Phase I Study of ZN-c3 and Bevacizumab ± Pembrolizumab in Metastatic CCNE1 Amplified and TP53 Mutant Solid Tumors

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.

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.

What this study is about