Clinical Trial of OMTX705 in Combination With Gemcitabine/Nab-Paclitaxel and Tislelizumab in Patients With Advanced/Metastatic Pancreatic Adenocarcinoma

Phase 1b Dose Escalation Trial of OMTX705, an Anti-Fibroblast Activation Protein Antibody-Drug Conjugate, in Combination With Gemcitabine/Nab-Paclitaxel and Tislelizumab in Patients With Advanced/Metastatic Pancreatic Adenocarcinoma

This is a Phase 1b dose escalation trial of OMTX705, an anti-fibroblast activation protein (FAP) antibody-drug conjugate (ADC), in combination with gemcitabine/nab-paclitaxel and tislelizumab in patients with advanced/metastatic pancreatic ductal adenocarcinoma (PDAC).

The trial will be conducted in two parts (Part 1 and Part 2). Both parts will enroll participants with advanced PDAC that, in general, are eligible to receive gemcitabine/nab-paclitaxel. Part 1 is intended to determine the safe recommended dose of OMTX705 in combination with gemcitabine/nab-paclitaxel (1A) and in combination with gemcitabine/nab-paclitaxel+tislelizumab (1B). Both 1A and 1B will enroll in a standard 3+3 design. Only one dose level of OMTX705 will be selected for Part 2 by a Data Safety Monitoring Board (DSMB). In Part 2, 3 parallel randomized arms will be opened simultaneously with 1:1:1 randomization (N=15 each): OMTX705+gemcitabine/nab-paclitaxel (arm 2A), OMTX705+tislelizumab+gemcitabine/nab-paclitaxel (arm 2B) and gemcitabine/nab-paclitaxel (arm 2C, reference arm).

Inclusion Criteria:

1. Capable of giving signed informed consent.
2. Male and female participant aged 18 years and older.
3. Participants must have histologically or cytologically confirmed PDAC: a) Metastatic PDAC who have not received therapy or received 1 prior line of systemic cytotoxic therapy (Part 1 and Part 2) and if trial treatment is given in the second line setting; b) Non-resectable locoregional PDAC who have not received therapy or received 1 prior line of systemic cytotoxic therapy (Part 1 only); c) A previous treatment with a targeted agent (for example KRAS inhibitor in the context of a clinical trial) without chemotherapy not counted as previous line of therapy. This situation should be discussed with the medical monitor.
4. Participants should have documented disease progression if previously locally advanced disease or be in 2nd line for stage IV or, in the opinion of the investigator, despite of lack of documented PD per image, require a change in the therapy.
5. Participants should be considered in general eligible for standard GA, for first or second line for metastatic disease (Part 1 and 2) or as palliative therapy for non-resectable locoregional cancer (Part 1 only). Patients who received polychemotherapy (FOLFIRINOX or similar) as neoadjuvant/adjuvant treatment and recur locally or distant <6 months after the completion of systemic therapy, will be classified as second line.
6. Measurable disease by RECIST v1.1 on CT PET/CT or magnetic resonance imaging (MRI) scan.
7. Eastern Cooperative Group Performance (ECOG) performance status 0-1.
8. Adequate bone marrow, hepatic and renal function: a) Total bilirubin ≤1.5 times upper limit of normal (ULN) or total bilirubin n <3.0 × ULN with direct bilirubin within normal range in participants with documented Gilbert's syndrome; b) AST and ALT ≤3 times ULN, (if liver metastases are present, then ≤5 times ULN is allowed); c) Serum creatinine ≤1.5 x ULN or creatinine clearance ≥40 mL/min (measured or calculated using the Cockroft-Gault formula); d) Hemoglobin ≥9.0 g/dL (whole or partial blood transfusions not allowed in the two previous weeks); e) ANC ≥1.5 x 109/L (growth factors like granulocyte-colony stimulating factor are not allowed in the two previous weeks); f) Platelet count ≥100 x 109/L (platelet in the two previous weeks transfusions not allowed).
9. Women of childbearing potential (WOCBP) and men with sexual partners who are WOCBP must be willing to adhere to highly effective contraceptive requirements and must agree to avoid impregnating a partner or becoming pregnant, respectively, during the study, and for at least 90 days after the last dose of any IMP. Men with sexual partners who are WOCBP should adhere to contraception requirements for 180 days after the last dose of any IMP.
10. Suitable venous access for safe drug administration and the study-required drug concentration and pharmacodynamics sampling.
11. A valid archival tumor sample.
12. Pretreatment fresh biopsy is optional in Part 1 dose escalation. In Part 2, a fresh pretreatment biopsy and on-treatment is required unless biopsy is associated with significant risk and per discussion with the sponsor medical monitor (or designee).

