The Safety and Pharmacokinetics Preliminary Efficacy of IMP7068 in Patients With Advanced Solid Tumors

Overview

A Phase 1 Dose Escalation and Expansion Study of IMP7068 Monotherapy in Advanced Solid Tumors

Full Title of Study: “A Phase 1, Open-Label, Multi-Center, Dose Escalation and Expansion Study to Evaluate Safety, Tolerability, Pharmacokinetics, and Anti-Tumor Activity of the WEE1 Inhibitor IMP7068 Monotherapy in Patients With Advanced Solid Tumors”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: N/A
    • Intervention Model: Sequential Assignment
    • Primary Purpose: Treatment
    • Masking: None (Open Label)
  • Study Primary Completion Date: April 30, 2023

Detailed Description

This is A Phase 1, Open-Label, Multi-Center, Dose Escalation and Expansion Study to Evaluate Safety, Tolerability, Pharmacokinetics, and Anti-Tumor Activity of the WEE1 Inhibitor IMP7068 Monotherapy in Patients with Advanced Solid Tumors The study will include a dose-escalation stage and a dose-expansion stage. The dose-escalation stage is designed to determine the maximum tolerated dose (MTD) and select recommended Phase 2 dose (RP2D) of IMP7068 monotherapy. The dose-expansion stage will be conducted with RP2D to further evaluate the preliminary anti-tumor activity, safety and tolerability. A total of approximately 150 patients will be enrolled in the study. Approximately 50 patients will be enrolled into Part 1 dose escalation of IMP7068 monotherapy. A total of 100 patients each with advanced solid tumor will be evaluated in Part 2 dose-expansion of IMP7068 monotherapy.

Interventions

  • Drug: IMP7068
    • To evaluate the safety tolerability, pharmacokinetics, and anti-tumor activity of the WEE1 inhibitor IMP7068 monotherapy in patients with advanced solid tumors

Arms, Groups and Cohorts

  • Other: IMP7068
    • Part 1: Dose Escalation The study will begin with open-label dose escalation in IMP7068 monotherapy treatment to determine the Maximum tolerated dose (MTD) Part 2: Dose Expansion The dose-expansion stage will commence after the Recommended Phase 2 Dose (RP2D) is determined during the dose-escalation stage. A total of 100 patients each with advanced solid tumor who has exhausted available treatment options will be evaluated.

Clinical Trial Outcome Measures

Primary Measures

  • Part 1 Dose Escalation: Incidence of treatment emergent adverse events (TEAEs)
    • Time Frame: Day 1 through to 30 days after last dose (approximately 4 cycles (84 days plus 30 day follow-up )); Each cycle is 21 days
  • Part 1 Dose Escalation: Severity of treatment emergent adverse events (TEAEs), according to the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE), version 5.0
    • Time Frame: Day 1 through to 30 days after last dose (approximately 4 cycles (84 days plus 30 day follow-up )); Each cycle is 21 days
  • Part 1 Dose Escalation: Number of patients with changes in Vital Signs
    • Time Frame: Screening (Day -28) through 30 days after last dose, estimated to be 5 months
  • Part 1 Dose Escalation: Number of patients with changes in Physical Examination
    • Time Frame: Screening (Day -28) through 30 days after last dose, estimated to be 5 months
  • Part 1 Dose Escalation: Number of patients with changes in single and triplicate 12-lead Electrocardiogram (ECG)
    • Time Frame: Screening (Day -28) through 30 days after last dose, estimated to be 5 months
  • Part 1 Dose Escalation: Number of patients with changes in Laboratory Test – Serum chemistry
    • Time Frame: Screening (Day -28) through 30 days after last dose, estimated to be 5 months
  • Part 1 Dose Escalation: Number of patients with changes in Laboratory Test – Hematology
    • Time Frame: Screening (Day -28) through 30 days after last dose, estimated to be 5 months
  • Part 1 Dose Escalation: Number of patients with changes in Laboratory Test – Coagulation parameters
    • Time Frame: Screening (Day -28) through 30 days after last dose, estimated to be 5 months
  • Part 1 Dose Escalation: Number of patients with changes in Laboratory Test – Urinalysis
    • Time Frame: Screening (Day -28) through 30 days after last dose, estimated to be 5 months
  • Part 1 Dose Escalation: Recommended Phase 2 Dose (RP2D) of IMP7068 monotherapy
    • Time Frame: Day 1 through to start of dose expansion phase (approximately 1 year)
    • Recommended Phase 2 Dose (RP2D) of IMP7068 monotherapy (selected by the safety monitoring committee (SMC) based on pharmacokinetics, target saturation at steady state, pharmacodynamics, safety, tolerability and preliminary anti-tumor effects of the dose range studied)
  • Part 2 Dose Expansion: Overall Response Rate (ORR)
    • Time Frame: Day 1 through 30 days after last dose, estimated to be 5 months
    • Overall Response Rate (ORR) for all cohorts (percentage of patients who had a best response rating of complete response (CR) and partial response (PR), according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, which was maintained ≥4 weeks)

