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Participants must be classified into one of the following cohorts of recurrent or |
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|
persistent endometrial cancer of any histology |
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The MSI/POLE cohort includes endometrial cancers that are |
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-MSI-H as determined by immunohistochemical complete loss of expression (absence of |
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|
nuclear immunoreactivity) of at least one of the mismatch repair genes MSH2, MSH6, MLH1 and |
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PMS2. This test is now done routinely for every newly diagnosed endometrial cancer patient |
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in most centers in the US |
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And/OR |
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-POLE-mutated, i.e. endometrial cancers known to harbor mutations in the exonuclease |
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domain (amino acid residues 268-471) of polymerase e (POLE) as determined by targeted |
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sequencing or other next generation sequencing assay. Any Clinical Laboratory Improvement |
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Amendments (CLIA)-approved genomic test documenting mutations in the exonuclease domain of |
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POLE gene (amino acid residues 268-471) in the tumor will be accepted as proof of presence |
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of POLE mutations and will lead to classification into this patient cohort |
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The MSS cohorts include |
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Endometrial cancers that are MSS as determined by normal immunohistochemical nuclear |
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expression of all the mismatch repair genes MSH2, MSH6, MLH1 and PMS2. Tumors which |
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have not been sequenced for POLE mutations (i.e. their POLE mutations status is |
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Prior Therapy |
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unknown) but are MSS, will be included in this cohort |
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All patients must have measurable disease as defined by RECIST 1.1. Measurable |
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Prior hormonal therapy is allowed |
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disease is defined as at least one lesion that can be accurately measured in at |
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Patients must NOT have received any class of drugs targeted to the PD-1/PD-L1 pathway |
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least one dimension (longest diameter to be recorded). Each lesion must be >= 10 |
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mm when measured by CT, MRI or caliper measurement by clinical exam; or >= 20 mm |
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when measured by chest x-ray. Lymph nodes must be > 15 mm in short axis when |
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measured by CT or MRI |
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There is no upper limit of prior therapies but patients must have had one prior |
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Participants must have normal organ and marrow function as defined below |
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chemotherapeutic regimen for management of endometrial carcinoma. Initial treatment |
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absolute neutrophil count >1,500/mcL |
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may include chemotherapy, chemotherapy and radiation therapy, and/or |
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platelets >100,000/mcL |
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consolidation/maintenance therapy. Any platinum based chemotherapy (single agent |
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platinum or any platinum doublet) administered in conjunction with primary radiation |
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total bilirubin within normal institutional limits |
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as a radio-sensitizer WILL be counted as a systemic chemotherapy regimen. Furthermore |
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patients who have only received chemotherapy in the adjuvant setting will be eligible |
