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

A Phase II Open Label, Dose-finding run-in and Cohort Expansion Study to Evaluate the Safety, Tolerability and Effectiveness of Tinodasertib in Combination With Pembrolizumab or Irinotecan in Metastatic Colorectal Cancer

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

Study Overview

• Status: Recruiting
• Conditions: Metastatic Colorectal Cancer
• Intervention / Treatment: Drug: Pembrolizumab; Drug: Irinotecan; Drug: Tinodasertib

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 120
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: HARISH DAVE, MEDICAL; Phone Number: +1 301 275 4356; Email: harishd@aumbiosciences.com
• Study Contact Backup: Name: JOHN PATAVA, PhD; Phone Number: +61 498 071 249; Email: johnp@aumbiosciences.com

Study Locations

• Australia
  • New South Wales
    • Camperdown, New South Wales, Australia, 2050
      • Recruiting
      • Chris O'Brien Lifehouse
      • Contact: Kate Mahon, MD
    • Wollongong, New South Wales, Australia, 2500
      • Recruiting
      • Prince of Wales Hospital
      • Contact: Morteza Aghmesheh, Prof
  • Queensland
    • Benowa, Queensland, Australia, 4217
      • Recruiting
      • Pindara Private Hospital, Gold Coast Cancer Care
      • Principal Investigator: Marco Matos, MD
  • Victoria
    • Malvern, Victoria, Australia, 3144
      • Recruiting
      • Cabrini Hospital
      • Contact: Shehara Mendis, MD
    • Wendouree, Victoria, Australia, 3355
      • Recruiting
      • Ballarat Oncology and Haematology
      • Contact: George Kannourakis, Prof

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Main Inclusion criteria:

1. The participant provides written informed consent for the trial.
2. Subjects are at least 18 years of age at the time of signing the Informed Consent Form

3. Subjects with histologically or cytologically confirmed diagnosis of locally advanced or metastatic CRC.

   1. Locally determined histological diagnosis is acceptable for study entry in Module 1.
   2. Subjects can be enrolled in module 1 regardless of microsatellite stability status.
   3. Only subjects with CRC MSS will be enrolled in module 2, arm B'.

4. Subjects who have had >2 lines of prior therapy for their CRC.

   1. Prior use of irinotecan or irinotecan containing regimens is permitted
   2. 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
   3. 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.
   4. 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.
5. 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.
6. Have measurable disease per RECIST 1.1 as assessed by the local site investigator/radiologist.
7. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
8. Have a predicted life expectancy of greater or equal to 3 months.
9. Have adequate organ function
10. HIV infected participants must be on anti-retroviral therapy (ART) and have a well-controlled HIV infection/disease
11. 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.
12. Women of non-childbearing potential: Evidence of post-menopausal status is required.
13. 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.

Main Exclusion Criteria

1. 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.
2. Has known active CNS metastases and/or carcinomatous meningitis.
3. Has received prior systemic anti-cancer therapy including investigational agents within 4 weeks or 5 half-lives, whichever is shorter prior to study treatment.
4. 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.
5. Has had an allogeneic tissue/solid organ transplant.
6. Pregnant or breastfeeding
7. 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.
8. 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.
9. Has a known psychiatric or substance abuse disorder that would interfere with the participant's ability to cooperate with the requirements of the study.
10. Gastrointestinal (GI) tract disease causing the inability to take oral medication.
11. 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.
12. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, or have had history of radiation pneumonitis.
13. Has received a live or live-attenuated vaccine within 30 days prior to the first dose of study intervention.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Module 1: Arm A: Multiple dose finding cohorts; Monotherapy with Tinodasertib administered orally QOD	Drug: Tinodasertib; MNK inhibitor; Other Names: AUM001
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 350mg/m2 Q3W	Drug: Pembrolizumab; PD-1 Inhibitor; Other Names: KEYTRUDA®; KEYNOTE-D65; Drug: Irinotecan; Topoisomerase inhibitor; Drug: Tinodasertib; MNK inhibitor; Other Names: AUM001
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 350mg/m2 IV Q3W (arm C')	Drug: Pembrolizumab; PD-1 Inhibitor; Other Names: KEYTRUDA®; KEYNOTE-D65; Drug: Irinotecan; Topoisomerase inhibitor; Drug: Tinodasertib; MNK inhibitor; Other Names: AUM001

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adverse events and Serious Adverse events	Incidence 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 5.0	1 complete cycle (21 days)
Objective response rate based on Response Evaluation Criteria in Solid tumors (RECIST) Version 1.1		Approximately 2 years from date of participant enrolment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PK evaluation	Evaluation of Plasma concentrations of AUM001 as monotherapy or in combination with Pembrolizumab/Irinotecan	Approximately 6 months from date of participant enrolment

Collaborators and Investigators

• Sponsor: AUM Biosciences Pte Ltd
• Collaborators: Merck Sharp & Dohme LLC

Study record dates

Study Major Dates

• Study Start (Actual): April 14, 2023
• Primary Completion (Estimated): September 30, 2024
• Study Completion (Estimated): October 15, 2026

Study Registration Dates

• First Submitted: July 7, 2022
• First Submitted That Met QC Criteria: July 13, 2022
• First Posted (Actual): July 18, 2022

Study Record Updates

• Last Update Posted (Actual): February 28, 2024
• Last Update Submitted That Met QC Criteria: February 25, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Topoisomerase Inhibitors; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Topoisomerase I Inhibitors; Pembrolizumab; Irinotecan
• Other Study ID Numbers: AUM001-2001-MK3475-D65; KEYNOTE-D65 (Other Identifier: Merck Sharpe & Dohme Corp.); MK-3475-D65 (Other Identifier: Merck Sharpe & Dohme Corp.)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No