Secondary Measures

  • Part 1 Dose Escalation: Pharmacokinetic parameter derived from plasma IMP7068 concentration following single oral doses for maximum observed plasma drug concentration (Cmax)
    • Time Frame: Time Frame: Single-Dose Phase: Day 1, 2, 3 and 4
  • Part 1 Dose Escalation: Pharmacokinetic parameter derived from plasma IMP7068 concentration following single oral doses for time to reach Cmax (Tmax)
    • Time Frame: Time Frame: Single-Dose Phase: Day 1, 2, 3 and 4
  • Part 1 Dose Escalation: Pharmacokinetic parameter derived from plasma IMP7068 concentration following single oral doses for area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration (AUC0-last)
    • Time Frame: Time Frame: Single-Dose Phase: Day 1, 2, 3 and 4
  • Part 1 Dose Escalation: Pharmacokinetic parameter derived from plasma IMP7068 concentration following single oral doses for area under the plasma concentration-time curve from time zero to time tau (AUC0-tau)
    • Time Frame: Time Frame: Single-Dose Phase: Day 1, 2, 3 and 4
  • Part 1 Dose Escalation: Pharmacokinetic parameter derived from plasma IMP7068 concentration following single oral doses dose-normalized Cmax (Cmax [dn])
    • Time Frame: Time Frame: Single-Dose Phase: Day 1, 2, 3 and 4
  • Part 1 Dose Escalation: Pharmacokinetic parameter derived from plasma IMP7068 concentration following single oral doses for dose-normalized AUC0-tau (AUC0-tau [dn])
    • Time Frame: Time Frame: Single-Dose Phase: Day 1, 2, 3 and 4
  • Part 1 Dose Escalation: If the data are available, Pharmacokinetic parameter derived from plasma IMP7068 concentration following single oral doses area under the plasma concentration time curve from time zero to infinity (AUC0-inf)
    • Time Frame: Time Frame: Single-Dose Phase: Day 1, 2, 3 and 4
  • Part 1 Dose Escalation: If the data are available, Pharmacokinetic parameter derived from plasma IMP7068 concentration following single oral doses terminal elimination half life (t1/2)
    • Time Frame: Time Frame: Single-Dose Phase: Day 1, 2, 3 and 4
  • Part 1 Dose Escalation: If the data are available, Pharmacokinetic parameter derived from plasma IMP7068 concentration following single oral doses apparent clearance (CL/F)
    • Time Frame: Time Frame: Single-Dose Phase: Day 1, 2, 3 and 4
  • Part 1 Dose Escalation: If the data are available, Pharmacokinetic parameter derived from plasma IMP7068 concentration following single oral doses apparent volume of distribution (Vz/F)
    • Time Frame: Time Frame: Single-Dose Phase: Day 1, 2, 3 and 4
  • Part 1 Dose Escalation: Pharmacokinetic parameter derived from plasma IMP7068 concentration following repeated oral doses for Cmax
    • Time Frame: Repeat-Dose Schedule 1 and Schedule 2: Each Cycle = 21 Days; Cycle 1 Day 1,2, 3, 4, 5, 6 and 8, Cycle 2 Day 1 and Cycle 3 Day 1; Repeat Dose Schedule 3: Cycle 1 Day 1, 2, 3, 4, 5 and 8, Cycle 2 Day 1 and Cycle 3 Day 1
  • Part 1 Dose Escalation: Pharmacokinetic parameter derived from plasma IMP7068 concentration following repeated oral doses for Tmax
    • Time Frame: Repeat-Dose Schedule 1 and Schedule 2: Each Cycle = 21 Days; Cycle 1 Day 1,2, 3, 4, 5, 6 and 8, Cycle 2 Day 1 and Cycle 3 Day 1; Repeat Dose Schedule 3: Cycle 1 Day 1, 2, 3, 4, 5 and 8, Cycle 2 Day 1 and Cycle 3 Day 1
  • Part 1 Dose Escalation: Pharmacokinetic parameters derived from plasma IMP7068 concentration following repeated oral doses for AUC0-last
    • Time Frame: Repeat-Dose Schedule 1 and Schedule 2: Each Cycle = 21 Days; Cycle 1 Day 1,2, 3, 4, 5, 6 and 8, Cycle 2 Day 1 and Cycle 3 Day 1; Repeat Dose Schedule 3: Cycle 1 Day 1, 2, 3, 4, 5 and 8, Cycle 2 Day 1 and Cycle 3 Day 1
  • Part 1 Dose Escalation: Pharmacokinetic parameter derived from plasma IMP7068 concentration following repeated oral doses for AUC0-tau
