Clinical trial NCT05868174: Combination of 177Lu-TLX250 and Peposertib in Patients With Carbonic Anhydrase IX -Expressing Solid Tumors
Official title: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: Solid Tumor, Adult
Advanced Solid Tumor
Advanced Renal Cell Carcinoma
Keywords: CAIX
Lead sponsor: Telix Pharmaceuticals (Innovations) Pty Limited
Sponsor class: INDUSTRY
Collaborators: name: Merck KGaA, Darmstadt, Germany
First posted: 2023-05-22
Enrollment: 36
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SEQUENTIAL
Intervention model description: Dose escalation/de-escalations will be supported by the guidance given by outputs of the Bayesian model-based dose-escalation design.
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Safety parameter Dose Limited Toxicity (DLT)
timeFrame: 42 days
measure: Safety parameter Laboratory Examinations
timeFrame: 42 days
measure: Safety parameter Vital signs
timeFrame: 42 days
measure: Safety parameter ECG
timeFrame: 42 days
measure: Safety parameter Adverse Events and Treatment-Related Adverse Events
timeFrame: 42 days
measure: Disease impact causing changes in Eastern Cooperative Oncology Group (ECOG) Performance scale.
timeFrame: Screening/Baseline, Day1, Day 29, D57 and End of Treatment
Secondary outcomes:
measure: Overall Survival (OS)
timeFrame: Every 3 months ± 2 weeks for 24 months after the last 177Lu-TLX250 administration
measure: Tumor objective response rate (ORR)
timeFrame: Every 3 months ± 2 weeks for 12 months after the last 177Lu-TLX250 administration
measure: Progression-free survival (PFS)
timeFrame: Every 3 months ± 2 weeks for 12 months after the last 177Lu-TLX250 administration
measure: Immunogenicity by formation of ADA(HACA) in blood
timeFrame: 84 days
Other outcomes:
Locations:
city: North Ryde
country: Australia
facility: Macquarie University
state: New South Wales
city: Adelaide
country: Australia
facility: Ashford (Icon) Cancer Centre
city: Brisbane
country: Australia
facility: Princess Alexandra Hospital
city: Melbourne
country: Australia
facility: Austin Health
city: Perth
country: Australia
facility: GenesisCare Murdoch
Study officials:
References: