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.
This trial is a Phase 1b/2a/3 trial designed to evaluate the safety and efficacy of adding
oral AL3818(Anlotinib, INN: Catequentinib) to standard platinum-based chemotherapy
concurrently and continued as a maintenance therapy for up to 12 months, in subjects with
recurrent or metastatic endometrial, ovarian, fallopian, primary peritoneal, or cervical
carcinoma. AL3818 is a novel small molecule dual receptor tyrosine kinase inhibitor, which
shows highly selective inhibition of fibroblast growth factor receptor (FGFr) and vascular
endothelial growth factor receptor (VEGFR). Preclinical studies of this agent in mouse
models, including various cancer xenografts, have demonstrated that treatment of
tumor-bearing mice with AL3818 induces tumor reductions.
Phase 1 & 2: This study is divided into two parts. The objective of Part 1 is the evaluation
of the safety and tolerability of adding oral AL3818 to standard carboplatin plus paclitaxel
chemotherapy for a cycle of 21 days to determine the recommended Phase II dose (RP2D). Phase
1 / Part 1 is now complete. Part 2-The objective of Part 2 is evaluation of preliminary
efficacy and the safety of adding oral AL3818 at the RP2D determined in Part 1 to carboplatin
and paclitaxel chemotherapy for 6 cycles. Continuous maintenance mono therapy with 14 days on
and 7 days off regimen at the RP2D will be conducted up to 12 months and is extendable beyond
until disease progression. Phase I is closed and Phase 2 is closed.
Phase 3: This study is currently a Phase III, multi-center, randomized trial with active
control designed to evaluate the efficacy and safety of AL3818 8 mg plus background treatment
(Active Arm) vs background treatment alone (Control Arm), where three background treatments,
weekly paclitaxel, pegylated liposomal doxorubicin (PLD), and topotecan are utilized. Oral
AL3818 8 mg may be given concurrently with background treatment or alone if the background
treatment must be discontinued due to its toxicity for up to 24 cycles of therapy, in
subjects with recurrent or metastatic platinum-resistant ovarian, fallopian tube, or primary
peritoneal cancer. Phase 3 is open.
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).
3. (Intentionally left blank)
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.
9. (Intentionally left blank)
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.
