A Phase I/II trial of MK-3475 (pembrolizumab) in children's solid tumors and lymphoma

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Merck Sharp & Dohme LLC

Participant type

Pediatric, Patients

Age range

0-17 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

19 Mar 2015 → ongoing

Decision date (initial)

2023-04-04

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Merck Sharp & Dohme LLC

External identifiers

EU CT number

2022-501257-36-00

EudraCT number

2014-002950-38

WHO UTN

U1111-1279-9249

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacokinetic, Pharmacogenomic, Pharmacodynamic, Safety, Dose response, Efficacy

1. To define the rate of Dose-Limiting Toxicities (DLTs) at the Maximum Tolerated Dose (MTD) or Maximum Administered Dose (MAD) of pembrolizumab when administered as monotherapy.
2. To determine the safety and tolerability of pembrolizumab based on adverse events (AEs).
3. To evaluate antitumor activity of pembrolizumab based on response evaluation criteria in solid tumors (RECIST) 1.1 per site assessment.
4. To evaluate antitumor activity of pembrolizumab based on Objective Response Rate (ORR) according to RECIST 1.1 per site assessment.
5. To determine the safety and tolerability of pembrolizumab based on AEs and clinical and laboratory measures in the relapsed refractory classical Hodgkin lymphoma (rrcHL) cohort.
6. To evaluate antitumor activity of pembrolizumab in the rrcHL cohort based on the ORR based on assessments every 12 weeks.

Secondary objectives 8

1. To characterize PK of pembrolizumab.
2. To characterize pharmacodynamics of pembrolizumab.
3. To evaluate clinical activity of pembrolizumab as measured by site assessment: • DOR, DCR, and PFS by RECIST 1.1.•Overall survival.
4. To evaluate antitumor activity of pembrolizumab by IWG 2007 response criteria by following endpoints: • ORR, DOR and PFS per site assessment. • DOR and PFS per BICR assessment. • Overall survival.
5. To assess at least 5 of the following markers NRAS, BRAF, MEK, KIT, PDGF, TP53, RB1 and BRCA1, Akt phosphorylation, IL-17 and PD-L1, at time of progression
6. To assess change in vaccinated antibody concentrations, and memory B- and T-cell counts.
7. To evaluate relationship between baseline tumor PD-L1 expression and clinical efficacy outcomes.
8. To assess PD-L1 and PD-L2 expression and other biomarkers to compare the extent of pre-pembrolizumab PD-L1 expression in tissue biopsies for pembrolizumab responders versus nonresponders.

Conditions and MedDRA coding

Treatment of advanced melanoma, or advanced, relapsed or refractory PD-L1 positive malignant solid tumor or other lymphoma, relapsed or refractory classical Hodgkin lymphoma (rrcHL), advanced, relapsed or refractory microsatellite-instability-high (MSI-H) solid tumors, or any advanced relapsed or refractory solid tumor that is tumormutational- burden ≥10 mut/Mb (TMB-H), excluding MSIH/ deficient mismatch repair (dMMR) tumors, as measured by the F1CDx™ assay in children from 6 months (or 3 years for rrcHL Cohort) to less than 18 years old.

Regulatory references

EMA paediatric investigation plan (PIP)

EMEA-001474-PIP01-13

Plan to share IPD

Yes

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 13

1. Between 6 months and <18 years of age on day of signing informed consent is documented.
2. Histologically- or cytologically-documented, locally-advanced, or metastatic solid malignancy or lymphoma that is incurable and has failed prior standard therapy, or for which no standard therapy exists, or for which no standard therapy is considered appropriate
3. Any number of prior treatment regimens
4. Tissue (or lymph node biopsy for rrcHL participants) available from an archival tissue sample or, if appropriate, a newly obtained core or excisional biopsy of a tumor lesion not previously irradiated
5. Advanced melanoma or PD-L1-positive advanced, relapsed, or refractory solid tumor or lymphoma
6. Measurable disease based on RECIST 1.1 (Or based on IWG [Cheson, 2007] [i.e., measurement must be >15 mm in longest diameter or >10 mm in short axis] for rrcHL participants)
7. Participants with neuroblastoma with only metaiodobenzylguanidine (MIBG)-positive evaluable disease may be enrolled
8. Lansky Play Scale ≥50 for participants from 6 months up to and including 16 years of age; or Karnofsky score ≥50 for participants >16 years of age
9. Adequate organ function
10. Female participants of childbearing potential should have a negative urine or serum pregnancy test within 72 hours before the first dose of study medication
11. Female participant is not a woman of childbearing potential (WOCBP) or is a WOCBP who is abstinent from heterosexual intercourse or using contraception during the intervention period and for at least 120 days after the last dose of study intervention
12. Contraceptive use by men should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
13. Demonstrate adequate organ function.

