Advanced Lung Tumor Treated by Osimertinib Plus Anlotinib

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Brief Title

Advanced Lung Tumor Treated by Osimertinib Plus Anlotinib

Official Title

Safety and Efficacy of Osimertinib Combined With Anlotinib in EGFRm+, Treatment-naïve IIIb/IV NSCLC Patients: a Prospective, Single Arm, Phase Ib/IIa Study

Brief Summary

      This is a prospective, single arm, phase Ib/IIa study. Up to 25 patients will be enrolled
      into the study (Part A: 2-18; Part B: 7-19). The study has been designed to allow an
      investigation of the optimal combination dose and schedule whilst of Osimertinib plus
      Anlotinib in patients with EGFRm+, treatment-naïve IIIb/IV Non-Small Cell Lung Cancer (NSCLC)
      ensuring the safety of patients with intensive safety monitoring. There are two main parts to
      this study; Part A, Combination dose finding and Parts B, Dose expansion.
    

Detailed Description

      Part A has been designed to identify the recommended dose of the combination of Osimertinib
      plus Anlotinib for further clinical evaluation based upon assessment of the safety and
      tolerability data collected during the first 21 days (cycle 1, 21 days per cycle). A cycle of
      study treatment will be defined as 21 days. Dosing will begin at Osimertinib 80mg QD
      continuously and Anlotinib 8mg QD from day1 to 14 of a 21-day cycle. In the first 6 patients,
      a delay of at least 21 days (the first group of 3 patients) and a delay of at least 7 days
      (the second group of 3 patients) will be mandatory between the administration of the first
      dose to the first patient and administration of first dose to subsequent patients. Patients
      will be enrolled to ensure a minimum of 3 and a maximum of 6 evaluable patients per cohort.
      Dose escalation and de-escalation will follow the scheme below, according to the following
      logic:If no dose-limiting toxicity (DLT) is observed (for definition see Section 4.1.3) in a
      cohort of 3 evaluable patients then dose escalation may occur. Dose increases will be
      permitted after review of data from a minimum of 3 evaluable patients has been performed.

        -  If one patient experiences a DLT in a group of 3 evaluable patients then the cohort will
           be expanded to include 6 evaluable patients. If only one DLT is observed in the complete
           cohort of 6 evaluable patients then dose escalation may occur.

        -  If 2 or more patients experience a DLT in a group of up to 6 patients, irrespective of
           the number of patients enrolled, the dose will be considered not tolerated and
           recruitment to the cohort and dose escalation will cease.

      Safety will be intensively monitored in part A. If RP2D was not reached in Part A, Part B
      would not be initiated. If RP2D was reached in Part A, eligible patients in part B will be
      enrolled and receive Osimertinib (80mg QD, continuously) plus Anlotinib (RP2D, QD from day 1
      to 14 of a 21-day cycle) till disease progression (PD) or unacceptable toxicity, with the aim
      to further evaluate the safety, tolerability and efficacy in terms of ORR, DCR, DOR, PFS,
      overall survival at 12 months.

      For all eligible patients (Part A and Part B), tissue and/or blood samples at baseline and PD
      will be collected to understand the resistance profile.
    

Study Phase

Phase 1/Phase 2

Study Type

Interventional


Primary Outcome

Recommended Phase II Dose(RP2D)

Secondary Outcome

 Dose-limiting toxicity (DLT)

Condition

Non-Small Cell Lung Cancer With EGFR Mutation

Intervention

Osimertinib

Study Arms / Comparison Groups

 Osimertinib + Anlotiib
Description:  Escalating doses and expanding doses of Anlotinib administered with Osimertinib

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

25

Start Date

November 19, 2020

Completion Date

November 30, 2025

Primary Completion Date

November 30, 2022

Eligibility Criteria

        Inclusion Criteria:

          -  For inclusion in the study subjects should fulfil the following criteria:

               1. Provision of informed consent prior to any study specific procedures.

               2. Aged at least 18 years.

               3. Histologically or cytologically confirmed locally advanced/metastasis NSCLC,
                  adenocarcinoma of the lung (AJCC Eighth Edition TNM Stage ⅢB to stage Ⅳ), not
                  amenable to curative surgery or radiotherapy.

               4. WHO/Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0-1 with no
                  deterioration over the previous 2 weeks and a minimum life expectation of at
                  least 12 weeks.

               5. The tumour harbours one of the most common EGFR mutations known to be associated
                  with EGFR-TKI sensitivity (exon 19 deletion; L858R) either alone or in
                  combination with other EGFR mutations as confirmed by a local test.

               6. No prior systemic anti-cancer, EGFR-TKI, or immunotherapy therapy for their
                  locally advanced or metastasis disease (biopsy will be at time of diagnosis of
                  locally advanced/metastasis disease).

               7. At least one lesion is measurable based on Response Evaluation Criteria in Solid
                  Tumours (RECIST 1.1).

               8. Adequate bone marrow reserve and organ function as follows:

          -  Absolute neutrophils count (ANC) ≥1.5x109/L (band neutrophil and segmented
             neutrophil), platelets >100x109/L and Hb ≥90g/L.

          -  Hepatic: total bilirubin ≤1.5 times upper limit of normal (ULN).

          -  Alkaline phosphatase, alanine transaminase (ALT) and aspartate transaminase (AST)≤3.0
             ULN (or ≤5 ULN in case of known liver involvement).

