Clinical Trials /

Her2-positive Lung Cancer Treated With Dedicated Drug

NCT03845270

Description:

HER2 (erbB-2/neu) is a member of the erbB receptor tyrosine kinase family. ERBB2 gene which encodes human epidermal growth factor 2 (HER2) is a major proliferative driver activating downstream signaling through PI3K-AKT and MEK-ERK. HER2 overexpression or gene amplification is associated with sensitivity to trastuzumab and lapatinib in breast cancer. Among actual lung cancer biomarker, HER2 remains apart. HER2 involvement is known for a long time but clinical research has been stopped for many years since the first clinical trials in unselected patients were negative. Recently trastuzumab + pertuzumab + docetaxel has been tested for first-line treatment of HER2-positive metastatic breast cancer (CLEOPATRA trial). Analysis of the primary end point showed that patients who received pertuzumab, trastuzumab, and docetaxel (pertuzumab group) had a significantly longer median progression-free survival, as assessed by independent reviewers an did those who received placebo, trastuzumab, and docetaxel (control group) (hazard ratio favoring the pertuzumab group, 0.62). There is thus a strong rational for treating HER2 mutated lung cancer patient with these drugs.

Related Conditions:
  • Non-Small Cell Lung Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Her2-positive Lung Cancer Treated With Dedicated Drug
  • Official Title: Phase II Trial of Trastuzumab in Combination With Pertuzumab in Pretreated Patients With Non-small Cell Lung Cancer (NSCLC) Harboring a Her2 Mutation and Receiving Docetaxel

Clinical Trial IDs

  • ORG STUDY ID: IFCT-1703
  • NCT ID: NCT03845270

Conditions

  • Non Small Cell Lung Cancer Metastatic
  • Non Small Cell Lung Cancer Stage III
  • HER2 Gene Mutation

Interventions

DrugSynonymsArms
pertuzumab + trastuzumab + docetaxelpertuzumab + trastuzumab + docetaxel

Purpose

HER2 (erbB-2/neu) is a member of the erbB receptor tyrosine kinase family. ERBB2 gene which encodes human epidermal growth factor 2 (HER2) is a major proliferative driver activating downstream signaling through PI3K-AKT and MEK-ERK. HER2 overexpression or gene amplification is associated with sensitivity to trastuzumab and lapatinib in breast cancer. Among actual lung cancer biomarker, HER2 remains apart. HER2 involvement is known for a long time but clinical research has been stopped for many years since the first clinical trials in unselected patients were negative. Recently trastuzumab + pertuzumab + docetaxel has been tested for first-line treatment of HER2-positive metastatic breast cancer (CLEOPATRA trial). Analysis of the primary end point showed that patients who received pertuzumab, trastuzumab, and docetaxel (pertuzumab group) had a significantly longer median progression-free survival, as assessed by independent reviewers an did those who received placebo, trastuzumab, and docetaxel (control group) (hazard ratio favoring the pertuzumab group, 0.62). There is thus a strong rational for treating HER2 mutated lung cancer patient with these drugs.

Trial Arms

NameTypeDescriptionInterventions
pertuzumab + trastuzumab + docetaxelExperimentalCycle 1 : D1 : pertuzumab 840 mg, D2 : trastuzumab 8 mg/kg + docetaxel 75 mg/m² Subsequent cycle : D1 : pertuzumab 420 mg + trastuzumab 6 mg/kg + docetaxel 75 mg/m²
  • pertuzumab + trastuzumab + docetaxel

Eligibility Criteria

        Inclusion Criteria:

          1. Patient having signed an informed consent form

          2. Histologically or cytologically confirmed NSCLC (per 2015 8th edition TNM
             classification)

          3. Not suitable for radiation, inoperable stage III or stage IV

          4. HER2 exon 20 mutation or insertion among which: in-frame insertions in exon 20 between
             codons 775 and 881 including the 12bp insertion with a duplication / insertion of 4
             amino acids (YVMA) at codon 775, the 3bp insertion with a complex
             insertion-substitution G776>VC and point mutations L755S and G776C. Other
             mutation/insertion should be discussed with the PI. Analysis must be performed in
             INCa-labelled laboratories or platforms according to a validated procedure.

          5. Prior treatment with at least one regimen of platinum-based chemotherapy with
             documented disease progression.

             Note: taxanes are allowed provided that no grade >2 associated adverse event occurred.

          6. Presence of at least one lesion that can be measured by CT scan (RECIST v1.1)

          7. Age ≥ 18 years

          8. Adequate organ function, as evidenced by the following laboratory results:

             ANC > 1500 cells/mm3 Platelet count > 100,000 cells/mm3 Hemoglobin > 9.0 g/dL Patients
             are allowed to receive transfused RBC to achieve this level. Total bilirubin ≤ 1.5 ×
             ULN, except in patients with previously documented Gilbert's syndrome, in which case
             the direct bilirubin should be less than or equal to the ULN SGOT and SGPT ≤ 2.5 × ULN
             Alkaline phosphatase ≤ 2.5 × ULN, Alkaline phosphatase < 5×ULN and SGOT and SGPT <
             5×ULN for patients with hepatic and/or bone metastases Clearance creatinine ≥ 30
             mL/min INR and aPTT ≤ 1.5 x ULN This applies only to patients who are not receiving
             therapeutic anticoagulation; patients receiving therapeutic anticoagulation should be
             on a stable dose.

