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

Inclusion Criteria:

Eligible participants must meet the following inclusion criteria. The criteria below
apply to participants enrolling in Phase 1 and Phase 2, unless otherwise specified.

1. Have signed and dated an Institutional Review Board (IRB)/Independent Ethics
Committee (IEC)-approved Informed Consent Form (ICF) prior to any study-specific
evaluation.

2. Be ≥ 18 years of age at the time the ICF is signed.

3. Have consented to submission of fresh or archival tumor tissue, if available.

4. Have adequate organ function confirmed by the following laboratory values obtained
within the Screening Period prior to administration of [68Ga]Ga FAP 2286 and prior
to first cycle of chemotherapy in the combination groups:

a. Bone Marrow Function (independent of transfusion or growth factor support within
21 days prior to planned first administration of [177Lu]Lu FAP 2286): i. Absolute
neutrophil count (ANC) ≥ 1.5 × 109/L; ii. Platelets > 100 × 109/L; and
iii.Hemoglobin ≥ 9 g/dL. b. Hepatic Function: i. Aspartate aminotransferase (AST)
and alanine aminotransferase (ALT) ≤ 3 × institutional upper limit of normal (ULN);
if liver metastases, then ≤ 5 × the institutional ULN; ii. Serum Bilirubin ≤ 1.5 ×
institutional ULN or if known Gilbert's syndrome then ≤ 3 × institutional ULN; iii.
Serum albumin ≥ 30 g/L (3 g/dL) and iv. INR ≤ 1.5 x ULN and activated partial
thromboplastin time (aPTT)≤1.5 x ULN. This applies to participants who are not
receiving therapeutic anticoagulation, participants receiving therapeutic
anticoagulation should be on a stable dose.

c. Renal Function: i. Estimated glomerular filtration rate (eGFR) ≥ 60 mL/min using
the Cockcroft Gault formula.

5. Have an Eastern Oncology Group (ECOG) performance status of 0 or 1.

6. Have a life expectancy of ≥ 6 months.

7. Have measurable disease per RECIST v1.1 meeting the following criteria:

1. At least 1 lesion of ≥ 10 mm in the longest diameter for a non lymph node or ≥
15 mm in the short axis diameter for a lymph node that is serially measurable
according to RECIST v1.1 using conventional CT and/or MRI.

• Lesions that have had external beam radiotherapy or loco-regional therapies
such as radiofrequency ablation must show subsequent evidence of substantial
size increase to be deemed a target lesion.

For Phase 1 only:

8. Have a histologically and/or cytologically confirmed advanced/metastatic solid tumor
not amenable to treatment with curative intent:

a. Tumor must be refractory to or have progressed following prior treatment and have
no satisfactory alternative treatment options.

For Phase 2 only:

9. Have cytologically or histologically and radiologically confirmed recurrent or
metastatic disease as outlined below:

a. Pancreatic Cancer monotherapy group: i. Pancreatic ductal adenocarcinoma (ductal
adenocarcinoma and related subtypes eligible; endocrine and neuroendocrine tumors
excluded) ii. Participants must have progressed after at least 1, but no more than
two prior chemotherapy regimens for locally advanced unresectable or metastatic
disease.

Criteria b through h removed during Protocol amendment 7. i. Pancreatic Cancer
combination group (with mFOLFIRINOX) i. Pancreatic ductal adenocarcinoma (ductal
adenocarcinoma and related subtypes eligible; endocrine and neuroendocrine tumors
excluded); ii. Participants have not received prior systemic therapy for metastatic
disease.

j. Non-small cell lung cancer monotherapy group i. Non-small cell lung cancer
(adenocarcinoma and squamous eligible; endocrine, neuroendocrine and small cell
tumors are excluded) ii. Participants must have progressed after at least 1 but not
more than 2 prior systemic regimens including chemotherapy and immunotherapy, if
eligible.

