| Eligibility |
Inclusion Criteria:
1. Patients must have histologically confirmed metastatic solid tumors harboring CCNE1
amplification and TP53 mutation pre-identified in a Clinical Laboratory Improvement
Amendments (CLIA)-certified laboratory, either refractory to standard therapy or for
which no effective standard therapy that increases survival for at least 3 months is
available, or they declined standard of care therapy.
2. Measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST)
1.1.
3. Male or female aged =18 years.
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
Adequate organ functions as defined below:
Absolute neutrophil count (ANC) = 1,500 /µL. Hemoglobin (Hb) = 8 g/dL. Platelets =
100,000 /µL. Total bilirubin = 1.5 x upper limit of normal (ULN); or total bilirubin <
3.0 x ULN with direct bilirubin = ULN in patients with well documented Gilbert's
Syndrome.
ALT = 3 ULN or = 5 ULN if liver metastases persist. Serum albumin = 3 g/dL. Urinalysis
= 1 proteinuria, or urine protein/creatinine ratio (UPCR) = 1 mg/mg (= 113.2 mg/mmol),
or 24-h urine protein = 1 g.
PT/INR or partial thromboplastin time (PTT) test < 1.3 the laboratory ULN if not on
therapeutic anticoagulation.
Calculated creatinine clearance (CrCl) = 60 mL/min by the Cockcroft-Gault method* or
24-hour urine collection.
* CrCl = (140-age) x (weight/kg) x Fa / (72 x serum creatinine mg/dL). a where F= 0.85
for females and F=1 for male
5. Women of child-bearing potential (WOCBP) must have a negative serum pregnancy test
within 7 days prior to initiation of therapy (C1D1), and must agree to use effective
birth control during the study prior to the first dose and for at least 6 months after
the last dose (or longer based on local requirements). Female patients are not
considered to be of child-bearing potential if they are post-menopausal (no menses for
12 months without an alternative medical cause) or permanently sterile (hysterectomy,
bilateral salpingectomy, or bilateral oophorectomy). Male patients must agree to
abstain or use barrier contraception (i.e. condoms), and avoid sperm donation for the
duration of the study and for 6 months after treatment stops.
6. Ability to read and fully understand the requirements of the trial, willingness to
comply with all trial visits and assessments, and willingness and ability to sign an
institutional review board (IRB)-approved written informed consent document (ICD).
Patients with Impaired Decision Making Capacity (IDMC) must have a close caregiver or
Legally Authorized Representative (LAR).
7. Any prior palliative radiation must have been completed at least 14 days prior to the
start of study drugs, and patients must have recovered from any acute adverse effects
prior to the start of study treatment (Radiotherapy for extended field within 4 weeks
or limited field radiotherapy within 2 weeks).
8. Fridericia's corrected QT interval (QTcF =QT/?(60/HR) ) = 460 milliseconds (ms) for
males and = 480 ms for females on ECG conducted at rest during Screening.
Note: Patients with an atrioventricular pacemaker or other condition (for example,
right bundle branch block) that renders the QT measurement invalid are an exception
and this criterion does not apply.
9. Ability to take oral medications without medical history of malabsorption or other
chronic gastrointestinal disease, or other conditions that may hamper compliance
and/or absorption of the study agents. Note: Patient may not have a percutaneous
endoscopic gastrostomy (PEG) tube or be receiving total parenteral nutrition (TPN).
10. Provision of an archival tissue block, or 10 formalin-fixed paraffin-embedded (FFPE)
slides, or fresh tumor biopsy.
11. Prior treatment with VEGF inhibition or immunotherapy is allowed. But prior treatment
with Wee1 kinase inhibition is not allowed.
Exclusion Criteria:
1. Any treatment specifically for systemic tumor control given within 3 weeks before the
initiation of therapy; within 2 weeks if cytotoxic agents were given weekly, within 6
weeks for nitrosoureas or mitomycin C; within 5 half-lives for targeted agents with
half-lives and pharmacodynamic effects lasting < 5 days; or failure to recover from
toxic effects of any previous therapy. A drug that has not received regulatory
approval for any indication within 14 or 21 days of treatment for a
non-myelosuppressive or myelosuppressive agent, respectively: patients must recover
for previous cancer therapy, and are ready to proceed with further cancer therapy.
