This randomized phase I trial studies the side effects and best way to give ipilimumab with
or without dabrafenib, trametinib and/or nivolumab in treating patients with melanoma that
has spread to other parts of the body (metastatic) or cannot be removed by surgery.
Monoclonal antibodies, such as ipilimumab and nivolumab, may interfere with the ability of
cancer cells to grow and spread. Dabrafenib and trametinib may stop the growth of tumor cells
by blocking some of the enzymes needed for cell growth. It is not yet known whether
ipilimumab works better with or without dabrafenib, trametinib, and/or nivolumab in treating
melanoma.
PRIMARY OBJECTIVES:
I. To evaluate the safety and tolerability of ipilimumab (part 1) or ipilimumab plus
nivolumab (part 2) following lead-in of v-raf murine sarcoma viral oncogene homolog B1 (BRAF)
and mitogen-activated protein kinase kinase (MEK) inhibitors, either alone or in combination,
in patients with BRAFV600 mutant melanoma.
SECONDARY OBJECTIVES:
I. To determine the response rate to ipilimumab (part 1) or ipilimumab plus nivolumab (part
2) after BRAF and MEK inhibitors, either alone or in combination, compared to no prior kinase
inhibitor treatment.
II. To determine the safety and tolerability of dabrafenib and trametinib combination in the
setting of prior ipilimumab alone or ipilimumab preceded by BRAF and MEK inhibitors, either
alone or in combination (part 1).
III. To determine the safety and tolerability of dabrafenib and trametinib combination in the
setting of prior ipilimumab plus nivolumab without prior BRAF/MEK inhibition or ipilimumab
plus nivolumab preceded by BRAF and MEK inhibitors, either alone or in combination (part 2).
IV. To determine the response rate to dabrafenib and trametinib in the setting of prior
ipilimumab alone or ipilimumab preceded by BRAF and MEK inhibitors, either alone or in
combination (part 1).
V. To determine the response rate to dabrafenib and trametinib in the setting of prior
ipilimumab plus nivolumab without prior MEK/BRAF inhibition or prior ipilimumab plus
nivolumab preceded by BRAF/MEK inhibitors (part 2).
VI. To obtain peripheral blood and tumor tissue for biomarker analysis. VII. To describe the
immune impact of kinase inhibitor therapy on the immune response associated with ipilimumab
treatment (part 1) or ipilimumab plus nivolumab treatment (part 2).
VIII. To observe and record anti-tumor activity.
OUTLINE: Patients are randomized to 1 of 4 treatment arms for Part 2 (Part 1 closed to
accrual 8/25/2015).
PART 1: (Closed to accrual as of 8/25/2015) ARM A1: Patients receive dabrafenib orally (PO)
twice daily (BID) and trametinib PO once daily (QD) for 25 days. Patients then receive
ipilimumab intravenously (IV) over 90 minutes. Treatment with ipilimumab repeats every 3
weeks for 4 courses in the absence of disease progression or unacceptable toxicity.
ARM B1: Patients receive trametinib PO QD for 25 days. Patients then receive ipilimumab IV
over 90 minutes. Treatment with ipilimumab repeats every 3 weeks for 4 courses in the absence
of disease progression or unacceptable toxicity.
ARM C1: Patients receive dabrafenib PO BID for 25 days. Patients then receive ipilimumab IV
over 90 minutes. Treatment with ipilimumab repeats every 3 weeks for 4 courses in the absence
of disease progression or unacceptable toxicity.
ARM D1: Patients receive ipilimumab IV over 90 minutes. Treatment repeats every 3 weeks for 4
courses in the absence of disease progression or unacceptable toxicity.
PART 2:
ARM A2: Patients receive dabrafenib PO BID and trametinib PO QD for 25 days followed by
nivolumab IV over 60 minutes and ipilimumab IV over 90 minutes every 3 weeks for 4 doses,
followed by nivolumab monotherapy IV every 2 weeks continuously for up to 42 courses.