    • Time Frame: Repeat-Dose Schedule 1 and Schedule 2: Each Cycle = 21 Days; Cycle 1 Day 1,2, 3, 4, 5, 6 and 8, Cycle 2 Day 1 and Cycle 3 Day 1; Repeat Dose Schedule 3: Cycle 1 Day 1, 2, 3, 4, 5 and 8, Cycle 2 Day 1 and Cycle 3 Day 1
  • Part 1 Dose Escalation: Pharmacokinetic parameter derived from plasma IMP7068 concentration following repeated oral doses for minimum plasma concentration during the dosing interval (Cmin)
    • Time Frame: Repeat-Dose Schedule 1 and Schedule 2: Each Cycle = 21 Days; Cycle 1 Day 1,2, 3, 4, 5, 6 and 8, Cycle 2 Day 1 and Cycle 3 Day 1; Repeat Dose Schedule 3: Cycle 1 Day 1, 2, 3, 4, 5 and 8, Cycle 2 Day 1 and Cycle 3 Day 1
  • Part 1 Dose Escalation: Pharmacokinetic parameter derived from plasma IMP7068 concentration following repeated oral doses for observed accumulation ratio for Cmax (Rac_Cmax)
    • Time Frame: Repeat-Dose Schedule 1 and Schedule 2: Each Cycle = 21 Days; Cycle 1 Day 1,2, 3, 4, 5, 6 and 8, Cycle 2 Day 1 and Cycle 3 Day 1; Repeat Dose Schedule 3: Cycle 1 Day 1, 2, 3, 4, 5 and 8, Cycle 2 Day 1 and Cycle 3 Day 1
  • Part 1 Dose Escalation: Pharmacokinetic parameter derived from plasma IMP7068 concentration following repeated oral doses for observed accumulation ratio for AUC0-tau (Rac_AUC0-tau)
    • Time Frame: Repeat-Dose Schedule 1 and Schedule 2: Each Cycle = 21 Days; Cycle 1 Day 1,2, 3, 4, 5, 6 and 8, Cycle 2 Day 1 and Cycle 3 Day 1; Repeat Dose Schedule 3: Cycle 1 Day 1, 2, 3, 4, 5 and 8, Cycle 2 Day 1 and Cycle 3 Day 1
  • Part 1 Dose Escalation: Pharmacokinetic parameter derived from plasma IMP7068 concentration following repeated oral doses for observed accumulation ratio for Cmax (dn)
    • Time Frame: Repeat-Dose Schedule 1 and Schedule 2: Each Cycle = 21 Days; Cycle 1 Day 1,2, 3, 4, 5, 6 and 8, Cycle 2 Day 1 and Cycle 3 Day 1; Repeat Dose Schedule 3: Cycle 1 Day 1, 2, 3, 4, 5 and 8, Cycle 2 Day 1 and Cycle 3 Day 1
  • Part 1 Dose Escalation: Pharmacokinetic parameter derived from plasma IMP7068 concentration following repeated oral doses for observed accumulation ratio for AUC0-tau (dn)
    • Time Frame: Repeat-Dose Schedule 1 and Schedule 2: Each Cycle = 21 Days; Cycle 1 Day 1,2, 3, 4, 5, 6 and 8, Cycle 2 Day 1 and Cycle 3 Day 1; Repeat Dose Schedule 3: Cycle 1 Day 1, 2, 3, 4, 5 and 8, Cycle 2 Day 1 and Cycle 3 Day 1
  • Part 1 Dose Escalation: If the data are available, Pharmacokinetic parameter derived from plasma IMP7068 concentration following repeated oral doses terminal elimination half life (t1/2)
    • Time Frame: Repeat-Dose Schedule 1 and Schedule 2: Each Cycle = 21 Days; Cycle 1 Day 1,2, 3, 4, 5, 6 and 8, Cycle 2 Day 1 and Cycle 3 Day 1; Repeat Dose Schedule 3: Cycle 1 Day 1, 2, 3, 4, 5 and 8, Cycle 2 Day 1 and Cycle 3 Day 1
  • Part 1 Dose Escalation: If the data are available, Pharmacokinetic parameter derived from plasma IMP7068 concentration following repeated oral doses apparent clearance (CL/F)
    • Time Frame: Repeat-Dose Schedule 1 and Schedule 2: Each Cycle = 21 Days; Cycle 1 Day 1,2, 3, 4, 5, 6 and 8, Cycle 2 Day 1 and Cycle 3 Day 1; Repeat Dose Schedule 3: Cycle 1 Day 1, 2, 3, 4, 5 and 8, Cycle 2 Day 1 and Cycle 3 Day 1
  • Part 1 Dose Escalation: If the data are available, Pharmacokinetic parameter derived from plasma IMP7068 concentration following repeated oral doses apparent volume of distribution (Vz/F)
    • Time Frame: Repeat-Dose Schedule 1 and Schedule 2: Each Cycle = 21 Days; Cycle 1 Day 1,2, 3, 4, 5, 6 and 8, Cycle 2 Day 1 and Cycle 3 Day 1; Repeat Dose Schedule 3: Cycle 1 Day 1, 2, 3, 4, 5 and 8, Cycle 2 Day 1 and Cycle 3 Day 1
  • Part 1 Dose Escalation: Objective response rate (ORR): percentage of patients who had a best response
