Advance tumor

• To evaluate the safety and tolerability of FLX475 as a single agent and in combination with pembrolizumab in subjects with advanced cancer • To evaluate the anti-tumor activity of FLX475 as a single agent and in combination with pembrolizumab in subjects with advanced solid tumors

FLX475

FLX475
MK-3475

tablet

5/25/50/75
100

Primary Outcome Measures :
Safety and tolerability of FLX475 as a single agent and in combination with pembrolizumab measured by the incidence of adverse events, including dose-limiting toxicities and maximum tolerated dose [ Time Frame: Approximately 18 weeks ]

Overall response rate in subjects treated with FLX475 as a single agent and in combination with pembrolizumab [ Time Frame: Through study completion (approximately 2 years) ]

1. All subjects must have histologically or cytologically confirmed, advanced or metastatic
tumors and (1) have disease progression after treatment with other available therapies for
advanced or metastatic disease that are known to confer clinical benefit or (2) do not
tolerate or refuse standard treatment(s).
2. Subject must have one of the following diagnoses to be eligible for enrollment into a dose
escalation cohort (Parts 1a and 1b), or otherwise have pre-approval from the Sponsor
medical monitor for any diagnoses not listed below:
a. Stage IIIB/IV squamous or non-squamous non-small cell lung carcinoma (NSCLC)
b. Recurrent or metastatic head and neck squamous cell carcinoma (HNSCC;
specifically of the oral cavity, oropharynx, hypopharynx, or larynx; and
nasopharyngeal carcinoma)
c. Metastatic triple-negative breast cancer
d. Locally advanced or metastatic urothelial carcinoma (UC)
e. Locally advanced, recurrent, or metastatic gastric cancer (GC)
f. Locally advanced, recurrent, or metastatic esophageal or esophagogastric junction
cancer
g. Recurrent or metastatic cervical squamous cell carcinoma or endocervical
adenocarcinoma
h. Metastatic melanoma
i. Recurrent EBV+ classical Hodgkin lymphoma
3. Subject must have one of the following diagnoses to be eligible for enrollment into a
corresponding expansion cohort (Parts 2a and 2b):
Part 2a
• Cohorts M1-M2 (FLX475 Monotherapy): Subjects with a documented Epstein-Barr
virus positive (EBV+
) malignancy (as determined by standard methods, e.g. EBER ISH
or LMP-1 IHC) who are ineligible for standard therapy • M1: EBV+Nasopharyngeal cancer (N = 10 Stage 1)
• M2: EBV+
Hodgkin or non-Hodgkin lymphoma (N = 10 Stage 1)
Any EBV+
indications that pass Stage 1 will be combined into a single Stage 2 EBV+
basket expansion of up to 19 additional subjects.
• Cohorts M3-M4 (FLX475 Monotherapy): Subjects with any of the following tumor
types whose disease progressed during treatment with standard available therapies, or
who are not eligible for such therapy, and who are also able to and consent to providing
tumor biopsies at screening and during study treatment:
• M3: Recurrent or metastatic HNSCC (specifically of the oral cavity, oropharynx,
hypopharynx, or larynx) with no prior treatment with anti-PD-1 or anti-PD-L1
therapy (N = 10-29)
• M4: Recurrent or metastatic cervical squamous cell carcinoma with no prior
treatment with anti-PD-1 or anti-PD-L1 therapy (N = 10-29)
Part 2b
• Cohort C1 (FLX475/Pembrolizumab Combination Therapy): Subjects with
recurrent/metastatic HNSCC (specifically of the oral cavity, oropharynx, hypopharynx, or
larynx) with no prior treatment with anti-PD-1 or anti-PD-L1 therapy (N = 10–29)
• Cohort C2 (FLX475/Pembrolizumab Combination Therapy): Subjects with
recurrent/metastatic HNSCC (specifically of the oral cavity, oropharynx, hypopharynx, or
larynx) and documented disease progression or relapse more than 3 months after
initiation of prior anti-PD-1 or anti-PD-L1 therapy (N = 10–29)
• Cohort C3 (FLX475/Pembrolizumab Combination Therapy): Subjects with
Stage IIIB/IV squamous or nonsquamous NSCLC and documented disease progression or
relapse more than 3 months after initiation of prior anti-PD-1 or anti-PD-L1 therapy
(N = 10–29)
• Cohort C4 (FLX475/Pembrolizumab Combination Therapy): Subjects with metastatic
triple-negative breast cancer (TNBC) with disease progression after treatment with
available therapies known to confer clinical benefit and with no prior treatment with
