A Study of 177Lu-FAP-2286 in Advanced Solid Tumors

Fibroblast activation protein (FAP) is a cell surface protein that is highly expressed on the surface of cancer-associated fibroblasts (CAFs) present in the tumor microenvironment of most epithelial cancers, whereas limited expression of FAP is observed in normal tissues. In some cancers of mesenchymal origin, notably sarcoma and mesothelioma, FAP expression has also been observed on the tumor cells themselves. Given the restricted expression profile, FAP is a promising target for peptide-targeted radionuclide imaging and therapeutic agents. Phase 1 of this study is designed to evaluate the safety and establish the recommended intravenous (IV) Phase 2 dose (RP2D) for \[177Lu\]Lu FAP 2286 monotherapy in participants with FAP expressing solid tumors. Phase 2 is designed to evaluate the safety and efficacy of \[177Lu\]Lu FAP 2286 as monotherapy in participants with pancreatic ductal adenocarcinoma (PDAC), non-small cell lung cancer (NSCLC), and breast cancer (BC) and in combination with chemotherapy in participants with untreated PDAC or relapsed NSCLC. Participants in both Phase 1 and 2 will be selected for treatment with \[177Lu\]Lu FAP 2286 based on \[68Ga\]Ga FAP 2286 imaging for determining tumor FAP expression.

Screening Period: All participants will undergo screening assessments including disease assessments per CT or MRI per RECIST v1.1 criteria prior to administration of \[68Ga\]Ga FAP 2286. Each participant must provide informed consent and agree to provide an archival tumor tissue sample, if available, and blood samples for biomarker assessment. Participants must meet all entry criteria as specified in the protocol. In Phase 1 only, participants will also undergo FDG-PET imaging. In the Phase 2 part, \[177Lu\]Lu FAP 2286 will be investigated in monotherapy and in combination with chemotherapy. All participants in the combination group may begin chemotherapy prior to \[177Lu\]Lu FAP 2286. Participants meeting entry criteria will be enrolled and participants who have not had prior PET/CT imaging with \[68Ga\]Ga FAP 2286 in the previous 3 months (applicable only to Phase 1) will undergo PET imaging with \[68Ga\]Ga FAP prior to initiating treatment with \[177Lu\]Lu FAP 2286. Participants must have a positive \[68Ga\]Ga FAP PET/CT scan, as described in the criteria for continuation to \[177Lu\]Lu FAP 2286 therapy, in order to be treated with \[177Lu\]Lu FAP 2286. Treatment Period: A single IV dose of \[177Lu\]Lu FAP 2286 will be initially administered every 6 weeks (window of - 1 to + 7 days) up to a maximum of 6 doses in Phase 1. In Phase 2, \[177Lu\]Lu FAP 2286 will be administered every 4 weeks (28 days ± 3 days). All participants will be monitored for safety throughout the Treatment Period. All participants will be assessed for disease status per RECIST v1.1 every 6 weeks (42 days). Participants will receive \[177Lu\]Lu FAP 2286 until the maximum doses allowed are administered, confirmed radiographic disease progression assessed by investigator based on RECIST v1.1 criteria, unequivocal clinical disease progression, unacceptable toxicity or inability to tolerate further treatment, loss to follow-up, or withdrawal of consent. Safety data will be periodically reviewed by the DCRC during dose escalation and by a Data Monitoring Committee (DMC) during dose expansion. End of Treatment (EOT) Visit: In Phase 1, participants will have an EOT Visit 6 to 8 weeks after the last dose of \[177Lu\]Lu FAP 2286 except in cases of participant death, loss to follow up, or withdrawal of consent for further follow up. Participants in Phase 2 will have an EOT visit within 28 days from the last dose of study treatment except in case of participant death, loss to follow-up, or withdrawal of consent for further follow-up. Post treatment safety follow-up: In Phase 2, after discontinuation of study treatment for any reason, all participants will have safety follow-up for 6 weeks (+/- 1 week) after their last study treatment administration, except in case of death, loss to follow-up or withdrawal of consent as per the schedule of assessments. Long-term Follow-up (LFTU) Period: Upon completion of the EOT Visit, participants will enter the LTFU Period. The LTFU Period will include safety, disease, and survival assessments, as applicable. * Safety assessments will be performed every 12 weeks (+/- 1 week) for 2 years, then every 6 months until 5 years. * Disease assessments will be performed for all participants who complete the EOT for a reason other than radiographic disease progression. Participants should continue to have tumor scans performed until radiographic disease progression, death, loss to follow-up, withdrawal from study, study closure or initiation of subsequent anticancer treatment. * Survival assessments will be performed for all participants.