Ignite Creation Date:
2024-05-06 @ 5:53 PM
Last Modification Date:
2024-10-26 @ 2:37 PM
Study NCT ID:
NCT05468359
Status:
RECRUITING
Last Update Posted:
2023-12-22
First Post:
2022-06-13
Brief Title:
Safety and Efficacy of Cyclophosphamide Sorafenib Bevacizumab and Atezolizumab in Pediatric Solid Tumor Patients
Sponsor:
St Jude Childrens Research Hospital
Organization:
St Jude Childrens Research Hospital
Study Overview
Official Title:
ANGIO-A Safety and Tolerability of Oral Cyclophosphamide and Sorafenib With Intravenous Bevacizumab With the Addition of Atezolizumab in Pediatric Solid Tumor Patients
Status:
RECRUITING
Status Verified Date:
2023-12
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
No
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
This is a phase III study to evaluate the safety of combining intravenous IV atezolizumab and bevacizumab every three weeks with daily oral cyclophosphamide and pharmacokinetic PK-guided sorafenib in children and adolescent and young adults AYA with relapsed or refractory solid malignancies Part 1 and then evaluate the response rate of this combination in children AYA with relapsed or refractory hepatocellular carcinoma HCC and other rare solid malignancies Part 2
Primary Objectives Part 1
To establish the safety associated with the administration of the combination of cyclophosphamide PK-guided sorafenib bevacizumab and atezolizumab in children and AYA with relapsed or refractory solid tumors
To determine if sorafenib systemic exposure can be successfully targeted to an AUC between 20 and 55 hrµgmL by Day 21 of cycle 1 in 60 of evaluable patients when given in combination with cyclophosphamide bevacizumab and atezolizumab in children and AYA with relapsed or refractory solid tumors
Part 2
To evaluate the response rate CRPR of the combination of cyclophosphamide PK-guided sorafenib bevacizumab and atezolizumab in children and AYA with relapsed or refractory HCC following two cycles of therapy
To determine if the use of PK-guided sorafenib dosing to maintain a systemic exposure between 20 and 55 reduces the interpatient pharmacokinetic variability of sorafenib and the incidence of sorafenib- induced skin toxicities in children and AYA with relapsed or refractory HCC and other rare solid tumors
Parts 1 2
To determine if the combination of cyclophosphamide PK-guided sorafenib and atezolizumab will result in increased intratumoral T-cell infiltration of CD8C45RO cells between baseline and following two courses of therapy in pediatric children and AYA with relapsed or refractory solid tumors following two cycles of therapy
To characterize the pharmacokinetics of atezolizumab in combination with cyclophosphamide PK-guided sorafenib and bevacizumab in children and AYA with relapsed or refractory solid tumors
To assess the feasibility of performing contrast enhanced ultrasound and explore the correlation between quantitative CEUS parameters and clinical response
Secondary Objectives
Part 1
To describe the response rate CRPR of the combination of cyclophosphamide PK-guided sorafenib bevacizumab and atezolizumab in children and AYA with relapsed or refractory solid tumors following two cycles of therapy
Part 2
To describe the response rate CRPR of the combination of cyclophosphamide PK-guided sorafenib bevacizumab and atezolizumab in children and AYA with relapsed or refractory fibrolamellar carcinoma desmoplastic small round cell tumor malignant rhabdoid tumor and other rare solid tumors following two cycles of therapy
Parts 12
To describe the number of children with liver tumors initially judged unresectable at diagnosis that can have their primary tumor resected after treatment with oral cyclophosphamide and sorafenib with intravenous bevacizumab and atezolizumab
To describe changes in immune cells in the peripheral blood at periodic times before and after treatment with this combination chemoimmunotherapy
To describe the PFS EFS and OS in patients treated with the combination of cyclophosphamide PK-guided sorafenib bevacizumab and atezolizumab in patients with relapsed or refractory HCC DSRCT MRT FL-HCC and other rare solid tumors
Primary Objectives Part 1
To establish the safety associated with the administration of the combination of cyclophosphamide PK-guided sorafenib bevacizumab and atezolizumab in children and AYA with relapsed or refractory solid tumors
To determine if sorafenib systemic exposure can be successfully targeted to an AUC between 20 and 55 hrµgmL by Day 21 of cycle 1 in 60 of evaluable patients when given in combination with cyclophosphamide bevacizumab and atezolizumab in children and AYA with relapsed or refractory solid tumors
Part 2
