| Eligibility |
Inclusion Criteria:
- Patient must have a diagnosis of BRAF^V600E/K-mutated metastatic melanoma
- Patient must have had documented radiographic or clinical evidence of progressive
disease while on combination BRAF/MEK inhibitor therapy. For Phase 2 only, no more
than one intervening therapy since progression on BRAF/MEK inhibitor therapy is
allowed. Subjects who have evidence of progression while on, or within 4 weeks of
completing, combination BRAF/MEK inhibitor therapy in the adjuvant setting will be
eligible
- PHASE 2 ONLY: Patient must have EZH2 alteration (somatic mutation or copy number
alteration). Can be performed on either archival or fresh specimen. EZH2 alterations
need to be documented by a Clinical Laboratory Improvement Act (CLIA)/Clinical
Laboratory Improvement Program (CLIP)-certified next generation sequencing platform
(Foundation One, Tempus, Guardant360, etc.)
- PHASE 2 ONLY: Patient must have measurable disease
- PHASE 2 ONLY: Patient must have at least one tumor lesion amenable to biopsy. If
possible, this lesion should be different from the lesion used for following tumor
measurements but is not required
- PHASE 2 ONLY: Patient must agree to planned pre-treatment and planned on-treatment
biopsy. A pre-treatment biopsy will be optional if patient has an archival tissue
block or 5 formalin-fixed paraffin-embedded (FFPE) slides available from specimen used
to document presence of eligible EZH2 alteration that is deemed adequate for
evaluation
- Patient must be >=18 years
- Because no dosing or adverse event data are currently available on the use of
tazemetostat in combination with dabrafenib and trametinib in patients < 18 years
of age, children are excluded from this study
- Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status =< 2
(Karnofsky >= 50%)
- Patients with symptomatic central nervous system (CNS) metastases are eligible if
previously treated with surgery and/or radiation with no evidence of radiologic CNS
recurrence or progression for 4 weeks and on a stable/tapering dose of steroid for at
least one week prior to start of study drug. Patients with new or progressive
asymptomatic CNS metastases are eligible
- Hemoglobin >= 9 g/dL
- Albumin >= 2.5 g/dL
- Leukocytes >= 3,000/mcL
- Absolute neutrophil count >= 1,500/mcL
- Platelets >= 100,000/mcL
- Serum bilirubin =< 1.5 x institutional upper limit of normal (ULN) except subjects
with known Gilbert's syndrome
- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 2.5 x institutional ULN
- Creatinine =< 1.5 mg/dL OR calculated creatinine clearance (Cockcroft-Gault formula)
>= 50 mL/min
- Glomerular filtration rate (GFR) >= 60 mL/min/1.73 m^2
- Patients with a prior (or concurrent, if enrolling in Phase 1) malignancy whose
natural history or treatment does not have the potential to interfere with the safety
or efficacy assessment of the investigational regimen are eligible for this trial
- Patient must be able to swallow and retain oral medication and must not have any
clinically significant gastrointestinal abnormalities that may alter absorption such
as malabsorption syndrome or major resection of the stomach or bowels
- Prothrombin time (PT)/international normalized ratio (INR) and partial thromboplastin
time (PTT) =< 1.3 x institutional ULN. Prophylactic low dose warfarin may be given to
maintain central catheter patency
- The effects of tazemetostat, and the combination of tazemetostat, dabrafenib and
trametinib on the developing human fetus are unknown. Women of childbearing potential
and all male patients must agree to the following:
- For women of childbearing potential: agreement to remain abstinent (refrain from
heterosexual intercourse) or use contraceptive methods that result in a failure
rate of < 1% per year during the treatment period, for 6 months after
tazemetostat discontinuation, or for 6 months after discontinuation of the
combination of tazemetostat, dabrafenib and trametinib. Should a woman become
pregnant or suspect she is pregnant while she is participating in this study, she
should inform her treating physician immediately
- A woman is considered to be of childbearing potential if she is
postmenarcheal, has not reached a postmenopausal state (>= 12 continuous
months of amenorrhea with no identified cause other than menopause), and has
not undergone surgical sterilization (removal of ovaries and/or uterus)
- Examples of contraceptive methods with a failure rate of < 1% per year
include bilateral tubal ligation, male sterilization, established, proper
use of hormonal contraceptives that inhibit ovulation, hormone-releasing
intrauterine devices, and copper intrauterine devices
- Due to the potential of enzyme induction with tazemetostat, female subjects
who use hormonal contraceptives should use an additional barrier method of
birth control while on study treatment and for 6 months after
discontinuation of tazemetostat or the combination of tazemetostat,
dabrafenib and trametinib
- The reliability of sexual abstinence should be evaluated in relation to the
duration of the clinical study and the preferred and usual lifestyle of the
patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or
post ovulation methods) and withdrawal are not acceptable methods of
contraception
- Women of childbearing potential must have a negative urine or serum pregnancy
test at screening
- For men: agreement to remain abstinent (refrain from heterosexual intercourse) or
use contraceptive measures and agreement to refrain from donating sperm, as
defined below:
- With female partners of childbearing potential or pregnant female partners,
men must remain abstinent or use a condom during the treatment period and
for at least 4 months after the last dose of study drug. Men must refrain
from donating sperm during this same period. In addition, female partners of
male subjects should adhere to the following:
- Intrauterine device (IUD) (must provide medical documentation of IUD)
- Hormonal contraceptive (partner must be on a stable dose of the same
hormonal contraceptive product for at least 4 weeks before receiving
study drug) AND a condom (hormonal contraceptives must be supplemented
with condoms)
- The reliability of sexual abstinence should be evaluated in relation to the
duration of the clinical study and the preferred and usual lifestyle of the
patient. Periodic abstinence and withdrawal are not acceptable methods of
contraception
- Ability to understand and the willingness to sign a written informed consent document.
