Brief Summary:
The purpose of this study is to evaluate the long-term safety and efficacy of pembrolizumab
(MK-3475) in participants from previous Merck pembrolizumab-based parent studies who
transition into this extension study.
This study will consist of three phases: 1) First Course Phase, 2) Survival Follow-up Phase
or 3) Second Course Phase. Each participant will transition to this extension study in one of
the following three phases, depending on the study phase they were in at the completion of
the parent study. Participants who were in the First Course Phase of study treatment with
pembrolizumab or lenvatinib in their parent study will enter the First Course Phase of this
study and complete up to 35 doses or more every 3 weeks (Q3W) or 17 doses or more every 6
weeks (Q6W) of study treatment with pembrolizumab or a pembrolizumab-based combination or
lenvatinib according to arm assignment. Participants who were in the Follow-up Phase in the
parent study (post-treatment or Survival Follow-up Phase) will enter the Survival Follow-up
Phase of this study. Participants who were in the Second Course Phase in their parent study
will enter Second Course Phase of this study and complete up to 17 doses Q3W or 8 doses Q6W
of study treatment with pembrolizumab or a pembrolizumab-based combination according to arm
assignment.
Any participant originating from a parent trial where crossover to pembrolizumab was
permitted upon disease progression may be eligible for 35 doses as Q3W or 17 doses Q6W of
pembrolizumab (approximately 2 years), if they progress while on the control arm and
pembrolizumab is approved for the indication in the country where the potential eligible
crossover participant is being evaluated.
Inclusion Criteria:
- Treated on the parent pembrolizumab studies established by the Sponsor as MK-3475-587
ready.
- Currently receiving pembrolizumab, pembrolizumab based combinations or lenvatinib from
parent studies or in a follow-up phase.
Additional eligibility criteria for participants who enter Second Course Phase once they
are enrolled on MK-3475-587:
- Has not received any anticancer systemic treatment since the last dose of
pembrolizumab or a pembrolizumab-based combination in First Course Phase.
- Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
- Demonstrates adequate organ function.
- Have resolution of any toxic effect(s) of First Course Phase trial treatment with
pembrolizumab or a pembrolizumab-based combination to Grade 1 or less (except
alopecia) before trial treatment in Second Course Phase is started. If participant
received major surgery or radiation therapy of >30 Gray (Gy), they must have recovered
from the toxicity and/or complications of the intervention.
- A female participant is eligible to enroll if she is not pregnant, not breastfeeding,
and ≥1 of the following conditions applies: A woman of childbearing potential (WOCBP)
who agrees to use contraception during the study treatment period and for ≥120 days
(corresponding to time needed to eliminate any study combination treatment(s) plus 30
days (a menstruation cycle) for study treatments with risk of genotoxicity.
Additional eligibility criteria for participants who enter dosing with Lenvatinib:
- Adequately controlled blood pressure (BP) to <150/90 mmHg, with or without
antihypertensive medications.
- For male agrees to be abstinent from penile-vaginal intercourse OR agrees to use a
highly effective contraceptive method while receiving study drug and for 7 days after
the last dose of lenvatinib.
- Is female and not pregnant/breastfeeding and at least one of the following applies
during the study and for ≥4 days after: is not a woman of childbearing potential
(WOCBP), is a WOCBP and uses highly effective contraception (low user dependency
method OR a user dependent hormonal method in combination with a barrier method) or is
a WOCBP who is abstinent from heterosexual intercourse.
Exclusion Criteria:
-There are no exclusion criteria to participate in MK-3475-587.
Participants are excluded from entering Second Course trial treatment once they are
enrolled on MK-3475-587 if any of the following criteria applies:
- Has severe hypersensitivity (≥ Grade 3) to pembrolizumab and/or any of its excipients.
- Has received a live vaccine within 30 days prior to the first dose of Second Course
Phase trial treatment.
- 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 to the Cycle 1 Day 1 of Second Course
Phase.
- Has a known additional malignancy that is progressing or requires active treatment.
Exceptions include early stage cancers (carcinoma in situ or Stage 1) treated with
curative intent, melanoma (non-ulcerated, thin primary), basal cell carcinoma of the
skin, squamous cell carcinoma of the skin, in situ cervical cancer, or in situ breast
cancer that has undergone potentially curative therapy.
- Has known active central nervous system metastases and/or carcinomatous meningitis.
- Has an active autoimmune disease that has required systemic treatment in the past 2
years (i.e., 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) is not considered a form
of systemic treatment and is allowed.
- Has a history of (non-infectious) pneumonitis that required steroids or has current
pneumonitis. Note: Participants that experienced pneumonitis during First Course that
did not meet the criteria for permanent discontinuation are eligible.
