For adults patients : - Screening phase (Cohort 2): Able to comply with scheduled follow-up and with management of toxicity.

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.

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.

For adults patients : - Screening phase (Cohort 2): Patient affiliated to a social security regimen or beneficiary of the same according to local requirements.

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.

For pediatric patients, able to swallow tablets.

For pediatric patients, evaluable or measurable disease as defined by standard imaging criteria for the patient’s tumor type (RECIST v1.1…).

For pediatric patients, life expectancy ≥ 3 months.

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.

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.

For pediatric patients, Patient affiliated to a social security regimen or beneficiary of the same according to local requirements.

Exclusion Criteria

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).

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

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.

Currently taking medications with a known risk of prolonging the QT interval or inducing Torsades de Pointes

High dose chemotherapy followed by peripheral stem cell transplantation within less than 6 months.

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.

Diagnosis of prior or active autoimmune disease.

Evidence of interstitial lung disease.

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.

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

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)

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).

Vaccinated with live, attenuated vaccines within 4 weeks of the first dose of study drug.

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).

Uncontrolled hypertension

Active viral hepatitis or known human immunodeficiency virus (HIV) infection or any other uncontrolled infection.

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

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

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

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Primary Outcome Measures

Name	Time	Method
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).		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).
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.		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 Outcome Measures

Name	Time	Method
Overall survival		Overall survival
Progression-free survival		Progression-free survival
Incidence of adverse events and serious adverse events, defined according to the NCI CTCAE v5.0 in all cycles of treatment.		Incidence of adverse events and serious adverse events, defined according to the NCI CTCAE v5.0 in all cycles of treatment.
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).		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).
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.		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.
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.		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.
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.		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.
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.		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.
Identification of predictive biomarkers of immunotherapy based on genetic, immunological and metabolomic profiling of immune and tumor cells		Identification of predictive biomarkers of immunotherapy based on genetic, immunological and metabolomic profiling of immune and tumor cells

Trial Locations

Locations (10)

Institut Gustave Roussy; 🇫🇷 Villejuif, France

Centre Leon Berard; 🇫🇷 Lyon, France

Centre Hospitalier Universitaire De Bordeaux; 🇫🇷 Bordeaux, France

Institut Curie; 🇫🇷 Paris, France

Les Hopitaux Universitaires De Strasbourg; 🇫🇷 Strasbourg Cedex, France

Centre Hospitalier Universitaire D'Angers; 🇫🇷 Angers, France

Centre Hospitalier Regional De Marseille; 🇫🇷 Marseille, France

Centre Hospitalier Universitaire De Nantes; 🇫🇷 Nantes, France

Institut Bergonie; 🇫🇷 Bordeaux, France

Centre Oscar Lambret; 🇫🇷 Lille, France

Institut Gustave Roussy

🇫🇷Villejuif, France

Pablo BERLANGA CHARRIEL

Site contact

0142116541

pablo.berlanga@gustaveroussy.fr