| Eligibility |
Inclusion Criteria:
Inclusion Criteria AGE: = 18 years of age Weight: >30 kg Life expectancy of at least 12
weeks
Part A and B (Phase 1): Patients with histologically confirmed soft tissue or bone sarcoma
of the following subtypes:
- MFH/ undifferentiated pleomorphic sarcoma
- Unclassified sarcoma
- Rhabdomyosarcoma
- Malignant peripheral nerve sheath tumor (MPNST)
- Osteosarcoma
- Ewing or Ewing-like sarcoma
- Synovial sarcoma
- Desmoplastic small round blue cell tumor (DSRCT)
Patients must have progressed or demonstrated disease that is refractory to standard
therapies.
Patients for whom no standard of care treatments exist are eligible.
Part C (Phase 2): Patients with progressive, relapsed, unresectable or metastatic NF
associated MPNST.
MEASURABLE DISEASE:
Patients must have evaluable or measurable disease (Phase 1) and measurable disease by
RECISTv1.1 (Phase 2).
- Patients must have fully recovered from the acute toxic effects of all prior
chemotherapy, immunotherapy, or radiotherapy prior to entering on this study excluding
chronic grade 1 toxicities and alopecia.
- No limitation on the number of prior chemotherapy regimens that the patient may have
received prior to study entry.
- Myelosuppressive chemotherapy: The last dose of all myelosuppressive anticancer drugs
must be at least 3 weeks (=21 days) and 42 days if prior nitrosourea prior to study
entry.
- Immunotherapy: The last dose of immunotherapy (monoclonal antibody or vaccine) must be
at least 4 weeks prior to study entry.
- Biologic (anti-cancer agent): The last dose of all biologic agents for the treatment
of the patient's cancer (such as retinoids or tyrosine kinase inhibitors) must be at
least 7 days prior to study entry. Prior therapy with a MEK, Ras, or Raf inhibitor
used for treatment of malignant sarcoma is not allowed. Prior therapy of MEK, Ras, or
Raf inhibitor for other tumor such as plexiform neurofibroma or glioma is allowed.
- Radiation therapy: The last dose of radiation to more than 25% of marrow containing
bones (pelvis, spine, skull) must be at least 4 weeks prior to study
- Radiation therapy: The last dose of radiation to more than 25% of marrow containing
bones (pelvis, spine, skull) must be at least 4 weeks prior to study entry. The last
dose of all other local palliative (limited port) radiation must be at least 2 weeks
prior to study entry.
- Stem Cell Transplantation. At least 2 months post-autologous stem cell transplant.
- Growth Factors. The last dose of colony stimulating factors, such as filgrastim,
sargramostim, and erythropoietin, must be at least 1 week prior to study entry, the
last dose of long-acting colony stimulating factors, such as pegfilgrastim, must be at
least 2 weeks prior to study entry.
- Karnofsky performance level = 50% (See Appendix II).
- Patients who are unable to walk because of paralysis or motor weakness, but who are
able to use a wheelchair will be considered ambulatory for the purpose of calculating
the performance score.
Hemoglobin =9.0 g/dL (transfusion permissible)
- Peripheral absolute neutrophil count (ANC) of =1000/µL
- Platelet count =100,000/µL (transfusion independent (no transfusion within at least 7
days prior to enrollment))
- Total bilirubin must be = 1.5 times the upper limit of normal (ULN)
- SGOT (AST)/SGPT (ALT) must be = 3.0 times ULN unless liver metastases are present, in
which case it must be = 5x ULN
RENAL FUNCTION:
Serum creatinine = 1.5 times ULN or measured reatinine clearance >50 mL/min or calculated
creatinine clearance > 50 mL/min by the Cockcroft- Gault formula (Cockgraft and Gault 1976)
or by the 24 hour urine collection for determination of creatinine clearance
- Normal ejection fraction (ECHO or cardiac MRI) =53% (or the institutional normal; if a
range is given then the upper value of the range will be used)
- QTC or QTcF = 450msec
Fertile men and women of childbearing potential must agree to use an effective method of
birth control.
Female participants of childbearing potential must be willing to practice highly effective
contraception as detailed below from the time of screening until 3 months after
discontinuing the study.
They must not be breastfeeding and must have negative pregnancy test prior to start of
dosing.
For a female participant to be considered as of not childbearing potential, she should
fulfil one of the following:
Post-menopausal women, defined as either women aged more than 50 years and have amenorrhea
for at least 12 months following cessation of all exogenous hormonal treatments, or, women
under 50 years who have amenorrhea for at least 12 months following cessation of exogenous
hormonal treatments, and have serum follicle-stimulating hormone (FSH) and luteinizing
hormone (LH) levels in the postmenopausal range for the institution.
or
- Have documentation of irreversible surgical sterilization by hysterectomy, bilateral
oophorectomy or bilateral salpingectomy (but not tubal ligation)
- Have medically confirmed, irreversible premature ovarian failure.
