| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| -Anal Squamous Cell Carcinoma (CA)-Biliary Adenocarcinoma -Neuroendocrine Tumors (well- and moderately-differentiated) -Endometrial CA (sarcomas and mesenchymal tumors are excluded)-Cervical Squamous and Vulvar Squamous Cell CA-Small Cell Lung CA-Malignant Pleural Mesothelioma-Thyroid CA (Papillary or Follicular Subtype)-Salivary Gland CA (sarcomas and mesenchymal tumors are excluded)-Other advanced solid tumor with the exception of colorectal carcinoma which is Microsatellite Instability -High |
|
| 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 | LLT |
| E.1.2 | Classification code | 10065143 |
| E.1.2 | Term | Malignant solid tumour |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 |
1: To evaluate the ORR to pembrolizumab, based on RECIST 1.1 as assessed by independent central radiologic review, in biomarkerunselected
subjects with any one of multiple types of advanced (metastatic and/or unresectable) solid tumors (Groups A-J)
2: To evaluate the ORR to pembrolizumab, based on RECIST 1.1 as assessed by independent central radiologic review, in biomarkerselected subjects with any one of multiple types of advanced solid tumors (Groups A-K) .The primary biomarkers to be evaluated are (1) tumor expression of PD-L1 by IHC (Groups A-J), (2) tumor GEP by RNA analysis (Groups A-J), and (3) tumor MSI by DNA analysis (Groups A-J) or routine local testing (Group K).
4: (Group M only): To evaluate the ORR to pembrolizumab, based on RECIST 1.1 as assessed by independent central radiologic review, in
subjects who have advanced solid tumors that have failed at least one systemic line of therapy and which are TMB-H (=10 mut/Mb, F1CDx assay), excluding dMMR/MSI-H tumors. |
|
| E.2.2 | Secondary objectives of the trial |
The following secondary objectives will be evaluated across the ten specified tumor types (Groups A-J):
-To evaluate DOR (based on RECIST 1.1 as assessed by independent central radiologic review) in subjects receiving pembrolizumab and the relationship between DOR and tumor PD-L1 expression and GEP score
-To evaluate PFS (based on RECIST 1.1 as assessed by independent central radiologic review ) in subjects receiving pembrolizumab and the relationship between PFS and tumor PD-L1 expression and GEP score
- To evaluate OS in subjects receiving pembrolizumab and the relationship between OS and tumor PD-L1 expression and GEP score
The following secondary objectives will be evaluated across all tumor types (Groups A-K):
-To determine the safety and tolerability of pembrolizumab
Refer to protocol for complete list |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Be willing and able to provide documented informed consent/assent for the trial. The subject may also provide consent/assent for Future
Biomedical Research. However, the subject may participate in the main trial without participating in Future Biomedical Research.
2.Be ≥18 years of age on the day of signing informed consent.
3.Have a histologically or cytologically-documented, advanced (metastatic and/or unresectable) solid tumor that is incurable and for which prior standard first-line treatment has failed. Patients must have progressed on or be intolerant to therapies that are known to provide clinical benefit. There is no limit to the number of prior treatment regimens.
4. Have one of the following advanced (unresectable and/or metastatic) tumor types:
(A) Anal Squamous Cell Carcinoma,
(B) Biliary Adenocarcinoma (gallbladder or biliary tree (intrahepatic or extrahepatic cholangiocarcinoma) except Ampulla of Vater Cancers,
(C) Neuroendocrine Tumors (well- and moderately-differentiated), of the lung, appendix, small intestine, colon, rectum, or pancreas,
(D) Endometrial Carcinoma (sarcomas and mesenchymal tumors are excluded),
(E) Cervical Squamous Cell Carcinoma, (F)Vulvar Squamous Cell Carcinoma, (G) Small Cell Lung Carcinoma,
(H) Mesothelioma (Malignant Pleural Mesothelioma), Thyroid Carcinoma (Papillary or Follicular Subtypes),
(J) Salivary Gland Carcinoma (sarcomas and mesenchymal tumors are excluded)
OR
(K) Any advanced solid tumor (except CRC), which is MSI-H.
(L) Any advanced solid tumor (including CRC*) which is dMMR/MSI-H in patients from mainland China who are of Chinese descent. (M) Any advanced solid tumor that has failed at least one line of therapy and is TMB-H (≥10 mut/Mb, F1CDx assay), excluding dMMR/MSI-H tumors.
5. Have submitted an evaluable tissue sample for biomarker analysis from a tumor lesion not previously irradiated (exceptions may be considered after consultation with and approval by the Sponsor) (See Laboratory Manual for detailed instructions). The tumor tissue submitted for analysis must be from a single tumor tissue specimen and of sufficient quantity and quality to allow assessment of ALL required primary biomarkers.