ARM B2: Patients receive trametinib PO QD for 25 days followed by nivolumab IV over 60
minutes and ipilimumab IV over 90 minutes every 3 weeks for 4 doses, followed by nivolumab
monotherapy IV every 2 weeks continuously for up to 42 courses.
ARM C2: Patients receive dabrafenib PO BID for 25 days followed by nivolumab IV over 60
minutes and ipilimumab IV over 90 minutes every 3 weeks for 4 doses, followed by nivolumab
monotherapy IV every 2 weeks continuously for up to 42 courses.
ARM D2: Patients receive nivolumab IV over 60 minutes and ipilimumab IV over 90 minutes every
3 weeks for 4 doses, followed by nivolumab monotherapy IV every 2 weeks continuously for up
to 42 courses.
After 12 weeks of treatment with ipilimumab, or ipilimumab and nivolumab followed by
nivolumab monotherapy, all patients may continue to receive dabrafenib PO BID and trametinib
PO QD in the absence of disease progression.
After completion of study treatment, patients are followed up for 14 weeks.
Inclusion Criteria:
- Study participants must have histologically or cytologically confirmed unresectable or
metastatic malignant melanoma
- Study participants must have measurable disease, defined as at least one lesion that
can be accurately measured in at least one dimension (longest diameter to be recorded
for non-nodal lesions and short axis for nodal lesions) as >= 20 mm with conventional
techniques or as >= 10 mm with spiral computed tomography (CT) scan, magnetic
resonance imaging (MRI), or calipers by clinical exam
- Study participants must have completed any prior treatment at least 3 weeks prior to
treatment on this protocol; prior treatments may have included chemotherapy however
may not have included BRAF or MEK inhibitors or immunotherapies (interleukin-2,
ipilimumab, anti-programmed death [PD]1 antibodies etc.) excluding vaccine therapy;
prior treatment with interferon in the adjuvant setting is allowed, though prior
treatment with ipilimumab in the adjuvant setting is not; prior radiation therapy is
allowed though must have included no more than 3000 centigray (cGy) to fields
including substantial marrow
- Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
- Absolute neutrophil count (ANC) >= 1.2 x 10^9/L
- Hemoglobin >= 9 g/dL
- Platelets >= 100 x 10^9/L
- Albumin >= 2.5 g/dL
- Serum bilirubin =< 1.5 x institutional upper limit of normal (ULN) except subjects
with known Gilbert's syndrome
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x
institutional ULN
- Serum creatinine =< 1.5 mg/dL OR calculated creatinine clearance (Cockcroft-Gault
formula) >= 50 mL/min
- Prothrombin time (PT)/international normalized ratio (INR) and partial thromboplastin
time (PTT) =< 1.3 x institutional ULN; subjects receiving anticoagulation treatment
may be allowed to participate with INR established within the therapeutic range prior
to randomization
- Left ventricular ejection fraction >= institutional lower limit of normal (LLN) by
echocardiogram (ECHO)
- 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
- Patients must have BRAFV600E or BRAFV600K mutations, identified by a Food and Drug
Administration (FDA)-approved test at a Clinical Laboratory Improvement Amendments
(CLIA)-certified laboratory (lab); if test at CLIA-certified lab used a non-FDA
approved method, information about the assay must be provided
- Therapeutic level dosing of warfarin can be used with close monitoring of PT/INR by
the site; exposure may be decreased due to enzyme induction when on treatment, thus
warfarin dosing may need to be adjusted based upon PT/INR; consequently, when
discontinuing dabrafenib, warfarin exposure may be increased and thus close monitoring
via PT/INR and warfarin dose adjustments must be made as clinically appropriate;
prophylactic low dose warfarin may be given to maintain central catheter patency
- Women of child-bearing potential must agree to use adequate contraception (barrier
method of birth control, or abstinence; hormonal contraception is not allowed) for the
duration of study participation, and for at least 2 weeks after treatment with
dabrafenib or for 6 months after dabrafenib in combination with 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
- All prior treatment-related toxicities must be Common Terminology Criteria for Adverse
Events (CTCAE) version (v)4 grade =< 1 (except alopecia) at the time of randomization
- Ability to understand and the willingness to sign a written informed consent document
Exclusion Criteria:
- Prior systemic anti-cancer therapy (chemotherapy with delayed toxicity, extensive
radiation therapy, immunotherapy, biologic therapy, or vaccine therapy) within the