anti-PD-1 or anti-PD-L1 therapy (N = 10–29).
4. Men and women ≥ 18 years of age on day of signing informed consent.
5. Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of 0 or 1
(Subjects with stable ECOG PS of 2 due to a non-cancer-related condition may be
permitted with the approval of the medical monitor.)
6. Evaluable disease (i.e., by imaging and/or tumor markers) at baseline for dose
escalation (Parts 1a and 1b). For expansion cohorts (Parts 2a and 2b), subjects must
have at least one measurable lesion at baseline by computed tomography (CT) or magnetic resonance imaging (MRI) per Response Evaluation Criteria in Solid Tumors
(RECIST v1.1). Lesions situated in a previously irradiated area are considered
measurable if progression has been demonstrated in such lesions. Liver metastases of
eligible tumor types are permitted.
7. Subjects with brain metastases that improve or are stable upon repeat MRI after at least
30 days after radiation therapy (and who are not receiving steroids) are permitted.
8. Subjects who enroll and are treated in Parts 1a or 2a of this study (FLX475
monotherapy dose escalation or expansion cohorts), and who complete at least three
3-week cycles of study treatment including the first response assessment, but who have
documented PD and discontinue study treatment without significant treatment-related
toxicity, may be eligible to crossover to receive combination therapy, provided an
appropriate combination-therapy cohort is open to enrollment, they otherwise meet
selection criteria, and it is determined by the investigator, in consultation with the
Sponsor’s medical monitor, to be in the subjects’ best interest to receive combination
therapy. Subjects in Part 1a (monotherapy dose escalation) could potentially crossover
to an available Part 1b (combination dose escalation) cohort, while subjects in Part 2a
(monotherapy expansion) could potentially crossover to a basket combination therapy
cohort (C5).
9. Considered by the investigator to be an appropriate candidate for a Phase 1 clinical
study, with a life expectancy of ≥ 12 weeks
10. All acute toxic effects of any prior therapy have resolved to Grade 0 or 1 or to baseline
level before the start of study treatment (except that up to Grade 2 alopecia,
neurotoxicity, and bone marrow abnormalities may be permitted with Sponsor
agreement).
11. Adequate organ function as defined in Table 1. Specimens must be collected within
21 days prior to the start of study treatment.
12. Subjects enrolled must be willing and able to provide tissue from a newly obtained core
or excisional biopsy of a tumor lesion not previously irradiated (unless subsequent
progression demonstrated; minimum of 3 cores). Subjects in dose escalation for whom
newly obtained pretreatment samples cannot be provided (e.g., inaccessible or subject
safety concern) may submit an archived specimen only upon agreement from the
Sponsor (not applicable for Part 2 expansion cohorts). Formalin-fixed,
paraffin-embedded tissue blocks are preferred to slides. In addition, subjects must be
willing to provide a tumor biopsy (minimum of 3 cores) while on treatment at Cycle 3
Day 1 (±7 days) and may be asked to provide additional biopsies at other timepoints
such as the time of discontinuation due to progression.
13. For women of childbearing potential, negative results on a serum pregnancy test prior
to starting study treatment.
14. For women of childbearing potential, willingness to use an effective method of
contraception (e.g., oral contraceptives, double-barrier methods such as a condom and a
diaphragm, intrauterine device) during the study and for 120 days following the final
dose of study treatment or to abstain from sexual intercourse for this period of time.
15. For male subjects of childbearing potential having intercourse with females of
childbearing potential, willingness to abstain from heterosexual intercourse or use of a
protocol-recommended method of contraception (e.g., partner use of oral contraceptives
or an intrauterine device, or double-barrier methods such as a condom and a
diaphragm) from the start of study treatment to 30 days following the final dose of
study treatment and to refrain from sperm donation from the start of study treatment to
30 days following the final dose of study treatment.

