| Eligibility |
Inclusion Criteria:
- Patients must be informed of the investigational nature of this study and must be
willing to give written informed consent in accordance with institutional and federal
guidelines. Patients must be able to comply with the requirements and assessments of
the study protocol
- Must have histologically or cytologically documented rare tumor as defined per
protocol that is metastatic or locally advanced and unresectable. Patients with
locally advanced cutaneous squamous cell carcinoma that are technically resectable but
in whom surgery is expected to lead to substantial function impairment or
disfigurement are eligible
- Must be refractory or intolerant to standard lines of therapy
- Must have completed prior chemotherapy, immunotherapy, or radiation therapy at least
14 days prior to start of treatment and all toxicity must be resolved to Common
Terminology Criteria for Adverse Events (CTCAE) v4.0 grade 1 (with the exception of
CTCAE v4.0 grade 2 neuropathy) prior to start of treatment
- Presence of radiographically evaluable disease
- Eastern Cooperative Oncology Group (ECOG) performance status of =< 2
- Tissue Parameters: a. Representative formalin-fixed paraffin-embedded (FFPE) tumor
specimens in paraffin blocks (blocks are preferred) or at least 4 unstained slides,
with an associated pathology report, for testing of tumor PD-L1 expression (tumor
tissue from bone metastases is not evaluable for PD-L1 expression and is therefore not
acceptable). b. Tumor tissue should be of good quality based on total and viable tumor
content. Fine needle aspiration, brushing, cell pellet from pleural effusion, bone
metastases, and lavage samples are not acceptable. For core-needle biopsy specimens,
at least three cores should be submitted for evaluation. c. Patients who do not have
tissue specimens meeting eligibility requirements must be willing to undergo a biopsy
during the screening period
- Absolute neutrophil count (ANC) >= 1,000/mcL (obtained within 14 days prior to
enrollment)
- Platelets >= 75,000/mcL (obtained within 14 days prior to enrollment)
- Hemoglobin >= 9 g/dL (obtained within 14 days prior to enrollment)
- Calculated creatinine clearance > 30 ml/min (obtained within 14 days prior to
enrollment)
- Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline
phosphatase (ALP) =< 3 x institutional upper limit of normal (IULN) without liver mets
or =< 5 x IULN with liver metastases (obtained within 14 days prior to enrollment)
- Bilirubin =< 1.5 mg/dL (obtained within 14 days prior to enrollment)
- Able to swallow pills
- Negative serum pregnancy test within 7 days prior to commencement of dosing in
premenopausal women. Women of non-childbearing potential may be included without serum
pregnancy test if they are either surgically sterile or have been postmenopausal for
>= 1 year
- Fertile men and women must use an effective method of contraception during treatment
and for at least 6 months after completion of treatment as directed by their
physician. Effective methods of contraception are defined as those that result in a
low failure rate (i.e., less than 1% per year) when used consistently and correctly
(e.g., implants, injectables, combined oral contraception or intra-uterine devices).
At the discretion of the Investigator, acceptable methods of contraception may include
total abstinence in cases where the lifestyle of the patient ensures compliance.
(Periodic abstinence [e.g., calendar, ovulation, symptothermal, post ovulation
methods] and withdrawal are not acceptable methods of contraception)
- For individual baskets:
- Appendiceal adenocarcinoma
- Not considered candidate for curative surgery
- Cutaneous squamous cell carcinoma
- Patients with either metastatic or locally advanced cutaneous squamous cell
carcinoma that are technically resectable but in whom surgery is expected to
lead to substantial function impairment or disfigurement are eligible
- Small bowel adenocarcinoma
- Must be refractory or intolerant to at least one line of fluorouracil
(5FU)-based chemotherapy for metastatic disease
Exclusion Criteria:
- Presence of brain metastases (unless they have been adequately treated with
radiotherapy or surgery and stable for at least 30 days prior to enrollment provided
patient is neurologically asymptomatic and without corticosteroid treatment for at
least 7 days prior to enrollment)
- Uncontrolled intercurrent illness including, but not limited to diabetes,
hypertension, severe infection, severe malnutrition, unstable angina, class III-IV New
York Heart Association (NYHA) congestive heart failure, ventricular arrhythmias,
active ischemic heart disease, or myocardial infarction within 6 months prior to
enrollment
- History of or evidence of retinal pathology on ophthalmologic examination that is