last 3 weeks; chemotherapy regimens without delayed toxicity within the last 2 weeks
preceding the first dose of study treatment
- 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
- Study participants with a history of prior treatment with BRAF or MEK inhibitors
- Study participants who had prior treatment with anti-PD-1, anti-PD-L1, anti-PD-L2,
anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell
co-stimulation or immune checkpoint pathways
- Patients with active autoimmune disease or history of autoimmune disease that might
recur, which may affect vital organ function or require immune suppressive treatment
including systemic corticosteroids, should be excluded; these include but are not
limited to patients with a history of immune related neurologic disease, multiple
sclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome, myasthenia
gravis; systemic autoimmune disease such as systemic lupus erythematosus (SLE),
connective tissue diseases, scleroderma, inflammatory bowel disease (IBD), Crohn's,
ulcerative colitis, hepatitis; and patients with a history of toxic epidermal
necrolysis (TEN), Stevens-Johnson syndrome, or phospholipid syndrome should be
excluded; patients with vitiligo, endocrine deficiencies including thyroiditis managed
with replacement hormones including physiologic corticosteroids are eligible; patients
with rheumatoid arthritis and other arthropathies, Sjögren's syndrome and psoriasis
controlled with topical medication and patients with positive serology, such as
antinuclear antibodies (ANA), anti-thyroid antibodies should be evaluated for the
presence of target organ involvement and potential need for systemic treatment but
should otherwise be eligible
- Patients are permitted to enroll if they have vitiligo, type I diabetes mellitus,
residual hypothyroidism due to autoimmune condition only requiring hormone
replacement, psoriasis not requiring systemic treatment, or conditions not
expected to recur in the absence of an external trigger (precipitating event)
- Study participants who have a condition requiring systemic treatment with either
corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive
medications within 14 days of study drug administration; inhaled or topical steroids
and adrenal replacement doses < 10 mg daily prednisone equivalents are permitted in
the absence of active autoimmune disease; patients are permitted to use topical,
ocular, intra-articular, intranasal, and inhalational corticosteroids (with minimal
systemic absorption); physiologic replacement doses of systemic corticosteroids are
permitted, even if < 10 mg/day prednisone equivalents; a brief course of
corticosteroids for prophylaxis (e.g., contrast dye allergy) or for treatment of
non-autoimmune conditions (e.g., delayed-type hypersensitivity reaction caused by
contact allergen) is permitted
- Patients who have had evidence of active or acute diverticulitis, intra-abdominal
abscess, gastrointestinal (GI) obstruction and abdominal carcinomatosis which are
known risk factors for bowel perforation should be evaluated for the potential need
for additional treatment before coming on study
- Study participants with known immune impairment who may be unable to respond to
anti-cytotoxic T-lymphocyte antigen 4 (CTLA 4) antibody and/or anti-PD-1 antibody
- Study participants with brain metastases are excluded unless these have been
definitively treated and are radiographically stable for at least 1 month; the study
participant must also demonstrate a stable physical exam and must have discontinued
systemic steroids for treatment of edema related to brain metastases or treatment for
over 7 days
- Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs
chemically related to the study treatments, their excipients, and/or dimethyl
sulfoxide (DMSO)
- Current use of a prohibited medication; patients receiving any medications or
substances that are strong inhibitors or inducers of cytochrome P450, family 3,
subfamily A (CYP3A) or cytochrome P450, family 2, subfamily C, polypeptide 8 (CYP2C8)
are ineligible; 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
- 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)
- Patients with history of rat sarcoma (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 the Bazett's formula QTcB >= 480 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 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
- Any condition which in the investigator's opinion makes the subject unsuitable for
study participation
- History of retinal vein occlusion (RVO)
- History of interstitial lung disease or pneumonitis