2. Uncontrolled intercurrent illness including but not limited to:
- ongoing or active infection requiring intravenous antibiotics
- symptomatic congestive heart failure (New York Heart Association Class III or IV)
- history of myocardial infarction, unstable angina, stroke or transient ischemic
attack within 6 months before study enrollment
- lesions invading or encasing any major blood vessels and cavitating pulmonary
lesion(s) or known endotracheal or endobronchial disease manifestation
- Uncontrolled hypertension defined as sustained blood pressure (BP) > 140 mm Hg
systolic or > 90 mm Hg diastolic despite optimal antihypertensive treatment
- history or current evidence of uncontrolled ventricular arrhythmia
- congenital long QT syndrome, or any known history of torsade de pointes, or
family history of unexplained sudden death
- clinically significant bleeding or active gastric or duodenal ulcer
- chronic diarrhea diseases considered to be clinically significant
- Abdominal fistula, GI perforation, bowel obstruction, or intra-abdominal abscess
within 6 months before first dose of study treatment, or any gastrointestinal
disorders associated with a high risk of perforation or fistula formation.
- other severe acute or chronic medical or psychiatric condition or laboratory
abnormality that may increase the risk associated with study participation, or
may interfere with the interpretation of study results, and in the judgment of
the Investigator would make the patient inappropriate for entry into this study.
Note: Subjects with a diagnosis of incidental, subsegmental pulmonary embolism or deep
vein thrombosis are allowed if stable, asymptomatic, and treated with a stable dose of
permitted anticoagulation (see exclusion criterion #6) for at least 1 week before
first dose of study treatment.
3. Unresolved clinically significant Grade 1 or higher toxicity from prior therapy.
4. History of allergic reactions to the study drugs, or any component of the products.
5. Presence of other active invasive cancers that do not harbor CCNE1 amplification and
TP53 mutation and requires active treatment other than hormonal therapy.
6. Having not recovered from a major surgical procedure or significant traumatic injury
(i.e., still needing additional surgical or medical care for these issues): major
surgical procedures = 28 days of treatment entry, or minor surgical procedures = 7
days. No waiting period required following port-a-cath or other central venous access
placement. Subjects must have complete wound healing from major surgery or minor
surgery before first dose of study treatment. Subjects with clinically relevant
ongoing complications from prior surgery are not eligible.
7. Currently receiving an investigational drug in a clinical trial or participating in
any other type of medical research judged not to be scientifically or medically
compatible with this study. If a patient is currently enrolled in a clinical trial
involving non-approved use of a therapeutic device for cancer control, then agreement
with the investigator and the sponsor is required to establish eligibility.
8. Has received a live vaccine within 30 days prior to the first dose of study drug.
Examples of live vaccines include, but are not limited to, the following: Bacille
Calmette-Guérin vaccine, measles, mumps, rabies, rubella, typhoid vaccine,
varicella/zoster, and yellow fever. Seasonal influenza vaccines for injection are
generally killed virus vaccines and are allowed; however, intranasal influenza
vaccines are live attenuated vaccines and are not allowed.
9. Received strong inhibitors and inducers and sensitive substrates of CYP3A4, as well as
strong and moderate p-glycoprotein (P-gp) inhibitors
(https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-intera
ctions-table-substrates-inhibitors-and-inducers), which cannot be discontinued within
2 weeks of the initiation of study therapy, withheld during the study until 2 weeks
after the last dose of study drug.
10. Symptomatic primary tumors or metastasis in the brain and/or central nervous system
that are uncontrolled with antiepileptics and/or require steroids at a dose of
prednisone > 10 mg/day or equivalent.
11. Evidence of leptomeningeal or lymphangitic carcinomatosis.
12. A history of another primary malignancy that is currently clinically significant,
requiring active intervention except for hormone therapy.
13. Lactation or pregnancy.
14. Human immunodeficiency virus requiring HAART treatment due to unknown drug-drug
interactions or has known history of active hepatitis B or C. However, patients with
history of active hepatitis B or C are eligible if their hepatitis is well controlled.
Screening tests for HIV, HBV and HCB are not mandatory.
Individuals must not meet these additional criteria if they participate in the study
to receive the pembrolizumab-based combination regimen:
15. Concurrent immunosuppressive therapy or steroid (> 10 mg/day prednisone or
equivalent).
16. History of autoimmune disease including but not limited to inflammatory bowel disease,
myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus,
rheumatoid arthritis, inflammatory bowel disease, Wegener's granulomatosis, Sjögren's
syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or
glomerulonephritis, which requires systemic therapy in the past 2 years.
Note: Patients with vitiligo, resolved childhood asthma/atopy, hypothyroidism on
stable hormone replacement, controlled asthma, Type I diabetes, Graves' disease, or
Hashimoto's disease, are not excluded.
17. History of grade = 3 immune-related adverse events with previous immunotherapy. Note:
Patients with adequately treated skin rash other than Steven-Johnson, toxic epidermal
necrolysis of other severe forms of dermatitis; or replacement therapy for
endocrinopathies, are not excluded.
18. History of interstitial lung disease or (non-infectious) pneumonitis that required
steroids or current pneumonitis.
19. History of grade = 3 allergic reaction to treatment with a monoclonal antibody.
20. Anti-PD-(L)1 naïve patients.
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