iii. Participants who have received adjuvant or neoadjuvant platinum-doublet
chemotherapy (after surgery and/or radiation therapy) and an immune checkpoint
inhibitor and developed recurrent or metastatic disease while on or within 12 months
of completing therapy are eligible iv. Participants with recurrent disease > 12
months after adjuvant or neoadjuvant platinum-based chemotherapy, who also
subsequently progressed during or after a platinum-doublet regimen and an immune
checkpoint inhibitor (given either together or sequentially to treat the
recurrence), are eligible v. Participants must have received platinum-based
chemotherapy for advanced or metastatic disease and immune checkpoint inhibitor
either together (in the same line of treatment) or sequentially (two different lines
of treatment) and then progressed.

k. Non small cell lung cancer combination group i. Non-small cell lung cancer
(adenocarcinoma and squamous eligible; endocrine, neuroendocrine and small cell
tumors are excluded) ii. Participants must have progressed after at least 1 but not
more than 2 prior systemic regimens including chemotherapy and immunotherapy, if
eligible.

iii. Participants who have received adjuvant or neoadjuvant platinum-doublet
chemotherapy (after surgery and/or radiation therapy) and an immune checkpoint
inhibitor and developed recurrent or metastatic disease while on or within 12 months
of completing therapy are eligible iv. Participants with recurrent disease > 12
months after adjuvant or neoadjuvant platinum-based chemotherapy, who also
subsequently progressed during or after a platinum-doublet regimen and an immune
checkpoint inhibitor (given either together or sequentially to treat the
recurrence), are eligible v. Participants must not have received prior taxane
therapy either as monotherapy or in combination.

l. Breast cancer monotherapy group i. HR positive HER2 negative

• Participant has a histologically and/or cytologically documented diagnosis of HR
positive HER2 negative metastatic breast cancer (based on the most recently analyzed
tissue sample tested by a local laboratory).

- Participants must have progressed on at least one line of hormone-based therapy
(either alone or in combination) and at least one, but not more than two lines
of chemotherapy (including cytotoxic, targeted and/or anti-drug conjugate
therapies) for metastatic disease.

ii. HER2 positive

• Participant has a histologically and/or cytologically documented diagnosis of HER2
positive metastatic breast cancer (based on the most recently analyzed tissue sample
tested by a local laboratory).

• Participant must have progressed on at least two lines of HER2 targeted therapy
for metastatic disease.

iii. Triple negative breast cancer (TNBC)

• Participant has a histologically and/or cytologically documented diagnosis of TNBC
(based on the most recently analyzed tissue sample tested by a local laboratory).

- Participants must have progressed on at least two lines of cytotoxic
chemotherapy (including cytotoxic, anti-drug conjugate, targeted therapies
and/or IO) for metastatic disease.

Key Exclusion Criteria:

Participants who meet any of the following criteria will be excluded from the study.
The criteria below apply to participants enrolling in Phase 1 or Phase 2.

1. Active malignancy except for the specific cancer under investigation in this study,
ie, participant known to have potentially fatal cancer present for which he/she may
be (but not necessarily) currently receiving treatment with the following
exceptions:

1. History of second malignancy that has been successfully treated, with no
evidence of active cancer for 3 years prior to enrollment;

2. Surgically cured low-risk tumors, such as early-stage cervical or endometrial
cancer, any cancer in situ, or non-melanoma skin cancers; and

3. Prior or concurrent malignancy whose natural history or treatment does not have
the potential to interfere with the safety or efficacy assessment of the
investigational regimen.

2. Symptomatic and/or untreated CNS metastases or leptomeningeal disease or with
primary tumor of CNS origin.

a. Participants with asymptomatic, previously treated CNS metastases are eligible
provided they have been clinically stable for at least 4 weeks and have completed
RT> 2 weeks prior to treatment. Participants may be on corticosteroids if on a
stable dose equivalent to prednisone 10 mg daily or less.

3. Received anticancer treatment with chemotherapy, antibody therapy or other
immunotherapy, gene therapy, vaccine therapy, angiogenesis inhibitors, or
experimental drugs ≤ 14 days prior (≤ 28 days prior in case of checkpoint inhibitor
therapy and other antibody therapies) to the administration of [177Lu]Lu FAP 2286.

