The research study procedures include screening for eligibility and study treatment including
evaluations and follow up visits.
- The name of the study device involved in this study is: NovoTTF-200A
- The name of the drug used in this study is: Pembrolizumab
- Eligible participants will be in this research study for up to 2 years, or until
progressive disease or unacceptable toxicity as is reflected in the protocol.
- This is a Phase I/II clinical trial.
- A Phase I clinical trial tests the safety and toxicity of adding an investigational
device NovoTTF-200A to standard-of-care drug Pembrolizumab to use for further
studies.
- A Phase II clinical trial tests how well the combination works for your brain
disease. "Investigational" means that the device is being studied.
The FDA (the U.S. Food and Drug Administration) has not approved NovoTTF-200A for your brain
metastasis from melanoma.
A metastatic brain tumor is usually found when a cancer patient begins to experience
neurological symptoms and a brain scan (CT or MRI) is ordered. However, some participants are
symptom-free and are only diagnosed with brain metastases with MRI or CT scans for another
reason.
The NovoTTF-200A System is a portable device which produces changing electrical fields,
called Tumor Treatment Fields ("TTFields") within the human body. TTFields stop the growth of
tumor cells resulting in cell death of the rapidly dividing cancer cells. TTFields may also
sensitize the tumor cells to immune therapies and this is the rationale for combining
NovoTTF-200A and Pembrolizumab.
The system is a portable, light-weighted, battery operated device designed to deliver
TTFields directly to the region where brain metastasis are. The device can be carried
backpack while working or doing other activities of daily living.
Inclusion Criteria:
- For phase 1 portion: Participants must have histologically confirmed melanoma (either
measurable or evaluable) that is metastatic to the brain (TNM classification: Any T,
Any N and M1d with or without M1a or M1b involvement). Direct pathological
confirmation of metastatic melanoma from the brain is not necessary, provided that the
lesions on neuroimaging (either gadolinium-enhanced MRI (preferred) or
contrast-enhanced CT of the head) possess typical characteristics of brain metastases
as determined by the treating investigator. Measurable lesions are defined as those
that can be accurately measured in at least one dimension (longest diameter to be
recorded) as ≥10 mm by MRI. Evaluable lesions are those that are <10 mm in all
dimensions.
- Both BRAF wild-type and mutated melanomas are eligible; BRAF mutated patients are
required to have previously progressed on or not tolerate BRAF/MEK targeted therapy.
- For phase 2 portion: Participants must have histologically confirmed and measureable
melanoma tumor that is metastatic to the brain (TNM classification: Any T, Any N and
M1d with or without M1a or M1b involvement). Direct pathological confirmation of
metastatic melanoma from the brain is not necessary, provided that the lesions on
neuroimaging (either gadolinium-enhanced MRI (preferred) or contrast-enhanced CT of
the head) possess typical characteristics of brain metastases as determined by the
treating investigator. Measurable lesions are defined as those that can be accurately
measured in at least one dimension (longest diameter to be recorded) as ≥10 mm by MRI.
- Both BRAF wild-type and mutated melanomas are eligible; BRAF mutated patients are
required to have previously progressed on or not tolerate BRAF/MEK targeted therapy.
- Age 18 or above.
- ECOG performance status 0-1 or Karnofsky ≥80 (see Appendix A)
- Life expectancy of greater than 6 months.
- Participants must have normal organ and marrow function as defined below:
- leukocytes ≥3,000/mcL
- absolute neutrophil count ≥1,500/mcL
- platelets ≥100,000/mcL
- total bilirubin within normal institutional limits
- AST(SGOT)/ALT(SGPT) ≤2.5 x institutional upper limit of normal
- creatinine within normal institutional limits
- creatinine clearance ≥60 mL/min/1.73 m2 for participants with creatinine levels above
institutional normal.
- albumin >2.5 mg/dL
- INR or PT ≤1.5 x ULN unless subject is receiving anticoagulant therapy (as long as PT
or PTT is within therapeutic range of intended use of anticoagulants)
- aPTT ≤1.5 x ULN unless subject is receiving anticoagulant therapy (as long as PT or
PTT is within therapeutic range of intended use of anticoagulants) All screening labs
should be performed within 14 days of treatment initiation. Screening labs can be used
as treatment day labs when they are obtained within 3 days of Cycle 1 Day 1.
- Have either measurable or evaluable disease in Phase I & must have measurable disease
in Phase II based on the RANO criteria for brain metastases (maximum tumor diameter is
3 cm).
- Have at least 1 untreated brain metastasis for response assessment. Subjects with
solitary melanoma brain metastasis should not be treated with either surgery or
radiation prior to trial entry.
- Confirm available archival or newly obtained tissue (either brain or systemic) from
prior core or excisional biopsy of a tumor lesion.
- Be willing to comply with NovoTTF-200A device treatment for at least 75% of the time.
- Must have caregiver or support available to assist transducer array exchange.
- Female subjects of childbearing potential should have a negative urine or serum
pregnancy within 14 days (or within 72 hours if deemed necessary by the treating
investigator) prior to receiving the first dose of study medication. If the urine test
is positive or cannot be confirmed as negative, a serum pregnancy test will be
required.
