LB-100 (PP2A Inhibitor) and Azenosertib (WEE1 Inhibitor) in Metastatic Colorectal Cancer Patients

Phase Ib Study With the Combination of LB-100 (PP2A Inhibitor) and Azenosertib (WEE1 Inhibitor) in Metastatic Colorectal Cancer Patients

This Phase Ib trial studies the side effects and best dose of LB-100 and azenosertib for the treatment of patients with metastatic colorectal cancer. Azenosertib blocks a protein that is involved in the repair of damaged DNA, this protein is called WEE1. Inhibiting WEE1 drives cancer cells into a state of cell division without repair of the damaged DNA, resulting in cell death. LB-100 has been shown to make anticancer drugs work better at killing cancer. LB-100 blocks a protein called PP2A. Blocking this protein increases the stress signals for the tumor cells that express PP2A. Research has shown that azenosertib and LB-100 may enhance each others effect when treating metastatic colorectal cancer.

Study Overview

• Status: Not yet recruiting
• Conditions: Metastatic Colorectal Cancer
• Intervention / Treatment: Drug: LB-100; Drug: Azenosertib

Detailed Description

The goal of this Phase Ib monocenter, open-label, non-randomized clinical trial is to evaluate the safety, tolerability, pharmacokinetics and preliminary efficacy of the combination of LB-100 and azenosertib in patients with metastatic colorectal cancer.

This study will consist of a dose escalation phase and a dose expansion phase. The dose escalation phase is designed to find the recommended phase II dose of LB-100 and azenosertib when given together. The dose expansion phase further explores the clinical activity, safety, tolerability and pharmacokinetics/dynamics of LB-100 and azenosertib.

Clinical assessments will be performed routinely to monitor safety. Anti-tumor activity will be measured by CT scan according to RECIST version 1.1 criteria. Tumor biopsies will be obtained for exploratory objectives.

• Study Type: Interventional
• Enrollment (Estimated): 43
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Merel Lucassen, MD; Phone Number: +31205129111; Email: me.lucassen@nki.nl

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Signed Informed Consent Form (ICF);
2. Age ≥ 18 years at time of signing ICF;
3. Ability to comply with the study protocol;
4. Histological or cytological confirmed colorectal cancer;
5. Disease progression during treatment with standard of care;
6. Measurable disease per Response Evaluation Criteria in Solid Tumours version 1.1 (RECIST v1.1). Previously irradiated lesions can be considered as measurable disease only if progressive disease has been unequivocally documented at that site since radiation;
7. Able and willing to undergo blood sampling and tumour biopsies at baseline, if no adequate archival material is available, and during therapy;
8. Availability of representative tumor specimen for exploratory biomarker research;
9. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1;
10. Life expectancy of at least 3 months;

11. Adequate hematologic and end-organ function as defined by:

    • Absolute neutrophil (segmented and bands) count ≥1.0×109/L
    • Platelets≥100×109/L
    • Hemoglobin ≥5.6 mmol/L
    • AST≤2.5×ULN
    • ALT≤2.5×ULN
    • Bilirubin ≤1.5×ULN
    • Estimated glomerular filtration rate ≥50 mL/min by CKD-EPI
12. Negative pregnancy test (urine or serum) for female patients with childbearing potential.

Exclusion Criteria:

