Combination of 177Lu-TLX250 and Peposertib in Patients With Carbonic Anhydrase IX -Expressing Solid Tumors

A Phase 1b Dose Escalation/Expansion Study of the Combination of 177Lu-TLX250 and Peposertib in Patients With Carbonic Anhydrase IX (CAIX)-Expressing Solid Tumors

This is an open label, single-arm, multicentre dose escalation (Part 1) and dose expansion (Part 2) study to evaluate different combinations of 3 radioactive dose levels of 177Lu-TLX250 administered intravenously with 3 different doses of peposertib in patients with CAIX-expressing solid tumors.

Study Overview

• Status: Recruiting
• Conditions: Advanced Solid Tumor; Solid Tumor, Adult; Advanced Renal Cell Carcinoma
• Intervention / Treatment: Diagnostic test: 89Zr-TLX250; Combination product: 177Lu-TLX250 and Peposertib

Detailed Description

Part 1 (dose escalation) will evaluate the combination of 3 different activities of 177Lu-TLX250 and 3 different dose levels of peposertib.

Patients with CAIX positive solid tumors will be enrolled in a given dose/activity level in Cohorts of approximately 2-6 patients.

Treatment cycles will have a fixed length of 84 days. Patients will be treated during 3 cycles, or until clinically significant progression or unacceptable toxicity.

Part 2 (dose expansion) patients will be enrolled in 2 Cohorts:

• Cohort A: 40 patients with metastatic or non-resectable ccRCC
• Cohort B: 20 patients with CAIX-positive solid tumors (excluding RCC).

Patients will be treated at the Recommended phase 2 dose of 177Lu-TLX250 in combination with peposertib at the dosing schedule of the selected Recommended phase 2 dose.

• Study Type: Interventional
• Enrollment (Anticipated): 36
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Medical Director, MD

Study Locations

• Australia
  • Adelaide, Australia
    • Recruiting
    • Ashford (Icon) Cancer Centre
    • Contact: Principal Investigator; Phone Number: 00; Email: info@telixpharma.com
    • Principal Investigator: Dainik Patel
  • Brisbane, Australia
    • Not yet recruiting
    • Princess Alexandra Hospital
    • Principal Investigator: Kenneth O'Byrne
    • Contact: Principal Investigator
  • Melbourne, Australia
    • Not yet recruiting
    • Austin Health
    • Principal Investigator: Andrew Scott
    • Contact: Princiapl Investigator
  • Perth, Australia
    • Recruiting
    • GenesisCare Murdoch
    • Contact: Principal Investigator; Phone Number: 0000; Email: info@telixpharma.com
    • Principal Investigator: Nat Lenzo
  • New South Wales
    • North Ryde, New South Wales, Australia
      • Not yet recruiting
      • Macquarie University
      • Contact: Principal Investigator
      • Principal Investigator: Howard Gurney

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Histologically confirmed advanced or metastatic solid tumor that has progressed on or during/after recognized standard of care therapies and are not eligible for resection, or patients that are not eligible or not consenting to recognized standard of care therapies.
• At least one measurable lesion on CT/MRI according to RECIST 1.1 with corresponding 89Zr-TLX250 uptake (i.e., CAIX positive).
• CAIX positivity in at least 75% of the total lesion volume (defined as 89Zr- TLX250 uptake with intensity significantly greater than normal liver [i.e., standardized uptake value [SUV]max at least 1.5 times SUV of normal liver]).
• ECOG status 0 or 1.
• Have adequate organ function during screening
• Must have a life expectancy of at least 6 months.

Exclusion Criteria:

• Prior 177Lu-TLX250 or other radioligand therapy; or any prior CAIX targeting therapy.
• Known hypersensitivity to compounds of similar chemical or biologic composition to peposertib, girentuximab radiolabelled by zirconium or lutetium, any excipient in the study medication or any other intravenously administered human proteins/peptides/antibodies.
• Administration of any radionuclide within 10 half-lives of the radionuclide prior to signature of the ICF.
• Patients who have had chemotherapy, definitive radiation, biological cancer therapy, or investigational agent/device within 28 days of first planned dose of study therapy.
• Patients who had > 2 prior lines of cytotoxic chemotherapy or had Grade 4 neutropenia or Grade 3/Grade 4 thrombocytopenia (both of a duration of at least 48 hours) during the last line of therapy. Note: This criterion may be removed in total or in part by the SRC upon review of the safety data from the initial dose level(s).
• Patients who cannot discontinue concomitant medications or herbal supplements that are strong inhibitors or strong inducers of cytochrome P450 (CYP) isoenzymes CYP3A4/5, CYP2C9, and CYP2C19. Concomitant use of CYP3A4/5 substrates with a narrow therapeutic index are also excluded.
• Patients who cannot discontinue concomitant H2-blockers or proton-pump inhibitors (PPIs). Patients may confer with the investigator to determine if such medications can be discontinued. These must be discontinued ≥ 5 days prior to study treatment. Patients do not need to discontinue calcium carbonate.
• Patients who are receiving therapeutic doses of anticoagulation, including but not limited to low-molecular weight heparin in therapeutic dosing or platelet aggregation inhibitors. Note: This criterion may be removed by the SRC upon review of the safety data from the initial dose level(s).
• Patients with ≥ 5 bone metastases and/or bulky (> 3cm in diameter) pelvic or femoral tumors, and/or metastases/tumor in the vertebral spine involving > 3 vertebrae.
• Any severe concomitant condition which makes it undesirable for the patient to participate in the study or which could jeopardize compliance with the protocol, in the opinion of the investigator.
• Presence of active and uncontrolled infections or other severe concurrent disease, which, in the opinion of the investigator, would place the patient at undue risk or interfere with the study.
• Requirement of concurrent use of other anti-cancer treatments or agents other than study medications. Supportive care therapies are permitted.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: 89Zr-TLX250, 177Lu-TLX250 and Peposertib; Diagnostic test: A single IV administration of 37 Megabecquerel (+/- 10%) 89Zr-DFO-girentuximab, containing a mass dose of 10 mg of girentuximab, followed by a diagnostic scan Treatment test: A single IV administration that could be 1887 - 2516 or 3145 Megabecquerel (+/- 10%) 177Lu-DOTA-girentuximab,containing a mass dose of 10 mg of girentuximab, on Day 1 of each 84-day cycle and p.o. administration of that could be 100-150 or 200 mg Peposertib BID on days 4-21 of each 84-day cycle.