Participants with impaired decision-making capacity (IDMC) who have a
legally-authorized representative (LAR) and/or family member available will also be
eligible
- Have progressed on, been intolerant to is, ineligible for, or has refused prior
standard of care anti-PD-1 based immunotherapy
Exclusion Criteria:
- Previous therapy with a demethylating agent (i.e. decitabine) or previous therapy with
an EZH2 inhibitor
- History of second malignancy not treated with curative intent
- History of life-threatening toxicity, including hypersensitivity, related to BRAF or
MEK inhibitor therapy, or known immediate or delayed hypersensitivity reaction or
idiosyncrasy to drugs chemically related to the study treatments, their excipients,
and/or dimethyl sulfoxide (DMSO)
- Active infection requiring intravenous therapy
- Presence of untreated or progressive symptomatic CNS melanoma metastases. Diffuse
leptomeningeal carcinomatosis or metastases causing spinal cord compression are
exclusionary. Previously treated lesions should be stable for >= 4 weeks (must be
documented by imaging). Subjects on a stable dose of corticosteroids for > 1 week can
be enrolled. Subjects must also be off of enzyme-inducing anticonvulsants for > 4
weeks
- Radiation therapy in the last 14 days. Palliative radiation to a localized area
without residual toxicity requires a washout of at least 7 days
- Prior systemic anti-cancer therapy (chemotherapy, targeted therapy, immunotherapy,
biologic therapy, or vaccine therapy) within the 3 weeks preceding the first dose of
study treatment. For Phase 2 only, prior chemotherapy regimens are not permitted
- Use of other investigational drugs within 28 days (or five half-lives, whichever is
shorter; with a minimum of 14 days from the last dose) preceding the first dose of
study treatment and during the study
- Unresolved toxicity of National Cancer Institute Common Terminology Criteria for
Adverse Events, version 5.0 (NCI CTCAE v5.0) grade 2 or higher from previous
anti-cancer therapy, except alopecia, at the time of randomization
- Current use of a prohibited medication. Patients must not be treated with any
medications or substances that are strong or moderate inhibitors or inducers of of
CYP3A or strong inhibitors or inducers of CYP2C8 within 14 days prior to the first
treatment through the end of the study. Current use of, or intended ongoing treatment
with: herbal remedies (e.g., St. John's wort), or strong inhibitors or inducers of
P-glycoprotein (Pgp) or breast cancer resistance protein 1 (Bcrp1) should also be
excluded
- Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral
therapy are ineligible because of the potential for pharmacokinetic interactions with
dabrafenib
- A history of hepatitis B virus (HBV) or hepatitis C virus (HCV) infection (with the
exception of cleared HBV and HCV infection, which will be allowed)
- History of interstitial lung disease or pneumonitis
- Clinically significant bleeding diathesis or coagulopathy, including known platelet
function disorders. Patients on anticoagulation with low molecular weight heparin or
low dose warfarin are allowed
- History of myeloid malignancies, including myelodysplastic syndrome (MDS)
- Has abnormalities known to be associated with MDS (e.g. del 5q, chr 7 abn) and
multiple primary neoplasms (MPN) (e.g. JAK2 V617F) observed in cytogenetic testing and
deoxyribonucleic acid (DNA) sequencing
- History of T-lymphoblastic lymphoma (T-LBL)/T-cell acute lymphoblastic leukemia
(T-ALL)
- Patients with history of RAS mutation-positive tumors are not eligible regardless of
interval from the current study. Note: Prospective RAS testing is not required.
However, if the results of previous RAS testing are known, they must be used in
assessing eligibility
- History or evidence of cardiovascular risks including any of the following:
- QT interval corrected for heart rate using Fridericia's formula (QT corrected by
Fridericia [QTcF]) >= 450 msec
- History of acute coronary syndromes (including myocardial infarction or unstable
angina), coronary angioplasty, or stenting within the past 24 weeks prior to
randomization
- History or evidence of current class II, III, or IV heart failure as defined by
the New York Heart Association (NYHA) functional classification system
- Intra-cardiac defibrillators
- Abnormal cardiac valve morphology (>= grade 2) documented by echocardiogram
(ECHO); (subjects with grade 1 abnormalities [i.e., mild regurgitation/stenosis]
can be entered on study). Subjects with moderate valvular thickening should not
be entered on study
- History or evidence of current clinically significant uncontrolled cardiac
arrhythmias; clarification: Subjects with atrial fibrillation controlled for > 30
days prior to dosing are eligible
- Treatment refractory hypertension defined as a blood pressure of systolic > 140
mmHg and/or diastolic > 90 mm Hg which cannot be controlled by anti-hypertensive
therapy
- Left ventricular ejection fraction (LVEF) < institutional lower limit of normal
(LLN) by ECHO or multigated acquisition scan (MUGA)
- Known cardiac metastases
- Patients with uncontrolled intercurrent illness
- Patients with psychiatric illness/social situations that would limit compliance with
study requirements
- Pregnant women are excluded from this study because of the potential for teratogenic
or abortifacient effects. Because there is an unknown but potential risk for adverse
events in nursing infants secondary to treatment of the mother with tazemetostat /
dabrafenib / trametinib, breastfeeding should be discontinued prior to treatment
- Patients with uncontrolled diabetes
- Patients with a history of retinal vein occlusion (RVO), retinal pigment epithelial
detachment (RPED) or other ophthalmologic toxicity
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