| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Adult patients with metastatic and/or unresectable Non-Small Cell Lung Cancer (NSCLC) who progressed on at least one line and not more than three lines of prior therapy for metastatic/unresectable NSCLC |
|
| E.1.1.1 | Medical condition in easily understood language |
| Patients with metastatic and / or unresectable non-small cell lung cancer who have progressed on at least 1 line and no more than 3 lines of previous treatment |
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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.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The main objective is to evaluate the overall anti-tumor activity of DS-1062a, as measured by objective response rate (ORR) based on investigator assessment, in patients with metastatic /unresectable NSCLC who have progressed on previous standard therapies for NSCLC. |
|
| E.2.2 | Secondary objectives of the trial |
a.To evaluate the efficacy of DS-1062a in terms of:
•Duration of response (DoR) based on investigator assessment.
•Progression Free Survival (PFS) based on investigator assessment.
•Clinical benefit rate (CBR).
•Overall survival (OS).
b. To evaluate the safety and tolerability of DS-1062a, in terms of:
•Frequency and severity of all adverse events (AEs), treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), and adverse events of special interest (AESIs), defined by the NCI-CTCAE v5.0.
•Treatment discontinuation, interruptions, and dose reductions due to any AEs.
•Frequency and severity of laboratory abnormalities defined by NCI-CTCAE v5.0.
•ECG abnormalities (including QT/QTc interval data) and Left Ventricular Ejection Fraction (LVEF) decrease (measured by echocardiography (ECHO) or multigated acquisition (MUGA) scan defined by New York Heart Association (NYHA) functional classification.
•ECOG performance status changes.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Age ≥18 years.
2. Patients with histologically confirmed diagnosis of advanced and/or unresectable NSCLC.
3. At least one line and not more than three lines of therapy and considered by the investigator as refractory to or progressed on standard treatment or for which no standard treatment is available:
a. For patients who have no known mutation or mutation without an approved targeted therapy, must have received an anti PD-1/PD-L1 containing therapy and a platinum-doublet regimen.
b. For patients who have known EGFR, BRAF, and MET mutation or ALK, ROS1, RET, NTRK fusion (if available): they must have progressed after one line of an approved targeted agent and one platinum-doublet regimen.
4. Patients must have metastatic site easily accessible to biopsy (with exception of bone metastasis) and must have accepted to perform pre-treatment, on-treatment and end-of-treatment biopsies.
5. Presence of at least one measurable lesion (different from the biopsy site) according to RECIST v1.1.
6. Patients must have an ECOG performance status ≤1 at the time of screening.
7. Patients must have a life expectancy of ≥ three months.
8. Has adequate bone marrow reserve and organ function, based on local laboratory data within 14 days prior to Cycle 1, Day 1 defined as in the table in the protocol.
9. Patients with asymptomatic and clinically stable treated brain metastasis, who require no treatment with corticosteroids and/or anticonvulsants, and if they have recovered from the acute toxic effect of radiotherapy.
10. Females of reproductive/childbearing potential must have a negative serum pregnancy test at screening and must agree to use a highly effective form of contraception or avoid intercourse during and upon completion of the study and for at least 7 months for females after the last dose of study drug. Methods considered as highly effective methods of contraception include:
a. Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation:
• Oral
• Intravaginal
• Transdermal
b. Progestogen-only hormonal contraception associated with inhibition of ovulation:
• Oral
• Injectable
• Implantable
c. Intrauterine device (IUD)
d. Intrauterine hormone-releasing system (IUS)
e. Bilateral tubal occlusion
f. Vasectomized partner
g. Complete sexual abstinence defined as refraining from heterosexual intercourse during and upon completion of the study and for at least 7 months for females after the last dose of study drug. Periodic abstinence (calendar, symptothermal, post-ovulation methods) is not an acceptable method of contraception.
Female patients must not donate, or retrieve for their own use, ova from the time of screening and throughout the study treatment period, and for at least 7 months after the final study drug administration.
Male patients must be surgically sterile or must withhold heterosexual intercourse or must be willing to use a highly effective birth control upon enrollment, during the treatment period, and for at least 4 months following the last dose of study drug.
Male patients must not freeze or donate sperm starting at screening and throughout the study period, and at least 4 months after the final study drug administration.
11. Patients must understand, sign and date the written informed consent from prior to any protocol-specific procedures performed. Patients should be able and willing to comply with study visits and procedures as per protocol.
12. Patients must be affiliated to a Social Security System or beneficiary of the same.
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|
| E.4 | Principal exclusion criteria |
1.Patient unwilling to participate to the biological investigations (...) as required in the protocol.
2.Patient with only bone metastasis will be excluded, except if they have an accessible primary tumor which could be biopsied at baseline, on-treatment and end-of-treatment.
3.Patient with any history of ILD (...), has current ILD, or is suspected to have such disease by imaging during screening.
4.Patient with clinically severe pulmonary compromise resulting from intercurrent pulmonary illnesses including, but not limited to: any underlying pulmonary disorder (...)/any autoimmune, connective tissue or inflammatory disorder with pulmonary involvement (...)/OR prior pneumonectomy;
5.Patient receiving chronic systemic corticosteroids dosed at >10 mg prednisone or equivalent or any form of immunosuppressive therapy prior to Cycle 1 Day 1. Patients who require use of bronchodilators, inhaled steroids, or local steroid injections may be included in the study.
