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PhI to Solid Tumors and PhII to Locally Advanced or mTNBC

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ClinicalTrials.gov Identifier: NCT05390710
Recruitment Status : Recruiting
First Posted : May 25, 2022
Last Update Posted : May 25, 2022
Sponsor:
Information provided by (Responsible Party):
Laekna Limited

Brief Summary:
PhI Dose Escalation with BOIN design in advanced Solid Tumor with Triple combination therapy to determine MTD and RP2D and Phase II is open label randomized four parallel arms to access anti tumour efficacy in mTNBC

Condition or disease Intervention/treatment Phase
Solid Tumor TNBC - Triple-Negative Breast Cancer Combination Product: LAE005 + Afuresertib + Nab-Paclitaxel Combination Product: LAE005 + Nab-Paclitaxel Combination Product: Afuresertib + Nab-Paclitaxel Drug: Nab-paclitaxel Phase 1 Phase 2

Detailed Description:
Phase I dose escalation for triple combination therapy with BOINcomb design,The safety (including DLT), tolerability, and PK are the study endpoints of phase I and to determine MTD and RP2D. Phase II is a multi-center, randomized, open-label, four parallel arms designed study to assess the anti-cancer efficacy, safety and biomarker correlation to efficacy. The therapies in the four treatment arms are: LAE005 + afuresertib + nab-paclitaxel; LAE005 + nab-paclitaxel; afuresertib + nab-paclitaxel; and nab-paclitaxel monotherapy, respectively. The ORRs based on RECIST 1.1 of four therapies are the primary endpoint, whereas the DOR, PFS, DCR are the secondary endpoints in phase II study.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 101 participants
Allocation: Randomized
Intervention Model: Sequential Assignment
Intervention Model Description: BOIN for Phase I with 1 treatment arm. phase II 4 arms randomized
Masking: None (Open Label)
Masking Description: Open Label for phase I and Phase II
Primary Purpose: Treatment
Official Title: A PhI Dose Escalation Study of LAE005+Afuresertib+Nab_Paclitaxel in Advanced Solid Tumors and PhII Study to Evaluate the Safety and Efficacy of LAE005+Afur+Nab_Paclitaxel or LAE005/Afur+Nab-Paclitaxel in Locally Advanced or mTNBC
Actual Study Start Date : June 12, 2021
Estimated Primary Completion Date : March 30, 2024
Estimated Study Completion Date : July 30, 2024

Resource links provided by the National Library of Medicine

Drug Information available for: Paclitaxel

Arm Intervention/treatment
Active Comparator: Triple combination
LAE005+Afuresertib+Nab-Paclitaxel
Combination Product: LAE005 + Afuresertib + Nab-Paclitaxel
LAE005: 1200 mg IV Q3W, Afuresertib: 125 mg QD, Nab paclitaxel:125 mg/m D1, D8 Q3W

Active Comparator: Double Combination 1
LAE005+Nab-Paclitaxel
Combination Product: LAE005 + Nab-Paclitaxel
LAE005: 1200 mg IV Q3W, Nab paclitaxel:125 mg/m D1, D8 Q3W

Active Comparator: Double Combination 2
Afuresertib+Nab-Paclitaxel
Combination Product: Afuresertib + Nab-Paclitaxel
Afuresertib: 125 mg QD, Nab paclitaxel:125 mg/m D1, D8 Q3W

Placebo Comparator: Control Arm
Nab-Paclitaxel
Drug: Nab-paclitaxel
Nab paclitaxel:125 mg/m D1, D8 Q3W




Primary Outcome Measures :
  1. To evaluate the safety. [ Time Frame: 1year ]
    Frequency and severity of AEs (including incidence rate of DLTs).

  2. recommended Phase II dose (RP2D) of LAE005 and afuresertib and nab-paclitaxel as a combination treatment in patients with advanced solid tumours (including mTNBC) [ Time Frame: 1year ]
    Frequency and severity of AEs (including incidence rate of DLTs).

  3. To evaluate the tolerability. [ Time Frame: 1year ]
    Frequency and severity of AEs (including incidence rate of DLTs).

  4. To determine the maximum tolerated dose (MTD) [ Time Frame: 1year ]
    Frequency and severity of AEs (including incidence rate of DLTs).


Secondary Outcome Measures :
  1. To assess the preliminary anti-tumor activity of LAE005 and afuresertib and nab-paclitaxel [ Time Frame: 1 year ]
    Disease Control Rate (DCR) base on RECIST 1.1;

  2. To characterize the AUC0-t of LAE005 and afuresertib in patients receiving combination treatment of LAE005 and afuresertib and nab-paclitaxel. [ Time Frame: 1 year ]
    Plasma concentrations and PK parameters of LAE005 and afuresertib, AUC0-t of afuresertib following combination treatment, calculated from PK samples obtained at various time points.

  3. To characterize the AUC0-inf of LAE005 and afuresertib in patients receiving combination treatment of LAE005 and afuresertib and nab-paclitaxel. [ Time Frame: 1 year ]
    Plasma concentrations and PK parameters of LAE005 and afuresertib, AUC0-inf of afuresertib following combination treatment, calculated from PK samples obtained at various time points.

  4. To characterize the Tmax of LAE005 and afuresertib in patients receiving combination treatment of LAE005 and afuresertib and nab-paclitaxel. [ Time Frame: 1 year ]
    Plasma concentrations and PK parameters of LAE005 and afuresertib, Tmax of afuresertib following combination treatment, calculated from PK samples obtained at various time points.

  5. To characterize the T1/2 of LAE005 and afuresertib in patients receiving combination treatment of LAE005 and afuresertib and nab-paclitaxel. [ Time Frame: 1 year ]
    Plasma concentrations and PK parameters of LAE005 and afuresertib, T1/2 of afuresertib following combination treatment, calculated from PK samples obtained at various time points.

  6. To assess the preliminary anti-tumor activity of LAE005 and afuresertib and nab-paclitaxel [ Time Frame: 1 year ]
    Best Overall Response Rate (BOR) base on RECIST 1.1;

  7. To assess the preliminary anti-tumor activity of LAE005 and afuresertib and nab-paclitaxel [ Time Frame: 1 year ]
    Duration of Response (DOR) base on RECIST 1.1;

  8. To assess the preliminary anti-tumor activity of LAE005 and afuresertib and nab-paclitaxel [ Time Frame: 1 year ]
    Progression-Free Survival (PFS) base on RECIST 1.1;



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Be ≥18 years of age on the day of signing the informed consent and be able to provide written informed consent for the trial.
  • In Phase I, patients with histologically or cytologically confirmed advanced solid tumors are allowed to be enrolled in this study. mTNBC is a preferred cancer type to be enrolled although all solid tumors are qualified in phase I. In Phase II, patients with histologically or cytologically confirmed unresectable locally advanced or metastatic TNBC characterized by absence of human epidermal growth factor 2 (HER2), estrogen receptor (ER), and progesterone receptor (PR) expression are allowed to be enrolled in this study.
  • In Phase I, patients with advanced solid tumors who have progressed after 0 to 3 lines of available standard of care (i.e. targeted therapy, immunotherapy and/or chemotherapy) are allowed to be enrolled in this study. If anti-cancer drugs have been used, the washout period is 4 weeks or 5 half-lives (whichever is longer). In phase II, mTNBC patients who have not received any systematic anti-cancer therapy or who have progressed after neoadjuvant or adjuvant therapy 1 year ago (more than 1 year ago from the last dose of neoadjuvant or adjuvant therapy to the randomization date) are allowed to be enrolled in this study.
  • In phase I, there is no biomarker test required. In phase II, the biomarker tests will be tested retrospectively. Patient is able to provide tumor biopsy samples and blood samples for PI3K/AKT/PTEN, BRCA gene alterations and PD-L1 expression level. Otherwise, archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion will be accepted for biomarker test. Formalin-fixed, paraffin embedded (FFPE) tumor tissue blocks are preferred to be sectioned on the slides.
  • Have measurable disease per RECIST 1.1 as assessed by local image study, that has not undergone radiotherapy.
  • Patients must have an Eastern Cooperative Oncology Group (ECOG) Performance Score of 0 or 1 in both Phase I and II.
  • Have adequate organ function as defined below. If the specimens are collected within 10 days prior to the start of study treatment, the same tests in Day 1 can be waived to avoid redundancy.
  • Hematological:
  • Absolute neutrophil count (ANC) ≥1500/μL
  • Platelets within the normal range in phase I, and platelet count ≥100,000/µl in phase II
  • Hemoglobin ≥9.0 g/dL or ≥5.6 mmol/L
  • Criteria must be met without erythropoietin dependency and without packed red blood cell (rRBC) transfusion within last 2 weeks.
  • Renal
  • Creatinine ≤1.5 × ULN OR
  • Measured or calculated per institutional standard creatinine clearance (GFR can also be used in place of creatinine or creatinine clearance) ≥30 mL/min for participant with creatinine levels >1.5 × institutional ULN.
  • Hepatic
  • Total bilirubin ≤1.5 ×ULN OR direct bilirubin ≤1.0 ×ULN for participants with total bilirubin levels >1.5 × ULN.
  • AST (SGOT) and ALT (SGPT) ≤2.5 × ULN (≤5 × ULN for participants with liver metastases).
  • Coagulation
  • International normalized ratio (INR) OR prothrombin time (PT)/Activated partial thromboplastin time (aPTT) ≤1.5 × ULN unless participant is receiving anticoagulant therapy, as long as PT or aPTT is within therapeutic range of intended use of anticoagulants.
  • Fasting glucose ≤126 mg/dL or ≤7.0 mmol/L for patients without type 2 diabetes and ≤167 mg/dL or ≤9.3 mmol/L for patients with type 2 diabetes; or glycosylated hemoglobin (HbA1c) ≤8%.
  • Life expectancy of 24 weeks or more based on investigator's assessment.
  • Patients have recovered from adverse events associated with chemotherapy, radiation and surgical operation as pre-treatment to Grade 1 or lower with CTCAE v5.0 excluding stable symptoms (e.g. alopecia, skin hyperpigmentation).
  • Patients must agree to use effective contraception during the study and for at least 90 days after discontinuation as following:
  • Total abstinence (if it is their preferred and usual lifestyle)
  • An intrauterine device (IUD) or hormone-releasing system (IUS)
  • A contraceptive implant
  • An oral contraceptive (with additional barrier method) OR
  • Have a vasectomized partner with confirmed azoospermia
  • Male patients must agree to use an adequate method of contraception from enrollment through 90 days after the last dose of study treatment.
  • Patient is able to swallow and retain oral medication without gastrointestinal diseases to interfere with drug absorption.