          -  Renal: Serum Creatinine ≤1.5ULN, creatinine clearance (CCr) ≥50mL/min 9. Female
             patients of childbearing potential must be using adequate contraceptive measures (see
             Restrictions, Section3.5), must not be breast feeding, and must have a negative
             pregnancy test prior of study treatments and confirmed prior to start of dosing on day
             1. Otherwise, they must have evidence of non-childbearing potential as defined below:

          -  Post-menopausal defined as aged more than 50 years and amenorrheic for at least 12
             months following cessation of all exogenous hormonal treatments

          -  Women under 50 years would be consider post-menopausal if they have been amenorrheic
             for 12 months or more following cessation of exogenous hormonal treatments and with
             luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal
             range for the institution

          -  Documentation of irreversible surgical sterilisation by hysterectomy, bilateral
             oophorectomy or bilateral salpingectomy but not tubal ligation 10. Male patients must
             be willing to use barrier contraception, i.e., condoms (see Restrictions, Section 3.5)
             11. Optional provision of an unstained, archived tumour tissue samples or fresh tissue
             and/or blood in a quantity sufficient to allow for central NGS testing (FFPE slices or
             fresh tumor tissue or blood at sufficient amount for NGS analysis).

        Exclusion Criteria:

        - Subjects must not enter the study if any of the following exclusion criteria are
        fulfilled:

          1. Patients with non-lung adenocarcinoma including lung squamous carcinoma, or mixed
             histology, etc.

          2. Treatment with any of the following:

               -  Major surgery (excluding placement of vascular access) within 4 weeks of the
                  first dose of study drug.

               -  Patients currently receiving (or unable to stop use prior to receiving the first
                  dose of study drug) medications or herbal supplements known to be potent inducers
                  of CYP3A4 (at least 3-week prior) (Appendix B). All patients must try to avoid
                  concomitant use of any medications, herbal supplements and/or ingestion of foods
                  with known inducer effects on CYP3A4.

               -  Treatment with an investigational drug within five half-lives of the compound or
                  3 months, whichever is greater.

          3. Any concurrent and/or other active malignancy that has required treatment within 5
             years of first dose of study drug.

          4. Any unresolved toxicities from prior systemic therapy (e.g., adjuvant chemotherapy)
             greater than CTCAE grade 1 at the time of starting study drug with the exception of
             alopecia and grade 2, prior chemotherapy-induced neuropathy.

          5. Spinal cord compression, symptomatic and unstable brain metastases, except for those
             patients who have completed definitive therapy, and have had a stable neurological
             status for at least 2 weeks after completion of definitive therapy. Patients may be on
             corticosteroids to control brain metastases if they have been on a stable dose for 2
             weeks (14 days) prior to the start of study treatment and are clinically asymptomatic.

          6. Any evidence of severe or uncontrolled systemic diseases, including uncontrolled
             hypertension and active bleeding diatheses, which in the investigator's opinion makes
             it undesirable for the patient to participate in the trial or which would jeopardise
             compliance with the protocol, or active infection including hepatitis B, hepatitis C
             and human immunodeficiency virus (HIV). Screening for chronic conditions is not
             required.

          7. Recent active digestive disease such as duodenal ulcers, ulcerative colitis, ileus,
             ect., intestinal perforation, intestine fistula, or other conditions may lead to
             gastrointestinal bleeding or perforation which regimented at investigators'
             discretion.

          8. Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to
             swallow the formulated product, or previous significant bowel resection that would
             preclude adequate absorption of Osimertinib and Anlotinib.

          9. Cardiac function evaluation: LVEF <50%, a recent history of MI in 6 months,
             severe/unstable angina or coronary bypass surgery, or cardiac insufficiency ≥ NYHA 2.
             Any of the following cardiac criteria:

               -  Mean resting corrected QT interval (QTc) >470 msec.

               -  Any clinically important abnormalities in rhythm, conduction, or morphology of
                  resting ECG, e.g., complete left bundle branch block, third-degree heart block,
                  second-degree heart block, interval >250 msec.

               -  Any factors that increase the risk of QTc prolongation or risk of arrhythmic
                  events such as heart failure, electrolyte abnormalities (including: Serum/plasma
                  potassium < LLN; Serum/plasma magnesium < LLN; Serum/plasma calcium < LLN),
                  congenital long QT syndrome, family history of long QT syndrome, or unexplained
                  sudden death under 40 years of age in first-degree relatives or any concomitant
                  medication known to prolong the QT interval and cause Torsades de Pointes.

               -  Past medical history of ILD, drug-induced ILD, radiation pneumonitis which
                  require steroid treatment, or any evidence of clinically active ILD.

               -  Previous allogenic bone marrow transplant.

               -  Pregnant or lactating woman who are breast feeding.

               -  A history of organ transplantation and long-term immunosuppressive medication.

               -  History of hypersensitivity to active or inactive of Osimertinib or Anlotinib or
                  drugs with a similar chemical structure or class to osimertinib or Anlotinib.

         10. Judgment by the Investigator that the patients should not participate in the study if
             the patient is unlikely to comply with study procedures, restrictions, and
             requirements.; or other conditions regimented at investigators' discretion.
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

, 13817833343, [email protected]

Location Countries

China

Location Countries

China

Administrative Informations


NCT ID

NCT04770688

Organization ID

ESR-18-13979


Responsible Party

Principal Investigator

Study Sponsor

Shanghai Chest Hospital


Study Sponsor

, , 


Verification Date

February 2021