6. If enrollment in Groups A-J has moved to biomarker enrichment, have a tumor that is positive for one or more of the pre-specified primary biomarker(s), as assessed by the central laboratory. These enrichment biomarkers may be PD-L1 expression by IHC (at a percentage to be prespecified), a positive tumor RNA GEP score (at a prespecified cut-off), and/or tumor MSI-H.
7. Have radiologically measurable disease based on RECIST 1.1. Independent central radiologic review must confirm the presence of radiologically measureable disease based on RECIST 1.1 for the subject to be eligible to participate in the trial (see Site Imaging Manual for detailed instructions). Tumor lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.
8. Have a performance status of 0 or 1 on the ECOG Performance Scale. This performance status must be confirmed within 3 days prior to the first dose of pembrolizumab or the subject must be excluded.
9. Life expectancy of at least 3 months.
10. Demonstrate adequate organ function as described in the protocol
11. 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 a failure rate of <1% per year), or be abstinent from heterosexual intercourse as their preferred and usual lifestyle 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 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 is as follows:
• MK-3475 (120 days)
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 (urine or serum as required by local regulations) within 72 hours (serum) or 24 hours (urine) before the first dose of study intervention.
• If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive |
|
| E.4 | Principal exclusion criteria |
1. Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigation device within 4 weeks of the first dose of treatment.
2. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment. The use of physiologic doses of corticosteroids may be approved after consultation with the Sponsor.
3. Has an active autoimmune disease that has required systemic treatment in the past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) or treatment with drugs (e.g. neomercazol, carbamazole, etc.) that function to decrease the generation of thyroid hormone by a hyperfunctioning thyroid gland (e.g in Graves' disease) is not considered a form of systemic treatment of an autoimmune disease.
4. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from an AE due to mAbs administered more than 4 weeks earlier.
5. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from an AE due to a previously administered agent.
6. Has a known additional malignancy within 2 years prior to enrollment with the exception of curatively treated basal cell carcinoma of the skin, squamous cell carcinoma of the skin, and/or curatively resected in situ cancers.
7. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided these brain metastases are stable (without evidence of progression by imaging over a period of at least 4 weeks and any neurologic symptoms have returned to baseline), they have no evidence of new or enlarging brain metastases (confirmed by imaging within 28 days of the first dose of trial treatment), and they are not using steroids for at least 7 days prior to trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability.
8. Has known glioblastoma multiforme of the brainstem.
9. Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or current pneumonitis/interstitial lung disease.
10. Has an active infection requiring systemic therapy.
11. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
12. Has known psychiatric or substance abuse disorders that would interfere with he participant's / subject's ability to cooperate with the requirements of the trial.
13. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 120 days after the last dose of trial treatment.
14. Has previously participated in any other pembrolizumab (MK-3475) trial, or received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, or any other immune-modulating mAb (including ipilimumab and any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways).
15. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). No HIV testing is required unless mandated by local health authority.
16. Has known active Hepatitis B (i.e. HBsAg positive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected). No testing for Hepatitis B and Hepatitis C is required unless mandated by local health authority.
17. Has received a live vaccine within 30 days of planned start of study therapy.
18. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients.
19. Has a known history of active tuberculosis (TB, Bacillus tuberculosis).
20. Has had an allogenic tissue/solid organ transplant.
21. Has melanoma or NSCLC (Group M only).
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| ORR based on RECIST 1.1 as assessed by independent central radiologic review |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
The trial incorporates an adaptive design in which multiple interim analyses may be performed. Results will be reviewed by the study team. The cutoffs for the three primary biomarker assays will be selected and specified before the first interim analysis. Details regarding the timing and conduct of the initial interim analysis will be further clarified in the sSAP. The planned sample size may be modified based on the interim results. The timing of additional interim analyses, the final analysis as well as the analysis plan will be documented in the sSAP. The sSAP will also be updated as the trial evolves.
The primary endpoint of ORR will be used for all interim analyses with or without a confirmatory assessment; however, a confirmatory assessment is required for the final analysis |
|
| E.5.2 | Secondary end point(s) |
Safety and Tolerability
Duration of response (DOR)
Progression-free survival (PFS)
Overall survival (OS)
(PK) for the 200 mg iv Q3W fixed dosing regimen |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Secondary efficacy endpoints will be summarized at the time that the primary analysis is conducted; however, these secondary endpoints are not likely to be mature at that time. |
|
| 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 | 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 | 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.8.3 |
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 | 22 |
| 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 |
| France |
| Netherlands |
| Spain |
| Germany |
| Italy |
| Denmark |
| Norway |
| 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 | 10 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 10 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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