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

Overview

This is an open-label, non-controlled, multicenter, dose escalation, first-in-human phase I clinical trial with an expansion phase designed to assess the safety, tolerability, PK and PD parameters, and preliminary antitumor activity of intravenous dosing of PEP-010 as single agent and in combination with paclitaxel. PEP-010 will be administered as single agent in patients with solid cancers who are not amenable to standard treatment, or in combination in patients who are eligible for the paclitaxel therapy.

Full Title of Study: “Dose Escalation, First-in-human Clinical Trial to Evaluate the Safety, Pharmacokinetics and Preliminary Antitumor Activity of PEP-010, Administered as Single Agent and in Combination With Paclitaxel in Patients With Metastatic Solid Cancer”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Non-Randomized
    • Intervention Model: Sequential Assignment
    • Primary Purpose: Treatment
    • Masking: None (Open Label)
  • Study Primary Completion Date: August 31, 2023

Detailed Description

PEP-010 will be administered on days 1, 2 and 3 every week. Treatment will be administered until disease progression, unacceptable toxicity, death or withdrawal of consent, whichever occurs first. Each cycle will be of 21 days duration. The initial starting dose of PEP-010, DL1 is selected based on pre-clinical data at 0.15 mg/kg. The other doses per injection from DL2 to DL7 are 0.3, 0.6; 1.2; 2.5; 5 and 10 mg/kg. For patients in Arm B, PEP-010 will be combined with Paclitaxel, at a dose of 80 mg/m², weekly until disease progression or unacceptable toxicity. Paclitaxel will be administered according to local guidelines. Main objective for Dose escalation cohorts is to determine the maximum tolerated dose (MTD) and the recommended phase 2 dose (RP2D) of PEP-010 when administered as single agent (MTD1/RP2D1), and in combination with paclitaxel (MTD2/RP2D2) by recording the dose-limiting toxicities (DLTs). Main objective for Expansion cohorts is to confirm the RP2Ds of PEP-010 as a single agent and/or in combination in patients with metastatic and/or recurrent cancer. Secondary objectives are – To evaluate the safety and tolerability of PEP-010 when administered as single agent, and in combination with paclitaxel. – To assess the pharmacokinetics (PK) of PEP-010 as single agent, and in combination with paclitaxel in Dose escalation cohorts. – To assess the pharmacodynamic (PD) effects of PEP-010 as single agent, and in combination with paclitaxel. – To evaluate the preliminary antitumor activity of PEP-010 alone and in combination with paclitaxel, using Objective Response Rate (ORR), Progression-Free Survival (PFS) according to RECIST1.1, duration of response, and Overall Survival (OS). – To assess the immunogenicity of PEP-010 as single agent, and in combination with paclitaxel in Dose escalation cohorts.

Interventions

  • Combination Product: Dose escalation, first-in-human phase I clinical trial with an Expansion phase
    • PEP-010 will be administered on days 1, 2 and 3 every week, as a 3-hour intravenous infusion. Treatment will be administered until disease progression, unacceptable toxicity, death or withdrawal of consent, whichever occurs first. Each cycle will be of 21 days duration.

Arms, Groups and Cohorts

  • Experimental: Arm A: PEP010 as single agent
    • In arm A, the dose escalation phase will use accelerated titration design (ATD) for the first 4 dose levels (0.15, 0.3, 0.6, 1.2 mg/kg), followed by 3+3 design
  • Experimental: Arm B: PEP010 in combination with paclitaxel.
    • In arm B, the dose escalation phase will begin with DL4 (1.2 mg/kg) and will follow a 3+3 design

Clinical Trial Outcome Measures

Primary Measures

  • Rate of occurrence of dose-limiting toxicities (DLT) within cycle 1 (21 days) after initiation of the study treatment for both parts.
    • Time Frame: 21 days after study treatment initiation
    • The DLT is defined as any clinically significant non-hematological toxicity ≥ grade 3 and any hematological toxicity ≥ grade 4 of treatment-related adverse event

Participating in This Clinical Trial

Inclusion Criteria

Part I and II, 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 noninclusion 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, Specific Part II: 14. Triple negative breast cancer and/or ovary cancer for the two first expansion cohorts 15. Whatever lines of treatment with a previous treatment of taxane family Exclusion Criteria:

1. Arm B: Allergy or hypersensitivity to components of the paclitaxel formulation, 2. Allergy or hypersensitivity to PEP-010 formulation (Trehalose, Tween 20) 3. Patients with known or suspected Central Nervous System (CNS) metastases including leptomenigeal metastasis (except patient with radiographically stable, asymptomatic previously irradiated lesion provided patient is ≥ 4 weeks beyond completing cranial irradiation and ≥ 3 weeks of corticosteroids therapy), 4. 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), 5. Concomitant cancer in the past 3 years except prostate cancer controlled by hormone therapy, cutaneous cancers (except melanoma) and in situ carcinoma, 6. Prior chemotherapy, radiotherapy (other than short cycle of palliative radiotherapy), immunotherapy within 21 days of first receipt of study drug, 7. Prior investigational agent within 30 days of first PEP-010 administration, 8. 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, 9. Prior relevant toxicities from chemotherapy or radiotherapy which have not regressed to grade ≤1 severity except alopecia (NCI-CTCAE version 5.0), 10. Patients with acute infection. 11. 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, 12. Patients with known HIV, HBV and HCV infections, 13. Patient with a positive screening test for Sars-Cov-2 14. Pregnant or lactating women, 15. Patients with altered mental status or psychiatric disorder that, in the opinion of the investigator, would preclude a valid patient informed consent, 16. Person deprived of liberty or under guardianship.

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Institut Curie
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Christophe LE TOURNEAU, MD, PhD, Principal Investigator, Institut Curie
  • Overall Contact(s)
    • Anne-Claire COYNE, PhD, 00 33 1 56 24 32 40, drci.promotion@curie.fr

References

1.Ezzalfani M. et al. The role of the expansion cohort in phase I trials in oncology: guidelines of the phase I HUB. Bull Cancer. 2015 Jan;102(1):73-82. doi:10.1016/j.bulcan. 2014.10.001. Epub 2015 Jan 2. Review. French. 2.M3(R2) guideline : Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals 3.ICH S9 – Nonclinical Evaluation for Anticancer Pharmaceuticals EMEA/CHMP/ICH/646107/2008 4.Masini et al. Histamin-releasing properties of polysorbate 80 in vitro and in vivo: correlation 1254 with its hypotensive action in the dog. Agents Actions 1985 Sep; 16(6):470-7. 5.Guideline on repeated dose toxicity – CPMP/SWP/1042/99 Rev 1 6.Storer B.E. Design and Analysis of Phase I Clinical Trials. Biometrics, Vol. 45, No. 3 (Sep., 1989), pp. 925-937. 7.Seshan V.E. et al. Clinical Trial Design and Data Analysis Functions, Package clinfun, version 1.0.15 (Apr 2018)

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