6.Patient with evidence of any leptomeningeal disease.
7.Patient with evidence of clinically active spinal cord compression or brain metastases, (...), or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms. (...). Patients must have a stable neurologic status for at least two weeks prior to Cycle 1 Day 1.
8.History of severe hypersensitivity reactions to either the drug substances or inactive ingredients (...) of DS-1062a.
9.History of severe hypersensitivity reactions to other monoclonal antibodies.
10.Inadequate washout period prior to Cycle 1 Day 1, defined as: Whole brain radiation therapy <14 days or stereotactic brain radiation therapy <7 days/Any cytotoxic chemotherapy, investigational agents or other anticancer drug(s) from a previous cancer treatment regimen or clinical study (other than EGFR TKI), <14 days or 5 half-lives, whichever is longer/Immune checkpoint inhibitor therapy <21 days/Major surgery (excluding placement of vascular access) < 28 days.Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation <28 days or palliative radiation therapy <14 days/Chloroquine or hydroxychloroquine ≤14 days/Live virus vaccination <28 days ;
11.Prior treatment with an anti-TROP-2 antibody including study drug.
12.Patient previously treated with an ADC containing a chemotherapeutic agent targeting topoisomerase I inhibitor.
13.Patient with unresolved toxicities from previous anticancer therapy, defined as toxicities (...) not yet resolved according to the NCI-CTCAE v5.0, grade ≤2 or baseline.
14.Any evidence of primary malignancy other than locally advanced or metastatic lung cancer within three years prior to Cycle 1 Day 1, except adequately resected non-melanoma skin cancer, curatively treated in-situ disease, or other solid tumors curatively treated.
15.Patient with clinically significant corneal disease.
16.Any evidence of severe or uncontrolled systemic diseases (...)
17.Uncontrolled or significant cardiovascular disease prior to Cycle 1 Day 1, including: .Corrected QT interval >470 ms for females and >450 ms for males (...) and assessed based on triplicate ECGs, approximately 1 minute apart.
b.LVEF <50% by either ECHO or MUGA.
c.Uncontrolled hypertension
d.Myocardial infarction within 6 months.
e.NYHA Classes 2 to 4 within 28 days.
f.Uncontrolled angina pectoris within six months.
g.Cardiac arrhythmia requiring antiarrhythmic treatment.
18. Active Hepatitis B and/or Hepatitis C infection, such as those with serologic evidence of viral infection within 28 days of Cycle 1, Day 1.
Patients with past or resolved HBV infection are eligible if:
a.HBsAg negative and anti-HBc positive; OR
b.HBsAg positive and HBV DNA viral load is documented to be ≤ 2000 IU/mL in the absence of anti-viral therapy and during the previous 12 weeks prior to the viral load evaluation with normal transaminases ; OR
c.HBsAg positive and HBV DNA viral load is documented to be ≤ 2000 IU/mL in the absence of anti-viral therapy and during the previous 12 weeks prior to the viral load evaluation with liver metastasis and abnormal transaminases AST/ALT < 3 ULN.
d.Patients with a history of Hepatitis C infection will be eligible for enrollment only if the viral load according to local standards of detection, is documented to be below the level of detection in the absence of anti-viral therapy during the previous 12 weeks (...).
19.Patients with known HIV or active COVID-19 infection.
20.Female patients who are pregnant or breastfeeding or intend to become pregnant during the study.
21.Patients with any (...) condition potentially hampering compliance with the study protocol and follow-up schedule; (...).
22.Patients under guardianship or deprived of his/her liberty by a judicial or administrative decision or incapable of giving his/her consent.
23.Participation in another clinical trial evaluating an experimental drug (except non-interventional research). |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint is to determine the ORR of DS-1062a in patients with advanced NSCLC. ORR is defined as the proportion of patients who achieved a confirmed complete response (CR) or partial response (PR) observed on treatment and assessed by investigators. Confirmation of response must be demonstrated with an assessment four weeks or later from the initial response. Treatment objective response will be radiologically assessed at three weeks after the first cycle and thereafter every six weeks using RECIST v1.1. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
a. The efficacy endpoints will be evaluated using RECIST v1.1 with the following parameters:
• DoR is applicable to patients with either CR or PR and is defined as the time from the first documented CR or PR until the date of disease progression, or until the date of death.
• PFS is defined as the time from date of the first dose of DS-1062a until to the earlier of the dates of the first objective documentation of progression or death from any cause, whichever occurs first. At the time of analysis, the patient alive and without progression will be censored at the date of the last tumor assessment.
• CBR is defined as the presence of at least a PR or CR, or a stable disease (SD) > six months under treatment. Reviewed RECIST v1.1 evaluation will be used.
• OS is defined as the time from date of the first DS-1062a dose until death. Patients alive at last follow-up will be censored at this date.
b. Safety and tolerability of DS-1062a will be evaluated continuously through frequency and severity of any AEs, TEAEs, SAEs, AESIs graded by NCI-CTCAE v5.0; proportion of treatment discontinuation, interruptions and dose reductions due to any AEs; frequency and severity of laboratory abnormalities defined by NCI-CTCAE v5.0; frequency and severity of QTcF prolongation; LVEF decrease or cardiac disfunction graded according to NYHA functional classification.
|
|
| 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 | 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.8.3 |
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 | |
| E.8.9.1 | In the Member State concerned months | 52 |
| E.8.9.1 | In the Member State concerned days | |
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