A Phase I/II Study of MK-3475 (Pembrolizumab) in children with advanced melanoma or a PD-L1 positive advanced, relapsed or refractory solid tumor or lymphoma (KEYNOTE-051)

Protocol # :
Solid Tumor
Classical Hodgkin Lymphoma
Microsatellite-instability-high Solid Tumor
Disease Sites
Lip, Oral Cavity and Pharynx
Small Intestine
Other Digestive Organ
Other Respiratory and Intrathoracic Organs
Bones and Joints
Soft Tissue
Mycosis Fungoides
Other Skin
Corpus Uteri
Other Female Genital
Other Male Genital
Urinary Bladder
Other Urinary
Eye and Orbit
Brain and Nervous System
Unknown Sites
Ill-Defined Sites
Other Endocrine System
Non-Hodgkin's Lymphoma
Hodgkin's Lymphoma
Kaposi's Sarcoma
Melanoma, Skin
Principal Investigator
Dubois, Steven

Trial Description

This is a two-part study of pembrolizumab (MK-3475) in pediatric participants who have any of
the following types of cancer:

- advanced melanoma (6 months to <18 years of age),

- advanced, relapsed or refractory programmed death-ligand 1 (PD-L1)-positive malignant
solid tumor or other lymphoma (6 months to <18 years of age),

- relapsed or refractory classical Hodgkin lymphoma (rrcHL) (3 years to <18 years of age),

- advanced relapsed or refractory microsatellite-instability-high (MSI-H) solid tumors (6
months to <18 years of age), or

- advanced relapsed or refractory tumor-mutational burden-high ≥10 mutation/Mb (TMB-H)
solid tumors (6 months to <18 years of age), or

- with adjuvant treatment of resected high-risk Stage IIB, IIC, III, or IV melanoma in
children 12 years to <18 years of age

Part 1 will find the maximum tolerated dose (MTD)/maximum administered dose (MAD), confirm
the dose, and find the recommended Phase 2 dose (RP2D) for pembrolizumab therapy. Part 2 will
further evaluate the safety and efficacy at the pediatric RP2D.

The primary hypothesis of this study is that intravenous (IV) administration of pembrolizumab
to children with either advanced melanoma; a PD-L1 positive advanced, relapsed or refractory
solid tumor or other lymphoma; advanced, relapsed or refractory MSI-H solid tumor; or rrcHL,
will result in an Objective Response Rate (ORR) greater than 10% for at least one of these
types of cancer. The 10% assessment does not apply to the MSI-H and TMB-H cohorts.

With Amendment 8, enrollment of participants with solid tumors and of participants aged 6
months to <12 years with melanoma were closed. Enrollment of participants aged ≥12 years to
≤18 years with melanoma continues. Enrollment of participants with MSI-H and TMB-H solid
tumors also continues.

Eligibility Requirements

Inclusion Criteria:

- Between 6 months and <18 years of age on day of signing informed consent is

- 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

- Any number of prior treatment regimens

- 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

- Advanced melanoma or PD-L1-positive advanced, relapsed, or refractory solid tumor or

- 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 with neuroblastoma with only metaiodobenzylguanidine (MIBG)-positive
evaluable disease may be enrolled

- 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

- Adequate organ function

- Female participants of childbearing potential should have a negative urine or serum
pregnancy test within 72 hours before the first dose of study medication

- 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

- Contraceptive use by men should be consistent with local regulations regarding the
methods of contraception for those participating in clinical studies.

- Demonstrate adequate organ function.

Exclusion Criteria:

- 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

- Diagnosis of immunodeficiency or receiving systemic steroid therapy or any other form
of immunosuppressive therapy within 7 days prior to the date of

- 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

- Prior radiotherapy within 2 weeks of start of study treatment

- 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

- Known active central nervous system (CNS) metastases and/or carcinomatous meningitis

- Tumor(s) involving the brain stem

- Severe hypersensitivity (≥ Grade 3) to pembrolizumab and/or any of its excipients

- 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

- Has a history of (non-infectious) pneumonitis that required steroids or current

- Active infection requiring systemic therapy

- 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

- 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)

- Human immunodeficiency virus (HIV)

- Hepatitis B or C

- Known history of active tuberculosis (TB; Bacillus tuberculosis)

- Received a live vaccine within 30 days of planned start of study medication

- 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].)

- 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

- Known psychiatric or substance abuse disorders that would interfere with the
requirements of the study