| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Metastatic non-squamous non-small cell lung cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
| Metastatic non-squamous non-small cell lung cancer |
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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) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10079440 |
| E.1.2 | Term | Non-squamous 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 compare the ORR of PD-1 inhibitor dostarlimab vs pembrolizumab administered in combination with chemotherapy as evaluated using RECIST v1.1 based on BICR in participants with metastatic non-squamous
NSCLC, without a known EGFR, ALK, ROS-1, or BRAF V600E mutation or other genomic aberration for which a targeted therapy is available, who have received no prior treatment of metastatic disease |
|
| E.2.2 | Secondary objectives of the trial |
•To evaluate the following measures of clinical benefit of PD 1 inhibitor administered in combination with chemotherapy:
- OS
- PFS evaluated using RECIST v1.1 based on Investigator assessment.
•To evaluate the safety of PD-1 inhibitor in combination with chemotherapy
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Participants are eligible to be included in the study only if all of the following criteria apply:
1. Participant must be ≥18 years old, must be able to understand the study procedures, and agrees to participate in the study by providing written informed consent (as described in Appendix 4 of protocol), which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.
2. Participant has histologically- or cytologically-confirmed metastatic non-squamous NSCLC with documented absence of a sensitizing EGFR, ALK, ROS-1, or BRAF V600E mutation or other genomic aberration for which an approved targeted therapy is available.. Mixed tumors will be categorized by the predominant cell type; if the tumor has predominantly squamous cell histology or if small cell elements are present, the
participant is ineligible.
3. Participants must have measurable disease, ie presenting with at least 1 measurable lesion per RECIST v1.1 as determined by the local site Investigator/radiology assessment.
Measurable lesions situated in a previously irradiated area may be considered target lesions if progression has been demonstrated in such lesions and if there are other target lesions. If there is only 1 target lesion that was previously irradiated, the participant is not eligible. See Appendix 1 of protocol for the definition of a measurable lesion.
4. Participant has documented PD-L1 status by the 22C3 pharmDx assay (Agilent/Dako). If no prior PD-L1 result is available at the time of Screening, the participant can be tested locally using the stated method, or central PD-L1 testing can be completed. Results are needed for stratification and must be available prior to randomization.
5. Participant has an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1.
6. Participant has a life expectancy of at least 3 months.
7. Participant has adequate organ function as defined in Table 5 of protocol. (Note: A complete blood count test should be obtained without transfusion or receipt of colony-stimulating factors within 2 weeks of obtaining the sample.)
8. Participant has recovered to Grade ≤1 from any prior treatment-related toxicities at the time of randomization. A participant with Grade 2 alopecia is an exception to this criterion and may qualify for this study.
9. Contraceptive use by male and female participants should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
a. Male participants are eligible to participate if they agree to the following during the Treatment Period and for at least 180 days after the last dose of study treatment
(Note: duration of contraceptive use after last dose of chemotherapy must be consistent with local requirements and local approved product labels; however, the minimum duration is 180 days after last dose of chemotherapy)
• Refrain from donating sperm
PLUS, either:
• Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent.
OR
• Must agree to use contraception/barrier as follows:
− Agree to use a male condom (and should also be advised of the benefit for a female partner to use a highly effective method of contraception, as a condom may break or leak) when having sexual intercourse with a woman of childbearing potential (WOCBP) who is not currently pregnant.
− Agree to use a male condom when engaging in any activity that allows for passage of ejaculate to another person.
b. A female participant is eligible to participate if she is not pregnant or breastfeeding, and 1 of the following conditions applies:
• Is a woman of non-childbearing potential (WONCBP), as defined in Appendix 5 of protocol.
OR
• Is a WOCBP, as defined in Appendix 5, using a contraceptive method that is highly effective (with a failure rate of <1% per year and, preferably, with low user dependency, as described in Appendix 5 of protocol) during the Treatment Period and for at least 180 days after the last dose of study treatment and agrees not to donate eggs (ova or oocytes) for the purpose of reproduction during this period. (Note: duration of
contraceptive use after last dose of chemotherapy may be longer than 180 days in
order to comply with local requirements and local approved product labels).Contraceptive use should be consistent with local regulations regarding the methods
of contraception for those participating in clinical studies.The Investigator should evaluate the potential for contraceptive method failure (eg, noncompliance and recently initiated) in relationship to the first dose of study treatment.
− A WOCBP must have a negative highly sensitive pregnancy test (urine or serum, as required by local guidelines) within 72 hours before the first dose of study treatment.
Refer protocol for other inclusion criteria. |
|
| E.4 | Principal exclusion criteria |
Participants are excluded from the study if any of the following criteria apply:
1. Participant has received prior systemic therapy for the treatment of metastatic NSCLC. Participants who have received neoadjuvant or adjuvant chemotherapy are eligible if the neoadjuvant/adjuvant therapy was completed at least 12 months prior to the development
of metastatic disease.
2. Participant has received prior therapy with a PD-(L)1 or PD-L2 inhibitor, a CTLA-4 inhibitor, a TIM-3 inhibitor, or any other immunotherapy agent (eg, OX40) for the treatment of cancer.
