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

Study Overview
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Brief Summary
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The purpose of the protocol is to determine safety, tolerability, recommended dose (RD), pharmacokinetics (PK), pharmacodynamics (PD) and preliminary anti-tumour activity of IPN60090 as a single agent (Part A) and in combination with pembrolizumab (Part B) or paclitaxel (Part C) in patients with advanced solid tumours and to evaluate food effect (Part D).

Official Title
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A Phase I, Open Label, Dose Escalation and Dose Expansion Study to Investigate the Safety, Pharmacokinetics, Pharmacodynamics and Anti-tumour Activity of IPN60090 as Single Agent and in Combination in Patients With Advanced Solid Tumours

Conditions
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Solid Tumor

Intervention / Treatment
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* Drug: IPN60090
* Drug: pembrolizumab
* Drug: paclitaxel
* Drug: IPN60090 single administration


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female patients ≥18 years of age Patients with solid tumours who have received at least one line of therapy for advanced disease Measurable or non-measurable evaluable disease per RECIST 1.1 Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) ≤1 Standard of care and/or any investigational therapies must have been completed at least 3 weeks prior to treatment Exclusion Criteria: Prior malignancy within the previous 2 years except for locally curable cancers that have been cured, such as basal or squamous cell skin cancer, or carcinoma in situ of the cervix, breast or bladder Known primary central malignancy or symptomatic central nervous system metastasis Major surgical intervention within 28 days before study drug administration Significant acute or chronic infections

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: IPN60090<br>Part 1: Dose escalation of IPN60090, Part 2: Dose expansion IPN60090 given as a Bis in Die (BID) oral dose administered up to Maximum Tolerated Dose (MTD) over a 21-day cycle | Drug: IPN60090<br>* Oral capsules given daily<br>|
| Experimental: IPN60090 in combination with pembrolizumab<br>Part 1: Dose escalation of IPN60090 in combination with pembrolizumab, Part 2: Dose expansion IPN60090 given as a Bis in Die (BID) oral dose, starting with pharmacologically active dose identified in 1dose escalation of IPN60090 as a single agent, over a 21-day cycle in combination with 200 mg pembrolizumab given every 21 days (Day 1 of every cycle) as IV infusion | Drug: IPN60090<br>* Oral capsules given daily<br>Drug: pembrolizumab<br>* An intravenous solution in single-use vial to be diluted for infusion.<br>|
| Experimental: IPN60090 in combination with paclitaxel<br>Part 1: Dose escalation of IPN60090 in combination with paclitaxel, Part 2: Dose expansion IPN60090 given as a BID oral dose, starting with pharmacologically active dose identified in dose escalation of IPN60090 as a single agent over a 21-day cycle in combination with 175 mg/m2 or 135 mg/m2 paclitaxel given every 21 days (Day 1 of every cycle) as IV infusion | Drug: IPN60090<br>* Oral capsules given daily<br>Drug: paclitaxel<br>* An intravenous solution in single-use vial to be diluted for infusion.<br>|
| Experimental: IPN60090 food effect<br>Part 1: Food Effect of IPN60090 IPN60090 given as a single oral dose as a single agent at the recommended dose (RD) under fasting and fed conditions followed by IPN60090 given as a BID oral dose administered at the RD over a 21-day cycle. | Drug: IPN60090 single administration<br>* Oral capsules given once<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (SAEs) in Part A | 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). | 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). | 
| Number of Participants With Dose-Limiting Toxicities (DLT) in Cycle 1 of Part A | 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). | Up to Cycle 1 Day 21 of Part A | 
| Recommended Dose of IPN60090 in Part A | 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. | Up to Cycle 1 Day 21 of Part A | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best Overall Response (BOR) in Part A | 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. | 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). | 
| Objective Response Rate (ORR) in Part A | 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. | 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). | 
| Disease Control Rate (DCR) in Part A | 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. | 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). | 
| Mean Progression Free Survival (PFS) in Part A | 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. | 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). | 
| Mean Overall Survival (OS) in Part A | 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. | 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). | 
| Mean Best Percent Change From Baseline in the Sum of Diameters of the Target Lesions at Minimum Post-Baseline in Part A | 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. | Baseline (within 28 days before start of study drug) and post-baseline, up to data cut-off for study termination (maximum of 247 days). | 
| Maximum Observed Concentration (Cmax) of IPN60090 in Part A | Blood samples were collected to determine Cmax of IPN60090. The pharmacokinetics (PK) of IPN60090 plasma concentrations were performed using noncompartmental analysis. | 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 | 
| Time to Reach Maximum Observed Concentration (Tmax) of IPN60090 in Part A | Blood samples were collected to determine Tmax of IPN60090. The PK of IPN60090 plasma concentrations were performed using noncompartmental analysis. | 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 | 
| Trough Plasma Concentration (Ctrough) of IPN60090 in Part A | Blood samples were collected to determine Ctrough of IPN60090. The PK of IPN60090 plasma concentrations were performed using noncompartmental analysis. | Pre-dose and 0.5, 1, 2, 4, 8 and 12 hours post-dose on Cycle 1 Day 14 in Part A | 
| Area Under the Concentration Versus Time Curve From Time Zero to the Last Quantifiable Concentration (AUC0-last) of IPN60090 in Part A | Blood samples were collected to determine AUC0-last of IPN60090. The PK of IPN60090 plasma concentrations were performed using noncompartmental analysis. | 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 | 
| Apparent Elimination Half-Life (T1/2) of IPN60090 in Part A | Blood samples were collected to determine T1/2 of IPN60090. The PK of IPN60090 plasma concentrations were performed using noncompartmental analysis. | Pre-dose and 0.5, 1, 2, 4, 8 and 12 hours post-dose on Cycle 1 Day 1 in Part A | 
| Apparent Total Body Clearance (CL/F) of IPN60090 in Part A | Blood samples were collected to determine CL/F of IPN60090. The PK of IPN60090 plasma concentrations were performed using noncompartmental analysis. | Pre-dose and 0.5, 1, 2, 4, 8 and 12 hours post-dose on Cycle 1 Day 1 in Part A | 
| Apparent Volume of Distribution (Vz/F) of IPN60090 in Part A | Blood samples were collected to determine Vz/F of IPN60090. The PK of IPN60090 plasma concentrations were performed using noncompartmental analysis. | Pre-dose and 0.5, 1, 2, 4, 8 and 12 hours post-dose on Cycle 1 Day 1 in Part A | 
| Target Engagement in Part A | 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%. | 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 |