Dose Escalation and Dose Expansion Study of IPN60090 in Patients With Advanced Solid Tumours

The maximum tolerated dose (MTD) is defined as the maximum dose of IPN60090 administered BID for 21 days, so that no more than 30% of participants experience a DLT. The MTD was determined using a Bayesian Optimal Interval design. The DLT assessment period was the first 21 days of treatment (one cycle).

Time frame: Up to Cycle 1 Day 21 of Part A

Population: DLT evaluable population included all participants from the safety population who were evaluable for DLT (participants who completed at least one cycle of treatment and received ≥75% of the total planned dose of IPN60090 over the DLT assessment period).

An adverse event (AE) is the development of an undesirable medical condition or the deterioration of a pre-existing medical condition following or during exposure to a study drug, whether or not considered causally related to the study drug. An undesirable medical condition can be symptoms, signs or the abnormal results of an investigation. An SAE is any AE that: results in death; is life-threatening; requires hospitalization or prolongation of existing hospitalization; results in persistent or significant disability or incapacity; results in congenital anomaly or birth defect; or is medically important. A TEAE is defined as any AE that began or worsened following the first administration of study drugs. AEs were recorded and graded according of the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v5.0. * Grade 1 = mild, * Grade 2 = moderate, * Grade 3 = severe, * Grade 4 = life threatening/disabling, * Grade 5 = death (related to AE).

Time frame: TEAEs were to be collected from the start of the first dose of IPN60090 (Cycle 1 Day 1) up to 30 days after the date of the decision to permanently discontinue study treatment, assessed until data cut-off for study termination (maximum of 219 days).

Population: Safety population included all participants who were exposed to (or started receiving) IPN60090.

The recommended dose was determined by the safety review committee following an ad-hoc review of the safety and tolerability data during Part A of the study.

Time frame: Up to Cycle 1 Day 21 of Part A

Population: DLT evaluable population included all participants from the safety population who were evaluable for DLT (participants who completed at least one cycle of treatment and received ≥75% of the total planned dose of IPN60090 over the DLT assessment period).

Blood samples were collected to determine T1/2 of IPN60090. The PK of IPN60090 plasma concentrations were performed using noncompartmental analysis.

Time frame: Pre-dose and 0.5, 1, 2, 4, 8 and 12 hours post-dose on Cycle 1 Day 1 in Part A

Population: The PK population for noncompartmental analysis included all participants who had no major protocol deviation affecting the PK variables and who had a sufficient number of IPN60090 plasma concentrations to estimate the main PK parameters. Summarized PK results are presented for IPN60090 120 mg, IPN60090 180 mg and IPN60090 240 mg reporting groups only.

Blood samples were collected to determine CL/F of IPN60090. The PK of IPN60090 plasma concentrations were performed using noncompartmental analysis.

Time frame: Pre-dose and 0.5, 1, 2, 4, 8 and 12 hours post-dose on Cycle 1 Day 1 in Part A

Population: The PK population for noncompartmental analysis included all participants who had no major protocol deviation affecting the PK variables and who had a sufficient number of IPN60090 plasma concentrations to estimate the main PK parameters. Summarized PK results are presented for IPN60090 120 mg, IPN60090 180 mg and IPN60090 240 mg reporting groups only.

Blood samples were collected to determine Vz/F of IPN60090. The PK of IPN60090 plasma concentrations were performed using noncompartmental analysis.

Time frame: Pre-dose and 0.5, 1, 2, 4, 8 and 12 hours post-dose on Cycle 1 Day 1 in Part A

Population: The PK population for noncompartmental analysis included all participants who had no major protocol deviation affecting the PK variables and who had a sufficient number of IPN60090 plasma concentrations to estimate the main PK parameters. Summarized PK results are presented for IPN60090 120 mg, IPN60090 180 mg and IPN60090 240 mg reporting groups only.

Blood samples were collected to determine AUC0-last of IPN60090. The PK of IPN60090 plasma concentrations were performed using noncompartmental analysis.

Time frame: Pre-dose and 0.5, 1, 2, 4, 8 and 12 hours post-dose on Cycle 1 Day 1 and Cycle 1 Day 14 in Part A

Population: The PK population for noncompartmental analysis included all participants who had no major protocol deviation affecting the PK variables and who had a sufficient number of IPN60090 plasma concentrations to estimate the main PK parameters. Summarized PK results are presented for IPN60090 120 mg, IPN60090 180 mg and IPN60090 240 mg reporting groups only.

The BOR is defined as the best response designation \[in the order of complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD)\] for each participant that is recorded between the date of the first dose of the study drug and the date of documented disease progression per RECIST 1.1 or the date of subsequent anticancer therapy whichever occurs first. Per RECIST v1.1, CR is disappearance of all target lesions; PR is \>=30% decrease in the sum of the longest diameter of target lesions; and overall response = CR + PR.

Time frame: RECIST assessments performed at baseline (within 28 days before start of study drug), every 6 weeks +/-1 week for first 24 weeks, then every 12 weeks +/-2 weeks thereafter. Up to data cut-off for study termination (maximum of 247 days).

Population: Efficacy population included all participants who received at least one dose of IPN60090.

