| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Pretreated Extensive-stage Small Cell Lung Cancer (ES-SCLC) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Pretreated Extensive-stage Small Cell Lung Cancer (ES-SCLC) |
|
| 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 | 10041068 |
| E.1.2 | Term | Small cell lung cancer extensive stage |
| 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 the antitumor activity of I-DXd in subjects with pretreated ES-SCLC |
|
| E.2.2 | Secondary objectives of the trial |
- To further assess the antitumor activity of I-DXd in subjects with pretreated ES-SCLC
- To assess the safety and tolerability of I-DXd in subjects with pretreated ES-SCLC
- To evaluate the PK of I-DXd
- To assess the immunogenicity of I-DXd |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Sign and date the ICF prior to the start of any study- specific qualification procedures
2.Subject must have at least one lesion, not previously irradiated, amenable to core biopsy and must consent to provide a pretreatment biopsy tissue sample and on-treatment biopsy. Fresh pretreatment biopsy may be waived for subjects who consent to provide archival tumor tissue from a biopsy performed within 6 months of consent and performed after treatment with their most recent cancer therapy regimen. If, after all efforts have been made, the fresh pretreatment biopsy is not feasible or the procedure is unsuccessful and an appropriate archival sample is not available, the subject may be considered for study eligibility only after discussion with the Sponsor
3.Male or female subjects aged ≥18 years
4.Histologically or cytologically documented ES-SCLC
5.At least one measurable lesion according to RECIST v1.1 as assessed by the investigator
6.Prior therapy with at least one prior platinum-based line as systemic therapy for extensive-stage disease with at least two cycles of therapy (except in case of early objective PD) and, beginning with protocol version 3.0, a minimum of two previous lines of systemic therapy. Subjects with or without prior immune-checkpoint inhibitor therapy are eligible. Subject must not have received more than three previous lines of systemic therapy (rechallenge with platinum chemotherapy will be considered as one separated prior line of therapy). Subjects treated with a platinum-based line of therapy for prior limited stage (LS)-SCLC may be eligible for the study if the disease has progressed on treatment or within 6 months from treatment completion: the platinum-based line of therapy will count as one prior line of therapy. One line of therapy will be defined as 1 or more drugs received prior to newly documented disease progression in the locally advanced or metastatic setting. Any switch between carboplatin and cisplatin for toxicity reasons will be regarded as one line overall
7.Documentation of radiological disease progression on or after most recent systemic therapy
8.ECOG PS of 0 or 1
9.Life-expectancy ≥3 months
10.Required baseline local laboratory data (within 7 days prior to Cycle 1 Day 1):
a.ALT and AST:
- ≤3 × ULN in subjects with no liver metastasis or
- ≤5.0 × ULN in subjects with liver metastasis
b.Total bilirubin ≤1.5 × ULN if no liver metastases or ≤3 × ULN in the presence of documented Gilbert’s syndrome (undocumented hyperbilirubinemia) or liver metastases at baseline
c.ANC ≥1.5 × 109/L (hematopoietic growth factors [eg, G-CSF, GM-CSF] support allowed up to 14 days before screening laboratory tests)
d.Platelet count ≥100 × 109/L (platelet transfusion is allowed up to 14 days before screening laboratory tests)
e.Hemoglobin ≥8.5 g/dL (transfusion and/or growth factor support allowed up to 14 days before screening laboratory tests)
f.Creatinine clearance ≥30 mL/min, as calculated using the Cockcroft-Gault equation
g.International normalized ratio (INR)/prothrombin time (PT) and either partial thromboplastin time (PTT) or activated partial thromboplastin time (aPTT) ≤1.5 × ULN, except for subjects receiving anti vitamin K derivative anticoagulant therapy who must have prothrombin time international normalization ratio within the therapeutic range as deemed appropriate by the investigator
11.If the subject is a female of childbearing potential, she must have a negative serum pregnancy test within 7 days before the first dose of study drug and must be willing to use a highly effective birth control upon enrollment, during the Treatment Period, and for 7 months following the last dose of study drug. A female is considered of childbearing potential following menarche and until becoming postmenopausal (no menstrual period for a minimum of 12 months) unless permanently sterile (undergone a hysterectomy, bilateral salpingectomy or bilateral oophorectomy) with surgery at least 1 month before the first dose or confirmed by FSH test
12.If male, the subject must be surgically sterile or willing to use highly effective birth control upon enrollment, during the Treatment Period, and for 4 months following the last dose of study drug.
