PhII Trial of Pembrolizumab in Advanced Solid Tumors

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Merck Sharp & Dohme LLC

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

2 Feb 2016 → ongoing

Decision date (initial)

2023-02-08

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Merck Sharp & Dohme LLC

External identifiers

EU CT number

2022-501253-37-00

EudraCT number

2015-002067-41

WHO UTN

U1111-1275-8374

ClinicalTrials.gov

NCT02628067

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacokinetic, Pharmacodynamic, Safety, Pharmacogenomic, Efficacy, Pharmacogenetic

1. To evaluate the ORR to pembrolizumab, based on RECIST 1.1 as assessed by independent central radiologic review, in biomarker unselected 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 biomarker selected subjects with any one of multiple types of advanced (metastatic and/or unresectable) 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-H (Groups A-K).
3. (Group L only): To evaluate the ORR to pembrolizumab, based on RECIST 1.1 as assessed by independent central radiologic review, in subjects from mainland China and of Chinese descent, who have solid tumors which are dMMR/MSI-H.
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.

Secondary objectives 11

1. 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 (Groups A-J)
2. 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 (Groups A-J)
3. To evaluate OS in subjects receiving pembrolizumab and the relationship between OS and tumor PD-L1 expression and GEP score (Groups A-J)
4. To determine the safety and tolerability of pembrolizumab (Groups A-K)
5. 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 MSI-H status (Groups A-K)
6. 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 MSI-H status (Groups A-K)
7. To evaluate OS in subjects receiving pembrolizumab and the relationship between OS and tumor MSI-H status (Groups A-K)
8. To evaluate DOR and PFS (based on RECIST 1.1 as assessed by central imaging vendor), and OS in subjects receiving pembrolizumab and their relationship to tumor MSI-H status (Group L)
9. To determine safety and tolerability of pembrolizumab (Group L)
10. To evaluate DOR and PFS (based on RECIST 1.1 as assessed by central imaging vendor), and OS in subjects who have advanced solid tumors that have failed at least one line of therapy and which are TMB-H (≥10 mut/Mb, F1CDx assay), excluding dMMR/MSI-H tumors. (Group M)
11. To determine safety and tolerability of pembrolizumab (Group M)

Conditions and MedDRA coding

(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, (I) Thyroid Carcinoma, (J) Salivary Gland Carcinoma (sarcomas and mesenchymal tumors are excluded), OR (K) Any advanced solid tumor, with the exception of colorectal carcinoma (CRC), which is microsatellite instability (MSI)-high (MSI-H). (L) Any advanced solid tumor (including CRC) which is mismatch repair deficient (dMMR)/MSI-H in subjects from mainland China who are of Chinese descent. (M) Any advanced solid tumor that has failed at least one line of therapy and is Tumor Mutational Burden-High (TMB-H) (≥10 mut/Mb, F1CDx assay), excluding subjects with dMMR/MSI-H tumors.

Study design 1 period

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 8

1. Histologically or cytologically-documented, advanced solid tumor of one of the following types: Anal Squamous Cell Carcinoma; Biliary Adenocarcinoma (gallbladder or biliary tree (intrahepatic or extrahepatic cholangiocarcinoma) except Ampulla of Vater cancers); Neuroendocrine Tumors (well- and moderately-differentiated) of the lung, appendix, small intestine, colon, rectum, or pancreas; Endometrial Carcinoma (sarcomas and mesenchymal tumors are excluded); Cervical Squamous Cell Carcinoma; Vulvar Squamous Cell Carcinoma; Small Cell Lung Carcinoma; Mesothelioma; Thyroid Carcinoma; Salivary Gland Carcinoma (sarcomas and mesenchymal tumors are excluded); Any advanced solid tumor, with the exception or colorectal carcinoma (CRC), which is Microsatellite Instability (MSI)-High (MSI-H) OR Any advanced solid tumor (including Colorectal Carcinoma [CRC]) which is Mismatch Repair Deficient (dMMR)/MSI-H in participants from mainland China who are of Chinese descent. (CRC participants will have a histologically proven locally advanced unresectable or metastatic CRC which is dMMR/MSI-H that has received 2 prior lines of therapy.) OR 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. Note: For participants to be eligible for enrollment they must have failed at least one line of standard of care systemic therapy (ie, not treatment naïve), with the exception of CRC participants who must have failed at least 2 lines of standard of care systemic therapy, as per CRC specific eligibility criteria. Participants must not have melanoma or NSCLC.
2. Progression of tumor or intolerance to therapies known to provide clinical benefit. There is no limit to the number of prior treatment regimens
3. Can supply tumor tissue for study analyses (dependent on tumor type)
4. Radiologically-measurable disease
5. Performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale within 3 days prior to first dose of pembrolizumab
6. Life expectancy of at least 3 months
7. Adequate organ function
8. Female participants of childbearing potential must be willing to use adequate contraception 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 is as follows: MK-3475 (120 days)

Exclusion criteria 19

1. Currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of study treatment
2. Diagnosis of immunodeficiency or receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study treatment
3. Active autoimmune disease that has required systemic treatment in the past 2 years
4. Prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study Day 1 or not recovered from an adverse event caused by mAbs administered more than 4 weeks earlier
5. Prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks of study Day 1 or not recovered from adverse events caused by a previously administered agent
6. 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. Known active central nervous system (CNS) metastases and/or carcinomatous meningitis
8. Has known glioblastoma multiforme of the brain stem
9. Has a history of (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease
10. Active infection requiring systemic therapy
11. Known psychiatric or substance abuse disorders that would interfere with the participant's ability to cooperate with the requirements of the study
12. Pregnant, breastfeeding, or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of study treatment
13. Previously participated in any other pembrolizumab (MK-3475) study, or received prior therapy with an antiprogrammed cell death (PD)-1, anti-PD-Ligand 1 (anti-PDL1), anti-PD-Ligand 2 (anti-PD-L2), or any other immunomodulating mAb or drug specifically targeting T-cell co-stimulation or checkpoint pathways
14. Known history of Human Immunodeficiency Virus (HIV)
15. Known active Hepatitis B or C
16. Received live vaccine within 30 days of planned start of study treatment
17. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients
18. Known history of active tuberculosis (TB, Bacillus tuberculosis)
19. Has had an allogenic tissue/solid organ transplant

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Objective Response Rate (ORR)

Secondary endpoints 5

1. Duration of Response (DOR)
2. Progression Free Survival (PFS)
3. Overall Survival (OS)
4. Percentage of Participants with Adverse Events
5. Percentage of Participants who Discontinued Study Intervention due to Adverse Events

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Merck Sharp & Dohme LLC

Sponsor organisation

Merck Sharp & Dohme LLC

Address

126 East Lincoln Avenue

City

Rahway

Postcode

07065-4607

Country

United States

Scientific contact point

Organisation

Merck Sharp & Dohme LLC

Contact name

Roman Groisberg

Public contact point

Organisation

Merck Sharp & Dohme LLC

Contact name

Roman Groisberg

Third parties 8

Locations

9 EU/EEA countries · 28 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Temporary halts 1 · Art. 38 CTR

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 79 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

17 submissions — initial application plus substantial / non-substantial modifications