| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Extensive-stage small-cell lung cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
| Extensive-stage small-cell lung cancer |
|
| 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 |
| 1. To compare overall survival for MK-7684A in combination with etoposide/platinum followed by MK-7684A to atezolizumab in combination with etoposide/platinum followed by atezolizumab. |
|
| E.2.2 | Secondary objectives of the trial |
1. To compare progression-free survival per RECIST 1.1 by blinded independent central review (BICR) for MK-7684A plus etoposide/platinum followed by MK-7684A to atezolizumab plus etoposide/platinum followed by atezolizumab.
2. To evaluate objective response rate per RECIST 1.1 by BICR for MK-7684A plus etoposide/platinum followed by MK-7684A compared to atezolizumab plus etoposide/platinum followed by atezolizumab.
3. To evaluate duration of response per RECIST 1.1 by BICR for MK-7684A plus etoposide/platinum followed by MK-7684A compared to atezolizumab plus etoposide/platinum followed by atezolizumab.
4. To evaluate safety and tolerability based on proportion of adverse events.
5. To evaluate change from baseline and time to true deterioration in global health status/quality of life, physical functioning, dyspnea, cough, chest pain for MK-7684A plus etoposide/platinum followed by MK-7684A compared to atezolizumab plus etoposide/platinum followed by atezolizumab.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Has histologically or cytologically confirmed diagnosis of ES-SCLC in need of first-line therapy.
2. Has ES-SCLC defined as Stage IV (T any, N any, M1a/b/c) by the American Joint Committee on Cancer, Eighth Edition or T3-T4 due to multiple lung nodules that are too extensive or have tumor/nodal volume that is too large to be encompassed in a tolerable radiation plan.
3. Is male or female, at least 18 years of age at the time of providing documented informed consent.
4. Male participants are eligible to participate if they agree to the following during the intervention period and for at least the time needed to eliminate each study intervention after the last dose of study intervention. The length of time required to continue contraception for each study intervention after the last dose of the intervention is as follows:
- Etoposide, cisplatin, or carboplatin: 95 days
- Blinded study intervention: no contraception measures
• 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 unless confirmed to be azoospermic as detailed below:
- Agree to use a male condom plus partner use of an additional contraceptive method when having penile-vaginal intercourse with a WOCBP who is not currently pregnant.
- Contraceptive use by men should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. If the contraception requirements in the local label for any of the study interventions is more stringent than the requirements above, the local label requirements are to be followed.
5. A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies:
• Is not a WOCBP
OR
• Is a WOCBP and using a contraceptive method that is highly effective, with low user dependency, or be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent basis) during the intervention period and for at least the time needed to eliminate each study intervention after the last dose of study intervention and agrees not to donate eggs (ova, oocytes) to others or freeze/store for her own use for the purpose of reproduction during this period. The length of time required to continue contraception for each study intervention after the last dose of the intervention is as follows:
- Etoposide, cisplatin, or carboplatin: 180 days
- Blinded study intervention: 5 months
The investigator should evaluate the potential for contraceptive method failure in relationship to the first dose of study intervention.
- A WOCBP must have a negative highly sensitive pregnancy test within 24 hours before the first dose of study intervention.
- If a urine test cannot be confirmed as negative, a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive.
- Additional requirements for pregnancy testing during and after study intervention are in Section 8.3.6 of the protocol.
- The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy.
- Contraceptive use by women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. If the contraception requirements in the local label for any of the study interventions is more stringent than the requirements above, the local label requirements are to be followed.
6. The participant (or legally acceptable representative) has provided documented informed consent/assent for the study. The participant may also provide consent/assent for FBR. However, the participant may participate in the study without participating in FBR.
7. Has measurable disease per RECIST 1.1 as assessed by the local site investigator/radiology. Lesions situated in a previously irradiated area are considered measurable if progression has been shown in such lesions. At least 1 lesion that meets the criteria for being measurable, as defined by RECIST 1.1, must be appropriate for selection as a target lesion.
8. Submits a pretreatment archival tumor tissue sample or newly obtained core, incisional, or excisional biopsy of a tumor lesion not previously irradiated where such sample exists. Biopsy/tissue is preferred, but cytology sample by fine needle aspiration is allowed. The sample may be submitted after enrollment but must be submitted within 4 weeks after randomization.
9. Has an ECOG performance status of 0 to 1 assessed within 7 days before allocation/randomization.
10. Has adequate organ function.
11. Has a predicted life expectancy of >3 months. |
|
| E.4 | Principal exclusion criteria |
1. Is considered a poor medical risk due to a serious, uncontrolled medical disorder or nonmalignant systemic disease. Examples include, but are not limited to, uncontrolled major seizure disorder, unstable spinal cord compression, or severe or life-threatening superior vena cava syndrome.
