Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Phase 1/2a/3 Evaluation of the Safety and Efficacy of Adding AL3818 (Anlotinib, INN: Catequentinib), a Dual Receptor Tyrosine Kinase Inhibitor, to Standard Platinum-Based Chemotherapy in Subjects With Recurrent or Metastatic Endometrial, Ovarian, Fallopian, Primary Peritoneal or Cervical Carcinoma
Brief Summary: This trial is a Phase 1b/2a/3 trial designed to evaluate the safety and efficacy of adding oral AL3818 (Anlotinib, INN: Catequentinib), a Dual Receptor Tyrosine Kinase Inhibitor, to standard platinum-based chemotherapy concurrently in Subjects with Recurrent or Metastatic Endometrial, Ovarian, Fallopian, Primary Peritoneal or Cervical Carcinoma.


Options:
A: Inclusion Critera

1. Female ≥ 18 years of age
2. Histologically proven diagnosis of:

   a. Endometrial and other uterine cancers with tumors of all histologies i. Recurrent Stage I to II endometrial and other uterine cancers, after at least one prior line of standard therapy, requiring further treatment with platinum-based chemotherapy ii. Advanced Stage III to IV endometrial and other uterine cancers requiring treatment with platinum-based chemotherapy

   b. Ovarian Cancer: Platinum-sensitive or platinum-resistant recurrent or metastatic ovarian, fallopian, or primary peritoneal cancer treated with at least one prior line of platinum-based chemotherapy and requiring further treatment.(Part 1/Phase Ib, Part 2/Phase 2a)

   Platinum-sensitive is defined as cancer progression ≥ 6 months after platinum- based chemotherapy. Platinum-resistant is defined as cancer progression \< 6 months after platinum-based chemotherapy.

   Histologic cell types eligible are endometrioid adenocarcinoma, serous adenocarcinoma, undifferentiated carcinoma, clear cell adenocarcinoma, mixed epithelial carcinoma, adenocarcinoma not otherwise specified.

   Phase III/Part 3:

(1) Platinum-resistant (progression within 6 months after last platinum-based chemotherapy) ovarian, fallopian, or primary peritoneal cancer that meets one of the following criteria: i. Subject has received at least two prior lines of systemic therapy including a bevacizumab-containing regimen as standard of care ii. Subject has received at least two prior lines of systemic therapy, has not received a prior bevacizumab-containing regimen and is not eligible for a bevacizumab containing regimen based on Investigator's assessment (2) Platinum-refractory (progression during first-line platinum-based chemotherapy) ovarian, fallopian, or primary peritoneal cancer after at least one prior line of systemic therapy (3) For groups 1-2 above: Subjects with positive deleterious or suspected deleterious, germline or somatic BRCA mutated status must have received a PARP inhibitor as a prior line of therapy.

c. Cervical cancer: recurrent or metastatic cervical cancer that is not amenable to curative treatment with surgery and/or radiation therapy after at least one prior line of standard therapy, requiring further treatment. Histologic cell types eligible are squamous cell carcinoma, adenosquamous carcinoma or adenocarcinoma

3. Have measureable disease defined by RECIST 1.1 confirmed by CT or MRI scan within 28 days of enrollment.

4. Life expectancy of ≥ 3 months at the time of enrollment.

5. Able to take orally administered study medication.

6. Have adequate baseline function and performance status within 28 days of enrollment:

1. Bone marrow function: absolute neutrophil count (ANC) ≥ 1,500/mm3, platelets ≥ 100,000/mm3
2. Renal function: creatinine ≤ 1.5 x institutional upper limit normal (ULN) or if creatinine is \> 1.5 x ULN, creatinine clearance must be \> 50 mL/min.
3. Hepatic function: bilirubin ≤ 1.5 x ULN or ≤ 3.0 x ULN for subjects with Gilbert Syndrome; AST and ALT ≤ 3.0 × ULN.
4. Coagulation profile: international normalized ratio (INR) is ≤ 1.5 and an aPTT or PTT \< 1.2 x ULN
5. ECOG performance ≤ 2

   7. Women of child-bearing potential must agree to use contraceptive measures starting 1 week before C1D1 until 4 weeks after the last dose of study treatment and have a negative serum pregnancy test within 28 days of enrollment.

