| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced or Metastatic Non-small Cell Lung Cancer (NSCLC) |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 estimate the antitumor activity of DS-1062a among subjects with advanced or metastatic NSCLC with actionable genomic alterations that has progressed on or after one or more kinase inhibitors and platinum-based chemotherapy, as measured by the overall response rate (ORR) as assessed by blinded independent central review (BICR) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1).
Confirmation of response (Complete Response/Partial Response) is required for ORR. |
|
| E.2.2 | Secondary objectives of the trial |
1) To further evaluate the efficacy of DS-1062a (Duration of Response, Best percentage change in the Sum of Diameters of measurable tumors, Disease Control Rate, Clinical Benefit Rate, Program-free Survival, Time to Response, Overall Response Rate, Overall Survival).
2) To further evaluate the safety of DS-1062a [treatment-emergent adverse event (TEAEs) and other safety parameters during the study].
3) To assess the PK of DS-1062a (PK profile).
4) To assess the immunogenicity of DS-1062a |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subjects must meet all of the following criteria to be eligible for enrollment into the study:
1. Sign and date the ICF prior to the start of any study- specific qualification procedures.
2. Adults ≥18 years (if the legal age of consent is >18 years old, then follow local regulatory requirements).
3. Has pathologically documented NSCLC that:
a. Is stage IIIB or stage IV NSCLC disease at the time of enrollment (based on the American Joint Committee on Cancer, Eighth Edition).
b. Has one or more of the following documented activating tumor genomic alterations: EGFR, ALK, ROS1, NTRK, BRAF, MET exon 14 skipping or RET.
4. Has documentation of radiographic disease progression while on or after receiving the most recent treatment regimen for advanced or metastatic NSCLC.
5. Subject must meet at least the following for advanced or metastatic NSCLC:
a. Has progressed on or after at least one kinase inhibitor
b. Has progressed on or after at least one regimen of platinum-based chemotherapy
6. Willing and able to undergo a mandatory pre-treatment tumor biopsy for the measurement of TROP2 expression levels, confirmation of genomic alteration status and evaluation of other biomarkers. Biopsies may be collected from a lesion that has been irradiated provided that it can be documented that the lesion has increased/appeared since radiation
occurred, and that the biopsy is collected at least 3 months after radiation. If available, a tumor biopsy that was recently collected (within 3 months of screening) after completion of the most recent anticancer treatment regimen and that has a minimum of 10 × 4 micron sections or a tissue block equivalent of 10 × 4 micron sections may be substituted for the biopsy collected during screening. Results from this biopsy will not be used to determine eligibility for the study. Screening biopsy should only be collected after all other eligibility criteria are met.
7. Archival tumor tissue from initial diagnosis is required, to the extent that archival tumor tissue is available.
8. Has measurable disease based on local imaging assessment using RECIST v1.1.
9. Has an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 - 1 at screening.
10. Within 7 days before Cycle 1 Day 1, has adequate bone marrow function defined as:
a. Platelet count ≥100,000/mm3 (platelet transfusion is not allowed within 1 week prior to screening assessment).
b. Hemoglobin ≥9.0 g/dL (red blood cell/plasma transfusion is not allowed within 1 week prior to screening assessment).
c. Absolute neutrophil count ≥1500/mm3 (granulocyte-colony stimulating factor administration is not allowed within 1 week prior to screening assessment).
11. Within 7 days before Cycle 1 Day 1, has:
- Adequate hepatic function, defined as:
▪ Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤2.5 × upper limit of normal (ULN) or AST/ALT ≤5.0 x ULN if transferase elevation is due to liver metastases).
▪ Total bilirubin (TBL) ≤1.5 × ULN or <3.0 mg/dL in the presence of documented Gilbert’s Syndrome (unconjugated hyperbilirubinemia).
OR
- Mild or moderate impaired hepatic function in a maximum of 12 subjects defined as:
▪ Mild hepatic dysfunction (a maximum of 6 subjects): TBL >ULN to ≤1.5 × ULN or AST >ULN.
▪ Moderate hepatic dysfunction (a maximum of 6 subjects): TBL >1.5 × ULN and ≤3 × ULN and any AST.
After a maximum of 12 subjects with mild or moderate hepatic dysfunction have been enrolled, subsequent subjects with mild or moderate hepatic dysfunction will be excluded.
12. Within 7 days before Cycle 1 Day 1, has adequate renal function, including mild or moderate renal function, defined as:
- Creatinine clearance ≥30 mL/min, as calculated using the Cockcroft-Gault equation.
13. Has a left ventricular ejection fraction (LVEF) ≥50% by either an ECHO or MUGA scan within 28 days before Cycle 1 Day 1.