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|
creatinine within normal institutional limits OR |
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|
for the study |
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Please note: creatinine clearance (CLCR) should be estimated according to the |
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|
Cockcroft-Gault formula as |
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|
Patients must NOT have received any prior PARP inhibitor therapy (for patients being |
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|
considered for the avelumab/talazoparib cohort only) |
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Patients must NOT have received prior axitinib (for patients being considered for the |
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|
avelumab/axitinib cohort only) |
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|
Age of 18 or greater years. Because insufficient dosing or adverse event data are |
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|
currently available on the use of Avelumab, talazoparib, and/or axitinib in |
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|
participants < 18 years of age, children are excluded from the study. Endometrial |
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|
cancer is very rare in the pediatric population |
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ECOG performance status 0 or 1 (reference Appendix A for ECOG performance status |
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|
criteria) |
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|
Ability to understand and the willingness to sign a written informed consent document |
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|
Availability of a formalin fixed paraffin embedded (FFPE) block of cancer tissue |
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|
Additional inclusion criteria for the avelumab/axitinib cohort |
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|
|
OR 15 unstained 5-micron slides from the original surgery or biopsy or from a |
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|
|
biopsy of recurrent disease |
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|
hemoglobin ≥ 9g/dL |
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|
AST(SGOT)/ALT(SGPT) ≤2.5 × institutional upper limit of normal |
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|
|
creatinine clearance ≥60 mL/min/1.73 m2 for participants with creatinine levels above |
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|
|
institutional normal |
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|
CLCR={[(140-age) × weight)]/(72 x SCR)} × 0.85 where CLCR (creatinine clearance) is |
|
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|
|
measured in mL/min, age is expressed in years, weight in kilograms (kg), and SCR (serum |
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|
|
creatinine) in mg/dL |
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|
NOTE: Patients with moderate renal impairment (defined as an estimated creatinine clearance |
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|
|
of 30-59 mL/min) will receive a reduced starting dose of Talazoparib at 0.75 mg PO QD |
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Participant must not be pregnant or breastfeeding given that avelumab is an agent with |
|
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|
|
unknown effects in pregnancy and breastfeeding and the potential for teratogenesis |
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|
|
Females of childbearing potential are defined as those who are not surgically sterile |
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|
|
(i.e., bilateral tubal ligation, bilateral oophorectomy, or complete hysterectomy) or |
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|
|
post-menopausal (defined as ≥ 12 months with no menses without an alternative medical |
|
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|
|
cause). Serum pregnancy test (for females of childbearing potential) negative at |
|
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|
|
screening |
|
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|
|
The effects of avelumab on the developing human fetus are unknown. For this reason and |
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|
|
because some immunomodulatory agents are known to be teratogenic, women of |
|
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|
|
child-bearing potential must agree to use adequate contraception (hormonal or barrier |
|
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|
|
method of birth control; abstinence) prior to study entry and for the duration of |
|