1. Unable to follow study procedures;
2. Any current treatment with investigational drugs;
3. Patients using prohibited medication;
4. Any unresolved grade ≥ 2 toxicities related to prior treatments (excluding alopecia) according to CTCAE version 5.0;
5. Participants with a clinically significant gastrointestinal disorder that in the opinion of the treating investigator could impact the absorption of azenosertib, including but not limited to refractory nausea and vomiting, inability to swallow the formulated product, or previous significant bowel resection that would preclude adequate absorption of azenosertib;
6. Patients with galactosemia;
7. History of another malignancy, except patients who have been disease free for at least 2 years, and/or patients with a history of completely resected non-melanoma skin cancer, and/or patients with indolent second malignancies, and/or patients with a history of low grade (Gleason score ≤6 = Grade Group 1) localized prostate cancer;
8. Symptomatic or untreated leptomeningeal disease;
9. Symptomatic or actively progressing central nervous system metastases. Patients with previously treated or untreated central nervous system metastases that are asymptomatic in the absence of corticosteroid and anti-convulsion therapy for at least 1 week are allowed to enrol. Brain metastasis must be stable, verified by imaging (e.g. brain MRI or CT);
10. Patients with cardiac comorbidities: myocardial infarction within 6 months prior to in-clusion, heart failure New York Hart Association (NYHA) class III or higher or a stroke within 6 months prior to inclusion;
11. Pregnant or breast-feeding (lactating) women;
12. Patients with known alcoholism, drug addiction and/or psychiatric or physiological condition which in the opinion of the investigator would impair study compliance;
13. Other severe, acute or chronic medical or psychological condition or laboratory ab-normality that may increase risk associated with study participation or study drug ad-ministration or that may interfere with the interpretation of study results in judgement of the investigator;
14. Pregnancy or breastfeeding, or intention of becoming pregnant during study treatment.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: LB-100 plus azenosertib; LB-100 IV over 15 minutes on day 1 and day 3 in a 21 day cycle in escalating doses. Azenosertib orally once daily on day 1, 2, 3, 4, 5 followed by no administration on day 6 and 7, repeated three times in a 21 day cycle in escalating doses in the absence of disease progression or unacceptable toxicity	Drug: LB-100; Intravenously on day 1 and 3 every cycle at escalating doses; Other Names: PP2 inhibitor; Drug: Azenosertib; Orally on day 1-5 every week at escalating doses; Other Names: ZN-c3; WEE1 inhibitor

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
The recommended phase II dose of LB-100 and azenosertib	up to 2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Disease control rate	Measured by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1	6 months
Objective response rate	Measured by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1	6 months
Duration of overall response	Measured by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1	up to 2 years
Progression free survival	Measured by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1	up to 2 years
Overall survival	The time from the first dose of study treatment to the time of death from any cause. Patients who are still alive at the time of analysis will be censored at the time of their last study assessment (for active patients) or at the last date know alive (for patients in follow-up).	Assessed up to 2 years
The incidence and severity of adverse events	As assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 5.0	Up to 2 years
The incidence of dose-limiting toxicity	As assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 5.0	21 days
Observed plasma concentrations of LB-100, its active metabolite endothall and azenosertib	Blood samples are obtained and plasma concentrations of LB-100, endothall and azenosertib are measured	Prior to initial dose and the first cycle on day 1 and 2. Each cycle is 21 days
Area under the plasma-time concentration curve of LB-100, its active metabolite endothall and azenosertib	Blood samples are obtained and plasma concentrations of LB-100, endothall and azenosertib are measured	Prior to initial dose and the first cycle on day 1 and 2. Each cycle is 21 days
Elimination half-life of LB-100, its active metabolite endothall and azenosertib	Blood samples are obtained and plasma concentrations of LB-100, endothall and azenosertib are measured	Prior to initial dose and the first cycle on day 1 and 2. Each cycle is 21 days
Total body clearance of LB-100, its active metabolite endothall and azenosertib	Blood samples are obtained and plasma concentrations of LB-100, endothall and azenosertib are measured	Prior to initial dose and the first cycle on day 1 and 2. Each cycle is 21 days

Collaborators and Investigators

• Sponsor: The Netherlands Cancer Institute
• Investigators: Principal Investigator: Neeltje Steeghs, MD, PhD, The Netherlands Cancer Institute - Antoni van Leeuwenhoek

Study record dates

Study Major Dates

• Study Start (Estimated): April 1, 2024
• Primary Completion (Estimated): November 1, 2026
• Study Completion (Estimated): November 1, 2026

Study Registration Dates

• First Submitted: October 25, 2023
• First Submitted That Met QC Criteria: October 25, 2023
• First Posted (Actual): October 31, 2023

Study Record Updates

• Last Update Posted (Actual): November 2, 2023
• Last Update Submitted That Met QC Criteria: October 31, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: Colorectal cancer; Gastrointestinal Neoplasms; Digestive System Neoplasms; WEE1; Azenosertib; LB100; PP2A
• 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; LB100
• Other Study ID Numbers: N23LAC

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