The purpose of Part 1 (Phase 1b) is to evaluate the general safety and tolerability of
repeated 21-day cycles of AL3818 therapy, and to reevaluate the maximum tolerated dose (MTD).
The purpose of Part 2 (Phase 2a) is to evaluate the efficacy of repeated 21-day cycles of
AL3818 therapy preliminary efficacy of AL3818 in subjects with recurrent or metastatic
endometrial, ovarian or cervical cancer.
Inclusion Criteria:
For a subject to be eligible for this study, she must meet all of the following criteria:
1. Female subjects 18 years of age or older
2. Subjects may be enrolled with previous histologically proven diagnosis of the
following:
a. Endometrial Cancer: Patients must have recurrent or persistent endometrial
carcinoma, which is refractory to curative therapy or established treatments.
i. Histologic diagnosis will be reviewed by the treating institution ii. Patients with
the following histologic epithelial cell types are eligible: Endometrioid
adenocarcinoma, serous adenocarcinoma, undifferentiated carcinoma, clear cell
adenocarcinoma, mixed epithelial carcinoma, adenocarcinoma not otherwise specified,
mucinous adenocarcinoma, squamous cell carcinoma, and transitional cell carcinoma.
iii. Initial treatment may have included chemotherapy, chemotherapy and radiation
therapy, and/or consolidation/maintenance therapy; antiangiogenic therapy (e.g.
bevacizumab) as part of adjuvant therapy is allowed. Chemotherapy administered in
conjunction with primary radiation as a radio-sensitizer will be counted as a systemic
chemotherapy regimen.
iv. Patients should have received no more than two prior cytotoxic or non-cytotoxic
therapies for management of recurrent or persistent disease (excluding endocrine
therapies which will not count in the number of regimens)
b. Ovarian cancer: Patients must have recurrent or persistent ovarian, fallopian tube
or primary peritoneal cancer, which is refractory to established treatments.
i. Patients with the following histologic epithelial cell types are eligible:
Endometrioid adenocarcinoma, serous adenocarcinoma, undifferentiated carcinoma, clear
cell adenocarcinoma, mixed epithelial carcinoma, adenocarcinoma not otherwise
specified.
ii. Patients must have received at least one prior platinum-based chemotherapeutic
regimen for the management of primary disease containing carboplatin, cisplatin, or
another organoplatinum compound.
iii. This initial therapy may have included high-dose therapy, consolidation, or
extended therapy administered after surgical or non-surgical assessment.
iv. Antiangiogenic therapy (e.g. bevacizumab) as part of adjuvant therapy is allowed.
v. Patients should have received no more than two prior cytotoxic or non-cytotoxic
therapies for management of recurrent or persistent disease
c. Cervix cancer: Subjects diagnosed with histologically confirmed squamous cell
carcinoma of the cervix.
i. Patients must have received at least one prior platinum based chemotherapeutic
regimen for the management of primary disease containing carboplatin, cisplatin or
another organoplatinum compound. The initial therapy may have included high-dose
therapy, consolidation or extended therapy administered after surgical or non-surgical
assessment. Antiangiogenic therapy (e.g. bevacizumab) as part of adjuvant therapy is
allowed. Chemotherapy administered in conjunction with primary radiation as a
radio-sensitizer will be counted as a systemic chemotherapy regimen.
ii. Patients should have received no more than two prior cytotoxic or non-cytotoxic
standard therapies for management of recurrent or persistent disease.
d. Other uterine cancers: Subjects diagnosed with other uterine cancers, such as
Leiomyosarcoma, and have received no more than two prior cytotoxic or non-cytotoxic
standard therapies for management of recurrent or persistent disease.
3. For Phase 2a only, all patients must express at least one FGFr 1, 2 or 3 amplification
(or mutation) from archived tissue or new biopsy. For non-amplified patients, approval
of the site coordinator or the sponsor is required prior to enrollment.
4. All patients must have measurable disease. Measurable disease is defined as at least
one lesion that can be accurately measured in at least one dimension (longest
dimension to be recorded). Each lesion must be ≥ 20mm when measured by conventional
techniques, including palpation, plain x-ray, CT, and MRI, or ≥ 10mm when measured by
spiral CT.
5. Life expectancy ≥ 3 months
6. Subject must be suitable for oral administration of study medication
7. Patients must have signed an approved informed consent and authorization permitting
release of personal health information.
8. Patient must have adequate:
1. Bone Marrow Function: Absolute neutrophil count (ANC) greater then or equal to
1,500/mm3, equivalent to Common Toxicity Criteria (CTC) grade 1. Platelets
greater than or equal to 100,000/mm3
2. Renal Function: Creatinine less than or equal to 1.5 x institutional upper limit
normal (ULN), CTC grade 1. Note: If creatinine is greater than 1.5 x ULN,
creatinine clearance must be greater than >50 mL/min.
3. Hepatic Function: Bilirubin less than or equal to 1.5 x ULN (CTC grade 1) or less
than or equal to 3.0 x ULN for subjects with Gilbert Syndrome; AST and ALT less
than or equal to 3.0 ×ULN.
4. Coagulation profile: PT such that international normalized ratio (INR) is ≤ 1.55
(or an in-range INR, usually between 2 and 3, if a patient is on a stable dose of
therapeutic warfarin or low molecular weight heparin) and a PTT < 1.2 times
control.
