First-in-human Phase I to Evaluate PEP-010 as Single Agent and in Combination With Paclitaxel or With Gemcitabine (CleverPeptide)

Inclusion criteria:

Part 1 Arms A and B:

1. Arm A: Patients must have histologically confirmed diagnosis of recurrent and/or metastatic solid tumors, who are not amenable to standard therapy, with exceptions as defined in the non-inclusion criteria,
2. Arm B: Patients must have histologically confirmed diagnosis of recurrent and/or metastatic solid tumors. Patients must be eligible for a treatment with paclitaxel as single agent. Patients who are eligible for standard of care paclitaxel-based combination therapy should not be included in the trial unless they have been previously exposed to that specific combination therapy. Specifically :

   * Patients with ovarian cancer must have received prior therapy with paclitaxel as part of standard of care in combination with carboplatin.
   * Patients with triple negative breast cancer are eligible for the trial since paclitaxel as single agent is standard of care in this disease.
3. Age ≥ 18 years,
4. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 or 1,
5. Patients must have measurable disease (as per RECIST version 1.1),
6. Patient ability to comply with the collection of tumor biopsies, and tumors must be accessible for biopsy,
7. Adequate bone marrow function as defined by: Absolute Neutrophil Count (ANC) of ≥ 1.5 x 109/L, platelet count of ≥ 100 x 109/L, and hemoglobin of ≥ 9 g/dL),
8. Adequate liver function, as determined by a serum total bilirubin ≤ 1.5 Upper Limit of Normal (ULN), AST and ALT ≤ 3 x ULN (≤ 5 x ULN if liver metastases),
9. Adequate renal function, as determined by a serum creatinine ≤ 1.5 x ULN,
10. Provision of signed written informed consent,
11. Patient ability to comply with protocol requirements,
12. If the patient is female:

    * Patient must be postmenopausal, surgically sterile, or they must agree to use a physical barrier method of contraception in addition to either an intrauterine device or hormonal contraception until at least 6 months after termination of study drug or must refrain from heterosexual activity during this same period.
    * Patients of childbearing potential must have a negative pregnancy test within the seven days prior to the first study drug administration.

    If the patient is male:

    \- Patient must abstain from heterosexual activity or must agree to use an acceptable method of contraception (e.g., condom) during the study for at least 6 months after termination of study drug.
13. Patients covered by a health insurance system;

Part 2 Cohort 1 Pancreatic Ductal adenocarcinoma (PDAC)

1. Age ≥ 18 years,
2. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 or 1,
3. Patients must have measurable disease (as per RECIST version 1.1),
4. Patient ability to comply with the collection of tumor biopsies, and tumors must be accessible for biopsy,
5. Adequate bone marrow function as defined by: Absolute Neutrophil Count (ANC) of ≥ 1.5 x 109/L, platelet count of ≥ 100 x 109/L, and hemoglobin of ≥ 9 g/dL),
6. Adequate liver function, as determined by a serum total bilirubin ≤ 1.5 Upper Limit of Normal (ULN), AST and ALT ≤ 3 x ULN (≤ 5 x ULN if liver metastases),
7. Adequate renal function, as determined by a serum creatinine ≤ 1.5 x ULN,
8. Provision of signed written informed consent,
9. Patient ability to comply with protocol requirements,
10. If the patient is female:

    * Patient must be postmenopausal, surgically sterile, or they must agree to use a physical barrier method of contraception in addition to either an intrauterine device or hormonal contraception until at least 6 months after termination of study drug or must refrain from heterosexual activity during this same period.
    * Patients of childbearing potential must have a negative pregnancy test within the seven days prior to the first study drug administration.

    If the patient is male:

    \- Patient must abstain from heterosexual activity or must agree to use an acceptable method of contraception (e.g., condom) during the study for at least 6 months after termination of study drug.
11. Patients covered by a health insurance system
12. Histologically confirmed metastatic pancreatic ductal adenocarcinoma (mixed histology is acceptable as long adenocarcinoma is the dominant histological subtype)
13. Patient should have received at least one previous line of systemic treatment in metastatic setting
14. No previous disease progression under taxane therapy or 12-month free interval since last taxane therapy.

