| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patient with a non small cell lung cancer and a poor general status |
|
| E.1.1.1 | Medical condition in easily understood language |
| Lung cancer in patient with a poor general condition |
|
| 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 | 20.0 |
| 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 | 20.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10057364 |
| E.1.2 | Term | Reduced general condition |
| E.1.2 | System Organ Class | 100000004867 |
|
| 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 |
SAVIMMUNE IFCT-1802 phase 2 trial aims to study the safety and efficacy of a first-line therapy with anti-PD-L1 monoclonal DURVALUMAB antibody, in a subset of patient with PS 2-3, but highly PD-L1 expressing tumors, who are usually excluded from clinical trials, and for whom, thus, there is no recognized indication for immunotherapy.
The hypothesis of this trial is that in such selected patients, tolerance of durvalumab would be acceptable, while its efficacy would rapidly improve general condition, resulting in significantly long survivals. |
|
| E.2.2 | Secondary objectives of the trial |
1) Safety and tolerance will be performrom the date of durvaled in all treated patients.
2) Disease Control Rate at 8 weeks (percentage of patients with objective response or stable disease according to RECISTS 1.1 in the intent to treat population).
3) Objective Response Rate at 8 weeks
4) PFS
5) OS
6) Performans status improvement rate
7) Quality of Life
8) Centrally-assessed PD-L1 tumor expression |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Subjects must have signed and dated an IRB/IEC approved written informed consent form in accordance with regulatory and institutional guidelines. This must be obtained before the performance of any protocol related procedures that are not part of normal subject care.
Subjects must be willing and able to comply with scheduled visits, treatment schedule, and laboratory testing.
2. Histologically or cytologically-proven NSCLC (squamous or non-squamous).
If the diagnosis is cytologically-proven, sufficient material is necessary with at least 100 tumor cells evaluated for PD-L1 IHC.
3. PD-L1 expression ≥25% of tumor cells as assessed by the local pathology laboratory using protocols validated.
4. Available tumor samples for centralized PD-L1 immunohistochemistry analysis.
5. No EGFR mutation and no ALK gene rearrangement.
6. Stage IV (8th classification TNM) M1a or M1b or M1c with 3 or lower of metastatic organ sites on PET-CT. Multiple lesions in a single organ are considered as one metastatic organ site. Any positive distant (non regional) lymph nodes were counted collectively as one metastatic organ site.
7. ECOG PS= 2 (in the first step) or 3 (in the second step) despite optimal symptomatic treatment.
8. Body weight >30kg
9. No prior systemic anticancer therapy (chemotherapy, immunotherapy including durvalumab, or EGFR or ALK inhibitors) given as primary therapy for advanced or metastatic disease. Neoadjuvant or adjuvant chemotherapy is not considered as chemotherapy for advanced or metastatic disease.
10. Limited field of radiation for palliation within 2 weeks of the first dose of durvalumab is allowed, provided the lung is not in the radiation field and irradiated lesion(s) cannot be used as target lesions.
11. Age 18-70 years.
12. Measurable tumor disease by CT per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.
13. Life expectancy > 8 weeks according to the investigator opinion.
14. Adequate biological functions:
neutrophils ≥ 1500/mm3 ; platelets ≥ 75 000/mm3 ; Hemoglobin ≥ 9 g/dL ;
Creatinine Clearance > 40 mL/min , AST and ALT ≤ 2,5 ULN unless liver metastases are present, AST and ALT ≤ 5 x ULN, serum bilirubine ≤ 1.5 x ULN except for patients with proved, Gilbert syndrome (≤ 5 x ULN) or patients with hepatic metastases (≤ 3 x ULN).
15. Other investigations detailed in Section 5 must have been performed within the timelines indicated.
16. Protocol treatment is to begin within 7 days of patient inclusion.
17. Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre-menopausal patients. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply:
- Women <50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy).
- Women ≥50 years of age would be considered post-menopausal if they have been aamenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses >1 year ago, had chemotherapy-induced menopause with last menses >1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy).
18. Females of childbearing potential who are sexually active with a nonsterilized male partner or men who are sexually active with women of childbearing potential must use a highly effective method of contraception prior the first dose of investigational product, and must agree to continue using such precautions for 90 days after the final dose of investigational product. Periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods of contraception. |
|
| E.4 | Principal exclusion criteria |
1. Pure or combined SCLC.
2. Known HER2, B-Raf, activating tumor mutations, or exon 14 c-MET splice mutations, or known ROS1 gene rearrangement.
3. Asymptomatic or symptomatic brain metastasis.
4. Carcinomatous meningitis.
5. Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g., colitis or Crohn's disease], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc]). The following are exceptions to this criterion:
- Patients with vitiligo or alopecia
- Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement
- Any chronic skin condition that does not require systemic therapy
- Patients without active disease in the last 5 years may be included but only after consultation with IFCT
- Patients with celiac disease controlled by diet alone
6. Immunosuppressive treatment including systemic treatment with corticosteroids with greater dose than 10 mg prednisone equivalent daily, within 15 days before enrollment. Inhaled, nasal or topic corticosteroids are allowed.