          9. WHO performance index of 0, 1 or 2

         10. LVEF ≥ 50% measured by ECHO

         11. Patient who is capable, according to the investigator, of complying with the study's
             requirements and restrictions

         12. Estimated life expectancy > 3 months

         13. A female is eligible to enter and participate in this study if she is of:

             Non-childbearing potential (i.e., physiologically incapable of becoming pregnant),
             including any female who has undergone:

               -  Hysterectomy.

               -  Bilateral oophorectomy (ovariectomy).

               -  Bilateral tubal ligation.

               -  Or who is post-menopausal:

               -  Patients not using hormone replacement therapy (HRT) must have experienced total
                  cessation of menses for ≥1 year and be greater than 45 years in age, OR, in
                  questionable cases, have a follicle stimulating hormone value >40 mIU/mL and an
                  estradiol value <40 pg/mL (<140 pmol/L).

               -  Patients must discontinue HRT prior to study enrolment due to the potential for
                  inhibition of cytochrome enzymes that metabolize estrogens and progestins. For
                  most forms of HRT, at least 2 4 weeks must elapse between the cessation of HRT
                  and determination of menopausal status; length of this interval depends on the
                  type and dosage of HRT. If a female subject is determined not to be
                  post-menopausal, they must use adequate contraception, as defined immediately
                  below.

             Childbearing potential, including any female who has had a negative serum pregnancy
             test within 2 weeks prior to the first dose of study treatment, preferably as close to
             the first dose as possible, and agrees to use adequate contraception during the study
             and for at least 7 months after the last dose of investigational product.
             Contraceptive methods acceptable to IFCT, when used consistently and in accordance
             with both the product label and the instructions of the physician, are as follow:

               -  An intrauterine device with a documented failure rate of less than 1% per year.

               -  Vasectomized partner who is sterile prior to the female subject's entry and is
                  the sole sexual partner for that female.

               -  Complete abstinence from sexual intercourse for 14 days before exposure to
                  investigational product, through the dosing period, and for at least 7 months
                  after the last dose of investigational product.

               -  Double-barrier contraception (condom with spermicidal jelly, foam suppository or
                  film; diaphragm with spermicide; or male condom and diaphragm with spermicide).

             Note: Oral contraceptives are not reliable due to potential drug drug interactions.

         14. Female patients who are lactating should discontinue nursing prior to the first dose
             of study drug and should refrain from nursing throughout the treatment period and for
             15 days following the last dose of study drug.

         15. A male with a female partner of childbearing potential is eligible to enter and
             participate in the study if he uses a barrier method of contraception or abstinence
             during the study and for at least 7 months after the last dose of investigational
             product.

         16. Patient will be eligible for inclusion in this study only if either affiliated to or a
             beneficiary of social security insurance.

        Exclusion Criteria:

          1. History of cancer except cancer dating from over two years ago and considered to be
             cured, appropriately treated carcinoma in situ of the cervix, non-melanoma skin
             carcinoma and stage I uterine cancer.

          2. Any approved anti-cancer therapy ≤ 21 days before enrollment. Note: TKIs approved for
             the treatment of NSCLC must be discontinued ≥ 7 days prior to the first study
             treatment on Cycle 1, Day 1. (The baseline scan must be completed after
             discontinuation of TKIs).

          3. Patients with concomitant EGFR, ALK, ROS1, MET, BRAF and KRAS mutation. Other
             molecular co-alterations should be discussed with IFCT before patient's enrollment.

          4. Previous treatment with an anti-HER2 agent.

          5. Any other investigational therapy ≤ 28 days before inclusion

          6. Previous irradiation <14 days before enrollment.

          7. Brain metastases that are symptomatic, or require any radiation, surgery, or
             corticosteroid therapy to control symptoms from brain metastases within 4 weeks before
             enrollment. Asymptomatic brain metastases with a fixed dose of steroids for at least 2
             weeks are eligible.

          8. Carcinomatous meningitis

          9. History of intolerance (including Grade 3 or 4 infusion reaction) or hypersensitivity
             to trastuzumab, pertuzumab or docetaxel or murine proteins or one of the excipients

         10. Pregnancy and breast-feeding

         11. Any evidence of severe or uncontrolled systemic disease. (E.g. unstable or
             uncompensated respiratory, cardiac, hepatic, or renal disease) or other significant
             clinical disorder or laboratory finding that makes it undesirable for the patient to
             participate in the study.

         12. Evidence of active pneumonitis during screening

         13. Current unstable ventricular arrhythmia requiring treatment, history of symptomatic
             congestive heart failure (CHF; New York Heart Association [NYHA] Classes II−IV) and
             history of myocardial infarction or unstable angina within 6 months before enrollment.

         14. Unresolved toxicity grade > 2 from previous anti-tumor treatments
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Objective Response Rate
Time Frame:6 weeks (confirmation needed at 12 weeks)
Safety Issue:
Description:Percentage of patient with confirmed objective response rate with RECIST 1.1

Secondary Outcome Measures

Measure:Overall Survival
Time Frame:About 24 months
Safety Issue:
Description:Time from enrollment until death due to any cause
Measure:Progression-free survival
Time Frame:About 24 months
Safety Issue:
Description:time from enrollment to first observation of progression (according to RECIST v1.1) or date of death (from any cause)
Measure:Duration of response
Time Frame:About 24 months
Safety Issue:
Description:Time from documentation of tumor response to disease progression.
Measure:Incidence, type and severity of non-serious and serious adverse event
Time Frame:About 24 months
Safety Issue:
Description:

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Intergroupe Francophone de Cancerologie Thoracique

Trial Keywords

  • IFCT
  • NSCLC
  • HER2

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