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|
|
study participation. Should a woman become pregnant or suspect she is pregnant while |
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|
|
she or her partner is participating in this study, she should inform her treating |
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|
|
physician immediately |
|
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|
|
Toxicities of prior therapy (excepting alopecia and sensory neuropathy) should be |
|
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|
|
|
resolved to < grade 2 per the revised NCI Common Terminology Criteria for Adverse |
|
|
|
|
|
Events (CTCAE) version 4. All appropriate treatment areas should have access to a copy |
|
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|
|
of the CTCAE version 4. A copy of the CTCAE version 4 can be downloaded from the CTEP |
|
|
|
|
|
website at: <http://ctep.cancer.gov> |
|
|
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|
|
Participants must have adequately controlled blood pressure (BP) with or without |
|
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|
|
antihypertensive medications, defined as systolic BP that must be ≤140 mmHg and |
|
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|
|
diastolic BP that must be ≤90 mmHg on two separate BP readings taken at least 1 hour |
|
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|
|
apart at screening |
|
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|
|
Participants must have LVEF ≥ lower limit of normal (LLN) as assessed by either |
|
|
|
|
|
multigated acquisition (MUGA) scan or echocardiogram (ECHO) |
|
|
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|
|
Participants who are receiving any other investigational agents
|
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|
|
Positive test for HBV surface antigen
|
|
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|
|
|
Active infection requiring systemic therapy
|
|
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|
|
|
Prior organ transplantation including allogeneic stem-cell transplantation
|
|
|
|
|
|
Known alcohol or drug abuse
|
|
|
|
|
|
Additional exclusion criteria for the avelumab/axitinib cohort
|
|
|
|
|
|
Current use or anticipated need for treatment with drugs or foods that are known to be
|
|
|
|
|
|
either
|
|
|
|
|
|
Participants who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for
|
|
|
|
|
|
nitrosoureas or mitomycin C) prior to entering the study or those who have not
|
|
|
|
|
|
recovered from adverse events due to agents administered more than 4 weeks earlier
|
|
|
|
|
|
Participants with known brain metastases should be excluded from this clinical trial
|
|
|
|
|
|
because of their poor prognosis and because they often develop progressive neurologic
|
|
|
|
|
|
dysfunction that would confound the evaluation of neurologic and other adverse events
|
|
|
|
|
|
History of allergic reactions attributed to avelumab or any component in its
|
|
|
|
|
|
formulations, or compounds of similar chemical or biologic composition to avelumab
|
|
|
|
|
|
Known severe hypersensitivity reactions to monoclonal antibodies (Grade ≥ 3 NCI CTCAE
|
|
|
|
|
|
v 4.03), any history of anaphylaxis, or uncontrolled asthma (that is, 3 or more
|
|
|
|
|
|
features of partially controlled asthma)
|
|
|
|
|
|
Participants with a history of treatment with an anti-PD-1, anti-PD-L1, anti-CTLA-4 or
|
|
|
|
|
|
other investigational agents that target immune checkpoint inhibitors
|
|
|
|
|
|
Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)
|
|
|
|
|
|
related illness, which may compromise the efficacy of immunostimulatory therapy
|
|
|
|
|
|
Positive Hepatitis C antibody and positive confirmatory HCV RNA test. The confirmatory
|
|
|
|
|
|
HCV RNA test is not required if the HCV antibody is negative. If Hepatitis C antibody
|
|
|
|
|
|
is positive, the confirmatory HCV RNA test should be done and if it is negative, then
|
|
|
|
|
|
participants are eligible
|
|
|
|
|
|
Subjects requiring hormone replacement with corticosteroids are eligible if the
|
|
|
|
|
|
steroids are administered only for the purpose of hormonal replacement and at doses ≤
|
|
|
|
|
|
mg or 10 mg equivalent prednisone per day
|
|
|
|
|
|
Current or prior use of immunosuppressive medication within 7 days prior to enrollment
|
|
|
|
|
|
with the following exceptions to this exclusion criterion
|
|
|
|
|
|
Intranasal, inhaled, topical steroids, or local steroid injections (eg
|
|
|
|
|
|
intra-articular injection)
|
|
|
|
|
|
Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of
|
|
|
|
|
|
prednisone or equivalent
|
|
|
|
|
|
Steroids as premedication for hypersensitivity reactions (eg, CT scan
|
|
|
|
|
|
premedication)
|
|
|
|
|
|
