MNK Inhibitor AUM001 in Combination With Either Pembrolizumab or Irinotecan to Treat Metastatic Colorectal Cancer

PHASE2RECRUITING

The study is a 2-part study of Tinodasertib alone or in combination with Pembrolizumab/Irinotecan in patients with CRC.

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Study details:

The study is conducted in 2 parts. First a dose escalation Run-in to identify the Maximum Tolerable Dose (MTD) and the Recommended Phase 2 Dose (RP2D) of Tinodasertib to be administered orally as monotherapy and in combination with intravenous pembrolizumab/irinotecan. Part 2 consists of a cohort expansion at the RP2D of Tinodasertib n combination with intravenous pembrolizumab/Irinotecan in patients with locally advanced or metastatic CRC to evaluate clinical activity and safety of Tinodasertib.

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Eligibility criteria

Researchers look for people who fit a certain description, called eligibility criteria. See if you qualify.

Inclusion criteria

  • The participant provides written informed consent for the trial.
  • Subjects are at least 18 years of age at the time of signing the Informed Consent Form
  • Subjects with histologically or cytologically confirmed diagnosis of locally advanced or metastatic CRC.
  • Locally determined histological diagnosis is acceptable for study entry in Module 1.
  • Subjects can be enrolled in module 1 regardless of microsatellite stability status.
  • Only subjects with CRC MSS will be enrolled in module 2, arm B'.
  • Subjects who have had >2 lines of prior therapy for their CRC.
  • Prior use of irinotecan or irinotecan containing regimens is permitted
  • CRC MSI-H patients should have been treated with a checkpoint inhibitor and have progressed on such therapy or found to be resistant, refractory or intolerant to the checkpoint inhibitor
  • Patients with an available molecularly targeted therapy such as antibodies targeting VEGF/R, EGFR, encorafenib/cetuximab, prior to study entry. Additionally, patients with driver mutations for which an FDA approved therapy is available such as BRAF V600E, HER2 or NTRK should have been offered such therapy prior to study entry.
  • CRC subjects will be eligible to enrol in Arm C' if they have failed an established 5-fluorouracil containing regimen and have progressed after oxaliplatin based or irinotecan-based combination therapy and do not have a driver mutation for which there is an approved targeted therapy.
  • Subject must have provided archival tumor tissue sample or newly obtained core or excisional or punch needle biopsy of a tumor lesion not previously irradiated.
  • Have measurable disease per RECIST 1.1 as assessed by the local site investigator/radiologist.
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
  • Have a predicted life expectancy of greater or equal to 3 months.
  • Have adequate organ function
  • HIV infected participants must be on anti-retroviral therapy (ART) and have a well-controlled HIV infection/disease
  • Women of childbearing potential must not be breastfeeding and must have a negative serum or urine pregnancy test. Must be willing to use an adequate method of contraception.
  • Women of non-childbearing potential: Evidence of post-menopausal status is required.
  • Male subjects: Non-sterilized male subjects who are not abstinent and intend to be sexually active with a female partner of childbearing potential must use a male condom plus spermicide. Male subjects should refrain from sperm donation throughout this period.
  • Exclusion criteria

  • Has a history of another malignancy within 2 years prior to first investigational product administration, unless the malignancy was treated with curative intent and the likelihood of relapse is <5% in 2 years.
  • Has known active CNS metastases and/or carcinomatous meningitis.
  • Has received prior systemic anti-cancer therapy including investigational agents within 4 weeks or 5 half-lives, whichever is shorter prior to study treatment.
  • Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment.
  • Has had an allogeneic tissue/solid organ transplant.
  • Pregnant or breastfeeding
  • Has a known history or Hepatitis B (defined as HbsAg reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection.
  • Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating investigator.
  • Has a known psychiatric or substance abuse disorder that would interfere with the participant's ability to cooperate with the requirements of the study.
  • Gastrointestinal (GI) tract disease causing the inability to take oral medication.
  • Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor, and was discontinued from that treatment due to a Grade 3 or higher irAE.
  • Participants must have recovered from all radiation-related toxicities, not require corticosteroids, or have had history of radiation pneumonitis.
  • Has received a live or live-attenuated vaccine within 30 days prior to the first dose of study intervention.
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    Eligibility

    Age eligible for study : 18 and older

    Healthy volunteers accepted : No

    Gender eligible for study: All

    Things to know

    Study dates

    Study start: 2023-04-14

    Primary completion: 2024-09-30

    Study completion finish: 2026-10-15

    study type

    Study type

    TREATMENT

    phase

    Phase

      PHASE2

    trial

    Trial ID

    NCT05462236

    Intervention or treatment

    DRUG: Tinodasertib

    DRUG: Pembrolizumab

    DRUG: Irinotecan

    Conditions

    • Metastatic Colorectal Cancer

    Find a site

    Closest Location:

    Chris O'Brien Lifehouse

    Research sites nearby

    Select from list below to view details:

    • Chris O'Brien Lifehouse

      Camperdown, New South Wales, Australia

    • Cabrini Hospital

      Malvern, Victoria, Australia

    • Prince of Wales Hospital

      Wollongong, New South Wales, Australia

    • Pindara Private Hospital, Gold Coast Cancer Care

      Benowa, Queensland, Australia

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    Study Plan

    This section provides details of the study plan, including how the study is designed and what the study is measuring.

    How is the study designed?

    Participant Group/ArmIntervention/Treatment
    EXPERIMENTAL: Module 1: Arm A: Multiple dose finding cohorts
    • Monotherapy with Tinodasertib administered orally QOD
    DRUG: Tinodasertib
    • MNK inhibitor
    EXPERIMENTAL: Module1: Arm B/C: Multiple cohorts of Tinodasertib with fixed dose of pembrolizumab or irinotecan
    • Combination doses with Tinodasertib administered orally QOD with intravenous pembrolizumab at 200mg Q3W or Irinotecan at 180mg/m2 Q2W
    DRUG: Tinodasertib
    • MNK inhibitor
    EXPERIMENTAL: Module 2: Arm B' and C': Dose Expansion
    • Combination therapy with Tinodasertib administered orally QOD at RP2D (as determined in Module 1) and either pembrolizumab at 200mg IV Q3W (arm B') or irinotecan 180mg/m2 IV Q2W (arm C')
    DRUG: Tinodasertib
    • MNK inhibitor

    What is the study measuring?

    Primary outcome

    Primary Outcome MeasurePrimary Outcome DescriptionPrimary Outcome Time Frame
    Adverse events and Serious Adverse eventsIncidence and severity of AEs and SAEs.Approximately 2 years from date of participant enrolment
    Incidence of DLT events and treatment emergent AEs (TEAEs)Grading of DLTs according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.01 complete cycle (21 days)
    Objective response rate based on Response Evaluation Criteria in Solid tumors (RECIST) Version 1.1Not SpecifiedApproximately 2 years from date of participant enrolment

    Secondary outcome

    Secondary Outcome MeasureSecondary Outcome DescriptionSecondary Outcome Time Frame
    PK evaluationEvaluation of Plasma concentrations of AUM001 as monotherapy or in combination with Pembrolizumab/IrinotecanApproximately 6 months from date of participant enrolment

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    References

    Clinical Trials Gov: MNK Inhibitor AUM001 in Combination With Either Pembrolizumab or Irinotecan to Treat Metastatic Colorectal Cancer

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