9. ECOG performance status ≤ 2.
10. Subjects of child-bearing potential must agree to use contraceptive measures starting
1 week before the administration of the first dose of AL3818 until 4 weeks after
discontinuing study drug.
11. Subjects of child-bearing potential must have a negative serum pregnancy test prior to
study entry and cannot be lactating.
12. Ability and willingness to comply with the study protocol for the duration of the
study and with follow-up procedures.
Exclusion Criteria
Subjects who meet any of the following criteria will be excluded from participation in the
study:
1. Subjects who have received prior treatment with an FGFr inhibitor or antagonist of
FGFr. Prior anti-VEGF or anti-angiogenic therapy is allowed in the adjuvant treatment
setting Prior anti-VEGF or anti-angiogenic therapy for the treatment of recurrent
disease is not allowed.
2. Patients who have received prior antiangiogenic therapy, including bevacizumab,
sorafenib, sunitinib, in the setting of advanced disease.
3. Patients with serious, non-healing wound, ulcer or bone fracture.
4. Patients with active bleeding or pathologic conditions that carry high risk of
bleeding, such as known bleeding disorder, coagulopathy, or tumor involving major
vessels.
5. Patient with history or evidence upon physical examination of CNS disease, including
primary brain tumor, seizures not controlled with standard medical therapy, any brain
metastases or history of cerebrovascular accident (CVA, stroke) transient ischemic
attack (TIA) or subarachnoid hemorrhage within 6 months of the first date of treatment
on this study.
6. However, patients with metastatic CNS tumors may participate in this trial, if the
patient is > 4 weeks from therapy completion (including radiation and/or surgery), is
clinically stable at the time of study entry and is not receiving corticosteroid
therapy.
7. Patients with proteinuria. Patients discovered to have a urine protein of 1+ on
dipstick or ≥ 30 mg/dl at baseline should undergo a 24-hour urine collection, which
must be an adequate collection and must demonstrate < 1000 mg protein/24 hr to allow
participation in the study.
8. Patients with clinically significant cardiovascular disease; this includes:
Uncontrolled hypertension; Myocardial infarction or unstable angina within 6 months
prior to registration; New York Heart Association (NYHA) Grade II or greater
congestive heart failure (Appendix F); Serious cardiac arrhythmia requiring
medication; Grade II or greater peripheral vascular disease (Appendix F).
9. Patients who are pregnant or nursing. To date, no fetal studies of AL3818 in animals
or humans have been performed. Therefore, AL3818 should not be administered to
pregnant women. Subjects will be apprised of the large potential risk to a developing
fetus. It is not known whether AL3818 is excreted in human milk. Because many drugs
are excreted in human milk, AL3818 should not be administered to nursing women. Women
of childbearing potential must agree to use contraceptive measures during study
therapy and for at least 3 months after completion of AL3818 therapy. Because many
drugs are excreted in human milk.
10. Patients with uncontrolled hypokalemia, hypomagnesaemia, and/or hypocalcaemia.
11. Hemoptysis within 3 months prior to first scheduled dose of AL3818.
12. Patients with acute or chronic liver disease, active hepatitis A or B with known
cirrhosis or liver dysfunction.
13. Cytotoxic chemotherapy, immunotherapy, or radiotherapy within 4 weeks (6 weeks in
cases of mitomycin C, nitrosourea, lomustine) prior to first scheduled dose of AL3818
or a major surgical procedure within 28 days or minor surgical procedure performed
within 7 days prior to first scheduled dose of AL3818.
14. Concomitant treatment with strong inhibitors or inducers of CYP3A4, CYP2C9 and CYP2C19
who cannot be switched to other alternative medications (See Appendix E).
15. Known history of human immunodeficiency virus infection (HIV).
16. Subjects with active bacterial infections (other than uncomplicated urinary tract
infection) and/or receiving systemic antibiotics.
17. Patients with 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
or whose previous cancer treatment contraindicates this protocol therapy.
18. History of non-malignant GI bleeding, gastric stress ulcerations, or peptic ulcer
disease within the past 3-months that in the opinion of the investigator may place the
patient 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.
21. History of uncontrolled hypertension that is not well managed by medication, as
documented by 2 baseline evaluations taken one hour apart with systolic blood pressure
>160 mm or diastolic blood pressure >90 mm Hg pressure, or that in the opinion of the
investigator may place the patient at risk when taking a VEGF inhibitor.
22. Pre-existing uncontrolled hypertension as documented by 2 baseline BP readings taken
at least one hour apart, defined as systolic bloodpressure (BP) >160 mm Hg or
diastolic BP > 90 mm Hg pressure.
23. QTcF>470 msec on screening ECG.
24. A history of additional risk factors for TdP (e.g., heart failure, hypokalemia, family
history of Long QT Syndrome).
25. The use of concomitant medications that prolong the QT/QTc interval.
26. Baseline echocardiogram (within 2 months) with left ventricular ejection fraction
(LVEF) < 50%.
27. 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.
28. History of pancreatitis and/or renal disease that includes histologically confirmed
glomerulonephritis, biopsy proven tubulointerstitial nephritis, crystal nephropathy,
or other renal insufficiencies.
29. Treatment with an investigational agent within the longest time frame of either 5
half- lives or 30 days of initiating study drug.
30. Known recreational substance abuse.
31. Known hypersensitivity to anti-angiogenic agents.