Exclusion Criteria:

  • A woman of child-bearing potential (WOCBP), who has a positive urine pregnancy test (e.g. within 72 hours) prior to treatment. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
  • Has received a live vaccine within 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist®) are live attenuated vaccines and are not allowed.
  • Has a history of autoimmune diseases or diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior the first dose of study drug.
  • Has a recent major surgery requiring hospitalization (<3 months from randomization) or use of IV antibiotics for systemic infection (< 2 months from randomization).
  • Has a known additional malignancy that is progressing or has required active treatment within the past 3 years (Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, that have undergone potentially curative therapy are not excluded).
  • History of seizure of condition that may predispose to seizure that needs anti-epileptic medications; brain arteriovenous malformation; or intracranial masses, such as schwannomas and meningiomas that are causing edema or mass effect.
  • Has known active CNS metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable, i.e., without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening), clinically stable and without requirement of steroid treatment for at least 14 days prior to first dose of study treatment.
  • Has severe hypersensitivity (≥Grade 3) to LAE005 or afuresertib and/or any of their excipients.
  • Has an active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed.
  • Has a history of (non-infectious) pneumonitis that required steroids or has concurrent pneumonitis.
  • New York Heart Association congestive heart failure of grade II or above, unstable angina, myocardial infarction within the past 6 months or serious cardiac arrhythmia associated with significant cardiovascular impairment within the past 6 months.
  • Prolongation of corrected QTc interval, as corrected by the Frederica's correction formula to ≥450 msec for males and ≥470 msec for females; unless prolonged QTc interval due to right bundle branch block or left bundle branch block with a pacemaker.
  • Presence of uncontrolled hypertension (systolic blood pressure >160 mmHg or diastolic BP>100 mmHg). Patients with a history of hypertension are allowed, provided that BP is controlled to within these limits by anti-hypertensive treatment.
  • Has a known history of Hepatitis B (defined as HBsAg reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] is detected) and HIV infection.
  • Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating investigator.
  • Has a known psychiatric or substance abuse disorder that would interfere with the participant's ability to cooperate with the requirements of the study.
  • Any medical contraindication to the use of nab-paclitaxel.
  • Patients receiving a strong CYP3CA, OATP, BRCP substrate or inducer. Please see related section for a list of these prohibited medications.
  • Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 90 days after the last dose of study treatment.
  • Has had an allogenic tissue/solid organ transplant.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05390710


Contacts
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Contact: Vivien NA Deng 18616809834 vivien.deng@laeknatp.com
Contact: Lingmin NA Cong 13817756812 lingmin.cong@laeknatp.com

Locations
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China, Anhui
The first affiliated hopsital of bengbu medical college Recruiting
Bengbu, Anhui, China
Contact: Tingjing Yao       13855200468@163.com   
China, Beijing
Cancer Hospital Chinese Academy of Medical Sciences Not yet recruiting
Beijing, Beijing, China
Contact: Professor Binghe XU       xubinghe@csco.org.cn   
Sponsors and Collaborators
Laekna Limited
Investigators
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Principal Investigator: Binghe NA Xu Cancer Institute and Hospital, Chinese Academy of Medical Sciences
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Responsible Party: Laekna Limited
ClinicalTrials.gov Identifier: NCT05390710    
Other Study ID Numbers: LAE203CN2101
First Posted: May 25, 2022    Key Record Dates
Last Update Posted: May 25, 2022
Last Verified: May 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Laekna Limited:
TNBC
Additional relevant MeSH terms:
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Triple Negative Breast Neoplasms
Neoplasms
Breast Neoplasms
Neoplasms by Site
Breast Diseases
Skin Diseases
Paclitaxel
Albumin-Bound Paclitaxel
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action