14. Has adequate blood clotting function defined as international normalized ratio/prothrombin time and either partial thromboplastin or activated partial thromboplastin ≤1.5 × ULN.
15. Has an adequate treatment washout period before Cycle 1 Day 1 defined as:
-Major surgery: ≥3 weeks
-Radiation therapy including palliative radiation to chest ≥4 weeks (palliative radiation therapy to other areas: ≥2 weeks)
-Anti-cancer chemotherapy (immunotherapy [non-antibody-based therapy]), retinoid therapy: ≥2 weeks or 5 times the t1/2 of the chemotherapeutic agent, whichever is longer; ≥6 weeks for nitrosoureas or mitomycin C, ≥1 week for TKIs approved for the treatment of NSCLC - baseline CT scan must be completed after discontinuation of TKI
-Antibody-based anti-cancer therapy: ≥4 weeks
-Chloroquine/Hydroxychloroquine: >14 days
16. Has a life expectancy ≥3 months based on investigator’s opinion.
Please refer to the protocol for full list of inclusion criteria. |
|
| E.4 | Principal exclusion criteria |
Subjects who meet any of the following criteria will be disqualified from entering the study:
1. Has spinal cord compression or clinically active central nervous system metastases, defined as untreated and symptomatic, or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms. Subjects with clinically inactive brain metastases may be included in the study. Subjects with treated brain metastases that are no longer symptomatic and who require no treatment with corticosteroids or anticonvulsants may be included in the study if they have recovered from the acute toxic effect of radiotherapy. A minimum of 2 weeks must have elapsed between the end of whole brain radiotherapy and study enrollment.
Note: A CT or magnetic resonance imaging (MRI) scan of the brain at baseline is required for all subjects. For those subjects in whom CNS metastases are first discovered at the time of screening, the treating investigator should consider delay of study treatment to document stability of CNS metastases with repeat imaging at least 4 weeks later (in which case, repeat of all screening activity may be required).
2. Has leptomeningeal carcinomatosis.
3. Prior treatment with:
a. An ADC containing a chemotherapeutic agent targeting topoisomerase I.
b. TROP2-targeted therapy.
4. Uncontrolled or significant cardiovascular disease, including:
a. Mean QT interval corrected for heart rate using Fridericia’s formula (QTcF) >470 milliseconds (msec) for females or >450 msec for males (based on the average of screening triplicate 12-lead ECG determinations).
b. History of myocardial infarction within 6 months prior to Cycle 1 Day 1.
c. History of uncontrolled angina pectoris within 6 months prior to Cycle 1 Day 1.
d. Symptomatic congestive heart failure (CHF) (New York Heart Association Class II to IV) at screening. Subjects with a history of Class II to IV CHF prior to screening, must have returned to class I CHF and have LVEF ≥50% (by either an ECHO or MUGA scan within 28 days of Cycle 1 Day 1) in order to be eligible.
e. History of serious cardiac arrhythmia requiring treatment.
f. LVEF <50% or institutional lower limit of normal by ECHO or MUGA scan. within 28 days before Cycle 1 Day 1.
g. Uncontrolled hypertension (resting systolic blood pressure >180 mmHg or diastolic blood pressure >110 mmHg) within 28 days before Cycle 1 Day 1.
5. Has a history of (non-infectious) ILD/pneumonitis that required steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening.
6. Clinically severe pulmonary compromise resulting from intercurrent pulmonary illnesses including, but not limited to, any underlying pulmonary disorder (ie, pulmonary emboli within 3 months of the study Cycle 1 Day 1, severe asthma, severe chronic obstructive pulmonary disease [COPD], restrictive lung disease, pleural effusion, etc.), or any autoimmune, connective tissue or inflammatory disorders with pulmonary involvement (ie, rheumatoid arthritis, Sjögren's syndrome, sarcoidosis, etc.), or prior pneumonectomy.
7. Clinically significant corneal disease.
8. Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals. Note: Subjects with localized fungal infections of skin or nails are eligible.
9. Has known HIV infection that is not well controlled. All of the following criteria are required to define an HIV infection that is well controlled: undetectable viral RNA load, CD4+ counts/levels >250, no history of AIDs-defining opportunistic infection within the past 12 months, and stable for at least 4 weeks on same anti-HIV retroviral medications. If an HIV infection meets the above criteria, monitoring of the subjects’ viral RNA load as well as the CD4+ count levels would be important. Subjects should be tested for HIV prior to Cycle 1 Day 1 if required by local regulations or Institutional Review Board (IRB)/Ethics Committee (EC).
10. 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.
