| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Nonsmall 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 evaluate the efficacy of cobolimab + dostarlimab + docetaxel relative to docetaxel alone in participants with advanced NSCLC who have progressed on prior anti-PD-(L)1 or anti PD- L1therapy and chemotherapy
To evaluate the efficacy of dostarlimab +docetaxel relative to docetaxel alone in participants with advanced NSCLC who
have progressed on prior anti-PD-(L)1 or anti PD- L1 therapy and chem otherapy |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate the efficacy of cobolimab + dostarlimab + docetaxel relative to dostarlimab + docetaxel
To evaluate additional measures of clinical benefit for cobolimab + dostarlimab +docetaxelrelative to docetaxel alone
To evaluate additional measures of clinicalbenefit fordostarlimab + docetaxel relative t o docetaxel alone
To evaluate additional measures of clinical benefit for cobolimab + dostarlimab +docetaxelrelative to dostarlimab +
docetaxel
To evaluate the safety and tolerability of cobolimab + dostarlimab + docetaxel and dostarlimab + docetaxelvs
docetaxel alone |
|
| 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 is ≥18 years old, is able to understand the study procedures, and agrees to
participate in the study by providing written informed consent (as described in Appendix 5), which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.
Note: Participants in Korea are eligible if they are 19 years or older at the time consent is obtained.
2.Participant has histologically or cytologically proven advanced or metastatic NSCLC, and only squamous or nonsquamous cell carcinoma.
3.Participant has received no more than 2 prior lines of therapy for advanced or metastatic disease, which must only include a platinum-based (eg, cisplatin, carboplatin) doublet chemotherapy regimen and an anti-PD-1 or anti PD- L1 antibody.
Participants previously treated with targeted therapies, including angiogenesis inhibitors (eg, bevacizumab, ramucirumab, lenvatinib), are not eligible.
a. Two components of treatment must have been received in the same line or as separate lines of therapy as follows:
-A maximum of 1 line of therapy containing a platinum-based chemotherapy in the metastatic setting
and-A maximum of 1 line of therapy containing an anti-PD-(L)1 or anti PD-L1 antibody Note the following:
−An anti-PD-1 or anti PD- L1 antibody received during a previous clinical study meets this requirement if the antibody has been approved for an indication in at least 1 country.
−Participants from the Phase 3 PACIFIC clinical study (NCT02125461) who received the experimental regimen (chemoradiotherapy followed by durvalumab) (Antonia, 2017) or participants who received a regimen similar to the PACIFIC regimen (chemoradiotherapy followed by an anti-PD-1 or anti PD- L1 antibody) as part of standard of care and have relapsed within 1 year of the first
dose of chemoradiotherapy fulfill the protocol requirement for platinum-based chemotherapy and anti-PD-1 or anti PD- L1 antibody therapy. These regimens are considered 1 line of therapy for stratification purposes.
−The anti-PD-1 or anti PD- L1 antibody can be administered with the platinum-based chemotherapy, and this is considered 1 line of therapy with both agents and no other lines are allowed.
−The anti-PD-1 or anti PD- L1 antibody may be counted as a prior treatment if the antibody is approved in at least 1 country for the treatment of cancer.
Participants who have completed 2 years of treatment with pembrolizumab or another anti-PD-1 or anti PD- L1 antibody, discontinued from that therapy, experienced disease progression, and are then retreated with an anti-PD-(L)1 antibody will be considered as having had 1 line of anti-PD-1 or anti PD- L1 therapy.
−Adjuvant or neoadjuvant systemic anticancer therapy will not count toward the 2 lines of therapy unless disease recurs during the first year following the start of adjuvant chemotherapy.
4. Participant has measurable disease, that is, presenting with at least 1 measurable lesion per RECIST v1.1 as determined by the local site Investigator/radiology assessment.
Target lesions situated in a previously irradiated area are considered measurable if disease 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 for the definition of a measurable lesion.
5. Participant has documented radiological disease progression on prior platinum-based chemotherapy and on prior anti-PD-(L)1 or anti PD- L1 therapy according to RECIST v1.1.
6. Participant agrees to submit an archival FFPE tumor tissue specimen that was collected on or after diagnosis of metastatic disease from location(s) not irradiated prior to biopsy.
Both tissue block and freshly cut slides are acceptable. If archival tissue is not available, the participant must undergo biopsy prior to study entry. See the Study Reference Manual for further details
a. Participants are also encouraged, but not required, to have a fresh tumor tissue biopsy of a primary or metastatic tumor prior to dosing
(samples will be used to enable biomarker analysis).
7. Participant has documented PD-L1 status by the 22C3 pharmDx assay (Agilent/Dako) SP263 assay (Roche), or a LDT with published evidence of concordance with the 22C3 pharmDx assay. If a prior PD-L1 result by 1 of these testing methods is not available at the time of Screening, the participant must submit archival or fresh tumor tissue to be tested locally using 1 of these testing methods, or, if not available, centrally, using the 22C3 pharmDx assay. Results are required for stratification and must be available prior to randomization.