    • Time Frame: Within the first year: every 6 weeks, thereafter every 12 weeks to end of treatment (EOT) visit (approximately 84 days), documented disease progression, withdrawal of consent, loss to follow-up, death or termination of the study (whichever occurs first)
  • Part 1 Dose Escalation: Progression-free survival (PFS): duration of time from date of first dose to date of disease progression (according to RECIST v1.1) or death due to any cause, whichever comes first)
    • Time Frame: Within the first year: every 6 weeks (±7 days); thereafter: every 12 weeks (±7 days); or when clinically indicated (Approximately 1 year )
  • Part 1 Dose Escalation: Overall survival (OS): time from date of first dose to death due to any cause
    • Time Frame: Every 12 weeks±14 days after the last dose, until up to 2 years, withdrawal of consent, loss to follow-up, death, or termination of the study, whichever occurs first
  • Part 1 Dose Escalation: Duration of response (DOR): duration of time a patient is evaluated as either complete response (CR) or partial response (PR) as best response until the first date that the criteria for progression are met, or death.
    • Time Frame: Day 1 through 30 days after last dose, estimated to be 5 months
  • Part 1 Dose Escalation: Disease control rate (DCR): proportion of patients who had a best response rating of complete response (CR) or partial response (PR), or stable disease (SD), which was maintained ≥6 weeks from Day 1 of Cycle 1
    • Time Frame: Day 1 through 30 days after last dose, estimated to be 5 months
  • Part 2 Dose Expansion: Progression-free survival (PFS) duration of time from date of first dose to date of disease progression (according to RECIST v1.1) or death due to any cause, whichever comes first)
    • Time Frame: Day 1 through 30 days after last dose, estimated to be 5 months
  • Part 2 Dose Expansion: Duration of response (DOR) duration of time a patient is evaluated as either CR or PR as best response until the first date that the criteria for progression are met, or death
    • Time Frame: Day 1 through 30 days after last dose, estimated to be 5 months
  • Part 2 Dose Expansion: Incidence of Treatment emergent adverse events (TEAE)
    • Time Frame: Day 1 through 30 days after last dose, estimated to be 5 months
  • Part 2 Dose Expansion: Severity of Treatment emergent adverse events (TEAE) according to the NCI-CTCAE, version 5.0
    • Time Frame: Day 1 through 30 days after last dose, estimated to be 5 months
  • Part 2 Dose Expansion: Number of patients with changes in Vital Signs
    • Time Frame: Screening (Day -28) through 30 days after last dose, estimated to be 5 months
  • Part 2 Dose Expansion: Number of patients with changes in Physical Examination
    • Time Frame: Screening (Day -28) through 30 days after last dose, estimated to be 5 months
  • Number of patients with changes in single and triplicate 12-lead Electrocardiogram (ECG)
    • Time Frame: Screening (Day -28) through 30 days after last dose, estimated to be 5 months
  • Number of patients with changes in Laboratory Test – Serum chemistry
    • Time Frame: Screening (Day -28) through 30 days after last dose, estimated to be 5 months
  • Number of patients with changes in Laboratory Test – Hematology
    • Time Frame: Screening (Day -28) through 30 days after last dose, estimated to be 5 months
  • Number of patients with changes in Laboratory Test – Coagulation parameters
    • Time Frame: Screening (Day -28) through 30 days after last dose, estimated to be 5 months
  • Number of patients with changes in Laboratory Test – Urinalysis
    • Time Frame: Screening (Day -28) through 30 days after last dose, estimated to be 5 months

