| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Non-small cell lung cancer |
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| E.1.1.1 | Medical condition in easily understood language |
| Non-small cell lung cancer |
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| 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 | 10061873 |
| E.1.2 | Term | Non-small cell lung cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 |
| To assess anti tumor activity of three immune experimental strategies (combo with PDL1 inhibitor MEDI4736 - Durvalumab) compared to docetaxel alone, the standard chemotherapy line, in advanced NSCLC patients progressing on standard 2nd to 3rd line PD-1/PD-L1monotherapy treatment. |
|
| E.2.2 | Secondary objectives of the trial |
Secondary objectives of this study are to (better) characterize:
• Safety and tolerability of each arm of treatment
• PharmacoKinetics / PharmacoDynamics parameters of each drug
• Overall Response Rate
• Overall & Progression Free Survival
• Immunogenicity of the injected drugs
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Able and willing to give a signed informed consent which includes compliance with the
requirements and restrictions listed in the informed consent form (ICF) and in this protocol. Written informed consent obtained from the patient prior to performing any protocol-related procedures, including screening evaluations.
2. Age > 18 years.
3. Patients must have histologically confirmed diagnosis of advanced (proven advanced stage) or recurrent NSCLC, (both squamous and non-squamous pathologies are accepted; patients with a mixed NSCLC and SCLC component are ineligible)
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
5. Body weight >35kg
6. Patients with evidence of radiological progression after more than 6 and less
than 18 weeks of a registered second or third line PD1 or PD-L1 inhibitor in monotherapy (to include , Nivolumab, Pembrolizumab, Atezolizumab) Patients who have received immunotherapy in the maintenance setting can only have had one prior regimen containing PD-1/L1 inhibitor. No intervening treatment between the immunotherapy and entry into this study is permitted. Atezolizumab)
7. Patients with known actionable molecular alteration (EGFR activating mutation, ALK
rearrangement, ROS1 rearrangement) should have received a commercially available specific inhibitor
8. As of Week 1 Day 1, subjects with central nervous system (CNS) metastases must have been
treated and must be asymptomatic and meet the following:
a. No concurrent treatment, inclusive of but not limited to surgery, radiation, and/or corticosteroids
b. At least 14 days after CNS treatment, clinically stable with no symptoms of CNS metastasis or sequelae of radiation and at least 14 days since last dose of corticosteroids
NOTE: Subjects with clinical symptoms or cord compression or with leptomeningeal disease are excluded from the study
9. Adequate organ and bone marrow function as defined below:
- Haemoglobin ≥9.0 g/dL(transfusion to achieve this level is not permitted within 2 weeks of first study drug administration)
- Absolute neutrophil count (ANC) 1.5 x (> 1500 per mm3)
- Platelet count ≥100 x 109/L (>100,000 per mm3)
- Serum bilirubin ≤1.5 x institutional upper limit of normal (ULN). This will not apply to patients with confirmed Gilbert’s syndrome , who will be allowed only in consultation with their physician.
- Normal thyroid function, subclinical hypothyroidism (TSH < 10 mIU/mL) or have controlled thyroid disorder
- AST (SGOT) and/ALT (SGPT) ≤2.5 x institutional upper limit of normal with total bilirubin < 1 x ULN unless liver metastases are present, in which case it must be ≤5x ULN, or AST(SGOT) and ALT (SGPT) ≤≤ 1 ULN with total bilirubin > 1 x ULN to ≤ 1.5 ULN
9. 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 amenorrheic 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).
