Antiemetics

Gastrointestinal Agents

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Emetics

Dose escalation step Dose escalation will be conducted on the grid defined by the 4 doses of PLX038 (800 mg/m², 1000 mg/m², 1300 mg/m² and 1700 mg/m² IV every 21 days D1=D22) and 3 doses of Tuvusertib (90 mg, 130 mg and 180 mg QD for 10 days from D3, D3-12). Premedication with anti-emetic agents is not required prior to the initial infusion, but may be used for an individual patient, as needed.

Expansion cohorts Two expansion cohorts are planned, investigating the efficacy and safety in pre-specified populations of interest.

Patients will be treated at the RP2D; 25 evaluable patients are needed in each cohort, to account for possible non evaluable patients, up to 28 patients will be enrolled in each cohort.

Patients enrolled in the phase I part at the RP2D and fulfilling the eligibility criteria of one of the expansion cohorts will be counted in those 25 evaluable patients.

Dose escalation will be conducted on the grid defined by the 4 doses of PLX038 (800 mg/m², 1000 mg/m², 1300 mg/m² and 1700 mg/m² IV every 21 days D1=D22) and 3 doses of Tuvusertib (90 mg, 130 mg and 180 mg QD for 10 days from D3, D3-12). Premedication with anti-emetic agents is not required prior to the initial infusion, but may be used for an individual patient, as needed.

All included patients will receive PLX038 + Tuvusertib until progression of disease, unacceptable toxicity, patient withdrawal of consent, investigator decision, lost to follow-up, death, patient non-compliance, or study termination by Sponsor.

PLX038 + Tuvusertib

Fouzia Azzouz

François-Clément Bidard, Study Principal Investigator

François-Clément BIDARD

Phase I with a dose finding cohort, followed by expansion cohorts in pre-specified tumor types.

This is an open label, multi-centric phase I with, first, a dose escalation step using an adaptation of the Bayesian Optimal INterval (BOIN) drug-combination, followed by 2 dose expansion cohorts using the Simon 2-stage design.

Dose escalation step Dose escalation will be conducted on the grid defined by the 4 doses of PLX038 (800 mg/m², 1000 mg/m², 1300 mg/m² and 1700 mg/m² IV every 21 days D1=D22) and 3 doses of Tuvusertib (90 mg, 130 mg and 180 mg QD for 10 days from D3, D3-12). Premedication with anti-emetic agents is not required prior to the initial infusion, but may be used for an individual patient, as needed.

starting combination level is c1 (PLX038 800mg/m2 and Tuvusertib 90mg). Groups of 3 patients will be sequentially enrolled. One week between the enrollment of the 1st patient and the 2 following patients is mandatory at a new combination level. The decision to (de)-escalate one of the two agents depends on the outcome of all patients treated at the current combination.

Expansion cohorts Two expansion cohorts are planned, investigating the efficacy and safety in pre-specified populations of interest.

Patients will be treated at the RP2D; 25 evaluable patients are needed in each cohort, to account for possible non evaluable patients, up to 28 patients will be enrolled in each cohort.

Patients enrolled in the phase I part at the RP2D and fulfilling the eligibility criteria of one of the expansion cohorts will be counted in those 25 evaluable patients.

A Study on Tuvusertib (Oral ATR Inhibitor) in Combination With PLX038 (Topo1 Inhibitor) in Patients With Advanced Solid Tumors

A Phase I Study on Tuvusertib (Oral ATR Inhibitor) in Combination With PLX038 (Topo1 Inhibitor) With Dose Expansion Cohorts in Patients With Advanced Solid Tumors

Sponsor will share de-identified data sets. Documents generated under the project will be disseminated in accordance with Institut Curie policies.

Dose limiting toxicities (DLTs) experienced during 21 days from the first IV infusion of PLX038 + Tuvusertib

Best tumor response (defined as PR or CR in the first 6 months of treatment, assessed by investigators per RECIST v1.1 criteria)

Serious Adverse Events (SAEs) according to NCI CTCAE v5.0 by grade and their relationship to PLX038 + Tuvusertib.

Adverse Events (AEs) according to NCI CTCAE v5.0 by grade and their relationship to PLX038 + Tuvusertib.

Maximum Plasma Concentration effect of PLX038, SN38 and Tuvusertib

ORR defined as the percentage of patients with complete response (CR) or partial response (PR), as the best response measured at the disease assessmement after initiation of treament according to RECIST v1.1

TTR calculated from the initiation of treatment to best tumour response (CR/PR)

DoR defined as the time period from best tumour response to disease progression (according to RECIST v1.1)

PFS measured from the inclusion in the study to the first documented progression (according to RECIST v1.1) or death from any cause.

DoR defined as the time period from best tumour response to disease progression

PFS measured from the inclusion in the study to the first documented progression

OS is defined as the time from inclusion to the event death.

Association between PLX038 + Tuvusertib efficacy and homologous recombination (HR) defect (assessed by HR genes mutational status and BCRAness phenotype), replication stress-related biomarkers such as SFLN11 expression, RB1 loss; genomic alterations in DDR genes

Association between PLX038 + Tuvusertib efficacy and quantitative changes of blood biomarkers (e.g. ctDNA) during therapy.

Spots Global Cancer Trial Database for advanced triple negative breast