Diagnostic test: 89Zr-TLX250; Single IV administration followed by 89Zr-DFO-girentuximab PET/CT (or PET/MRI) scan at screening and approximately 8-10 weeks (±1 week) after Cycle 3 Day 1, as well as at the end of treatment visit (if feasible). The PET/CT should be obtained within 4-7 days after 89Zr-TLX250 administration; Other Names: 89Zr-DFO-girentuximab; Combination product: 177Lu-TLX250 and Peposertib; Dose escalation and de-escalation for the determination of the Maximum tolerated combination/ Recommended phase 2 dose. All subjects will receive 177Lu-TLX250 intravenously on day 1 and Peposertib BID on days 4-21 of each 84-day cycle.; Other Names: 177Lu-DOTA-girentuximab

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety parameter Dose Limited Toxicity (DLT)	Dose level toxicity evaluation using Partial Ordering Bayesian Logistic Regression Model Method (PO-BLRM)	42 days
Safety parameter Laboratory Examinations	Frequency of occurrence and severity of abnormal findings in safety investigations regarding Laboratory examinations	42 days
Safety parameter Vital signs	Frequency of occurrence and severity of abnormal findings in safety investigations regarding the vital signs	42 days
Safety parameter ECG	Frequency of occurrence and severity of abnormal findings in the 12-lead ECG (ECG QT interval)	42 days
Safety parameter Adverse Events and Treatment-Related Adverse Events	Assessment of AEs graded by the Common Terminology Criteria for Adverse Events (CTCAE) Criteria, Version 5.0	42 days
Disease impact causing changes in Eastern Cooperative Oncology Group (ECOG) Performance scale.	Quality of life ( in terms of their ability to care for themself, daily activity, and physical ability (walking, working) is to be evaluated using the ECOG Performance Scale.	Screening/Baseline, Day1, Day 29, D57 and End of Treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival (OS)	Overall Survival (OS), determined from enrollment , until death from any cause	Every 3 months ± 2 weeks for 24 months after the last 177Lu-TLX250 administration
Tumor objective response rate (ORR)	Tumor response in terms of objective response rate (ORR) (solid tumor tissue response and overall radiological response [tumor response by RECIST 1.1 and overall radiological response by RECIST 1.1])	Every 3 months ± 2 weeks for 12 months after the last 177Lu-TLX250 administration
Progression-free survival (PFS)	Progression free survival (PFS) defined as the time from enrollment to disease progression confirmed by radiology, clinical progression or death (whichever comes first)	Every 3 months ± 2 weeks for 12 months after the last 177Lu-TLX250 administration
Immunogenicity by formation of ADA(HACA) in blood	This outcome will be measured by analyzing the incidence of ADA(HACA) formation in blood on day 1, day 22, Day 43, Day 57 of each cycle (each cycle is 84 days) and at the end of treatment visit.	84 days

Collaborators and Investigators

• Sponsor: Telix International Pty Ltd
• Collaborators: Merck KGaA, Darmstadt, Germany

Study record dates

Study Major Dates

• Study Start (Actual): May 23, 2023
• Primary Completion (Anticipated): December 1, 2024
• Study Completion (Anticipated): December 1, 2026

Study Registration Dates

• First Submitted: April 24, 2023
• First Submitted That Met QC Criteria: May 11, 2023
• First Posted (Actual): May 22, 2023

Study Record Updates

• Last Update Posted (Actual): May 24, 2023
• Last Update Submitted That Met QC Criteria: May 22, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Keywords: CAIX
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Kidney Diseases; Urologic Diseases; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Kidney Neoplasms; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Neoplasms; Carcinoma, Renal Cell; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protein Kinase Inhibitors; Peposertib
• Other Study ID Numbers: 177Lu-TLX250-001

Drug and device information, study documents

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