3. Participant has received radiation to the lung that is >30 Gy within 6 months of the first dose of study treatment.
4. Participant has completed palliative radiotherapy within 7 days of the first dose of study treatment.
5. Participant is ineligible if any of the following hepatic characteristics are present:
a. ALT >2.5×upper limit of normal (ULN) without liver metastases/tumor infiltration
b. ALT >5×ULN with liver metastases/tumor infiltration
c. Bilirubin >1.5×ULN (isolated bilirubin >1.5×ULN is acceptable if bilirubin is fractionated and direct bilirubin is <35%)
d. Current active liver or biliary disease (with the exception of Gilbert’s syndrome or asymptomatic gallstones, liver metastases, or otherwise stable chronic liver disease per Investigator assessment)
Note: Stable chronic liver disease should generally be defined by the absence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, persistent jaundice, or cirrhosis
6. Participant has a corrected QT interval (QTc) >450 msec (or QTc >480 msec for participants with bundle branch block).
Notes:
• The QTc is the QT interval corrected for heart rate according to Bazett’s formula (QTcB), Fridericia’s formula (QTcF), and/or another method, machine-read or manually over-read.
• The specific formula that will be used to determine eligibility and discontinuation for an individual participant should be determined prior to initiation of the study. In other words, several different formulae cannot be used to calculate the QTc for an individual participant and then the lowest QTc value used to include or discontinue the participant from the study.
• For purposes of data analysis, QTcB, QTcF, another QT correction formula, or a composite of available values of QTc will be used as specified in the Reporting and Analysis Plan (RAP).
7. Participant has had major surgery within 3 weeks of the first dose of study treatment or has not adequately recovered from any AEs (Grade ≤1) and/or complications from any major surgery. Surgical implantation of a port catheter is not exclusionary.
8. Participant has an additional malignancy or a history of prior malignancy, with the exception of adequately treated basal or squamous skin cancer, cervical carcinoma in situ, superficial bladder cancer without evidence of disease, other in situ cancers or had a malignancy treated with curative intent and with no evidence of disease recurrence for 5 years since the initiation of that therapy.
9. Participant has known active brain metastases and/or leptomeningeal metastases. Participants who have received prior therapy for their brain metastases and have radiographically stable central nervous system disease may participate, provided they are neurologically stable for at least 2 weeks before study entry and must be off corticosteroids within 3 days prior to the first dose of study treatment. Stable brain metastases by this definition should be established prior to the first dose of study treatment. Participants with known untreated, asymptomatic brain metastases (ie, no neurological symptoms, no requirements for corticosteroids, no or minimal surrounding edema, and no lesions >1.5 cm) may participate, but will require regular imaging of the brain as a site of disease.
10. Participant has tested positive for the presence of hepatitis B surface antigen or has a positive hepatitis C antibody test result at Screening, or within 3 months prior to first dose of study treatment.
11. Participant has an active infection requiring systemic therapy within 1 week prior to the anticipated first dose of study treatment.
12. Participant has known HIV (positive for HIV-1 or HIV-2 antibodies).
13. Participant has active autoimmune disease that required systemic treatment in the past 2 years, is immunocompromised in the opinion of the Investigator, or is receiving systemic immunosuppressive treatment. (Note: Participants with splenectomy are allowed.) Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc) is not considered a form of systemic treatment.
Refer Protocol for other Exclusion criteria.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| •The primary efficacy endpoint ORR will be evaluated by RECIST v1.1 based on BICR and will be defined as the proportion of participants with BOR of CR or PR in the analysis population. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Week 6, Week 12, every 9 weeks thereafter until week 58 and then every 12 weeks until discontinuation of study treatment due to disease progression with clinical instability, start of subsequent anticancer treatment, withdrawal of informed consent, or death, whichever comes first.
|
|
| E.5.2 | Secondary end point(s) |
•OS is defined as the time from the date of randomization to the date of death by any cause.
•PFS will be evaluated using RECIST v1.1 based on Investigator assessment and will be defined as the time from the date of randomization to the date of PD or death by any cause, whichever occurs first.
•Assess the incidence of TEAEs, SAEs, irAEs, TEAEs leading to death, and AEs leading to discontinuation occurring while participants are on treatment or up to 90 days after the last dose of study treatment. Clinical laboratory parameters (hematology, chemistry, thyroid function, urinalysis), vital signs, ECOG performance status, ECG parameters, physical examinations, and usage of concomitant medications will be collected.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
OS: Week 6, Week 12, every 9 weeks thereafter until week 58 and then every 12 weeks until discontinuation of study treatment, 180 days after end of treatment and thereafter every 90 days until end of study or death, which comes first.
PFS: Week 6, Week 12, every 9 weeks thereafter until week 58 and then every 12 weeks until discontinuation of study treatment due to disease progression with clinical instability, start of subsequent anticancer treatment, withdrawal of informed consent, or death, whichever comes first.
Assessment of AE/SAE/AESI are continuous until 90 days after end of treatment.
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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 | No |
| 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 | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| 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 | 9 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 37 |
| 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 |
| Argentina |
| Brazil |
| China |
| Korea, Republic of |
| United States |
| France |
| Hungary |
| Italy |
| Poland |
| Romania |
| 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
|
| The end of the study is defined as 5 years after the first participant received the first dose of study treatment. |
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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 | 5 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
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