- Non-small cell lung cancer (NSCLC) participants only: Has interstitial lung disease.
- Has an active infection requiring systemic therapy.
- Has a known history of human immunodeficiency virus (HIV) infection.
- Has a known history of or is positive for hepatitis B or hepatitis C. For parent
studies where inclusion of participants with hepatitis was permitted, MK-3475-587 will
follow the parent study eligibility criteria for hepatitis.
- Is pregnant or breastfeeding or expecting to conceive or father children within the
projected duration of the study, starting with the Second Course Phase eligibility
Visit through 120 days after the last dose of study treatment.
- Has severe cardiovascular disease, i.e., arrhythmias, requiring chronic treatment,
congestive heart failure (New York Heart Association Class III or IV) or symptomatic
ischemic heart disease.
- Has hepatic decompensation (Child-Pugh score >6 [class B and C]).
- Has uncontrolled thyroid dysfunction.
- Has uncontrolled diabetes mellitus.
- Has had an allogeneic tissue/solid organ transplant.
- Has a known history of active tuberculosis (TB; Bacillus tuberculosis).
Additional exclusion criteria for participants who enter dosing with Lenvatinib:
- Has had major surgery within 3 weeks prior to first dose of study intervention(s).
- Has preexisting ≥Grade 3 gastrointestinal or non-gastrointestinal fistula.
- Has urine protein ≥1 g/24 hours.
- Has LVEF below the institutional (or local laboratory) normal range, as determined by
multigated acquisition scan (MUGA) or echocardiogram (ECHO).
- Has radiographic evidence of encasement or invasion of a major blood vessel, or of
intratumoral cavitation.
- Prolongation of QT intervals corrected for heart rate using Fridericia's (cube root)
correction (QTcF) interval to >480 ms.
- Has clinically significant cardiovascular disease within 12 months from first dose of
study intervention, including New York Heart Association Class III or IV congestive
heart failure, unstable angina, myocardial infarction, cerebral vascular accident, or
cardiac arrhythmia associated with hemodynamic instability.
- Gastrointestinal malabsorption or any other condition that might affect the absorption
of lenvatinib.
- Active hemoptysis (bright red blood of at least 0.5 teaspoon) within 3 weeks prior to
the first dose of study drug.
- Has a history of any contraindication or has a severe hypersensitivity to any
components of lenvatinib.
Primary outcome:
1. Overall Survival (OS) (Time Frame - Up to approximately 10 years):
OS is defined as the time from randomization or start of study treatment for non-randomized participants (on the parent study) to death due to any cause. Participants without documented death at the time of analysis will be censored at the date of the last follow-up.
Secondary outcome:
1. Duration of Response (DOR) Per Evaluation Criteria Used in the Parent Study (Time Frame - Up to approximately 10 years):
DOR is determined by disease assessment and is defined as the time from the earliest date of qualifying response on the parent study until earliest date of disease progression or death from any cause, whichever comes first based upon investigator assessment. The DOR will be presented.
2. Duration of Complete Response (DOCR) Per Evaluation Criteria Used in the Parent Study (Time Frame - Up to approximately 10 years):
DOCR is determined by disease assessment and is defined as the time from the date of complete response (CR) on the parent study until earliest date of disease progression or death from any cause, whichever comes first based upon investigator assessment. The DOCR will be presented.
3. Number of Participants Who Experience Serious Adverse Events (SAEs) (Time Frame - Up to approximately 42 months (Up to 90 days after last dose of study treatment)):
A SAE is defined as any untoward medical occurrence that, at any dose: Results in death, Is life-threatening, Requires inpatient hospitalization or prolongation of existing hospitalization, Results in persistent or significant disability/incapacity or Is a congenital anomaly/birth defect. The number of participants who experience a SAE in this study will be presented.
4. Number of Participants Who Experience Adverse Events of Special Interest (AEOSI) (Time Frame - Up to approximately 40 months (Up to 30 days after last dose of study treatment)):
AEOSI for this study include selected preferred terms from Medical Dictionary for Regulatory Activities (MedDRA) version 20.1 for the following higher-level terms: Pneumonitis, Colitis, Hepatitis, Nephritis, Adrenal Insufficiency, Hypophysitis, Hyperthyroidism, Hypothyroidism, Thyroiditis, Type 1 Diabetes Mellitus, Severe Skin Reactions Including Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN): or If grade 3 or higher, Uveitis, Pancreatitis, Myositis, Guillain-Barre Syndrome, Myocarditis, Encephalitis, Sarcoidosis, Infusion Reactions and Myasthenic Syndrome. The number of participants who experience an AEOSI in this study will be presented.