considered a risk factor for neurosensory retinal detachment, central serous
chorioretinopathy, retinal vein occlusion (RVO), or neovascular macular degeneration
- Patients will be excluded from study participation if they currently are known to have
any of the following risk factors for RVO: a. Glaucoma with intraocular pressure >= 21
mmHg b. Grade >= 2 serum cholesterol c. Grade >= 2 hypertriglyceridemia d. Grade >= 2
or symptomatic hyperglycemia (fasting) e. Grade >= 2 uncontrolled hypertension
(patients with a history of hypertension controlled with anti-hypertensive medication
to grade =< 1 are eligible)
- Active malignancy (other than colorectal carcinoma [CRC]) or a history of prior
malignancy within the past 3 years. Adequately treated basal cell or squamous cell
skin cancer, in situ cervical cancer, ductal carcinoma in situ, other low grade
lesions such as incidental appendix carcinoid, or any other cancer from which the
patient has been disease and treatment free for two years are allowed. Prostate cancer
patients on active surveillance are eligible
- Pregnant or nursing patients due to risk of fetal or nursing infant harm. Women/men of
reproductive potential who do not agree to use an effective contraceptive method while
on study and for at least 6 months after study treatment
- Exclusion criteria related to study medication (any cancer immunotherapy including
CD137 agonists, anti-PD-1, anti-PD-L1, or anti-CTLA4 or any MEK or ERK inhibitor)
- Left ventricular ejection fraction (LVEF) < institutional lower limit of normal or <
50%
- History or risk of autoimmune disease, including but not limited to systemic lupus
erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis
associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjogren's
syndrome, Bell's palsy, Guillain-Barre syndrome, multiple sclerosis, autoimmune
thyroid disease, vasculitis, or glomerulonephritis a. Patients with a history of
autoimmune hypothyroidism on a stable dose of thyroid replacement hormone may be
eligible. b. Patients with controlled type 1 diabetes mellitus on a stable insulin
regimen may be eligible. c. Patients with eczema, psoriasis, lichen simplex chronicus
of vitiligo with dermatologic manifestations only (e.g., patients with psoriatic
arthritis would be excluded) are permitted provided that they meet the following
conditions:
- Patients with psoriasis must have a baseline ophthalmologic exam to rule out
ocular manifestations
- Rash must cover less than 10% of body surface area (BSA)
- Disease is well controlled at baseline and only requiring low potency topical
steroids (e.g., hydrocortisone 2.5%, hydrocortisone butyrate 0.1%, fluocinolone
0.01%, desonide 0.05%, alclometasone dipropionate 0.05%)
- No acute exacerbations of underlying condition within the last 12 months (not
requiring psoralen plus ultraviolet A radiation [PUVA], methotrexate, retinoids,
biologic agents, oral calcineurin inhibitors; high potency or oral steroids)
- History of idiopathic pulmonary fibrosis, pneumonitis (including drug induced),
organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing
pneumonia, etc.), or evidence of active pneumonitis on screening chest computed
tomography (CT) scan a. History of radiation pneumonitis in the radiation field
(fibrosis) is permitted
- History of human immunodeficiency virus (HIV) infection or active hepatitis B (chronic
or acute) or hepatitis C infection. a. Patients with past or resolved hepatitis B
infection (defined as having a negative hepatitis B surface antigen [HBsAg] test and a
positive anti-HBc [antibody to hepatitis B core antigen] antibody test) are eligible.
b. Patients positive for hepatitis C virus (HCV) antibody are eligible only if
polymerase chain reaction (PCR) is negative for HCV ribonucleic acid (RNA)
- Active tuberculosis or severe infections within 4 weeks prior to cycle 1, day 1,
including but not limited to hospitalization for complications of infection,
bacteremia, or severe pneumonia
- Treatment with systemic immuno-stimulatory agents (including but not limited to
interferon [IFN] or interleukin [IL]-2) within 6 weeks or five half-lives of the drug
(whichever is shorter) prior to cycle 1, day 1
- History of severe allergic, anaphylactic, or other hypersensitivity reactions to
chimeric or humanized antibodies or fusion proteins
- Prior allogeneic bone marrow transplantation or prior solid organ transplantation
- For individual baskets:
- Appendiceal adenocarcinoma
- Must not have clinically symptomatic malignant bowel obstruction
- Cutaneous squamous cell carcinoma
- None
- Small bowel adenocarcinoma
- Must not have clinically symptomatic malignant small bowel obstruction
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