To evaluate the response rate CRPR of the combination of cyclophosphamide PK-guided sorafenib bevacizumab and atezolizumab in children and AYA with relapsed or refractory HCC following two cycles of therapy
To determine if the use of PK-guided sorafenib dosing to maintain a systemic exposure between 20 and 55 reduces the interpatient pharmacokinetic variability of sorafenib and the incidence of sorafenib- induced skin toxicities in children and AYA with relapsed or refractory HCC and other rare solid tumors
Parts 1 2
To determine if the combination of cyclophosphamide PK-guided sorafenib and atezolizumab will result in increased intratumoral T-cell infiltration of CD8C45RO cells between baseline and following two courses of therapy in pediatric children and AYA with relapsed or refractory solid tumors following two cycles of therapy
To characterize the pharmacokinetics of atezolizumab in combination with cyclophosphamide PK-guided sorafenib and bevacizumab in children and AYA with relapsed or refractory solid tumors
To assess the feasibility of performing contrast enhanced ultrasound and explore the correlation between quantitative CEUS parameters and clinical response
Secondary Objectives
Part 1
To describe the response rate CRPR of the combination of cyclophosphamide PK-guided sorafenib bevacizumab and atezolizumab in children and AYA with relapsed or refractory solid tumors following two cycles of therapy
Part 2
To describe the response rate CRPR of the combination of cyclophosphamide PK-guided sorafenib bevacizumab and atezolizumab in children and AYA with relapsed or refractory fibrolamellar carcinoma desmoplastic small round cell tumor malignant rhabdoid tumor and other rare solid tumors following two cycles of therapy
Parts 12
To describe the number of children with liver tumors initially judged unresectable at diagnosis that can have their primary tumor resected after treatment with oral cyclophosphamide and sorafenib with intravenous bevacizumab and atezolizumab
To describe changes in immune cells in the peripheral blood at periodic times before and after treatment with this combination chemoimmunotherapy
To describe the PFS EFS and OS in patients treated with the combination of cyclophosphamide PK-guided sorafenib bevacizumab and atezolizumab in patients with relapsed or refractory HCC DSRCT MRT FL-HCC and other rare solid tumors
Detailed Description:
Exploratory Objectives Parts 1 2
To determine the number of HCC and FL-HCC xenografts that can be successfully established from children with relapsed or refractory HCC enrollment on MAST with biopsy for fresh tissue required
To evaluate the immune cell infiltrates in children with relapsed or refractory solid tumors before and after two cycles of cyclophosphamide sorafenib bevacizumab and atezolizumab
To evaluate the number type specificity repertoire and activity of intratumoral T cells after two cycles of therapy compared to baseline
To characterize changes in tumor associated macrophages polarization between baseline and after two cycles of cyclophosphamide sorafenib bevacizumab and atezolizumab
To measure changes in tumor mutational burden and mutation heterogeneity
To explore associations between T stem cell epigenetic signatures and response to treatment
To explore the association between baseline CD45ROCD8 T-cell infiltration and PD-L1 expression and response to treatment
To characterize tumor heterogeneity and microenvironment using single-cellnuclear RNA sequencing pre- and post-treatment
To longitudinally assess and quantify numerous metrics of quality of life QoL family distress and functional impairment for patients enrolled on ANGIOA and their primary caretakers
To qualitatively assess patient and family physical emotional and psychosocial experiences prior to and after receipt of therapy on ANGIOA through semi-structured interviews
To assess the acceptability and feasibility of capturing patientcaregiver interview data at the time of enrollment and discontinuation on ANGIOA
To evaluate the correlation of CEUS imaging characteristics with the expression of CD34 in biopsy samples
To establish HCC organoid and spheroid HCCoid cultures from patient tumor samples and study the correlation between the biological features of the HCCoids and the progression of their parental tumors in patients
To study the interaction between HCCoids and liver cells from different developmental stages to understand the contribution of the developmental microenvironment to HCC development