Active autoimmune disease that might deteriorate when receiving an immunostimulatory
|
|
|
|
|
|
agent. Patients with diabetes type I, vitiligo, psoriasis, hypo- or hyperthyroid
|
|
|
|
|
|
disease not requiring immunosuppressive treatment are eligible
|
|
|
|
|
|
Severe gastrointestinal conditions such as clinical or radiological evidence of bowel
|
|
|
|
|
|
obstruction within 4 weeks prior to study entry, uncontrolled diarrhea in the last 4
|
|
|
|
|
|
weeks prior to enrollment, or history of inflammatory bowel disease
|
|
|
|
|
|
Uncontrolled intercurrent illness including, but not limited to symptomatic congestive
|
|
|
|
|
|
heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric
|
|
|
|
|
|
illness/social situations that would limit compliance with study requirements
|
|
|
|
|
|
Clinically significant (i.e., active) cardiovascular disease: cerebral vascular
|
|
|
|
|
|
accident/stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months
|
|
|
|
|
|
prior to enrollment), unstable angina, congestive heart failure (≥ New York Heart
|
|
|
|
|
|
Association Classification Class II), or serious cardiac arrhythmia requiring
|
|
|
|
|
|
medication
|
|
|
|
|
|
Individuals with a history of a different malignancy are ineligible except for the
|
|
|
|
|
|
following circumstances: Individuals with a history of other malignancies are eligible
|
|
|
|
|
|
if they have been disease-free for at least 5 years and are deemed by the investigator
|
|
|
|
|
|
to be at low risk for recurrence of that malignancy. Individuals with the following
|
|
|
|
|
|
cancers are eligible if diagnosed and treated within the past 5 years: breast cancer
|
|
|
|
|
|
in situ, cervical cancer in situ, and basal cell or squamous cell carcinoma of the
|
|
|
|
|
|
skin
|
|
|
|
|
|
All other significant diseases (for example, inflammatory bowel disease, uncontrolled
|
|
|
|
|
|
asthma), which, in the opinion of the Investigator, might impair the subject's
|
|
|
|
|
|
tolerance of trial treatment
|
|
|
|
|
|
Any psychiatric condition that would prohibit the understanding or rendering of
|
|
|
|
|
|
informed consent
|
|
|
|
|
|
Vaccination within 4 weeks of the first dose of avelumab and while on trial is
|
|
|
|
|
|
prohibited except for administration of inactivated vaccines
|
|
|
|
|
|
Patients may not use natural herbal products or other "folk remedies" while
|
|
|
|
|
|
participating in this study. Herbal medications include, but are not limited to St
|
|
|
|
|
|
John's Wort, Kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone (DHEA)
|
|
|
|
|
|
yohimbe, saw palmetto, and ginseng
|
|
|
|
|
|
Participants having >1+ proteinuria on urinalysis or UPCR >1 will undergo a 24-hour
|
|
|
|
|
|
urine collection for quantitative assessment of proteinuria. Participants with urine
|
|
|
|
|
|
protein >1 g/24-hours will be ineligible
|
|
|
|
|
|
Participants with concern for bowel or serosal involvement will be ineligible, due to
|
|
|
|
|
|
the risk of perforation or fistulization with anti-angiogenic agents
|
|
|
|
|
|
Participants will be ineligible if they have active gastrointestinal bleeding, as
|
|
|
|
|
|
evidenced by clinically significant hematemesis, hematochezia, or melena in the past 3
|
|
|
|
|
|
months without evidence of resolution documented by endoscopy or colonoscopy
|
|
|
|
|
|
Participants will be ineligible if using anticoagulant therapy with oral vitamin K
|
|
|
|
|
|
antagonists, novel oral anticoagulants (NOACs), or direct oral anticoagulants (DOACs)
|
|
|
|
|
|
inclusive of direct thrombin inhibitors and direct factor Xa inhibitors. Therapeutic
|
|
|
|
|
|
use of low molecular weight heparin is allowed. Low dose heparin required for
|
|
|
|
|
|
maintenance of patency of central venous access devices are allowed
|
|
|
|
|
|
Grade ≥3 hemorrhage within 4 weeks preceding Cycle 1 Day 1 treatment
|
|
|
|
|
|
Ongoing cardiac dysrhythmias of CTCAE Grade≥2, or prolongation of the QTc interval to
|
|
|
|
|
|
>500 msec
|
|
|
|
|
|
Strong CYP3A4/5 inhibitors, including administration within 10 days prior to
|
|
|
|
|
|
Cycle 1 Day 1 treatment, including but not limited to grapefruit juice
|
|
|
|
|
|
grapefruit-related fruits (Seville oranges, pomelos), ketoconazole, miconazole
|
|
|
|
|
|
itraconazole, voriconazole, posaconazole, clarithromycin, telithromycin
|
|
|
|
|
|
indinavir, saquinavir, ritonavir, nelfinavir, amprenavir, fosamprenavir
|
|
|
|
|
|
nefazodone, lopinavir, troleandomycin, mibefradil, conivaptan. The topical use of
|
|
|
|
|
|
these medications is allowed if systemic absorption is considered minimal
|
|
|
|
|
|
Strong CYP3A4/5 inducers, including administration within 10 days prior to Cycle
|
|
|
|
|
|
Day 1 treatment, including but not limited to phenobarbital, rifampin
|
|
|
|
|
|
phenytoin, carbamazepine, rifabutin, rifapentine, clevidipine, St. John's wort
|
|
|
|