1. History of known antidrug antibodies or severe allergic, anaphylactic, or other
infusion-related reaction to a previous biologic agent (for subjects to be treated with
pembrolizumab).
2. History of severe hypersensitivity (≥ Grade 3) to pembrolizumab and/or any of its
excipients (for subjects to be treated with pembrolizumab)
3. In subjects who received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD-L2
agent or an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g.,
CTLA-4, OX-40, CD137), any history of discontinuing prior treatment due to Grade 3–4
immune-related adverse events (irAEs).
4. Has received prior systemic anticancer therapy including investigational agents within
4 weeks (or < 5 half-lives for investigational/noncytotoxic agents, whichever is shorter)
prior to first dose of study treatment.
5. Any active autoimmune disease or documented history of serious autoimmune disease
within the past 2 years requiring systemic therapy (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) is not considered a form of systemic treatment and is allowed.
6. History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced
pneumonitis, idiopathic pneumonitis, (non-infectious) pneumonitis that required steroids,
or clinical symptoms of active pneumonitis.
7. Known carcinomatous meningitis and/or active central nervous system (CNS) metastasis.
Participants with previously treated brain metastases may participate provided they are
radiologically stable, i.e., without evidence of progression for at least 4 weeks by repeat
imaging (note that the repeat imaging should be performed during study screening),
clinically stable, and without requirement of steroid treatment for at least 14 days prior to
first dose of study treatment.
8. History of another malignancy that has progressed or has required active treatment within
the past 2 years except for the following: adequately treated local basal cell or squamous
cell carcinoma of the skin; in situ cervical carcinoma; adequately treated papillary,
noninvasive bladder cancer; asymptomatic prostate cancer without known metastatic
disease and not requiring therapy or requiring only hormonal therapy, and with normal
prostate specific antigen for ≥ 1 year prior to start of study treatment; other adequately
treated Stage 1 or 2 cancers currently in complete remission, or any other cancer that has
been in complete remission for ≥ 2 years.
9. Significant cardiovascular disease, including myocardial infarction, arterial
thromboembolism, or cerebrovascular thromboembolism within 6 months prior to start of
study treatment, symptomatic dysrhythmias or unstable dysrhythmias requiring medical
therapy, angina requiring therapy, symptomatic peripheral vascular disease, clinically significant history of syncope, New York Heart Association (NYHA) Class 3 or 4
congestive heart failure (Appendix 3), or chronic Grade 3 hypertension (diastolic blood
pressure ≥ 100 mmHg or systolic blood pressure ≥ 160 mmHg).
10. Significant screening electrocardiogram (ECG) abnormalities including atrial fibrillation
(unstable or newly diagnosed), double (left and right) bundle-branch block,
second-degree atrioventricular block type II, third-degree atrioventricular block,
Grade ≥ 2 bradycardia, QTcF interval > 450 msec, PR interval > 220 msec, or unstable
cardiac arrhythmia requiring medication. Chronic asymptomatic atrial fibrillation stably
controlled with medications is permitted.
11. Known family history of sudden cardiac death.
12. Ongoing risk for bleeding due to active peptic ulcer disease or bleeding diathesis.
13. Significant active gastrointestinal disease (e.g., malabsorption syndrome, resection of the
stomach or small bowel, symptomatic inflammatory bowel disease, gastrointestinal
perforation, or partial or complete bowel obstruction) that might impair absorption of
study treatment.
14. Evidence of an ongoing, uncontrolled systemic bacterial, fungal, or viral infection or an
uncontrolled local infection requiring therapy at the time of start of study treatment.
Note: Subjects with localized fungal infections of skin or nails are eligible.
15. Known human immunodeficiency virus (HIV) infection or subjects who are HIV
seropositive.
16. Known history of Hepatitis B (defined as Hepatitis B surface antigen reactive) or known
active Hepatitis C virus (defined as detection of HCV RNA [qualitative]) infection.
17. Diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (at doses
exceeding 10 mg daily of prednisone equivalent) or any other form of
immunosuppressive therapy within 14 days prior to the first dose of study treatment.
18. Prior allogeneic organ transplant.
19. Receipt of live vaccine within 30 days prior to study entry or within 30 days of receiving
study treatment. Examples of live vaccines include, but are not limited to, measles,
mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus
Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection
are generally killed virus vaccines and are allowed; however, intranasal influenza
vaccines (e.g., FluMist®) are live attenuated vaccines and are not allowed.
20. Has undergone prior allogeneic hematopoietic stem cell transplantation within the last
5 years. (Subjects who have had a transplant more than 5 years before the start of study
treatment are eligible as long as there are no symptoms of graft-versus-host-disease).
21. Females who are pregnant, breastfeeding, or expect to become pregnant within the
projected duration of the study, starting with the screening visit through 120 days after
the final dose of study treatment. Males who plan to father children within the projected
duration of the study, starting with the screening visit through 30 days after the final dose
of study treatment.
22. Major surgery within 28 days (or inadequate recovery from the toxicity or complications
of the intervention) before the start of study treatment.
23. Radiotherapy within 14 days of start of study treatment. Subjects must have recovered
from all radiation-related toxicities, not require corticosteroids, and not have had
radiation pneumonitis. A 7-day washout is permitted for palliative radiation (i.e.,
≤ 14-day course of radiotherapy) to non-CNS lesions.
24. Subjects currently receiving treatment with any medications that have the potential to
prolong the QT interval and that cannot be either discontinued or substituted with a
different medication prior to starting study treatment.
Note: See Appendix 8 for a list of proscribed drugs.
25. Subjects currently receiving treatment with strong cytochrome P450 (CYP)3A4 inhibitors
or inducers should discontinue such treatment or be switched to a different medication
prior to starting study treatment.
Note: See Appendix 8 for a list of proscribed drugs.
26. Current participation in another study of an investigational agent or device.
27. Any illness, medical condition, organ system dysfunction, or social situation, including
mental illness or substance abuse, deemed by the investigator to be likely to interfere
with a subject’s ability to sign informed consent, adversely affect the subject’s ability to
cooperate and participate in the study, or compromise the interpretation of study results.