13.Male subjects must not freeze or donate sperm starting at enrollment, throughout the Treatment Period, and for at least 4 months following the last dose of the study drug. Preservation of sperm may be considered prior to enrollment in this study
14.Female subjects must not donate, or retrieve for their own use, ova from the time of enrollment and throughout the Treatment Period, and for at least 7 months following the last dose of the study drug. They should refrain from breastfeeding throughout this time. Preservation of ova may be considered prior to enrollment in this study
15.Is willing and able to comply with scheduled visits, drug administration plan, laboratory tests, other study procedures, and study restrictions |
|
| E.4 | Principal exclusion criteria |
1.Prior treatment with orlotamab, enoblituzumab, or other B7-H3 targeted agents including I-DXd
2.Prior discontinuation of an ADC that consists of an exatecan derivative (eg, trastuzumab deruxtecan)
3.Inadequate washout period before randomization, defined as
a.Major surgery (placement of vascular access will not be regarded as a major surgery) <4 weeks; surgery for low invasive cases (eg, colostomy, <4 weeks)
b Radiation therapy to the lung >30 Gy <6 months; palliative radiotherapy affecting lung areas at lower dose <3 weeks; any other palliative radiotherapy <2 weeks
c.Cranial irradiation, including WBRT and SRS, ≤2 weeks
d.Any systemic anticancer therapy <3 weeks or 5 half-lives whichever is longer and <6 weeks for nitrosoureas or mitomycin C
e.Antibody-based anticancer therapy <3 weeks
f.Chloroquine or hydroxychloroquine ≤14 days
g.Hormonal therapy <2 weeks
4.Clinically active brain metastases, spinal cord compression or leptomeningeal carcinomatosis, defined as untreated or symptomatic or requiring therapy with steroids or anticonvulsants to control associated symptoms
5.Any of the following conditions within the past 6 months: cerebrovascular accident, transient ischemic attack or another arterial thromboembolic event
6.Clinically significant corneal disease
7.Uncontrolled or significant cardiovascular disease including
a.Corrected QT interval (by Fridericia’s formula) >470 ms (females) or >450 ms (males) based on average of the screening triplicate 12-lead ECG determinations
b.Diagnosed or suspected long QT syndrome or known family history of long QT syndrome
c.History of clinically relevant ventricular arrhythmias, such as ventricular tachycardia, ventricular fibrillation or Torsade de Pointes
d.Bradycardia of less than 50 bpm unless the subject has a pacemaker
e.History of second-or third-degree heart block
f.Acute myocardial infarction within 6 months prior to screening
g.Uncontrolled angina pectoris within 6 months prior to screening
h.CHF defined as NYHA Class II to IV
i.Coronary/peripheral artery bypass graft or any coronary/peripheral angioplasty within 6 months prior to screening
j.Grade ≥3 hypertension
k.Complete left or right bundle branch block
l.LVEF <50% by either an ECHO or a MUGA scan
8.History of (non-infectious) ILD/pneumonitis that required corticosteroids, current ILD/pneumonitis, or suspected ILD/pneumonitis that cannot be ruled out by imaging at screening
9.Clinically severe pulmonary compromise resulting from intercurrent pulmonary illnesses including, but not limited to, any underlying pulmonary disorder, and potential pulmonary involvement caused by any autoimmune, connective tissue or inflammatory disorders, prior complete pneumonectomy, or requirement for supplemental oxygen
10.Chronic steroid treatment (dose of 10 mg daily or more prednisone equivalent) except for low-dose inhaled steroids (for asthma/COPD) or topical steroids (for mild skin conditions), or intra-articular steroid injections
11.History of malignancy other than SCLC within the 3 years prior to enrollment except adequately resected non-melanoma skin cancer, curatively treated in situ disease, superficial GI tumors and non-muscle invasive bladder cancer curatively resected by endoscopic surgery
12.History of allogeneic bone marrow, stem cell, or solid organ transplant
13.Unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to NCI-CTCAE V5.0 Grade ≤1 or baseline
14.History of hypersensitivity to the drug substances, inactive ingredients in the drug product or severe hypersensitivity reactions to other monoclonal antibodies