   8. Provide written informed consent and authorization permitting release of Protected Health Information.

   9. Ability and willingness to comply with the study protocol for the duration of the study and with follow-up procedures.

Exclusion Criteria

1. Serious, non-healing wound, ulcer or bone fracture.
2. Major surgical procedure within 28 days or minor surgical procedure performed within 7 days prior to C1D1 (a major surgical procedure is defined as requiring general anesthesia).
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4. Active bleeding or pathologic conditions that carry high risk of bleeding, such as known bleeding disorder, coagulopathy, or tumor involving major vessels.
5. History or evidence upon physical examination of central nervous system (CNS) disease including primary brain tumor; seizures not controlled with standard medical therapy; and history of cerebrovascular accident (CVA, stroke), transient ischemic attack (TIA), or subarachnoid hemorrhage within 6 months of enrollment.

   a. Subjects with metastatic CNS tumors may participate in this study if the subject is \> 28 days from therapy completion (including radiation and/or surgery), is clinically stable at the time of study enrollment, and is not receiving corticosteroid therapy.
6. Proteinuria on urinalysis within 28 days of enrollment. Subjects discovered to have a urine protein of 1+ on dipstick or ≥ 30 mg/dl at baseline should undergo a 24-hour urine collection and demonstrate \< 1000 mg protein per 24 hours or spot urine protein (mg/dL) to creatinine (mg/dL) ratio must be \<1.0 to allow participation in the study.
7. Clinically significant cardiovascular disease including uncontrolled hypertension; myocardial infarction or unstable angina within 6 months prior to enrollment; New York Heart Association (NYHA) Grade II or greater congestive heart failure (Appendix E); serious cardiac arrhythmia requiring medication; and Grade II or greater peripheral vascular disease.
8. Women who are pregnant or nursing.
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10. Clinically significant, uncontrolled hypokalemia, hypomagnesaemia, and/or hypocalcaemia.
11. Hemoptysis within 3 months prior to enrollment.
12. Acute or chronic liver disease, active hepatitis A or B with known cirrhosis or liver dysfunction.
13. Cytotoxic chemotherapy, immunotherapy, or radiotherapy within 28 days (42 days in cases of mitomycin C, nitrosourea, lomustine) prior to enrollment.
14. Concomitant treatment with strong inhibitors or inducers of CYP3A4, CYP2C9 and CYP2C19 within 14 days prior to enrollment and during the study unless there is an emergent or life-threatening medical condition that required it.
15. Known history of human immunodeficiency virus infection (HIV).
16. Active bacterial infections requiring systemic antibiotics (excluding uncomplicated urinary tract infection).
17. Other invasive malignancies, with the exception of non-melanoma skin cancer, who had (or have) any evidence of other cancer present within the last 5 years prior to enrollment or whose previous cancer treatment contraindicates this protocol therapy.
18. History of non-malignant gastrointestinal bleeding, gastric stress ulcerations, or peptic ulcer disease within the past 3-months prior to enrollment that in the opinion of the investigator may place the subject at risk of side effects on an anti-angiogenesis product.
19. History of significant vascular disease (e.g. aortic aneurysm, aortic dissection).
20. Intra-abdominal abscess within the last 3 months of enrollment.
21. Pre-existing uncontrolled hypertension as documented by two baseline blood pressure readings taken at least five minutes apart, defined as systolic BP \>160 mm Hg or diastolic BP \> 90 mm Hg pressure.
22. QTc \> 470 msec on screening ECG per Fridericia's formula.
23. History of or existing risk factors for Torsades de pointes (TdP) (e.g., heart failure, hypokalemia, family history of Long QT Syndrome).
24. Concurrent use of concomitant medications that prolong the QT/QTc interval.
25. Baseline echocardiogram (within 56 days of enrollment) with left ventricular ejection fraction (LVEF) \< 50%.
26. History of difficulty swallowing, malabsorption, active partial or complete bowel obstruction, or other chronic gastrointestinal disease or condition that may hamper compliance and/or absorption of AL3818.
27. History of pancreatitis; history of renal disease that includes histologically confirmed glomerulonephritis, biopsy proven tubulointerstitial nephritis, crystal nephropathy or other renal insufficiencies.
28. Treatment with an investigational agent within 28 days of enrollment.
29. Known recreational substance abuse.
30. Anticoagulation therapy with warfarin. Subjects treated with heparin, low molecular weight heparin, or any other anticoagulant may be included provided the subject has been on a stable therapeutic dose of the anticoagulant for at least 14 days prior to enrollment.
31. Known hypersensitivity to AL3818 or components of the formulation.
B: Inclusion Criteria:

1. Age ≥18 years, female;
2. Recurrent epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer proven to be platinum-resistant by histology or cytology;
3. ECOG score was 0-1;
4. Expected survival time \> 12 weeks;
5. Normal or abnormal bone marrow, kidney, and liver function of the patient has no clinical significance, and the specific situation will be comprehensively determined by the investigator;
6. Patients not previously treated with PARPi or targeted drugs;
7. The patient has taken effective contraceptive measures within 14 days prior to screening and is willing to sign the notification until the last medication No pregnancy plan and voluntary use of effective contraceptive measures within the next 6 months;
8. The subject or his/her legal guardian can communicate well with the investigator, understand and comply with the requirements of this study, and understand and sign the informed consent.

Exclusion Criteria:

1. Known allergy to fluzopalil or study drug components;
2. Patients with any factors affecting oral administration (such as previous gastric or small bowel resection, or current atrophic gastritis, chronic intestinal disease, gastrointestinal bleeding, dysphagia, gastrointestinal obstruction, or diarrhea greater than grade 1, including those who have recovered but have not recovered);
3. Patients who underwent major surgery or gastrointestinal surgery affecting drug absorption, open biopsy, severe traumatic injury, wound unhealed or did not recover from major surgery within 1 month before the trial;
4. Before the first administration, patients have used strong CYP3A inhibitors (such as itraconazole, telithromycin, clarithromycin, ritonavir, etc.) or medium CYP3A inhibitors (such as ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil, etc.); Patients who had used strong CYP3A inducers (e.g., phenobarbide, enzyluamide, phenytoin, rifampicin, rifambutin, rifapentine, carbamazepine, nevirapine and St. John's herb) or medium CYP3A inducers (e.g., Bosentan, efavirenz, modafinil, etc.) and did not reach 3 elimination half-lives;
5. Pregnant or lactating women or subjects who cannot use contraception as required;
6. Those who have special requirements on diet and cannot accept uniform diet;
7. As judged by the researcher, there are other circumstances that are not suitable for the researcher.
C: Inclusion criteria:

* first diagnosis of histologically confirmed epithelial ovarian cancer, fallopian tube or primary peritoneal cancer
* International Federation of Gynecology and Obstetrics (FIGO) Stages IIB - IV
* females, age 18 years or older
* life expectancy of at least 6 months
* Eastern Cooperative Oncology Group (ECOG) performance status 0, 1 or 2
* prior surgery, defined as either (a) debulking surgery with maximum surgical effort at cytoreduction with the goal of no residual disease or (b) biopsy or limited surgery in patients with stage IV disease for whom surgical debulking was not considered appropriate, if diagnosis is confirmed by histology and no surgery is planned prior to disease progression (including interval debulking surgery)
* patient has given written informed consent which must be consistent with the International Conference on Harmonization - Good Clinical Practice (ICH-GCP) and local legislation
* planned application of first dose of chemotherapy after wound healing, but no later than 10 weeks after surgery

Exclusion criteria:

* histologic diagnosis of a benign or borderline tumour or of a malignant tumour of non-epithelial origin of the ovary, the fallopian tube or the peritoneum
* planned surgery within 124 weeks after randomisation in this trial, including interval debulking surgery
* clinically relevant non-healing wound, ulcer or bone fracture
* clinical symptoms or signs of gastrointestinal obstruction that require parenteral nutrition or hydration
* brain metastases
* pre-existing sensory or motor neuropathy Common Terminology Criteria for Adverse Events (CTCAE) grade 2 or higher, except due to trauma
* history of major thromboembolic event
* known inherited or acquired bleeding disorder
* significant cardiovascular diseases
* clinically relevant pericardial effusion
* history of a cerebral vascular accident, transient ischemic attack or subarachnoid haemorrhage within the past 6 months
* inadequate safety laboratory values
* serious infections in particular if requiring systemic antibiotic (antimicrobial, antifungal) or antiviral therapy, including Hepatitis B, Hepatitis C, Human Immunodeficiency Virus (HIV)
* poorly controlled diabetes mellitus or other contraindication to high dose corticosteroid therapy
* gastrointestinal disorders or abnormalities that would interfere with absorption of the study drug
* other malignancy diagnosed within the past 5 years. In exception to this rule, the following malignancies may be included if adequately treated: non-melanomatous skin cancer, cervical carcinoma in situ, carcinoma in situ of the breast, low risk endometrial cancer
* prior systemic therapy for ovarian cancer (e.g. chemotherapy, monoclonal antibody therapy, oral targeted therapy, hormonal therapy)
* prior systemic cytotoxic chemotherapy
* prior treatment with BIBF 1120 or any other angiogenesis inhibitor
* prior radiotherapy
* serious illness or concomitant non-oncological disease such as neurologic, psychiatric or infectious disease or a laboratory abnormality that may increase the risk associated with study participation or study drug administration
* Women of childbearing potential who are sexually active and not using a highly effective method of birth control during the trial and for at least twelve months after the end of active therapy.
* pregnancy or breast feeding
* psychological, familial, sociological or geographical factors potentially hampering compliance with the study protocol and follow-up schedule
* active alcohol or drug abuse
* patients unable to comply with the protocol
* any contraindications for therapy with paclitaxel or carboplatin
* treatment with other investigational drugs or participation in another clinical trial testing a drug within the past four weeks before start of therapy or concomitantly with this trial
D: Inclusion Criteria:

* Participants receiving a histologic diagnosis of epithelial ovarian cancer (EOC), peritoneal primary carcinoma, or fallopian tube cancer.
* Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.
* Life expectancy of at least 12 weeks.
* Adequate hematological, liver, renal and neurologic functions.
* For participants who receive therapeutic anticoagulation: stable anticoagulant regimen.
* Enrollment between 1 and 12 weeks after initial surgery is performed for the combined purpose of diagnosis, staging, and cytoreduction

Exclusion Criteria:

* Current diagnosis of borderline epithelial ovarian tumor or recurrent invasive epithelial ovarian, primary peritoneal, or fallopian tube cancer treated with surgery only.
* Prior radiotherapy to any portion of the abdominal cavity or pelvis.
* Prior chemotherapy for any abdominal or pelvic tumor, including neoadjuvant chemotherapy for ovarian, primary peritoneal, or fallopian tube cancer.
* Any prior targeted therapy (including, but not limited to, vaccines, antibodies, or tyrosine kinase inhibitors) or hormonal therapy for management of their epithelial ovarian or peritoneal primary cancer.
* Synchronous primary endometrial cancer.
* Have a prior history of primary endometrial cancer, except: Stage not greater than Stage IB; no more than superficial myometrial invasion, without vascular or lymphatic invasion; no poorly differentiated subtypes, including papillary serous, clear cell, or other International Federation of Gynecological Oncologists (FIGO) Grade 3 lesions.
* Cancer present within the last 5 years with the exception of non-melanoma-related skin cancers and other specific malignancies or whose previous cancer treatment contraindicates study treatment.
* Active hepatitis B virus (HBV) infection (chronic or acute) or active hepatitis C virus (HCV) infection.
* Serious non-healing wounds, ulcers, or bone fractures.
* Patients with clinically significant cardiovascular disease.
* Have known hypersensitivity to Chinese hamster ovary cell products or other recombinant human or humanized antibodies.
* Have known sensitivity to any component of paclitaxel.
* Undergo major surgical procedure within 28 days prior to randomization or anticipated during the course of the study.
* Have core biopsy or other minor surgical procedures within 7 days prior to the first dose of bevacizumab/placebo.
* History or evidence of thrombotic disorders within the last 6 months prior to enrollment.

Answer: A