10. Women must not be breastfeeding
11. Women and men of reproductive potential must agree to use highly effective(<1% failure rate)contraception. This applies for the period between signing of the informed consent and 6 months after the last administration of study drug . These procedures should be documented in source documents. The investigator or a designated associate is requested to advise the subject on how to achieve highly effective birth control. Highly effective contraception (<1% failure rate):
- Established use of injected or implanted hormonal methods of contraception
- Placement of certain intrauterine devices (IUD) or intrauterine systems (IUS)
- Hysterectomy, or vasectomy of the partner (provided that partner is the sole sexual partner of the woman of childbearing potential trial participant and that the vasectomized partner has received medical assessment of the surgical success)
In addition, the use of condoms for patients or their partners is required
- Total abstinence
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|
| E.4 | Principal exclusion criteria |
1. Individuals deprived of liberty or placed under the authority of a tutor
2. Patient unable to understand, read and/or sign an informed consent
3. Absence of a measurable target lesion according to RECIST criteria 1.1
4. Any symptomatic or untreated brain metastasis
5. Any previous treatment with Docetaxel
6. Prior randomisation or treatment with durvalumab, Ceralasertib, Savolitinib , Oleclumab, Monalizumab
7. Concurrent enrolment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study
8. Any previous treatment with a PD1 or PD-L1 inhibitor with the following events:
- Must not have experienced a toxicity that led to permanent discontinuation of prior immunotherapy.
- All AEs while receiving prior immunotherapy must have completely resolved or resolved to baseline prior to screening for this study.
- Must not have experienced a ≥Grade 3 immune related AE or an immune related neurologic or ocular AE of any grade while receiving prior immunotherapy. NOTE: Patients with endocrine AE of ≤Grade 2 are permitted to be enrolled if they are stably maintained on appropriate replacement therapy and are asymptomatic.
- Must not have required the use of additional immunosuppression other than corticosteroids for the management of an AE, not have experienced recurrence of an AE if re-challenged, and not currently require maintenance doses of > 10 mg prednisone or equivalent per day
- No intervening treatment between progression on ICI and entry into this study
9. Receipt of the last dose of, immunotherapy, ≤21 days prior to the first dose of study drug the washout is 30 days or 5 half-lives, whichever is longer, Patients are not permitted to have received more than one prior line of immunotherapy
10. The patient can receive a stable dose of bisphosphonates or denosumab for bone
metastases, before and during the study as long as these were started at least 5 days prior to the study treatment. ..
11. Current or prior use of steroids or other immunosuppressive medication within 28 days
before the first dose of durvalumab, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which do not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid. The following are exceptions to this criterion:
- Intranasal, inhaled, topical steroids, eyes drops or local steroid injections (e.g., intra articular injection)
- Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent
- Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication)
12. Any unresolved toxicity NCI CTCAE v5.0 Grade ≥2 from previous anticancer therapy with
the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria
- Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after consultation with the Study Physician.
- Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab or other IMP on study may be included only after consultation with the Study Physician. Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment is not allowed. Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., hormone replacement therapy) is acceptable.
13. Palliative radiotherapy (to a non target lesion) must have been completed at least 7 r
days before Cycle 1 Day 1 (with the exception of patients receiving radiation to more than 30% of the bone marrow or with a wide field of radiation who must have completed treatment within 28 days of the first dose of study treatment).
14. Major surgical procedure within 28 days prior to the first
dose of IP : patients must have recovered from any effects of any major surgery Note: Local surgery and other procedures (radiotherapy) of isolated lesions for palliative intent is acceptable..
15. History of allogenic organ or stem cell transplantation.
16. Active or prior documented autoimmune related inflammatory disorders treated with systemic immunosuppressive drugs within the last 3 months or history of clinically severe auto-immune disease(including inflammatory bowel disease, diverticulitis, systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome) The following are exceptions to this criterion:
- Patients with stable diabetes type 1, resolved childhood asthma/atopy, Sjorgren syndrome, controlled allergic rhinitis are allowed to participate
- 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 3 years may be included but only after consultation with the study physician
- Patients with celiac disease controlled by diet alone
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| the determination of 12-week Disease Control Rate (DCR) assessed in each arm of treatment |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
- the proportion of patients with complete response (CR) or partial response (PR) as best overall response over the treatment period.
- The Progression-free survival |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| 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 | Yes |
| E.8.1.1 | Randomised | Yes |
| 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 | Yes |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| 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 | 3 |
| 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 | Yes |
| 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
|
| A minimum of 12 months since the last dose of study drug administration for the last included patient. of follow-up period is planned, whatever their respective response to either tested combinations is. The study is expected to be completed by the quarter 4 of 2022, at the latest. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 6 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
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