4. Received prior radiopharmaceutical therapy (eg, radium 223 223Ra-dichloride,
[177Lu]Lu-DOTA-TATE, [177Lu]Lu-prostate-specific membrane antigen (PSMA)-617,
actinium 225 [225Ac]Ac PSMA-617, etc.) or prior EBRT to more than 25% of the bone
marrow or received any prior EBRT directly to kidney, or received any EBRT within 2
weeks prior to administration of [177Lu]Lu FAP 2286.

- Prior administration of a radiopharmaceutical unless 10 or more half-lives have
elapsed before injection/infusion of [68Ga]Ga-FAP-2286 or [177Lu]Lu FAP 2286.

5. Ongoing adverse effects from anticancer treatment NCI-CTCAE v5.0 (or higher) Grade
1, with the exception for alopecia and vitiligo.

Exclusion criteria 6 and 7 are removed with Protocol Amendment 7. 8. Impaired cardiac
function or clinically significant cardiac diseases, including any of the following:

1. Clinically significant and/or uncontrolled cardiac disease such as congestive heart
failure requiring treatment (New York Heart Association > Class 2), uncontrolled
hypertension, clinically significant arrhythmia, or congenital prolonged QT
syndrome;

2. Corrected QT interval (Fridericia's formula) > 450 msec for males or > 470 msec for
females at Screening; or

3. Acute coronary syndrome or acute myocardial infarction ≤ 6 months prior to
administration of [177Lu]Lu FAP 2286.

9. Active severe urinary incontinence, severe voiding dysfunction, or urinary
obstruction requiring an indwelling/condom catheter that, in the judgment of
the investigator, could prevent adhering to radiation safety instructions.

10. Severe chronic or active HIV infection:

a. Participants on effective antiretroviral therapy with undetectable viral load within 6
months prior to the first dose of [177Lu]Lu FAP 2286 are eligible.

Exclusion criteria 11 and 12 are removed with Protocol Amendment 7. 13. Non-study-related
minor surgical procedure ≤ 5 days, or major surgical procedure ≤ 21 days, prior to the
administration of [177Lu]Lu FAP 2286; in all cases, the participant must be sufficiently
recovered and stable before treatment administration.

14. The following are exclusion criteria, as applicable:

a. Female participants of childbearing potential: i. Refusal to use a highly effective
method of contraception or to practice true abstinence during treatment and for 6 months
following the last dose of investigational product; ii. Pregnant, suspected pregnancy, or
breast feeding; iii. Planning on getting pregnant during treatment and for 6 months
following the last dose of investigational product.

b. Male participants with female partners of childbearing potential: i. Refusal to use a
highly effective method of contraception or to practice true abstinence during treatment
and for 6 months following the last dose of investigational product.

c. All male participants: i. Refusal to use condoms during sex. ii. Planning to make
semen donations during treatment and for 6 months following the last dose of
investigational product.

15. Significant weight loss (> 10% of body weight) within 28 days prior to providing
informed consent for this study.

16. Presence of any other condition that may increase the risk associated with study
participation or interfere with the interpretation of study results, and, in the
opinion of the investigator, would make the participant inappropriate for entry into
the study.

17. Inability to complete the needed investigational and standard imaging examinations
due to any reason (e.g., severe claustrophobia, inability to lie still for the
entire imaging time).

18. Participants with known hypersensitivity to the active agent or excipients. 19.
Severe chronic or active infections (including active tuberculosis, HBV, or HCV
infection) requiring systemic antibacterial, antifungal or antiviral therapy within
2 weeks before enrollment.

Note: Antiviral therapy is permitted for participants with chronic HBV or HCV infection.
Participants receiving antivirals at Screening should have been treated for > 2 weeks
before enrollment. Inactive hepatitis B surface antigen (HbsAg) carriers treated and
stable hepatitis B participants (HBV DNA < 500 IU/mL or < 2500 copies/mL) can be
enrolled. Participants with detectable hepatitis B surface antigen (HbsAg) or detectable
HBV DNA should be managed per treatment guidelines. Participants positive for HCV
antibody are eligible only if PCR is negative for HCV RNA.