| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Non small cell lung cancer with a Her2 mutation |
|
| E.1.1.1 | Medical condition in easily understood language |
| Lung cancer with HER mutation |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10029519 |
| E.1.2 | Term | Non-small cell lung cancer stage III |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10029522 |
| E.1.2 | Term | Non-small cell lung cancer stage IV |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 23.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10075653 |
| E.1.2 | Term | HER2 gene amplification |
| E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| Evaluate the efficacy of trastuzumab in combination with pertuzumab and docetaxel in patients with HER2 mutated advanced NSCLC |
|
| E.2.2 | Secondary objectives of the trial |
- Confirmed Objective response rate (ORR) at 6 weeks
- Progression-Free Survival (PFS)
- Duration of response
- Overall survival
- Safety
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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 IFCT. 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 (except hematological toxicity).
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 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%
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:
• A non-hormonal 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.
• Two effective forms of non-hormonal 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.
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. |
|
| E.4 | Principal 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 |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| This event could occur at any point during the study. |
|
| E.5.2 | Secondary end point(s) |
- Confirmed Objective Response Rate at 6 weeks (ORR)
- Progression-Free Survival (PFS)
- Duration of response
- Overall survival
- Safety
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
- 6w, confirmed at least after 4w
- Time from enrollment until death due to any cause. For patients who do not die, time to death will be censored at the time of last contact.
- Time from enrollment to first observation of progression (according to RECIST v1.1) or date of death (from any cause). Patients who did not progress or not die will be censored on the date of their last tumor assessment, i.e. on the last date that we really know that the patient was progression free.
- Time from documentation of tumor response to disease progression. Patients who did not progress will be censored on the date of their last tumor assessment, i.e. on the last date that we really know that the patient was progression free.
- Safety will be measured by the incidence, nature, and severity of AEs. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 21 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| One year after the last treatment of the last patient |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
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