Part 1 safetytolerability Children with relapsed or refractory solid tumors with biopsy accessible and evaluable disease will be treated with two courses of oral PK-guided sorafenib starting area under the curve AUC target 20-55 ugmlhr oral cyclophosphamide 50 mgm2dose daily qd x 21 days IV bevacizumab 15 mgkgdose every q 21 days and IV atezolizumab 15 mgkg max dose 1200 mg q 21 days Tumor biopsies are required before starting treatment and after course two Section 41 Biopsied tissue will be used for enrollment on MAST and to evaluate changes in T-cell infiltration Sorafenib PK will be obtained and dose adjusted to target an AUC between 20 and 55 hrµgmL by Day 21 of C1 Tolerability will be defined after completion of Course 1 Part 2 will begin once the recommended phase 2 dose RP2D is determined
Part 2 efficacy Children and AYA with relapsed or refractory HCC will be treated with two courses of oral cyclophosphamide and sorafenib with IV bevacizumab and atezolizumab based on the RP2D from Part 1 Tumor response will be assessed after two courses according to immunologic and imaging criteria Section 41 Eligible patients with Fibrolamellar Carcinoma FL-HCC desmoplastic small round cell tumor DSRCT or non-central nervous system CNS malignant rhabdoid tumors MRT will be enrolled on separate strata but target accrual will be determined by patients with HCC
To determine the number of HCC and FL-HCC xenografts that can be successfully established from children with relapsed or refractory HCC enrollment on MAST with biopsy for fresh tissue required
To evaluate the immune cell infiltrates in children with relapsed or refractory solid tumors before and after two cycles of cyclophosphamide sorafenib bevacizumab and atezolizumab
To evaluate the number type specificity repertoire and activity of intratumoral T cells after two cycles of therapy compared to baseline
To characterize changes in tumor associated macrophages polarization between baseline and after two cycles of cyclophosphamide sorafenib bevacizumab and atezolizumab
To measure changes in tumor mutational burden and mutation heterogeneity
To explore associations between T stem cell epigenetic signatures and response to treatment
To explore the association between baseline CD45ROCD8 T-cell infiltration and PD-L1 expression and response to treatment
To characterize tumor heterogeneity and microenvironment using single-cellnuclear RNA sequencing pre- and post-treatment
To longitudinally assess and quantify numerous metrics of quality of life QoL family distress and functional impairment for patients enrolled on ANGIOA and their primary caretakers
To qualitatively assess patient and family physical emotional and psychosocial experiences prior to and after receipt of therapy on ANGIOA through semi-structured interviews
To assess the acceptability and feasibility of capturing patientcaregiver interview data at the time of enrollment and discontinuation on ANGIOA
To evaluate the correlation of CEUS imaging characteristics with the expression of CD34 in biopsy samples
To establish HCC organoid and spheroid HCCoid cultures from patient tumor samples and study the correlation between the biological features of the HCCoids and the progression of their parental tumors in patients
To study the interaction between HCCoids and liver cells from different developmental stages to understand the contribution of the developmental microenvironment to HCC development
Part 1 safetytolerability Children with relapsed or refractory solid tumors with biopsy accessible and evaluable disease will be treated with two courses of oral PK-guided sorafenib starting area under the curve AUC target 20-55 ugmlhr oral cyclophosphamide 50 mgm2dose daily qd x 21 days IV bevacizumab 15 mgkgdose every q 21 days and IV atezolizumab 15 mgkg max dose 1200 mg q 21 days Tumor biopsies are required before starting treatment and after course two Section 41 Biopsied tissue will be used for enrollment on MAST and to evaluate changes in T-cell infiltration Sorafenib PK will be obtained and dose adjusted to target an AUC between 20 and 55 hrµgmL by Day 21 of C1 Tolerability will be defined after completion of Course 1 Part 2 will begin once the recommended phase 2 dose RP2D is determined
Part 2 efficacy Children and AYA with relapsed or refractory HCC will be treated with two courses of oral cyclophosphamide and sorafenib with IV bevacizumab and atezolizumab based on the RP2D from Part 1 Tumor response will be assessed after two courses according to immunologic and imaging criteria Section 41 Eligible patients with Fibrolamellar Carcinoma FL-HCC desmoplastic small round cell tumor DSRCT or non-central nervous system CNS malignant rhabdoid tumors MRT will be enrolled on separate strata but target accrual will be determined by patients with HCC
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
True
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None