7. History of allogenic organ transplantation.
8. Stage 4 (very severe, FEV1<30% predicted) chronic obstructive pulmonary disease (COPD) according to GOLD classification.
9. NYHA (New York Heart Association) class 4 chronic heart failure
10. Pre-existing interstitial lung.
11. History of another primary malignancy except for :
• Malignancy treated with curative intent and with no known active disease ≥2 years before the first dose of IP and of low potential risk for recurrence
• Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
• Adequately treated carcinoma in situ without evidence of residual disease
Patients with a prostate adenocarcinoma history within the previous 5 years could be included in case of localized prostate cancer.
12. Living attenuated vaccine received within the 30 previous days.
13. Received any other experimental treatment or participation to any other therapeutic clinical trial.
14. Known allergy or hypersensitivity to any of the study drug or any of the study drug excipients.
15. Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., hormone replacement therapy) is acceptable.
16. Major surgical procedure within 28 days prior to the first dose of IP or planned surgical procedure during treatment.
17. Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent.
18. Active infection including tuberculosis, hepatitis B (known positive HBV surface antigen (HBsAg) result) and hepatitis C,. Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA. History of active tuberculosis or evident primo-infection for which there is no record or evidence of an active anti-tuberculous treatment (please consult IFCT in case of doubt).
19. Patient with human immunodeficiency vurys (positive HIV ½ antibodies)
20. Any condition that, in the opinion of investigator, could compromise the adherence to treatment and follow-up.
21. Mental illness or psychological condition, which in the opinion of investigator could compromise the expression of the informed consent.
22. No public health insurance. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Percentage of patients experiencing Grade 3-5 TRAEs |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
1) Safety and tolerance will be performed in all treated patients.
2) Disease Control Rate at 8 weeks (percentage of patients with objective response or stable disease according to RECISTS 1.1 in the intent to treat population).
3) Objective Response Rate at 8 weeks according to RECIST 1.1 in the intent to treat population.
4) PFS from the date of durvalumab initiation to progression date or death; PFS curves, PFS medians with 95% CIs, and PFS rates at 6 and 12 months with 95% CIs will be estimated using Kaplan-Meier methodology.
5) OS from the date of durvalumab initiation to the date of death. OS curves, OFS medians with 95% CIs, and OFS rates at 6 and 12 months with 95% CIs will be estimated using Kaplan-Meier methodology.
6) Performans status improvement rate, defined as the proportion of per-protocol patients whose PS was improved from baseline during durvalumab treatment.
7) Quality of Life will be evaluated using EORTC QLQ-C30/QLQ-LC13 and EQ-5D questionnaires. The questionnaires will be filled out by patients, in each center, before any medical visit with an investigator. All analyses will be performed according to the modified intention-to-treat principle (an ITT population with at least one available baseline HRQoL questionnaire).
The time until definitive HRQoL score deterioration (TUDD) of a QoL score is defined as the interval between randomization and the date at which a deterioration ≥5 points compared to the baseline HRQoL score is observed, with no further improvement in HRQoL score ⩾5 points, or if a patient dropped out after this decrease, resulting in missing data. The TUDD curves will be calculated using the Kaplan–Meier estimation.
8) Centrally-assessed PD-L1 tumor expression: prognostic and predictive value using SP263 antibodies on a Ventana centralized IFCT immunohistochemistery platform using protocols for Ventana platform validated by the prospective French study (Adam et al. Annal Oncol 2018). Tumours will be classified according to two PD-L1 expression classes: 25%-49% and 50%-100%, according to a consensus obtained by two pathologists. In case of discordance, slides will be read at the same microscope (IFCT multi-head microscope) with a third pathologist and a consensus will be defined. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1) Approximately 1 year
2) At 8 weeks.
3) At 8 weeks
4) PFS from the date of durvalumab initiation to progression date or death
5) OS from the date of durvalumab initiation to the date of death.
6) Approximately 1 year
7) Approximately 1 year
8) Approximately 1 year |
|
| 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 | 20 |
| 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
|
| The end of trial is defined as 100 days after the last treatment with durvalumab. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 39 |
| E.8.9.1 | In the Member State concerned days | |
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