- Female subjects of childbearing potential should be willing to use 2 methods of birth
control or be surgically sterile, use barrier methods of contraception, or abstain
from heterosexual activity for the course of the study through 120 days after the last
dose of study medication (Reference Section 5.8). Subjects of childbearing potential
are those who have not been surgically sterilized or have not been free from menses
for > 1 year.
- Male subjects should agree to use an adequate method of contraception, including
spermicide, starting with the first dose of study therapy through 120 days after the
last dose of study therapy.
- The effects of NovoTTF-200A and pembrolizumab on the developing human fetus are
unknown. For this reason, women of child-bearing potential and men must agree to use
adequate contraception (hormonal or barrier method of birth control; abstinence) prior
to study entry and for the duration of study participation. Should a woman become
pregnant or suspect she is pregnant while she or her partner is participating in this
study, she should inform her treating physician immediately. Men treated or enrolled
on this protocol must also agree to use adequate contraception prior to the study, for
the duration of study participation, and 4 months after completion of administration.
- Ability to understand and the willingness to sign a written informed consent document.
Exclusion Criteria:
- Participants who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for
nitrosoureas or mitomycin C) prior to first dose of treatment or those who have not
recovered from adverse events due to agents administered more than 4 weeks earlier.
Subjects with newly diagnosed brain metastasis during checkpoint inhibitor treatment
are eligible, as long as they have stable or regressing systemic melanoma and the only
site of relapse is in the brain.
- Participants who are receiving any other investigational agents.
- History of hypersensitivity to pembrolizumab or any of its excipients.
- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements.
- Pregnant or breastfeeding women, or those expecting to conceive or father children
within the projected duration of the trial (starting with the pre-screening or
screening visit through 120 days after the last dose of trial treatment), are excluded
from this study.
- A diagnosis of immunodeficiency or HIV.
- A known history of active TB (Bacillus Tuberculosis)
- Systemic steroid therapy at a dose equivalent to 4 mg daily of dexamethasone or more,
or any other form of immunosuppressive therapy within 7 days prior to the first dose
of trial treatment.
- Hypersensitivity to hydrogel.
- Prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study Day 1 or who
has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to the
agents.
-- Note: Subjects with Grade 2 hypothyroidism are an exception to this criterion and
may qualify for the study.
- Prior chemotherapy, targeted small molecule therapy, or radiation therapy within 4
weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline)
from adverse events due to a previously administered agent.
-- Note: Subjects with ≤ Grade 2 neuropathy, alopecia, anemia and decreased lymphocyte
count are an exception to this criterion and may qualify for the study.
- Known additional malignancy that is progressing or requires active treatment.
Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the
skin that has undergone potentially curative therapy or in situ cervical cancer.
- Known leptomeningeal metastasis. Confirmation of negative leptomeningeal metastasis,
either by CSF analysis or by neuroimaging staging (no leptomeningeal enhancement or
drop metastasis on gadolinium-enhanced head or total spine MRI, respectively) should
be determined by the treating investigator. However, it is recommended that both CSF
and neuroimaging be obtained because both modalities have limitations in sensitivity
and specificity.
- Subjects with previously treated brain metastases may participate provided they are
stable (without evidence of progression by imaging for at least four weeks prior to
the first dose of trial treatment and any neurologic symptoms have returned to
baseline), have no evidence of enlarging brain metastases, and are not using excessive
steroids (defined as a dexamethasone dose of >4 mg daily or equivalent) for at least 7
days prior to trial treatment. This exception does not include leptomeningeal
metastasis, which is excluded regardless of clinical stability.
- Active autoimmune disease that has required systemic treatment in the past 2 years
(i.e. with use of disease modifying agents, corticosteroids or immunosuppressive
drugs). Pre-existing hypothyroidism and type I diabetes mellitus (including those from
prior anti-cancer monoclonal antibody treatment) are not considered as active
autoimmune diseases. Replacement therapy (eg., thyroxine, insulin, or physiologic
corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is
not considered a form of systemic treatment.
- Known history of, or any evidence of active, non-infectious pneumonitis.
- Active infection requiring systemic therapy.
- A history or current evidence of any condition, therapy, or laboratory abnormality
that might confound the results of the trial, interfere with the subject's
participation for the full duration of the trial, or is not in the best interest of
the subject to participate, in the opinion of the treating investigator.
- Known psychiatric or substance abuse disorders that would interfere with cooperation
with the requirements of the trial.
- Known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA
[qualitative] is detected).
- Subject who received a live vaccine within 30 days of planned start of study therapy.
-- Note: Seasonal influenza vaccines for injection are generally inactivated flu
vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are
live attenuated vaccines, and are not allowed.
- Implanted pacemaker, defibrillator, deep brain stimulator, or documented clinically
significant arrhythmias.
- Evidence of increased intracranial pressure meets any of the follow criteria of raised
intracranial pressure:
- midline shift >5mm
- clinically significant papilledema
- nausea/vomiting related to raised intracranial pressure
- reduced level of consciousness related to raised intracranial pressure
- Subjects who received major surgery have not recovered adequately from the toxicity
and/or complications from the intervention prior to starting therapy
