| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Non-small-cell lung cancer |
|
| 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 | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
- To assess the ORR of SG in combination with pembrolizumab or pembrolizumab + a platinum agent.
- Determine the RP2D of SG in combination with pembrolizumab + a platinum agent. |
|
| E.2.2 | Secondary objectives of the trial |
To assess the effect of SG in combination with pembrolizumab or pembrolizumab + a platinum agent on the following:
- PFS
- OS
- DOR
- DCR
- Safety and tolerability |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Patients must meet all of the following inclusion criteria at screening/Day −1 to be eligible for participation in this study (no waivers for patient eligibility will be offered or permitted):
1) Female or male patients, 18 years of age or older, able to understand and give written informed consent.
2) Life expectancy ≥ 3 months.
3) Patients with the following pathologically documented NSCLC that meets all of the following criteria:
a) Has documented evidence of Stage IV NSCLC disease at the time of enrollment (based on the American Joint Committee on Cancer, Eighth Edition).
b) Has documented negative test results for EGFR and ALK.
c) Has no known genomic alterations in ROS1, NTRK, BRAF, RET mutations, or other actionable driver oncogenes with approved therapies for frontline treatment (actionable genomic alteration). (Testing is not required if status is unknown.).
d) Have provided tumor tissue from locations not radiated prior to biopsy. Formalin fixed specimens after the patient has been diagnosed with metastatic disease will be preferred
for evaluation of Trop-2 expression and determination of PD-L1 status prior to enrollment if not already performed by an approved 22C3 assay. Biopsies obtained prior to receipt of adjuvant/neoadjuvant chemotherapy will be permitted if recent biopsy is not feasible. Bone biopsies and fine-needle aspirations are not suitable tissues. If no tissue is available, a new biopsy may be obtained prior to enrollment to the study.
4) Measurable disease by CT or magnetic resonance imaging (MRI) as per RECIST Version 1.1 criteria (see Appendix 11.6) by investigator. Tumor lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions. Historical images within 28 days of the screening visit may be accepted as a screening image if deemed acceptable in the opinion of the investigator.
5) No prior systemic treatment for mNSCLC. Patients who received adjuvant or neoadjuvant therapy are eligible if the adjuvant/neoadjuvant therapy was completed at least 6 months prior to the development of metastatic disease for a platinum agent.
6) ECOG performance status score of 0 or 1 assessed within 7 days prior to treatment.
7) Adequate hematologic counts without transfusional or growth factor support within 10 days of study drug initiation (hemoglobin ≥ 9 g/dL, absolute neutrophil count [ANC] ≥ 1500/mm3, and platelets ≥ 100,000/μL).
8) Adequate hepatic function (bilirubin ≤ 1.5 ULN, AST and ALT ≤ 2.5 ULN or ≤ 5 ULN if known liver metastases, and serum albumin > 3 g/dL).
9) Creatinine clearance of at least 30 mL/min as assessed by the Cockcroft-Gault equation {Cockcroft 1976}. For patients assigned to cohorts with cisplatin, creatinine clearance must be at least 60 mL/min.
10) Patients with HIV must be on antiretroviral therapy (ART) and have a well-controlled HIV infection/disease defined as:
a) Patients on ART must have a CD4 + T-cell count > 350 cells/mm3 at time of screening.
b) Patients on ART must have achieved and maintained virologic suppression defined as confirmed HIV RNA level below 50 copies/mL or the lower limit of qualification (below the limit of detection) using the locally available assay at the time of screening and for at least 12 weeks prior to screening.
c) Patients on ART must have been on a stable regimen, without changes in drugs or dose modification, for at least 4 weeks prior to study entry.
d) The combination ART regimen must not contain any medications that may interfere with SN-38 metabolism.
11) Male patients and female patients of childbearing potential who engage in heterosexual intercourse must agree to use protocol-specified method(s) of contraception as described in Appendix 11.3. |
|
| E.4 | Principal exclusion criteria |
1) Mixed SCLC and NSCLC histology.
2) Active second malignancy.
3) NSCLC that is eligible for definitive local therapy alone.
4) Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug. Intermittent use of topical, inhalational, intranasal, and intraocular steroids is permitted.
5) Has an active autoimmune disease that has required systemic treatment in past 2 years (ie, with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment
and is allowed.
6) Has had an allogenic tissue/solid organ transplant.
7) Has severe (≥ Grade 3) hypersensitivity to SG, pembrolizumab, carboplatin, or cisplatin, their metabolites, or formulation excipient.
8) Requirement for ongoing therapy with or prior use of any prohibited medications listed in (Section 5.7).
9) Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or coinhibitory T-cell receptor (eg, CTLA-4, OX 40, CD137), and was discontinued from that treatment due to a Grade 3 or higher immune-related AEs (irAE).
10) Has received radiation therapy to the lung that is > 30 Gy within 6 months of the first treatment cycle.
11) Patients may not have received systemic anticancer treatment
within the previous 6 months or radiation therapy within 2 weeks, or stereotactic radiosurgery within 72 hours prior to enrolment.
12) Have previously received treatment with any of the following:
a) Topoisomerase 1 inhibitors. Any agent including an ADC containing a chemotherapeutic agent targeting topoisomerase 1.
b) Trop-2-targeted therapy.
13) Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment.
14) 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 enrollment, severe asthma, severe chronic obstructive pulmonary disease (COPD), restrictive lung disease, pleural effusion, etc); any autoimmune, connective tissue, or inflammatory disorders with pulmonary involvement (ie, rheumatoid arthritis, Sjogren syndrome, sarcoidosis, etc); or prior pneumonectomy.
15) Known active CNS metastases and/or carcinomatous meningitis.
16) Active chronic inflammatory bowel disease (ulcerative colitis, Crohn’s disease) or gastrointestinal (GI) perforation within 6 months of enrollment.
17) Has a history of (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.
18) Active serious infection requiring antibiotics.
19) Patients positive for HIV-1 or 2 with a history of Kaposi sarcoma and/or multicentric Castleman disease.
20) Active or chronic hepatitis B infection. Positive for hepatitis B surface antigen. Patients who test positive for hepatitis B core antibody will require hepatitis B virus DNA by quantitative PCR for confirmation of active disease.
21) Positive hepatitis C antibody and detectable hepatitis C virus (HCV) viral load.
22) Positive serum pregnancy test (Appendix 11.3) or women who are lactating.
23) Other concurrent medical or psychiatric conditions that, in the investigator’s opinion, may be likely to confound study interpretation or prevent completion of study procedures and follow-up examinations.
24) Received a live-virus vaccination within 30 days of planned treatment start. Seasonal flu vaccines that do not contain live virus are permitted. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
- ORR is defined as the proportion of patients who have measurable disease at baseline and achieve a complete response (CR) or partial response (PR) that is confirmed
at least 4 weeks later as assessed by an independent review committee (IRC) according to the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1.
- Incidence of DLT(s) (ie, percentage of patients who had DLTs) per dose level during the first 21 days of treatment in the safety run-in cohorts. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Individual Patient:
Patients are considered to have reached the end of the study when they
are no longer followed for long term or survival follow-up due to the
following reasons: death, patient withdrew consent for survival followup,
lost to follow-up, the sponsor terminated study, or completion of
survival follow-up.
All Patients:
The end of the entire study for all patients is defined as the date on
which the last patient remaining on study completes the last study
visit/call or when the sponsor decides to end the study. The sponsor
reserves the right to terminate the study at any time for any reason
(including safety). |
|
| E.5.2 | Secondary end point(s) |
- PFS is defined as the time from the date of the first dose until the date of objective disease progression or death (whichever comes first) as assessed by IRC per RECIST Version 1.1.
- OS is defined as the time from the date of first dose until death due to any cause.
- DOR is defined as the time from the first documentation of CR or PR to the earlier of the first documentation of progressive disease (PD) or death from any cause (whichever comes first) as assessed by IRC per RECIST Version 1.1.
- DCR is defined as the proportion of patients who achieve a CR, PR, or stable disease (SD) as assessed by IRC per RECIST Version 1.1.
- Incidence of treatment-emergent adverse events (TEAEs) and clinical laboratory abnormalities. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Individual Patient:
Patients are considered to have reached the end of the study when they
are no longer followed for long term or survival follow-up due to the
following reasons: death, patient withdrew consent for survival follow
up, lost to follow up, the sponsor terminated the study, or completion of
survival follow up. For any patient who dies during the follow-up period,
primary cause of death must be reported to the sponsor.
All Patients:
The end of the entire study for all patients is defined as the date on which the last patient remaining on study completes the last study visit/call or when the sponsor decides to end the study. |
|
| 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 | No |
| 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 | 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.8.2.4 | Number of treatment arms in the trial | 7 |
| 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 | 10 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 45 |
| 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 |
| Australia |
| Canada |
| Hong Kong |
| Korea, Democratic People's Republic of |
| Malaysia |
| Taiwan |
| United States |
| France |
| Germany |
| Italy |
| Spain |
| United Kingdom |
|
| 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
|
|
| 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 | 6 |
| E.8.9.1 | In the Member State concerned days | 7 |
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 1 |
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