Efficacy and Safety Study of OMTX705, Monotherapy and Pembrolizumab-combined, in Subjects With Advanced Solid Tumors.

Open-label, two parallel arm, multicenter, Phase 1 dose-escalation study to evaluate the safety and tolerability of OMTX705, both as monotherapy or in combination with pembrolizumab in the treatment of patients with advanced or metastatic cancer in whom there is no available standard therapeutic option.

The study consists of 2 parts:

* Part 1: Phase 1 dose-escalation with 2 parallel staggered escalation cohorts: one cohort of patients treated with OMTX705 as monotherapy and one cohort of patients receiving escalating doses of OMTX705 in combination with standard pembrolizumab. The combination arm will start once OMTX705 monotherapy safety has been evaluated.
* Part 2: Up to 4 cohort expansions to confirm the safety of OMTX705 as monotherapy and in combination with pembrolizumab and will provide additional efficacy information.

The classical 3+3 design will be followed to establish the maximum tolerated dose (MTD) or the provisional recommended dose for the expansion phase. Three to six patients per treatment cohort will be assigned to receive sequentially higher doses of OMTX705 on Days 1 and 8 in cycles of 21 days. The OMTX705 starting dose is 1.0 mg/kg

Dose escalation will be based on a review of all parameters critical to subject safety from C1D1 to the start of C2D1. A safety report will be reviewed by the safty review committee (SRC) to determine if progression to the next planned dose level should occur or if additional subjects or lower dose levels are needed.

Expansion phase (Part 2): Once MTD is identified, or if another dose is identified because observed efficacy, non-DLT safety, or because a dose is supported by the PK/PD model under development, a provisional recommended Phase 2 dose (RP2D) will be selected by the sponsor and SRC for cohort expansion. Up to 4 cohort expansions of up to 15 patients each will proceed to confirm the safety and for initial assessment of anti-tumor activity. Each expansion cohort can be enriched with patients with advanced/metastatic cancer with no therapeutic standard alternative indications in which antitumor activity has been observed during the escalation phase. The final decision on the expansion cohort enrichment will be made by the sponsor with the support of the SRC.

After treatment discontinuation, patients will have the EoT visit 30 (±2) days after the last dose of any component of the treatment for the evaluation of new AEs or recovery from previous ones. EoT visit can be anticipated for patients scheduled to receive the next line of systemic treatment to the day of the start of the new therapy if this happens less than 30 days after the last dose of study treatment.

Subjects who discontinue study treatment for reasons other than progressive disease (PD) will continue to attend PFS Follow-up (FU) Visits every 12 (±1) weeks from the EoT Visit until the occurrence of PD, loss to follow up, consent withdrawal, death, the start of subsequent systemic antineoplastic therapy, or study termination, whichever occurs first.

Only patients enrolled in Part 2 will be followed for survival. To assess survival status, subjects will be contacted (which may be by phone or hospital visit, whichever is preferable) every 3 months from the first dose of OMTX705.

Eligibility Criteria:
Inclusion Criteria:

1. Male and female patient aged 18 years and older.
2. Part 1 and 2, monotherapy and combination: Patients with histologically confirmed advanced (locoregionally recurrent, not amenable to curative therapy) or metastatic solid tumors that have no standard therapeutic option with a proven clinical benefit, or are intolerant to these therapies with the following selected tumor histologies: pancreatic ductal adenocarcinoma (PDAC), gastric cancer (including gastroesophageal junction tumors), head and neck squamous-cell carcinoma (HNSCC), esophageal cancer, non-small cell lung cancer (NSCLC), high grade serious ovarian cancer (HGSOC), breast cancer (BC), colorectal cancer (CRC), and leiomyosarcoma.
3. Subjects with tumors with actionable mutations should have progress to all approved targeted therapies or have them contraindicated.
4. Measurable disease by RECIST 1.1 on CT, PET/CT or MRI scan.
5. ECOG performance status 0-1
6. Serum albumin ≥3.0 g/dL
7. Adequate bone marrow, hepatic and renal function:

   1. Total bilirubin ≤1.5 times upper limit of normal (ULN).
   2. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 times ULN, (if liver metastases are present, then ≤5 times ULN is allowed).
   3. For Dose escalation Phase: Estimated creatinine clearance (CrCL) using the Cockcroft-Gault formula ≥60 mL/minute. Patients with calculated CrCL \<60 mL/min can be enrolled if measured CrCL is ≥60 mL/min.
   4. In the expansion phase CrCL should be ≥30 mL/min.
   5. Hemoglobin ≥9 g/dL (whole or partial blood transfusions not allowed in the 2 previous weeks).
   6. Absolute neutrophil count (ANC) ≥1.5 x 109/L (growth factors like G-CSF are not allowed in the 2 previous weeks).
   7. Platelet count ≥75 x 109/L (platelet in the 2 previous weeks transfusions not allowed)
8. Women of childbearing potential (WOCBP) and men with sexual partners who are WOCBP must be willing to adhere to contraceptive requirements as detailed in the protocol from at least 1 month prior to study entry to at least 4 months after the last dose of study treatment.
9. Suitable venous access for safe drug administration and the study-required drug concentration and pharmacodynamic sampling.

Exclusion Criteria:

1. 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. Subjects should have recovered from previous treatment toxicity to grade 1, baseline (except alopecia and peripheral neuropathy). Patients with endocrinopathies should have the replacement treatment in stable dosing.
2. History of uncontrolled brain metastasis. For asymptomatic subjects, screening brain imaging is not required.
3. Subject has received extended field radiotherapy ≤4 weeks before the start of treatment (≤1 weeks 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).
4. Active infection requiring parenteral or oral antibiotics.
5. Evidence of serious uncontrolled medical disorder that, in the opinion of the investigator or medical monitor, makes it unwise for the subject to participate in the study or that might jeopardize compliance with the protocol.
6. Drainage of ascitic or pleural fluid 2 or more times in the 4 weeks prior to the first dose of study drug or permanent drain in place for ascites or pleural effusion symptom management.
7. Psychiatric illness/social circumstances that would limit compliance with study requirements and substantially increase the risk of AEs or has compromised ability to provide written informed consent.
8. Clinical evidence of an active second invasive malignancy with the exception of stable prostate cancer on watchful waiting, in situ cervical cancer, breast ductal carcinoma in situ or localized non-melanoma skin cancers.
9. Uncontrolled or significant cardiovascular disease defined as NYHA classification III or IV.
10. Baseline QTc (using the Fridericia correction calculation) \> 470 msec.
11. Combination with pembrolizumab only: history of autoimmune disease requiring systemic immunosuppressive therapy (daily prednisone equivalent doses \>10 mg/day).
12. Combination with pembrolizumab only: Subjects who, according to the currently approved Keytruda® (pembrolizumab) USPI/SmPC, had, with a previous checkpoint inhibitor (approved or investigational) treatment, an immune-related adverse event (irAE) for which permanent discontinuation is mandated (any grade 4 event and grade 3 events of pneumonitis, hepatitis, and nephritis). Also, subjects 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.
13. Combination with pembrolizumab only: patients with a history of pneumonitis/interstitial lung disease, patients who received live vaccines within 30 days of enrollment, and patients who discontinued prior immune checkpoint inhibitors due to Grade 2 myocarditis are excluded from enrollment into pembrolizumab-containing cohorts.
14. Known hepatitis B virus surface antigen seropositive or detectable hepatitis C infection viral load.
15. Patients positive for human immunodeficiency virus (HIV) are NOT excluded from this study, but HIV-positive patients must meet the following criteria:

    1. have CD4+ T-cell (CD4+) counts ≥350 cells/µL.
    2. have not had an opportunistic infection within the past 12 months. Patients on prophylactic antimicrobials can be included in the trial.
    3. should be on established antiretroviral therapy for at least 4 weeks.
    4. have an HIV viral load less than 400 copies/mL prior to enrollment.
    5. known history of any other relevant congenital or acquired immunodeficiency other than HIV infection.
16. Known or suspected allergy to study treatment or related products, and specifically patients with a prior history of life-threatening reaction to polysorbate 20.
17. Women who are pregnant or breastfeeding or trying to become pregnant.
18. Male patients wishing fathering children, planning for future sperm banking, or expressing concerns about sterility.
19. Patients 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.