Participating in This Clinical Trial

Key Inclusion Criteria:

1. The patient must voluntarily participate in this clinical study. Be willing and able to provide written informed consent form (ICF) prior to any study activity. 2. Age ≥18 years on the day of signing the ICF (either from screening period for dose escalation stage or from pre-screening period for dose expansion stage), males or females. 3. The enrolled patients must have histologically or cytologically confirmed advanced solid tumor that is refractory to standard treatment or for which no standard treatment exists. The patients with known microsatellite-instability high (MSI- H) or deficient in mismatch repair (dMMR) disease are required to have received prior PD 1/PD-L1 therapy; those with known NTRK fusion are required to have received an approved TRK-inhibitor. The patients who are suitable for resection or other localized therapy that is potentially curative are not eligible. Key Exclusion Criteria:

1. Patients with active or untreated known CNS metastases and/or carcinomatous meningitis should be excluded. 2. Patients with serious acute or chronic infections. 3. Patients who have received prescription or non-prescription drugs or other products known to be sensitive to CYP3A4 substrates or CYP3A4 substrates with a narrow therapeutic index, or to be moderate to strong inhibitors/inducers of CYP3A4 which cannot be discontinued 7 days prior to Day 1 of dosing and withheld throughout the study until 2 weeks after the last dose of IMP7068. 4. Patients who are participating in or have participated in a study of an investigational agent and received study therapy or used an investigational device within 28 days of the first dose of treatment. 5. Patients have not recovered (i.e., to Grade ≤1 or to baseline, as evaluated by NCI-CTCAE Version 5.0) from prior anti-cancer therapy-induced AEs, except for alopecia. 6. Patients who have undergone a major surgery or have undergone a radical radiotherapy within 28 days prior to the study treatment, or have undergone a palliative radiotherapy within 14 days prior to the study treatment, or have used a radioactive drug (Strontium, Samarium, etc.) within 56 days prior to the study treatment. 7. Patients who are unable to swallow oral medications. Patients have gastrointestinal illnesses that may clinically significantly affect the absorption of oral medication IMP7068 at discretion of investigators.

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Impact Therapeutics, Inc.
  • Collaborator
    • Covance
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Contact(s)
    • Bitao Sarapa, 908-303-2808, bitao.sarapa@impacttherapeutics.com

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