5. Number of Participants Who Experience Clinically Significant Adverse Events (CSAE) (Time Frame - Up to approximately 40 months (Up to 30 days after last dose of study treatment)):
CSAE are AEs associated with lenvatinib treatment and include selected preferred terms from the lenvatinib CSAE preferred term list document. The number of participants who experience an CSAE in this study will be presented.
6. Number of Participants Who Experience Events of Clinical Interest (ECI) (Time Frame - Up to approximately 40 months (Up to 30 days after last dose of study treatment)):
ECIs for this study include: 1) An overdose of Sponsor's product, that is not associated with clinical symptoms or abnormal laboratory results or 2) An elevated aspartate aminotransferase (AST) or alanine aminotransferase (ALT) lab value that is ≥3X the upper limit of normal (ULN) and an elevated total bilirubin lab value that is ≥2X ULN and, at the same time, an alkaline phosphatase lab value that is <2X ULN, as determined by way of protocol-specified laboratory testing or unscheduled laboratory testing. The number of participants who experience an ECI in this study will be presented.
7. Number of Participants Who Discontinue Study Treatment Due to an AE (Time Frame - Up to approximately 39 months):
An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. The number of participants who discontinue study treatment due to an AE will be presented.
- Experimental: Pembrolizumab 200 mg
Participants receive pembrolizumab 200 mg via intravenous (IV) infusion on Day 1 of each 3-week cycle for up to 35 administrations or more for First Course participants and up to 17 administrations for Second Course participants. - Experimental: Pembrolizumab 400 mg
Participants receive pembrolizumab 400 mg via intravenous (IV) infusion on Day 1 of each 6-week cycle for up to 17 administrations or more for First Course participants and up to 8 administrations for Second Course participants. - Experimental: Pembrolizumab 200 mg + SOC: Per Parent Study)
Participants receive pembrolizumab 200 mg via IV infusion on Day 1 of each 3-week cycle PLUS standard of care (SOC) treatment (or per parent study if there is no SOC) for up to 35 administrations or more for First Course participants and up to 17 administrations for Second Course participants. Participants receiving a pembrolizumab-based combination treatment will receive the dose regimen of the combination drug(s) which is recommended per SOC or was used in the parent study protocol if there is no SOC recommendation. - Experimental: Pembrolizumab 400 mg + SOC (Per Parent Study)
Participants receive pembrolizumab 400 mg via IV infusion on Day 1 of each 6-week cycle PLUS SOC treatment (or per parent study if there is no SOC) for up to 17 administrations or more for First Course participants and up to 8 administrations for Second Course participants. Participants receiving a pembrolizumab-based combination treatment will receive the dose regimen of the combination drug(s) which is recommended per SOC or was used in the parent study protocol if there is no SOC recommendation. - Active Comparator: SOC (Per Parent Study)
Participants receive the dose matched non-pembrolizumab SOC treatment (e.g. chemotherapy) they were receiving as per parent study protocol. - Experimental: Lenvatinib 20 mg
Participants with body weight (BW)>60kg receive Lenvatinib 20mg orally once daily on a 21 or 42 day cycle. It is taken 0-4 hours after completion of pembrolizumabd administration in the clinic on cycle 1 day 1(C1D1), C2D1, C3D1, etc. Taken at home on all other days. - Experimental: Lenvatinib 24 mg
Participants with body weight (BW)>60 kg receive Lenvatinib 24 mg orally once daily on a 21 or 42 day cycle. It is taken 0-4 hours after completion of pembrolizumabd administration in the clinic on cycle 1 day 1(C1D1), C2D1, C3D1, etc. Taken at home on all other days. - Experimental: Lenvatinib 12 mg
Participants with body weight (BW)>60 kg receive Lenvatinib 12 mg orally once daily on a 21 or 42 day cycle. It is taken 0-4 hours after completion of pembrolizumabd administration in the clinic on cycle 1 day 1(C1D1), C2D1, C3D1, etc. Taken at home on all other days. - Experimental: Lenvatinib 8 mg
Participants with body weight (BW)<60 kg receive Lenvatinib 8 mg orally once daily on a 21 or 42 day cycle. It is taken 0-4 hours after completion of pembrolizumabd administration in the clinic on cycle 1 day 1(C1D1), C2D1, C3D1, etc. Taken at home on all other days.
- Pembrolizumab (MK-3475 / KEYTRUDA® / ):
200 or 400 mg IV infusion - Standard of Care (SOC):
IV infusion or oral tablets - Lenvatinib:
Oral capsules
Quelle: ClinicalTrials.gov
