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.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
15
Patient 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.
Karolinska University hospital
Stockholm, Stockholm County, Sweden
RECRUITINGPrimary 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
Time frame: From first dose to a minimum of 6 weeks post-dose.
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
Time frame: 8 days
Biodistribution of 177Lu-AKIR001 in the whole body
Elimination from whole body will be assessed in % injected dose according to dosimetry
Time frame: 8 days
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
Time frame: 29 days
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.
Time frame: From first dose to a minimum of 6 weeks post-dose.
Anti-tumor efficacy: radiological response
\- CR, PR or SD counts after completion of at least one infusion of \[177Lu\]Lu-AKIR001, as assessed by RECIST v1.1.
Time frame: 12 months
Long-term occurrence of adverse events
Long-term related AEs and AEs of interest in each cohort; a 5-year long-term safety period will start after first \[177Lu\]Lu-AKIR001 infusion.
Time frame: 5 years
Dosimetry of 177Lu-AKIR001
\- Absorbed dose per administered activity (Gy/GBq) per organ and selected tumour lesions
Time frame: 8 days
Anti-tumor efficacy: overall response rate
\- ORR based on the endpoints CR or PR according to RECIST v1.1.
Time frame: 12 months
Antitumor efficacy: duration of response
DoR, defined as the time from initial response (CR or PR) until the time of progression according to RECIST v1.1.
Time frame: 12 months
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