The DCR is defined as the percentage of participants in whom the BOR is equal to CR, PR or SD for Part A. The BOR is defined as the best response designation (in the order of CR, PR, SD, PD) for each participant that is recorded between the date of the first dose of the study drug and the date of documented disease progression per RECIST 1.1 or the date of subsequent anticancer therapy whichever occurs first. Per RECIST v1.1, CR is disappearance of all target lesions; PR is \>=30% decrease in the sum of the longest diameter of target lesions; and overall response = CR + PR.

Time frame: RECIST assessments performed at baseline (within 28 days before start of study drug), every 6 weeks +/-1 week for first 24 weeks, then every 12 weeks +/-2 weeks thereafter. Up to data cut-off for study termination (maximum of 247 days).

Population: Efficacy population included all participants who received at least one dose of IPN60090.

Blood samples were collected to determine Cmax of IPN60090. The pharmacokinetics (PK) of IPN60090 plasma concentrations were performed using noncompartmental analysis.

Time frame: Pre-dose and 0.5, 1, 2, 4, 8 and 12 hours post-dose on Cycle 1 Day 1 and Cycle 1 Day 14 in Part A

Population: The PK population for noncompartmental analysis included all participants who had no major protocol deviation affecting the PK variables and who had a sufficient number of IPN60090 plasma concentrations to estimate the main PK parameters. Summarized PK results are presented for IPN60090 120 mg, IPN60090 180 mg and IPN60090 240 mg reporting groups only.

All measurable lesions up to a maximum of two lesions per organ and five lesions in total, representative of all involved organs, identified as target lesions and measured at baseline. Baseline is defined as the last measurement prior to the first dose of study drug.

Time frame: Baseline (within 28 days before start of study drug) and post-baseline, up to data cut-off for study termination (maximum of 247 days).

Population: Efficacy population included all participants who received at least one dose of IPN60090. Only participants with valid baseline and at least one post-baseline value of the sum of diameters are included.

The OS is defined as the time from first dose of study drug to death due to any cause. Participants who were lost to follow-up or who were still alive at the time of analysis is censored at the last day the participant was known to be alive or data cut-off date, whichever occurred first.

Time frame: RECIST assessments performed at baseline (within 28 days before start of study drug), every 6 weeks +/-1 week for first 24 weeks, then every 12 weeks +/-2 weeks thereafter. Up to data cut-off for study termination (maximum of 247 days).

Population: Efficacy population included all participants who received at least one dose of IPN60090.

The PFS is defined as the time from first dose of study drug to the first documented objective disease progression (for RECIST 1.1), clinical disease progression collected at end of treatment, or death due to any cause, whichever occurred first. Per RECIST 1.1, progression is defined as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.

Time frame: RECIST assessments performed at baseline (within 28 days before start of study drug), every 6 weeks +/-1 week for first 24 weeks, then every 12 weeks +/-2 weeks thereafter. Up to data cut-off for study termination (maximum of 247 days).

Population: Efficacy population included all participants who received at least one dose of IPN60090.

The ORR is defined as the percentage of participants in whom the BOR is equal to CR and PR for Part A. The BOR is defined as the best response designation (in the order of CR, PR, SD, PD) for each participant that is recorded between the date of the first dose of the study drug and the date of documented disease progression per RECIST 1.1 or the date of subsequent anticancer therapy whichever occurs first. Per RECIST v1.1, CR is disappearance of all target lesions; PR is \>=30% decrease in the sum of the longest diameter of target lesions; and overall response = CR + PR.

Time frame: RECIST assessments performed at baseline (within 28 days before start of study drug), every 6 weeks +/-1 week for first 24 weeks, then every 12 weeks +/-2 weeks thereafter. Up to data cut-off for study termination (maximum of 247 days).

Population: Efficacy population included all participants who received at least one dose of IPN60090.

The target engagement is glutamate:glutamine (Glu:Gln) ratio in peripheral blood mononuclear cells. Glu:Gln ratio inhibition is calculated as (1 - post-baseline Glu:Gln ratio/Cycle 1 Day 1 predose Glu:Gln ratio) x 100%.

Time frame: At 2 and 12 hours postdose on Cycle 1 Day 1; predose, 2 and 12 hours postdose on Cycle 1 Day 14; and predose, 2 and 2-4 hours postdose on Cycle 1 Day 15 in Part A

Population: Efficacy population included all participants who received at least one dose of IPN60090.

Blood samples were collected to determine Tmax of IPN60090. The PK of IPN60090 plasma concentrations were performed using noncompartmental analysis.

Time frame: Pre-dose and 0.5, 1, 2, 4, 8 and 12 hours post-dose on Cycle 1 Day 1 and Cycle 1 Day 14 in Part A

Population: The PK population for noncompartmental analysis included all participants who had no major protocol deviation affecting the PK variables and who had a sufficient number of IPN60090 plasma concentrations to estimate the main PK parameters. Summarized PK results are presented for IPN60090 120 mg, IPN60090 180 mg and IPN60090 240 mg reporting groups only.

Blood samples were collected to determine Ctrough of IPN60090. The PK of IPN60090 plasma concentrations were performed using noncompartmental analysis.

Time frame: Pre-dose and 0.5, 1, 2, 4, 8 and 12 hours post-dose on Cycle 1 Day 14 in Part A

Population: The PK population for noncompartmental analysis included all participants who had no major protocol deviation affecting the PK variables and who had a sufficient number of IPN60090 plasma concentrations to estimate the main PK parameters. Summarized PK results are presented for IPN60090 120 mg, IPN60090 180 mg and IPN60090 240 mg reporting groups only.