15.Evidence of ongoing uncontrolled systemic bacterial, fungal, or viral infection
16.Has active or uncontrolled hepatitis B or C infection; subject is positive for hepatitis B or C virus within 28 days of enrollment
17.Active, known, or suspected autoimmune disease. The following examples may be enrolled as an exception
a.Type I diabetes mellitus, hypothyroidism only requiring hormone replacement
b.Skin disorders not requiring systemic treatment, or
c.Conditions not expected to recur in the absence of an external trigger
18.Any evidence of severe or uncontrolled systemic diseases or other factors that, in the investigator’s opinion, make it undesirable for the subject to participate in the study or would jeopardize compliance with the protocol
19.Has received a live vaccine within 30 days prior to the first dose of study drug
20.Female who is pregnant or breastfeeding or intends to become pregnant during the study
21.Prior or ongoing clinically relevant illness, medical condition, surgical history, physical finding, or laboratory abnormality that, in the investigators opinion, could affect the safety of the subject; alter the absorption, distribution, metabolism or excretion of the study drug; or confound the assessment of study results
22.Known HIV infection that is not well controlled |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Objective response rate (ORR), defined as the proportion of subjects with a BOR of confirmed CR or confirmed PR assessed by blinded independent central review (BICR) based on RECIST v1.1. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Every 6 weeks (±7 days) in the first 36 weeks after Day 1 of Cycle 1, and thereafter every 12 weeks (±7 days). |
|
| E.5.2 | Secondary end point(s) |
Efficacy endpoints:
- Progression-free survival (PFS), duration of response (DoR), disease control rate (DCR) and time to response (TTR) assessed by the investigator and BICR based on RECIST v1.1
- Overall survival (OS)
- Objective response rate (ORR) assessed by the investigator based on RECIST v1.1
Safety endpoints:
- Incidence of treatment-emergent adverse event (TEAEs), Grade 3 or above TEAEs, deaths, serious TEAEs, AESIs, and TEAEs associated with dose modification of study drug based on NCI-CTCAE V5.0.
- Physical examination findings (including ECOG PS), vital sign measurements, standard clinical laboratory parameters, ECG parameters, and ECHO/MUGA scan findings.
PK parameters:
- Plasma Pharmacokinetic (PK) parameters (eg, time to reach maximum plasma concentration [Tmax], half life [t1/2], maximum concentration (Cmax), lowest concentration [Ctrough], area under the curve [AUC]) for I-DXd, total anti-B7-H3 antibody, and MAAA-1181a
- I-DXd PopPK analysis
ADA:
- Antidrug antibodies (ADA) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Efficacy (ORR, PFS, DOR, DCR, TTR, OS): every 6 weeks (±7 days) in the first 36 weeks after Day 1 of Cycle 1, and thereafter every 12 weeks (±7 days)
Safety (TEAE, AESI etc.): continuously between first dose and final database lock (including Follow-up Period)
PK:
Cycle 1: pre-dose, EOI*, 3, 6 and 24h post start of infusion, Day 4, Day 8, Day 15 and Day 22**
Cycle 2: pre-dose and EOI
Cycle 3: pre-dose, EOI, 3 and 6h post start of infusion
Cycle 4 and every 2 cycles thereafter: pre-dose
*EOI is defined as at the end of IV infusion and flush
**if treatment planned at Cycle 2 Day 1 is interrupted or will be delayed
ADA:
Cycle 1, Cycle 2 and Cycle 3 Day 1 pre-dose,
Every 4 cycles pre-dose (Cycle 7 Day 1, Cycle 11 Day 1 etc.),
End of treatment
30-day safety FU visit |
|
| 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 | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| 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 | 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) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| different dosage of the same product |
|
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 19 |
| 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 |
| Taiwan |
| China |
| Japan |
| Korea, Republic of |
| United States |
| France |
| Germany |
| Spain |
|
| 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
|
| Overall end of study is defined as the date of completion of the last Long-term Follow-up (LTFU) Visit. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | 11 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 11 |
Print