Exclusion criteria 20

1. Currently participating and receiving study therapy in, or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the date of allocation/randomization
2. Diagnosis of immunodeficiency or receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the date of allocation/randomization
3. Prior systemic anti-cancer therapy including investigational agent within 2 weeks prior to study Day 1 or not recovered from adverse events due to a previously administered agent
4. Prior radiotherapy within 2 weeks of start of study treatment
5. Known additional malignancy that is progressing or requires active treatment with the exception of basal cell carcinoma of the skin, squamous cell carcinoma of the skin or carcinoma in situ (eg, breast carcinoma, cervical carcinoma in situ) with potentially curative therapy, or in situ cervical cancer
6. Known active central nervous system (CNS) metastases and/or carcinomatous meningitis
7. Tumor(s) involving the brain stem
8. Severe hypersensitivity (≥ Grade 3) to pembrolizumab and/or any of its excipients
9. Active autoimmune disease that has required systemic treatment in past 2 years; replacement therapy (such as thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is acceptable
10. Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis.
11. Active infection requiring systemic therapy
12. Pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial through 120 days after the last dose of study medication
13. Prior therapy with an anti-programmed cell death (PD)-1, anti-PD-ligand 1 (anti-PD-L1), anti-PD-L2 agent, or any agent directed to another stimulatory or inhibitory T-cell receptor (eg, cytotoxic lymphocyte associated protein-4 [CTLA-4], OX-40, CD137)
14. Human immunodeficiency virus (HIV)
15. Hepatitis B or C
16. Known history of active tuberculosis (TB; Bacillus tuberculosis)
17. Received a live vaccine within 30 days of planned start of study medication
18. Has undergone solid organ transplant at any time, or prior allogeneic hematopoietic stem cell transplantation within the last 5 years. (Participants who have had an allogeneic hematopoietic transplant >5 years ago are eligible as long as there are no symptoms of Graft Versus Host Disease [GVHD].)
19. History or current evidence of any condition, therapy, or laboratory abnormality, or known severe hypersensitivity to any component or analog of the trial treatment, that might confound the results of the trial, or interfere with the participant's participation for the full duration of the study
20. Known psychiatric or substance abuse disorders that would interfere with the requirements of the study

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 6

1. Objective Response Rate (ORR) by Response Evaluation Criteria in Solid Tumors and Other Lymphoma Version 1.1 (RECIST 1.1) per Site Assessment (Each Disease Indication Evaluated Separately)
2. ORR by RECIST 1.1 per Site or BIRC Assessment for MSI-H or TMBH Solid Tumors (Each Cohort Evaluated Separately)
3. ORR by International Working Group (IWG) Response Criteria (Cheson, 2007) per BICR Assessment for rrcHL Cohort
4. Number of Participants with Dose-Limiting Toxicities (DLTs)
5. Number of Participants Experiencing Adverse Events (AEs)
6. Number of Participants Discontinuing Study Drug Due to AEs

Secondary endpoints 18

1. ORR by IWG Response Criteria (Cheson, 2007) per Site Assessment (rrcHL Cohort)
2. DOR per RECIST 1.1 by Site Assessment (Advanced Melanoma, Solid Tumors and Other Lymphoma, Each Disease Indication Is Evaluated Separately)
3. DOR per RECIST 1.1 by Site or BIRC Assessment (MSI-H and TMBH, Each Cohort Is Evaluated Separately)
4. DOR per IWG 2007 (Cheson, 2007) Response by BICR Assessment (rrcHL Cohort)
5. DOR per IWG 2007 (Cheson, 2007) Response by Site Assessment (rrcHL Cohort)
6. DOR per Immune-related Response Evaluation Criteria in Solid Tumors (irRECIST) by Site Assessment (Solid Tumors and Other Lymphoma, Each Disease Indication Evaluated Separately)
7. DOR per Immune-related Response Evaluation Criteria in Solid Tumors (irRECIST) by Site Assessment (MSI-H and TMB-H, Each Cohort Is Evaluated Separately)
8. Progression-free Survival (PFS) Using RECIST 1.1 Criteria by Site Assessment (Solid Tumors and Other Lymphoma, Each Disease Indication Evaluated Separately)
9. PFS using RECIST 1.1 Criteria by Site or BIRC Assessment (MSI-H and TMB-H, Each Cohort Evaluated Separately)
10. PFS using IWG 2007 Criteria (Chesson 2007) by BICR Assessment (rrcHL Cohort)
11. PFS using IWG 2007 Criteria (Chesson, 2007) by Site Assessment (rrcHL Cohort)
12. PFS Using irRECIST Criteria by Site Assessment
13. Disease Control Rate by RECIST 1.1 Using Site Assessment (Solid Tumors and Other Lymphoma, Each Disease Indication Evaluated Separately)
14. Disease Control Rate by RECIST 1.1 Using Site or BIRC Assessment (MSIH and TMB-H, Each Cohort Evaluated Separately)
15. Disease Control Rate by irRECIST Using Site Assessment (Solid Tumors and Other Lymphomas, Each Disease Indication Evaluated Separately)
16. Overall Survival
17. Objective irRECIST Response Rate by Site Assessment (Each Disease Indication Evaluated Separately)
18. Area Under the Concentration Curve (AUC) for Pembrolizumab

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

Rohini Singh

Public contact point

Organisation

Merck Sharp & Dohme LLC

Contact name

Rohini Singh

Third parties 9

Locations

6 EU/EEA countries · 12 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 87 files

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

Application history

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