Exclusion Criteria:

1. Prior treatment with OMTX705 or nab-paclitaxel for the locally advanced (adjuvant or neoadjuvant) for metastatic disease. Previous use of gemcitabine as radiosensitizer or as part of neoadjuvant/adjuvant therapy is allowed if the treatment was completed 6 months before consent signature. Prior treatment with T-cell co-stimulating or immune checkpoint blockade therapies including anti-cytotoxic T-lymphocyte associated protein 4, anti-PD-1, and anti-PD-L1 therapeutic antibodies or any immune checkpoint inhibitor (except for participants to be enrolled in Part 1A).
2. Treatment with systemic anticancer treatments, investigational products, or major surgery within 4 weeks before the first dose of study drug or 5 half-lives, whichever is shorter. Participants should have recovered from previous treatment toxicity to Grade 1, baseline (excluding anemia, lymphopenia, alopecia, and skin pigmentation). Participants with endocrinopathies should have the replacement treatment in stable dosing.
3. History of uncontrolled brain metastasis. Participants with brain metastases are allowed if they are previously treated with surgery, whole-brain radiation, or stereotactic radiosurgery and have brain imaging during screening confirming that brain metastasis are stable (without evidence of progression by imaging using the identical imaging modality for each assessment, either MRI or CT and considered controlled with ≤10 mg/day prednisone equivalent at the time of receiving the first dose of OMTX705). For asymptomatic participants, screening brain imaging is not required.
4. Participant has received extended field radiotherapy ≤4 weeks before the start of treatment (≤1 week for limited field radiation for palliation), and who has not recovered to Grade 1 or better from related side effects of such therapy (except for alopecia).
5. Major surgical procedure or significant traumatic injury ≤21 days prior to ICF signature.
6. Cardiac arrhythmias requiring anti-arrhythmic therapy. Note: pacemakers, beta blockers, or digoxin are permitted.
7. Active infection requiring parenteral or oral antibiotics. Antibiotics given for prophylaxis are allowed. They are also allowed for minor localized infections like cystitis, amygdalates or localized skin infections.
8. Evidence of serious uncontrolled medical disorder that, in the opinion of the investigator or medical monitor, makes it unwise for the participant to participate in the study or that might jeopardize compliance with the protocol.
9. Drainage of ascitic or pleural fluid two or more times in the four weeks prior to the first dose of study drug or permanent drain in place (e.g., PleurX®) for ascites or pleural effusion symptom management.
10. Placement of a biliary stent, endoscopic retrograde cholangiopancreatography (ERCP) or biliary catheterization (internal or percutaneous) procedure <7 days before the first dose.
11. Psychiatric illness/social circumstances that would limit compliance with study requirements and substantially increase the risk of AEs or compromised ability to provide written informed consent.
12. Previous or concurrent cancer that is distinct in primary site or histology from PDAC within 3 years prior to randomization except for curatively treated cervical cancer in situ, non-melanoma skin cancer and superficial bladder tumors (Ta [non-invasive tumor], Tis [carcinoma in situ] and T1 [tumor invades lamina propria]); note: all cancer treatments for cancers that were distinct in a primary site other than PDAC must be completed at least 3 years prior to signature date of the ICF.
13. Uncontrolled or significant cardiovascular disease defined by the New York Hearth Association classification III or IV.
14. History of cerebrovascular stroke or myocardial infarction within the previous 3 months.
15. Grade ≥2 peripheral neuropathy.
16. Received a live vaccine within 30 days prior to first dose of study drug.
17. Known hepatitis B virus surface antigen seropositive or detectable hepatitis C infection viral load. Note: Participants who have positive hepatitis B surface antigen antibody can be included but must have an undetectable hepatitis B viral load. Participants receiving antiviral therapy for hepatitis B virus for any reason are excluded.
18. Participants positive for human immunodeficiency virus (HIV) are NOT excluded from this study, but HIV-positive participants must meet the following criteria: a) have CD4+ T-cell (CD4+) counts ≥350 cells/μL; b) have not had an opportunistic infection within the past 12 months. Participants on prophylactic antimicrobials can be included in the trial; c) should be on established antiretroviral therapy for at least four weeks; d) have an HIV viral load of less than 400 copies/mL prior to enrollment; e) known history of any other relevant congenital or acquired immunodeficiency other than HIV infection.
19. Known or suspected allergy to study treatment or related products, and specifically participants with a prior history of life-threatening reaction to polysorbate 20.
20. Women who are pregnant or breastfeeding or trying to become pregnant.
21. Male participants wishing fathering children, planning for future sperm banking, or expressing concerns about sterility.
22. Participants requiring the concomitant administration of medications that are strong inhibitors or inducers of CYP3A4, 2D6, 1A2, 2C9, 2B6, and 2C19. In case they are taking any of these drugs, they should be stopped at least 14 days prior to first dose.
23. Except Part1A: History of autoimmune disease requiring systemic immunosuppressive therapy (daily prednisone equivalent doses >10 mg/day).
24. Except Part 1A: Participants who discontinued prior treatment with any immune checkpoint due to irAEs, irrespective of grade, recovery, or need for continued steroid therapy. Also, participants without formal contraindication due to previous irAE are not eligible if the AE has not resolved to Grade 1 or better and/or still requires steroids (>10 mg of prednisone equivalent per day) for ongoing management.
25. Except Part 1A: participants with a history of pneumonitis/interstitial lung disease, and participants who discontinued prior immune checkpoint inhibitors due to Grade 2 myocarditis.