2. Has received prior treatment (systemic therapy including investigational agents, curativeintent radiotherapy, or curative-intent surgical resection) for SCLC.
3. Is expected to require any other form of antineoplastic therapy for SCLC while on study.
4. Has received a live or live-attenuated vaccine within 30 days before the first dose of study intervention. Administration of killed vaccines are allowed.
5. Has received an investigational agent or has used an investigational device within 4 weeks prior to study intervention administration.
6. 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 the first dose of study medication.
7. Has a known additional malignancy that is progressing or has required active treatment within the past 3 years.
8. Has known active CNS metastases and/or carcinomatous meningitis. Participants with brain metastases may participate only if they satisfy all of the following:
• Completed treatment (eg, whole brain radiation treatment, stereotactic radiosurgery, or equivalent) at least 14 days before the first dose of study intervention
• Have no evidence of new or enlarging brain metastases confirmed by posttreatment repeat brain imaging (preferably using the same modality) performed at least 4 weeks after treatment and within the screening period, and
• Are neurologically stable without the need for steroids at least 7 days before the first dose of study intervention as per local site assessment.
9. Has a history of severe hypersensitivity reaction (≥Grade 3) to any study intervention and/or any of its excipients (refer to the IB and/or approved product label(s) for a list of excipients).
10. 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.
11. Has a history of (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.
12. Has a known history of, or active, neurologic paraneoplastic syndrome.
13. Has an active infection requiring systemic therapy.
14. Has a known history of HIV infection. No HIV testing is required unless mandated by local health authority.
15. Has a known history of Hepatitis B (defined as HBsAg reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection.
16. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating investigator.
17. Has a known psychiatric or substance abuse disorder that would interfere with the participant’s ability to cooperate with the requirements of the study.
18. Has had an allogenic tissue/solid organ transplant.
19. Has had major surgery within 3 weeks before receiving the first dose of study intervention or has not recovered adequately from toxicity and/or complications from an intervention prior to receiving the first dose of study intervention.
20. Has symptomatic ascites or pleural effusion. A participant who is clinically stable following treatment for these conditions (including therapeutic thoraco- or paracentesis) is eligible. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 1. Up to approximately 37 months |
|
| E.5.2 | Secondary end point(s) |
1. Progression-Free Survival (PFS)
2. Objective Response Rate (ORR)
3. Duration of Response (DOR)
4. Percentage of Participants Who Experienced an Adverse Event (AE)
5. Percentage of Participants Who Discontinued Study Treatment Due to an AE
6. Change from Baseline in the Global Health Status/Quality of Life (Items 29 and 30) Combined Score on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30)
7. Change from Baseline in Physical Functioning (Items 1-5) Combined Score on the EORTC QLQ-C30
8.Change from Baseline in Dyspnea Score (Item 8) on the EORTC QLQ-C30
9. Change from Baseline in Cough Score (Item 31) on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Lung Cancer 13 (EORTC QLQ-LC13)
10. Change from Baseline in Chest Pain Score (Item 40) on the EORTC QLQ-LC13
11. Time to True Deterioration (TTD) in the Global Health Status/Quality of Life (Items 29 and 30) Combined Score on the EORTC QLQ-C30
12. TTD in Physical Functioning (Items 1-5) Combined Score on the EORTC QLQ-C30
13. TTD in Dyspnea Score (Item 8) on the EORTC QLQ-C30
14. TTD in Cough Score (Item 31) on the EORTC QLQ-LC13
15. TTD in Chest Pain Score (Item 40) on the EORTC QLQ-LC13
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Up to approximately 26 months
2. Up to approximately 37 months
3. Up to approximately 37 months
4. Up to approximately 60 months
5. Up to approximately 60 months
6. Baseline and up to approximately 37 months
7. Baseline and up to approximately 37 months
8. Baseline and up to approximately 37 months
9. Baseline and up to approximately 37 months
10. Baseline and up to approximately 37 months
11. Baseline and up to approximately 37 months
12. Baseline and up to approximately 37 months
13. Baseline and up to approximately 37 months
14. Baseline and up to approximately 37 months
15. Baseline and up to approximately 37 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 | 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) | No |
| 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 | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| 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) | 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 84 |
| 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 |
| Australia |
| Canada |
| China |
| Israel |
| Japan |
| Mexico |
| United States |
| Austria |
| Finland |
| France |
| Lithuania |
| Poland |
| Netherlands |
| Romania |
| Germany |
| Greece |
| Italy |
| Belgium |
| Hungary |
| Ireland |
| Portugal |
| Russian Federation |
| Turkey |
| Ukraine |
| United Kingdom |
|
| 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
|
|
| 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 | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| 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 | 0 |
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