For a full list of Inclusion criteria please refer to the Study Protocol Section 5.1 Inclusion Criteria pg57-61 |
|
| E.4 | Principal exclusion criteria |
Participants are excluded from the study if any of the following criteria apply:
1. Participant has been previously treated with an anti-PD-(L)11, anti PD- L1 or anti-PD-L2 agent thatresulted in permanent discontinuation due to an AE.
2. Participant has been previously treated with an anti-TIM-3 or anti-CTLA-4 agent or docetaxel.
3. Participant has a documented sensitizing EGFR, ALK, or ROS-1 mutation. Participants whose tumors have not been tested for these driver mutations and therefore who have unknown driver mutation status are not eligible. Participants with squamous histology do not need to be tested for these driver mutations.
4. Participant had radiological or clinical disease progression (ie, worsening performance status, clinical symptoms, and laboratory data) ≤8 weeks after initiation of prior anti-PD-1 or anti-PD-L1 antibody. The clinical disease progression should have been
confirmed by a subsequent radiological scan.
5. Participant has received radiation to the lung that is >30 Gy within 6 months prior to the first dose of study treatment.
6. Participant has completed palliative radiotherapy within 7 days prior to the first dose of study treatment.
7. Participant is ineligible if any of the following hepatic characteristics are present:
a.Alanine aminotransferase (ALT) >2.5×ULN
b.ALT and/or aspartate aminotransferase (AST) >1.5×upper limit of normal (ULN) concomitant with alkaline phosphatase (ALP) >2.5×ULN
c. Bilirubin >1×ULN
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 the Investigator’s 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.
8. Participant has a corrected QT interval (QTc) >450 msec (or QTc >480 msec for participants with bundle branch block).
Note the following:
-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 Statistical Analysis Plan (SAP).
9. Participant has had major surgery within 3 weeks prior to the first dose of study treatmentor 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.
10. 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, or bladder carcinoma in situ without evidence of disease, or had a malignancy treated with curative intent and with no evidence of disease recurrence for 5 years since the initiation of that therapy.
Participant has known new or progressive 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 4 weeks before study entry and are off corticosteroids within 3 days prior to the first dose of study treatment.12. Participant has tested positive for the following at Screening or within 3 months before the first dose of study treatment.
a.Presence of hepatitis B surface antigen.
b.Presence of hepatitis C antibody in the absence of an RNA test for hepatitis C virus. If a confirmatory RNA test is available, a positive test result will exclude a participant, while a negative test result (indicating absence of active infection) will allow the participant to enter into the study.
13. Participant has an active infection requiring systemic therapy within 1 week prior to the
anticipated first dose of study treatment.
14. Participant has known HIV (positive for HIV-1 or HIV-2 antibodies).
For a full list of Exclusion criteria please refer to the Study Protocol Section 5.2 Exclusion Criteria pg61-64 |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
efficacy of triplet compared to docetaxel alone-OS defined as survival from the date of randomization to the date of death by any cause
efficacy of doublet compared to docetaxel alone-OS defined as survival from the date of randomization to the date of death by any cause |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
efficacy of the triplet relative to the doublet-OS defined as survival from the date of randomization to the date of death by any cause
Confirmed ORR defined as the proportion of participants who have achieved confirmed CR or confirmed PR, evaluated using
RECIST v1.1 based on Investigator assessment
PFS defined as the length of time until disease progression, from the time of randomization to the earliest date of
assessment of disease progression based on RECIST v1.1 by Investigator assessment or death by any cause
DOR defined as the time from first documented response (CR/PR) until the time of first documentation of disease
progression based on RECIST v 1.1 by Investigator assessment or death, whichever occurs first
TTD in lung cancer defined as time from randomization to meaningful deterioration on a composite endpoint of dyspnea,
chest pain, and cough, from the EORTC-QLQ-LC13
Change from baseline as assessed by the EORTC-QLQ-C30 and the EORTC-QLQ-LC13 domains
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, and 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 |
Up to 44 months
From baseline (Day 1) up to 44 months |
|
| 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 | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | Yes |
| 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) | Yes |
| 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 | 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 | 3 |
| 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 | 8 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 85 |
| 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 |
| Taiwan |
| Australia |
| Brazil |
| Canada |
| Japan |
| Korea, Republic of |
| Mexico |
| Russian Federation |
| Thailand |
| Turkey |
| United Kingdom |
| United States |
| Belgium |
| Finland |
| France |
| Germany |
| Greece |
| Italy |
| Netherlands |
| Poland |
| Romania |
| Spain |
| Sweden |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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 study is defined as the completion of the last participant’s required study visit,
contact, or death, as applicable. |
|
| 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 | 3 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 11 |
| E.8.9.2 | In all countries concerned by the trial days | 17 |
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