Part 2 Cohort 2 Pancreatic Ductal adenocarcinoma (PDAC) or Ovarian Cancer (OC)

1. Age ≥ 18 years,
2. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 or 1,
3. Patients must have measurable disease (as per RECIST version 1.1),
4. Patient ability to comply with the collection of tumor biopsies, and tumors must be accessible for biopsy,
5. Adequate bone marrow function as defined by: Absolute Neutrophil Count (ANC) of ≥ 1.5 x 109/L, platelet count of ≥ 100 x 109/L, and hemoglobin of ≥ 9 g/dL),
6. Adequate liver function, as determined by a serum total bilirubin ≤ 1.5 Upper Limit of Normal (ULN), AST and ALT ≤ 3 x ULN (≤ 5 x ULN if liver metastases),
7. Adequate renal function, as determined by a serum creatinine ≤ 1.5 x ULN,
8. Provision of signed written informed consent,
9. Patient ability to comply with protocol requirements,
10. If the patient is female:

    * Patient must be postmenopausal, surgically sterile, or they must agree to use a physical barrier method of contraception in addition to either an intrauterine device or hormonal contraception until at least 6 months after termination of study drug or must refrain from heterosexual activity during this same period.
    * Patients of childbearing potential must have a negative pregnancy test within the seven days prior to the first study drug administration.

    If the patient is male:

    \- Patient must abstain from heterosexual activity or must agree to use an acceptable method of contraception (e.g., condom) during the study for at least 6 months after termination of study drug.
11. Patients covered by a health insurance system
12. Patient must be eligible but not previously treatment with gemcitabine.

    Specific Pancreatic Ductal adenocarcinoma (PDAC)
13. Histologically confirmed metastatic pancreatic ductal adenocarcinoma (mixed histology is acceptable as long adenocarcinoma is the dominant histological subtype)

    Specific ovarian cancer (OC)
14. Patient has been diagnosed with recurrent epithelial ovarian, peritoneal, or fallopian tube carcinoma.
15. Subjects had disease recurrence or progression during prior chemotherapy with platinum-based regimens or within 6 months after the last dose of chemotherapy with platinum-based regimens (for at least 4 cycles of treatment)
16. Patient should have received at least one previous line of treatment in platinum-resistant setting.

Non-inclusion criteria: Part 1 Arms A and B, Part 2 Cohorts 1 and 2

1. Arm B and Cohort 1: Allergy or hypersensitivity to paclitaxel or components of the paclitaxel formulation,
2. Cohort 2: Allergy or hypersensitivity to gemcitabine or components of the gemcitabine formulation,
3. Allergy or hypersensitivity to PEP-010 formulation (Trehalose, Tween 20),
4. Patients with known or suspected Central Nervous System (CNS) metastases including leptomeningeal metastasis (except patients with radiographically stable, asymptomatic previously irradiated lesion provided patient is ≥ 3 weeks beyond completing cranial irradiation),
5. Evidence of significant, uncontrolled concomitant diseases, which could affect compliance with the protocol or interpretation of results, including significant cardiovascular disease (such as New York Heart Association Class III or IV cardiac disease, myocardial infarction within the last 6 months, unstable arrhythmias, or unstable angina), or pulmonary disease (including obstructive pulmonary disease and history of symptomatic bronchospasm),
6. Concomitant cancer in the past 3 years except prostate cancer controlled by hormone therapy, cutaneous cancers (except melanoma) and in situ carcinoma,
7. Prior chemotherapy, radiotherapy (other than short cycle of palliative radiotherapy), immunotherapy within 21 days of first receipt of study drug,
8. Prior investigational agent within 28 days of first PEP-010 administration,
9. Hormone therapy within 14 days of first receipt of study drug, with exception of Gonadotropin-Releasing Hormone (GnRH) or Luteinizing-Hormone-Releasing Hormone (LHRH) agonists used for advanced prostate cancer, if indicated,
10. Prior relevant toxicities from chemotherapy or radiotherapy which have not regressed to grade ≤1 severity except alopecia (NCI-CTCAE version 5.0),
11. Patients with acute infection.
12. Any other uncontrolled diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding or any other medical condition that, in the opinion of the investigator, contraindicates the use of an investigational drug, or will impose excessive risk to the patient,
13. Patients with known HIV, HBV and HCV infections,
14. Patients with known active Sars Cov 2 infection
15. Pregnant or lactating women,
16. Patients with altered mental status or psychiatric disorder that, in the opinion of the investigator, would preclude a valid patient informed consent,
17. Person deprived of liberty or under guardianship.