Please refer to the protocol for full list of exclusion criteria. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Overall response rate (ORR) - Defined as the proportion of subjects who achieved a Best overall response (BOR) of confirmed Complete response (CR) or confirmed Partial response (PR). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Every 6 weeks (±7 days) from Cycle 1 Day 1 until documented disease progression as assessed by blinded independent central review, death (BICR), lost to follow-up, or withdrawal of consent regardless of discontinuing DS-1062a or starting new anticancer therapy (tumor assessment is not restricted to Treatment Period). Subjects experiencing clinical benefit to continue DS-1062a until documented disease progression, clinical progression, lack of efficacy, unacceptable toxicity, withdrawal of consent by subject, physician decision, protocol deviation, pregnancy, lost to follow-up, study termination by the sponsor, death, or other reasons. The ORR by BICR will be conducted after all subjects either followed for at least 9 months from study treatment or have discontinued, whichever occurs first. |
|
| E.5.2 | Secondary end point(s) |
1) Efficacy
- Duration of response (DoR) - defined as the time from the date of the first documentation of response (confirmed CR or confirmed PR) to the date of the first documentation of disease progression (PD) or death due to any cause, whichever occurs first.
- The best percentage change in the Sum of diameters (SoD) of measurable tumors is defined as the percentage change in the smallest SoD from all post-baseline tumor assessments, taking as reference the baseline SoD.
- Disease control rate (DCR) - defined as the proportion of subjects who achieved a BOR of confirmed CR, confirmed PR, or SD (stable disease).
- Clinical benefit rate (CBR) - defined as the proportion of subjects who achieved a BOR of confirmed CR, confirmed PR, or an SD that lasts for at least 180 days.
- Progression-free survival (PFS) - defined as the time from the start of study treatment to the earlier of the dates of the first documentation of PD or death due to any cause.
- Time to response (TTR) - defined as the time from the start of study treatment to the date of the first documentation of objective response (confirmed CR or confirmed PR) in responding subjects.
- Overall response rate (ORR) - defined as the proportion of subjects who achieved a BOR of confirmed CR or confirmed PR.
- Overall survival (OS) - defined as the time from the start of study treatment to the date of death due to any cause.
2) Safety
- Treatment-emergent adverse event (TEAEs), Serious adverse event (SAEs), Adverse event of special interest (AESIs), Eastern Cooperative Oncology Group performance status (ECOG PS), vital sign measurements, standard clinical laboratory parameters (hematology, serum chemistry, and urinalysis), ECG parameters, Echocardiogram/multigated acquisition (ECHO/MUGA) scan findings, and ophthalmologic findings. AEs will be coded using the most current version of MedDRA. AEs and laboratory test results will be graded using the National Cancer Institute-Common Terminology
Criteria for Adverse Events (NCI-CTCAE) v5.0.
3) PK
- Plasma concentrations at each time point and PK parameters (Cmax, Tmax, AUClast, AUCtau. If data permit: AUCinf, t1/2, CL, Vss, Vz, and Kel) of DS-1062a, total anti-TROP2 antibody, and MAAA-1181a (released drug) in the full PK sampling cohort.
4) Immunogenicity
Antidrug-antibody (ADA) prevalence: the proportion of subjects who are ADA positive at any point in time (including pre-existing ADA at baseline and treatment-emergent ADA).
ADA incidence: the proportion of subjects having treatment-emergent ADA. Titer and neutralizing antibodies will be determined when ADA is positive. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1) Efficacy: Please refer time point of evaluation for Primary end point.
2) Safety: After the subject signs the ICF and up to 35 days after the last dose of study medication.
3) PK: C1 (Cycle 1)–Day 1: Pre-dose (within 8 hours before infusion), post-dose (within 30 minutes and 3, 5, 7 hours after infusion start), 24 hours and 3, 7, 17 days after infusion start) C2, 3, 4, 6, 8–Day 1: Pre-dose (within 8 hours before infusion), post-dose (within 1 hour after infusion start)
4) Immunogenicity: C1-Day 1 (within 8 hours before infusion) and Day 8, C2 - (within 8 hours before infusion), C4 and subsequent cycles (within 8 hours before infusion) - Every 2 cycles from C4 - C8 then every 4 cycles from C8 to end of trial. Every 3 months (± 1 month) up to 1 year from the last dose. |
|
| 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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| 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 | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Immunogenicity, Biomarkers |
|
| 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 28 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| France |
| Germany |
| Hungary |
| Italy |
| Japan |
| Korea, Republic of |
| Netherlands |
| Spain |
| Taiwan |
| United States |
|
| 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 overall EOS will occur after the last subject last visit has occurred; or after all subjects have discontinued treatment and discontinued from the study, or have died; or an alternative study becomes available for subjects continuing to derive benefit from treatment with DS-1062a where the drug is offered to these subjects; or the study is discontinued by the sponsor for other reasons. |
|
| 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 | 1 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
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