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

• ClinicalTrials.gov Identifier: NCT03894540
• Recruitment Status: Terminated
• First Posted: March 28, 2019
• Results First Posted: November 22, 2021
• Last Update Posted: September 13, 2022
• Sponsor: Ipsen
• Information provided by (Responsible Party): Ipsen

Study Description

Brief Summary:

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).

Condition or disease	Intervention/treatment	Phase
Solid Tumor	Drug: IPN60090; Drug: pembrolizumab; Drug: paclitaxel; Drug: IPN60090 single administration	Phase 1

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 22 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: March 22, 2019
• Actual Primary Completion Date: December 21, 2020
• Actual Study Completion Date: December 21, 2020

Arms and Interventions

Arm	Intervention/treatment
Experimental: IPN60090; 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; Oral capsules given daily
Experimental: IPN60090 in combination with pembrolizumab; 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; Oral capsules given daily; Drug: pembrolizumab; An intravenous solution in single-use vial to be diluted for infusion.
Experimental: IPN60090 in combination with paclitaxel; 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; Oral capsules given daily; Drug: paclitaxel; An intravenous solution in single-use vial to be diluted for infusion.
Experimental: IPN60090 food effect; 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; Oral capsules given once

Outcome Measures

Primary Outcome Measures :

1. Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (SAEs) in Part A [ 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). ]

   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).
2. Number of Participants With Dose-Limiting Toxicities (DLT) in Cycle 1 of Part A [ Time Frame: Up to Cycle 1 Day 21 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).
3. Recommended Dose of IPN60090 in Part A [ Time Frame: Up to Cycle 1 Day 21 of 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.

Secondary Outcome Measures :

1. Best Overall Response (BOR) in Part A [ 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). ]
   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.
2. Objective Response Rate (ORR) in Part A [ 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). ]
   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.
3. Disease Control Rate (DCR) in Part A [ 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). ]
   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.
4. Mean Progression Free Survival (PFS) in Part A [ 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). ]
   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.
5. Mean Overall Survival (OS) in Part A [ 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). ]
   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.
6. Mean Best Percent Change From Baseline in the Sum of Diameters of the Target Lesions at Minimum Post-Baseline in Part A [ 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). ]
   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.
7. Maximum Observed Concentration (Cmax) of IPN60090 in Part A [ 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 ]
   Blood samples were collected to determine Cmax of IPN60090. The pharmacokinetics (PK) of IPN60090 plasma concentrations were performed using noncompartmental analysis.
8. Time to Reach Maximum Observed Concentration (Tmax) of IPN60090 in Part A [ 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 ]
   Blood samples were collected to determine Tmax of IPN60090. The PK of IPN60090 plasma concentrations were performed using noncompartmental analysis.
9. Trough Plasma Concentration (Ctrough) of IPN60090 in Part A [ Time Frame: Pre-dose and 0.5, 1, 2, 4, 8 and 12 hours post-dose on Cycle 1 Day 14 in Part A ]
   Blood samples were collected to determine Ctrough of IPN60090. The PK of IPN60090 plasma concentrations were performed using noncompartmental analysis.
10. Area Under the Concentration Versus Time Curve From Time Zero to the Last Quantifiable Concentration (AUC0-last) of IPN60090 in Part A [ 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 ]
    Blood samples were collected to determine AUC0-last of IPN60090. The PK of IPN60090 plasma concentrations were performed using noncompartmental analysis.
11. Apparent Elimination Half-Life (T1/2) of IPN60090 in Part A [ Time Frame: Pre-dose and 0.5, 1, 2, 4, 8 and 12 hours post-dose on Cycle 1 Day 1 in Part A ]
    Blood samples were collected to determine T1/2 of IPN60090. The PK of IPN60090 plasma concentrations were performed using noncompartmental analysis.
12. Apparent Total Body Clearance (CL/F) of IPN60090 in Part A [ Time Frame: Pre-dose and 0.5, 1, 2, 4, 8 and 12 hours post-dose on Cycle 1 Day 1 in Part A ]
    Blood samples were collected to determine CL/F of IPN60090. The PK of IPN60090 plasma concentrations were performed using noncompartmental analysis.
13. Apparent Volume of Distribution (Vz/F) of IPN60090 in Part A [ Time Frame: Pre-dose and 0.5, 1, 2, 4, 8 and 12 hours post-dose on Cycle 1 Day 1 in Part A ]
    Blood samples were collected to determine Vz/F of IPN60090. The PK of IPN60090 plasma concentrations were performed using noncompartmental analysis.
14. Target Engagement in Part A [ 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 ]
    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%.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Locations

United States, Texas

MD Anderson Cancer Center

Houston, Texas, United States, 77030

Sponsors and Collaborators

Ipsen

Investigators

• Study Director: Ipsen Medical Director; Ipsen

  Study Documents (Full-Text)

Documents provided by Ipsen:

Study Protocol  [PDF] December 10, 2019

Statistical Analysis Plan  [PDF] December 17, 2020

More Information

• Responsible Party: Ipsen
• ClinicalTrials.gov Identifier: NCT03894540
• Other Study ID Numbers: D-US-60090-001; 2018-003681-13 ( EudraCT Number )
• First Posted: March 28, 2019
• Results First Posted: November 22, 2021
• Last Update Posted: September 13, 2022
• Last Verified: August 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Neoplasms; Paclitaxel; Pembrolizumab; Antineoplastic Agents, Phytogenic; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents, Immunological