E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
locally advanced non-small cell lung cancer |
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E.1.1.1 | Medical condition in easily understood language |
lung cancer which is confined to the chest on 1 side and which has not spread to the rest of the body |
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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) |
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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) |
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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 the safety and feasibility of adding ipilimumab-nivolumab to a CRT induction protocol • To assess the efficacy of adding ipilimumab-nivolumab to CRT on the likelihood of a pCR and MPR
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E.2.2 | Secondary objectives of the trial |
• Local and distant recurrence rates, disease free survival (DFS) • Overall survival (OS) at 1 and 2 years
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Histologically confirmed NSCLC, a histological biopsy is mandatory 2. T3-4, N0-1 tumors based on size or upon ingrowth into the thoracic wall, mediastinum, vertebra or diaphragm 3. Patients that are irresectable upfront, but expected to be resectable after chemoradiotherapy induction, as per multidisciplinary tumor board evaluation 4. Be willing and able to provide written informed consent for the trial. 5. Be above 18 years of age on day of signing informed consent. 6. Have measurable disease based on RECIST 1.1. 9. 7. Have a performance status of 0-1 on the ECOG Performance Scale. 8. Demonstrate adequate organ function.
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E.4 | Principal exclusion criteria |
1. Known oncogenic drivers such as activating EGFR or BRAF mutations or ALK or ROS1 gene rearrangements 2. Prior surgery and/or radiotherapy on the ipsilateral thorax 3. Patients deemed inoperable 4. Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of day 0. Inhaled or topical steroids, and adrenal replacement steroid >10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease. 5. Additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy. 6. Active autoimmune disease requiring systemic steroid treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids. 7. Evidence of interstitial lung disease or active, non-infectious pneumonitis. 8. Active infection requiring systemic therapy. 9. Ahistory of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 10. Active Hepatitis B or C. 11. Psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial. 12. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways. 13. Patient is pregnant or breastfeeding, or expecting to conceive within the projected duration of the trial, starting with the pre-screening or screening visit through 23 weeks after the last dose of trial treatment. A Woman of Childbearing Potential (WOCBP) is defined as any female who has experienced menarche and who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) and is not postmenopausal. Menopause is defined as 12 months of amenorrhea in a woman over age 45 years in the absence of other biological or physiological causes. WOCBP receiving nivolumab will be instructed to adhere to contraception for a period of 5 months after the last dose of nivolumab. Men receiving nivolumab and who are sexually active with WOCBP will be instructed to adhere to contraception for a period of 7 months after the last dose of nivolumab. These durations have been calculated using the upper limit of the half-life for nivolumab (~25 days) and are based on the recommendation that WOCBP use contraception for 5 half-lives plus 30 days, and men who are sexually active with WOCBP use contraception for 5 half-lives plus 90 days after the last dose of nivolumab. Females should not breastfeed while receiving nivolumab and for any subsequent protocol-specified period. Investigators shall counsel WOCBP and male subjects who are sexually active with WOCBP on the importance of pregnancy prevention and the implications of an unexpected pregnancy. Investigators shall advise WOCBP and male subjects who are sexually active with WOCBP on the use of highly effective methods of contraception. Highly effective methods of contraception have a failure rate of < 1% when used consistently and correctly. Local laws and regulations may require use of alternative and/or additional contraception methods. One of the highly effective methods of contraception listed below is required during study duration and until the end of relevant systemic exposure, defined as 5 months after the end of study treatment. HIGHLY EFFECTIVE METHODS OF CONTRACEPTION Progestogen-only hormonal contraception associated with inhibition of ovulation (oral, implantable, or injectable) Hormonal methods of contraception including oral contraceptive pills containing a combination of estrogen and progesterone, vaginal ring, injectables, implants, and intrauterine hormone-releasing system (IUS), Bilateral tubal occlusion, Vasectomized partner, NOTE: A vasectomized partner is a highly effective contraception method provided that the partner is the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective method of contraception should be used. Intrauterine devices (IUDs). Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study drug. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle of the participant.It is not necessary to use any other method of contraception when complete abstinence is elected. WOCBP participants who choose complete abstinence must continue to have pregnancy tests, as specified in Section5. Alternate methods of highly effective contraception must be discussed in the event that the WOCBP participants chooses to forego complete abstinence. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Safety defined as (i) the percentage of patients with adverse events (NCI CTCAE), and with each adverse event, the grade and the relationship to ipi/nivo will be assessed, and (ii) complications that lead to delays in administering CRT, or to cancellation of surgery, as well as the rates of post-surgical morbidity. Pathologic complete responses, as well as the percentage of viable tumor in other cases, will be assessed on all the resection specimens. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
during the study and finally after finishing inclusion and follow up of the study |
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E.5.2 | Secondary end point(s) |
Clinical outcome parameters such as time to local or distant recurrence, and OS at 1 and 2 years will be registered. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
during the study and finally after finishing inclusion and follow up of the study |
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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) | Yes |
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
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
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
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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 | 3 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |