The goal of this clinical trial is to evaluate the safety and tolerability of increasing doses of \[177Lu\]Lu-AKIR001, both in relation to tolerable activity of lutetium-177 and the absorbed protein mass dose of AKIR-001 in patients with irresectable or metastatic CD44v6-expressing solid malignancies for whom no reasonable systemic treatment options are be available. The main question it aims to answer is:
• What is the toxicity profile of the study drug \[177Lu\]Lu-AKIR001 according to the rate of Dose Limiting Toxicities and (Severe) Adverse Events? Participants will receive one \[177Lu\]Lu-AKIR001 infusion followed by a 6-week safety follow-up period, which can be extended up to 12 weeks. Possible additional infusions of the trial drug, up to a maximum number of four, can be given when clinical benefit is noted and toxicity is deemed acceptable.
Participant must be 18 years of age or older
Willing and able to provide written informed consent
For BRAFv600E mutated tumours: BRAF/MEK inhibitors.
For BRAF-wildtype tumours at least one of the following: anthracycline- or taxane containing chemotherapy/ chemoradiotherapy, or other targeted therapies including vascular endothelial growth factor (VEGF) tyrosine kinase inhibitors (TKI), targeted therapies aimed at specific moleculo-pathological features (e.g., targeting NTRK, RET, ALK, PD-L1)
Symptomatic brain metastases that are not previously treated and/or that require ongoing steroid-treatment
Other malignancy diagnosed within the last five years, except for radically treated basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix
Chemo-, targeted or radiotherapy within the last 4 weeks before enrolment in the study.
Ongoing toxicities graded according to the Common Terminology Criteria for Adverse Events (CTCAE) > 1 from previous anti-cancer treatments.
Sequential
[177Lu]Lu-AKIR001
DrugPatient cohorts of a minimum of three and a maximum of 12 evaluable participants will be opened according to the decision tree defined in the protocol and will be consecutively completed. When one cohort has been completed and fully evaluated, the next cohort will be opened after all participants in the previous cohort have received at least one dose of the IMP without dose-limiting toxicities during a follow-up period of at least six weeks. The \[177Lu\]Lu-AKIR001 protein mass dose and activity are predefined for each cohort, and could be adjusted according to the results of previous cohort(s) to ensure the safety of participants. The initial design of the trial encompasses five cohorts to escalate both \[177Lu\]Lu-AKIR001 pmd, from 50 mg to 100 mg, and activity, from 0.75 to 3.0 GBq.
Primary Endpoint - rate of dose limiting toxicities
1. Rate of Dose Limiting Toxicities, according to the definition of (S)AEs according to the CTCAE version 5.0. 2. TEAEs, SAEs, clinically significant laboratory abnormalities and deaths 3. AEs ≥ grade 3 according to the CTCAE version 5.0 grading system (CTCAE v 5.0, 2017) during the treatment period
Biodistribution of 177Lu-AKIR001 in major organs and tissues
Uptake and elimination of the IMP from major organs and tissues will be assessed in % injected dose according to dosimetry
Biodistribution of 177Lu-AKIR001 in the whole body
Elimination from whole body will be assessed in % injected dose according to dosimetry
Pharmacokinetics of 177-Lu and AKIR001 in major organs
Blood concentration levels of lutetium-177 (Bq/mL) at different timepoints after \[177Lu\]Lu-AKIR001 infusion
Recommended Phase 2 Dose
* The MTA (GBq) per infusion is defined as the highest tolerated administered activity of the IMP, below which \<34% of participants experience DLT. * The MTCA is defined as the highest tolerated cumulative activity of the IMP over all treatments, below which \<34% of participants experience DLT.
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Karolinska University Hospital
Lead sponsor
Karolinska Institutet
Collaborator
Uppsala University
Collaborator
