Inclusion Criteria:
- - Histologically or cytologically confirmed solid tumors such as ER/PR(+), HER2(-)
breast cancer, SCLC, soft tissue sarcoma, endometrial cancer, bladder cancer that has
progressed on at least one standard therapy or for which there is no standard therapy.
(Metastases or recurrences do not need to be histologically confirmed.)
- - Patients with breast cancer whose tumors progressed after prior palbociclib.
- - Patients with any treatment-refractory solid tumor that is RB-deficient (9 patient
cohort expansion after phase Ib dose de-escalation phase).
Examples include SCLC, soft
tissue sarcoma, endometrial cancer, bladder cancer. Patients should have no available
standard therapy.
- - Patients must have at least one area of measurable disease per RECIST Version 1.1 for
solid tumors.
- - Recovered (< grade 1) from clinically significant effects of any prior surgery,
radiotherapy or other anti-neoplastic therapy, except alopecia.
- - Males or females age >18 years.
- - Life expectancy > 60 days as documented by treating investigator.
- - Eastern Cooperative Oncology Group (ECOG) performance status score 0 or 1.
- - Patients must have normal organ and marrow function as defined in detail in the study
protocol.
- - Women must not pregnant and not nursing.
- - Women of childbearing potential must have a negative pregnancy test (urine or serum)
within 7 days prior to starting the study drug (prior to Day 1 of treatment).
Both
males and females must agree to use effective birth control during the study (prior to
the first dose and for 7 months after the last dose for females and 4 months after the
last dose for males) if conception is possible during this interval. Female patients
are considered to not be of childbearing potential if they have a history of
hysterectomy or are post-menopausal defined as no menses for 12 months without an
alternative medical cause.
- - Post-menopausal women (surgical menopause or lack of menses >12 months) do not need to
have a pregnancy test, please document status.
(Female patients are considered to not
be of childbearing potential if they have a history of hysterectomy or are
post-menopausal defined as no menses for 12 months without an alternative medical
cause.).
- - Patient must be able to swallow capsules and retain orally administered medication and
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 be able to understand and willing to sign a written informed consent
document and to comply with the protocol.
- - Women of childbearing potential enrolled in this study must agree to use adequate
barrier birth control measures during the course of the study and for at least 7
months after the last dose on study.
- - Men enrolled in this study must agree to use adequate barrier birth control measures
during the course of the study and for at least 4 months after the last treatment on
study.
- - In addition to alopecia and stable peripheral neurotoxicity below grade 2, any
clinical toxicity associated with previous treatment prior to enrollment must be
restored to baseline or grade 1.
Exclusion Criteria:
- - Pregnant or breastfeeding women are excluded from this study.
- - History of allergic reactions attributed to compounds of similar chemical or biologic
composition to palbociclib or TAS-116.
- - Patients receiving any medications or substances that are substrates, inducers, or
inhibitors of the CYP3A enzyme.
- - Patients with a history of primary central nervous system tumors or brain metastases
or who have signs/symptoms attributable to brain metastases and have not been assessed
with radiologic imaging to rule out the presence of brain metastases.
- - Patients with treated brain metastases that are asymptomatic and have been clinically
stable for at least 4 weeks will be eligible.
Medical condition exclusions.
- - Patients may not be receiving any other investigational agents or anti-cancer
therapies.
- - Patients who have a history of another primary malignancy, with the exception of
locally excised nonmelanoma skin cancer and carcinoma in situ of uterine cervix.
A
patient who has had no evidence of disease from another primary cancer for 3 or more
years is allowed to participate in the study.
- - Patients with known history of hepatitis C or chronic active hepatitis B.
- - Patients with known diagnosis of human immunodeficiency virus (HIV) infection.
- - Any significant ophthalmologic abnormality.
- - Any other condition that may increase the risk of corneal epithelial damage.
- - Corrected visual acuity < 0.5 (using the international visual acuity measurement
standard)
- Patients who have any severe and/or uncontrolled medical conditions or other
conditions that, in the opinion of the Investigator and sponsor, could affect the
patient's participation in the study such as:
- Uncontrolled diabetes mellitus.
- - Nonmalignant medical illnesses that are uncontrolled or whose control may be
jeopardized by treatment with this study treatment.
- - Liver disease such as decompensated liver disease, chronic active hepatitis, or
chronic persistent disorders.
- - Autoimmune and ischemic disorders (>=Grade 2).
- - Ongoing or active infection symptomatic congestive heart failure, unstable angina
pectoris, cardiac arrhythmia within 6 months of registration, or psychiatric
illness/social situations that would limit compliance with study requirements.
- - Significant gastrointestinal abnormalities, including active ulcerative colitis,
chronic diarrhea associated with intestinal malabsorption, Crohn's disease, and/or
prior surgical procedures affecting absorption or requirement for intravenous
alimentation.
- - Patients with any comorbid medical disorder that, in the opinion of the Investigator
or sponsor, may increase the risk of toxicity.
- - Patients who have a history of noninfectious (toxic, autoimmune) hepatitis or
alcoholism.
- - Patients with a lifetime history of porphyria or psoriasis.
- - Patients with documented glucose-6-phosphate dehydrogenase deficiency.
- - Patients with a history of seizure disorder (except infant febrile seizures).
- - Patients with a lifetime history of dermatitis as an allergic/toxic reaction to any
medication.
- - Impaired cardiac function or clinically significant cardiac disease.
- - Impaired pulmonary function, history of interstitial lung disease (ILD) and/or
pneumonitis.
- - Weight loss of >10% in the past month.
Organ function and laboratory values exclusion.
- - Patients who have impaired cardiac function or clinically significant cardiac disease.
- - Chemotherapy, biologic therapy, targeted therapy, immunotherapy, radiotherapy, or
investigational agents within 5 half-lives or within 4 weeks (whichever is shorter)
prior to administration of first dose of study drug on Day 1 or have not recovered
from the side effects of such therapy.
- - Prior treatment with HSP90 inhibitor.
- - Major surgery/surgical therapy for any cause within 4 weeks of screening.
