Evaluation of Spartalizumab and Low-Dose Pazopanib in Refractory or Relapsed Solid Tumors in Pediatric and Adult Cohorts
- Trial ID
- 2024-513535-24-00
- Protocol
- CHUBX 2020/31
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to identify the recommended dose for phase II study (**RP2D**) of **spartalizumab** in association with a fixed dose of **pazopanib** in the pediatric cohort. Additionally, the study aims to estimate the efficacy of the combination of spartalizumab and pazopanib on the 6-month disease control rate in the adult cohort. This is clinically relevant as it seeks to optimize dosing strategies and evaluate the therapeutic potential of the drug combination in treating refractory or recurrent solid tumors.
Secondary objectives include:
- Describing the safety profile of the combination in both pediatric and adult cohorts.
- Estimating preliminary signs of efficacy on objective response rate, overall survival (**OS**), and progression-free survival (**PFS**) in the pediatric cohort.
- Estimating the proportion of long-term responder patients in the pediatric cohort.
- Estimating objective response rate, OS, and PFS in the adult cohort.
- Describing pharmacokinetic (**PK**) parameters of pazopanib with lower doses and determining if early PK points can predict pazopanib PK evolution.
- Excluding the implication of pazopanib in dose-limiting toxicity (**DLT**) observations.
- Determining if a pazopanib concentration target could relate to the response of spartalizumab.
- Performing an integrative assessment of prognostic factors of objective response rate, PFS, and OS.
Participants
The clinical trial involves participants diagnosed with **refractory or recurrent solid tumors**. The study population includes both pediatric and adult cohorts. Pediatric participants are aged between 5 and 18 years, while adult participants are 18 years and older. Both male and female subjects are included in the trial. Participants are required to have a performance status that allows for ambulatory activity, even if assisted by a wheelchair. The trial does not involve a vulnerable population. Participants must have adequate organ function, as defined by specific hematologic, cardiac, renal, and hepatic criteria. Lifestyle considerations such as diet and physical activity are not specified. The sponsor has not provided information regarding the total number of participants in the trial.
Plans and Procedures
The clinical trial is designed to evaluate the combination of **spartalizumab** and low-dose **pazopanib** in patients with refractory or recurrent solid tumors. This is a Phase I-II trial, which aims to identify the recommended dose for phase II (RP2D) in the pediatric cohort and to estimate the efficacy of the combination on the 6-month disease control rate in the adult cohort. The trial employs a randomized, double-blind, controlled design to ensure the reliability and validity of the results. The estimated duration of the trial is from May 2022 to November 2027, with participant involvement expected to last until the end of the study or until early termination criteria are met.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on specific criteria, such as age, performance status, and organ function. Following successful screening, participants will enter the treatment phase, where they will receive the investigational products via infusion and oral administration. Follow-up visits will occur regularly to monitor safety, efficacy, and pharmacokinetic parameters, including plasma concentration and clearance rates. The end-of-study visit will conclude the participant's involvement, where final assessments will be conducted to evaluate the overall response and progression-free survival.
The expected length of participant involvement varies, with the primary endpoint for the pediatric cohort being the Maximum Tolerated Dose (MTD) and for the adult cohort, the 6-month disease control rate. Conditions that may lead to early termination from the study include the occurrence of dose-limiting toxicities, adverse events, or disease progression. Participants will be closely monitored throughout the trial to ensure adherence to the protocol and to address any safety concerns promptly.
Treatment
The clinical trial involves the administration of **spartalizumab**, an investigational medication provided in the form of a **concentrate for solution for infusion**. Spartalizumab is a protein-based therapeutic agent developed by Novartis Pharma AG. The medication is administered via **infusion**, with the dosing schedule determined by the study protocol to identify the recommended dose for phase II studies. Participant compliance with the infusion schedule is monitored throughout the trial to ensure adherence to the treatment regimen.
In addition to spartalizumab, the trial includes the administration of **pazopanib**, marketed as Votrient, which is provided in the form of **film-coated tablets**. Pazopanib is a chemically synthesized compound developed by Novartis Europharm Limited. The tablets are administered orally, with a fixed dose regimen as specified in the study protocol. The trial aims to evaluate the efficacy of the combination of spartalizumab and pazopanib, with particular attention to the 6-month disease control rate in the adult cohort. Participant adherence to the oral dosing schedule is monitored to ensure compliance with the treatment protocol.
Efficacy
Efficacy in this clinical trial will be assessed through a combination of primary and secondary endpoints. For the pediatric cohort, the primary endpoint is the Maximum Tolerated Dose (MTD), defined as the dose closest to the target toxicity level of 25% of Dose Limiting Toxicities (DLTs) up to cycle 1, which consists of 4 weeks of treatment. For the adult cohort, the primary efficacy endpoint is the 6-month disease control rate, which is the proportion of participants achieving complete response (CR), partial response (PR), or stable disease (SD) 6 months after treatment initiation. Participants will be evaluated according to RECIST 1.1 criteria for solid tumors after every two treatment cycles.
Secondary endpoints include the incidence of adverse events and serious adverse events, as defined by the NCI CTCAE v5.0, overall response rate, progression-free survival, overall survival, and response duration. Pharmacokinetic parameters for **pazopanib** and **spartalizumab** will be measured at specified time points during the treatment cycles. Additionally, pharmacodynamic parameters, including angiogenic cytokines and lymphocyte immunophenotyping, will be assessed. The identification of predictive biomarkers of immunotherapy will also be explored through genetic, immunological, and metabolomic profiling of immune and tumor cells.
Inclusion and Exclusion Criteria
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 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 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.
- 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 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.
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).
- 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).
- 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.
- 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)
- Vaccinated with live, attenuated vaccines within 4 weeks of the first dose of study drug.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Not Yet Recruiting | 17 May 2022 | 74 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Votrient 200 mg film-coated tablets | Test | FILM‑COATED TABLETS | ORAL USE | — | — | PRD3045794 |
PDR001 | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INFUSION | — | — | PRD6759834 |