Highly effective methods of contraception are:
- Use of medroxyprogesterone acetate depot injection (Depo-proveraTM). (Please note: use
of any other oral, injected, or implanted hormonal methods of contraception cannot be
considered highly effective as it is currently unknown whether investigational agents
may reduce their effectiveness)
- Placement of a copper-banded intrauterine device (IUD) or intrauterine system (IUS)
- Bilateral tubal ligation
- Vasectomized partner
Barrier methods include:
Occlusive cap (e.g. diaphragm or cervical/vault caps) with spermicide
Male participants should either be surgically sterile or willing to use an effective
barrier method of contraception during the study and for 3 months following the last dose
of drug therapy if sexually active with a female of childbearing potential. If not done,
storage of sperm prior to receiving drug therapy will be advised to male participants with
a desire to have children.
Male subjects must agree to refrain from sperm donation during and until 90 days from drug
therapy discontinuation.
CNS DISEASE: Patients with central nervous system disease are eligible or enrollment if
they have received prior radiotherapy or surgery to sites of CNS metastatic disease and are
without evidence of clinical progression or stable disease at 4 weeks.
Exclusion Criteria:History of another primary malignancy except for
- A malignancy treated with curative intent and with no known active disease =5 years
prior to study entry
- Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of
disease
- Adequately treated carcinoma in situ without evidence of disease
- Stable optic pathway glioma or low grade glioma not receiving active therapy
History of leptomeningeal carcinomatosis.
Patients receiving other anti-cancer agents are not eligible.
Patients who cannot swallow whole pills.
History of allogeneic organ transplantation.
Current or prior use of immunosuppressive medications within 14 days prior to study entry.
The following are exceptions to this criterion:
intranasal, inhaled, topical steroids or local steroid injection (e.g., intra-articular
injection)
Systemic corticosteroids used at physiologic doses not to exceed 10mg/day of prednisone or
its equivalent.
Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication).
Patients should not receive immunizations with attenuated live vaccines within four weeks
of study entry or during study period.
Any recent major surgery within a minimum of 4 weeks prior to starting drug therapy.
Placement of vascular access device, percutaneous tumor biopsy, or bone marrows are not
considered major surgical procedures and no minimum time frame prior to starting study
drug.
Patients who have any known severe and/or uncontrolled medical therapy is required.
conditions or other conditions that could affect their participation in the study such as:
- Severely impaired lung function defined as spirometry and DLCO that is 50%of the
normal predicted value corrected for hemoglobin and alveolar volume and/or O2
saturation that is 88% or less at rest on room air. For patients who do NOT have
respiratory symptoms (e.g., dyspnea at rest, known requirement for supplemental
oxygen), pulmonary function test is not required.
- Cardiac conditions as follows:
- Uncontrolled hypertension (blood pressure =150/95 mmHg despite medical therapy.
- Acute coronary syndrome within 6 months prior to starting drug therapy
- Uncontrolled angina despite medical therapy (Canadian Cardiovascular Society
grade II-IV despite medical therapy
- Symptomatic heart failure NYHA Class II-IV prior or current cardiomyopathy or
severe valvular disease
- Prior or current cardiomyopathy including but not limited to the following: Known
hypertrophic cardiomyopathy; Known arrhythmogenic right ventricular
cardiomyopathy; or Previous moderate or severe impairment of left ventricular
systolic function (LVEF <45% on echocardiography or equivalent of MUGA) even if
full recovery has occurred
- Atrial fibrillation with a ventricular rate of >100 beats per minute on ECG at
rest
- Uncontrolled infection including tuberculosis (clinical evaluation that includes
clinical history, physical examination and radiographic findings, and TB testing in
line with local practice), hepatitis B (known positive HBV surface antigen (HBsAg)
result), hepatitis C. Patients with a past or resolved HBV infection (defined as the
presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible.
Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain
reaction is negative for HCV RNA.
- Active primary immunodeficiency
- Pre-existing renal disease including glomerulonephritis, nephritic syndrome, Fanconi
Syndrome, or renal tubular acidosis.
- Current gastrointestinal conditions such as refractory nausea and vomiting,
malabsorption syndrome, disease significantly affecting gastrointestinal function,
resection of small bowel, symptomatic inflammatory bowel disease, or ulcerative
colitis, or partial or complete bowel obstruction.
- Active or prior documented autoimmune or inflammatory disorders (including
inflammatory bowel disease (colitis, Crohn's), celiac disease, systemic lupus
erythematosus, Wegener syndrome, myasthenia gravis, Graves' disease, rheumatoid
arthritis, uveitis.
The following exceptions are:
- Patients with vitiligo or alopecia
- Patients with hypothyroidism (e.g., following Hashimoto's syndrome) stable on hormone
replacement
- Psoriasis that does not require systemic therapy
- Patients with celiac disease that is controlled by diet alone
• Ophthalmological conditions as follows:
- Current or past history of retinal vein occlusion
- Known intraocular pressure (IOP)>21 mmHg (or ULN adjusted by age) or uncontrolled
glaucoma.
- Subjects with ophthalmological findings secondary to long standing optic pathway
glioma (such as visual loss, optic nerve pallor, or strabismus) or long standing
orbito-temporal PN (such as vision loss, strabismus) will not be considered a
significant abnormality for purposes of this study.
Any Supplementation with vitamin E.
Hypersensitivity to investigational products, or drugs with similar chemical structures to
investigational products.
Patients unwilling or unable to comply with the protocol.
While not an exclusion criterion, unless clinically indicated, patients should avoid taking
other additional non-study medications that may interfere with the study medications. In
particular, participants should avoid medications that are known to either induce or
inhibit the hepatic activity of CYP1A2, CYP2C19, and CYP3A4.
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