Phase 1/2a Evaluation of AL3818 in Subjects With Recurrent or Metastatic Endometrial, Ovarian or Cervical Cancer (AL3818-US-001)

NCT02558348 | Terminated Phase 1 DMC

• 1 other identifier: AL3818-US-001
• Study Type: interventional
• Target: 12
• Locations: 1 country
• Sites: 2

Brief Summary

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.

Conditions

Endometrial Cancer; Ovarian Cancer; Cervical Cancer

Keywords

Dual receptor Tyrosine Kinase Inhibitor; Anti-angiogenic therapy

Outcome Measures

Primary Outcomes (3)

• Number of Participants with Adverse Events as a Measure of Safety and Tolerability of 21-Day cycles of AL3818 measured by incidence and severity of treatment-related adverse events (TRAE) - Part 1 (Phase 1b)

  Incidence and severity of treatment-related adverse events reported and their relationship to AL3818 will be assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.3). Safety data will be tabulated and summarized and descriptive statistics will be provided for changes in vital signs, weight, clinical laboratory tests (serum chemistry and hematology) and electrocardiogram (ECG) results.

  Cycle 1 (21 Days)

• Maximum Tolerated Dose (MTD) - Part 1 (Phase 1b)

  Reevaluation of the MTD determined by DLT events

  Cycle 1 (21 Days)

• Objective Response Rates (ORR) - Part 2 (Phase 2a)

  Evaluation by Response Evaluation Criteria In Solid Tumors (RECIST, v1.1) criteria

  After every three complete 21-Day cycles of therapy (Day 64)

Secondary Outcomes (5)

• Pharmacokinetics (PK) of plasma AL3818 - Part 1 (Phase 1b)

  Cycle 1 only: Day 1 (30mins, 60mins, 2 hours, 4 hours and 24 hours [prior to dosing on Day 2] ), Day 15 and Day 22 (Prior to dosing)

• Pharmacokinetics (PK) of plasma AL3818 - Part 1 (Phase 1b)

  Cycle 1 only: Day 1 (30mins, 60mins, 2 hours, 4 hours and 24 hours [prior to dosing on Day 2] ), Day 15 and Day 22 (Prior to dosing)

• Clinical Benefit Rate (CBR) - Part 2 (Phase 2a)

  After three 21-day cycles of treatment (Day 64)

• Overall Survival (OS) - Part 2 (Phase 2a)

  From the date the study treatment was initiated to the date of death, followed for 5 years.

• Progression-Free Survival (PFS) rate - Part 2 (Phase 2a)

  Duration of time from the start of treatment to the time of documented disease progression or death, whichever comes first, followed for 12 months.

Other Outcomes (1)

• Determine fibroblast growth factor receptor (FGFr 1, 2 and 3) amplification (or mutation) status of each subject - Part 2 (Phase 2a)

  Measured within 28 days of dosing on Day 1

Study Arms (1)

AL3818

EXPERIMENTAL

Part 1 (Phase 1b): Cohort 1 will initiate at a dose of 12 mg/day of AL3818, for 21-Day cycles (14 days of AL3818 treatment followed by 7 days of rest). After three subjects have completed the first cycle of therapy without a DLT, additional cohorts may be enrolled sequentially. After the first cohort has completed one full cycle of therapy without a DLT, two additional cohorts will be sequentially enrolled at 16 mg/day and 20 mg/day doses of AL3818 for the same 21-day cycles. Part 2 (Phase 2a): Each subject will receive a dose of up to 20 mg AL3818 or a maximum of the MTD from Part 1 (Phase 1b) of this study for continuous 21-Day cycles of therapy (14 days of AL3818 treatment followed by 7 days of rest).

Drug: AL3818

Interventions

AL3818 DRUG

Administered orally

Also known as: Anlotinib Hydrochloride

AL3818

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• For a subject to be eligible for this study, she must meet all of the following criteria:
• Female subjects 18 years of age or older
• 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.

You may not qualify if:

• Subjects who meet any of the following criteria will be excluded from participation in the study:
• 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.
• Patients who have received prior antiangiogenic therapy, including bevacizumab, sorafenib, sunitinib, in the setting of advanced disease.
• Patients with serious, non-healing wound, ulcer or bone fracture.
• Patients with active bleeding or pathologic conditions that carry high risk of bleeding, such as known bleeding disorder, coagulopathy, or tumor involving major vessels.
• 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.
• 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.
• 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.
• 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).
• 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.
• Patients with uncontrolled hypokalemia, hypomagnesaemia, and/or hypocalcaemia.
• Hemoptysis within 3 months prior to first scheduled dose of AL3818.
• Patients with acute or chronic liver disease, active hepatitis A or B with known cirrhosis or liver dysfunction.
• 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.
• Concomitant treatment with strong inhibitors or inducers of CYP3A4, CYP2C9 and CYP2C19 who cannot be switched to other alternative medications (See Appendix E).

Sponsors & Collaborators

• Advenchen Laboratories, LLC: lead

Study Sites (2)

University of Chicago Medical Center

Chicago, Illinois, 60637, United States

Location

Huntsman Cancer Institute, University of Utah

Salt Lake City, Utah, 84112, United States

Location

Related Publications (14)

• Niu G, Chen X. Vascular endothelial growth factor as an anti-angiogenic target for cancer therapy. Curr Drug Targets. 2010 Aug;11(8):1000-17. doi: 10.2174/138945010791591395.

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• Roskoski R Jr. Vascular endothelial growth factor (VEGF) signaling in tumor progression. Crit Rev Oncol Hematol. 2007 Jun;62(3):179-213. doi: 10.1016/j.critrevonc.2007.01.006. Epub 2007 Feb 26.

  PMID: 17324579 BACKGROUND

• Dickson C, Spencer-Dene B, Dillon C, Fantl V. Tyrosine kinase signalling in breast cancer: fibroblast growth factors and their receptors. Breast Cancer Res. 2000;2(3):191-6. doi: 10.1186/bcr53. Epub 2000 Mar 25.

  PMID: 11250709 BACKGROUND

• Cole C, Lau S, Backen A, Clamp A, Rushton G, Dive C, Hodgkinson C, McVey R, Kitchener H, Jayson GC. Inhibition of FGFR2 and FGFR1 increases cisplatin sensitivity in ovarian cancer. Cancer Biol Ther. 2010 Sep 1;10(5):495-504. doi: 10.4161/cbt.10.5.12585. Epub 2010 Sep 4.

  PMID: 20595807 BACKGROUND

• Hoeben A, Landuyt B, Highley MS, Wildiers H, Van Oosterom AT, De Bruijn EA. Vascular endothelial growth factor and angiogenesis. Pharmacol Rev. 2004 Dec;56(4):549-80. doi: 10.1124/pr.56.4.3.

  PMID: 15602010 BACKGROUND

• Kondo Y, Arii S, Mori A, Furutani M, Chiba T, Imamura M. Enhancement of angiogenesis, tumor growth, and metastasis by transfection of vascular endothelial growth factor into LoVo human colon cancer cell line. Clin Cancer Res. 2000 Feb;6(2):622-30.

  PMID: 10690548 BACKGROUND

• Yeramian A, Moreno-Bueno G, Dolcet X, Catasus L, Abal M, Colas E, Reventos J, Palacios J, Prat J, Matias-Guiu X. Endometrial carcinoma: molecular alterations involved in tumor development and progression. Oncogene. 2013 Jan 24;32(4):403-13. doi: 10.1038/onc.2012.76. Epub 2012 Mar 19.

  PMID: 22430211 BACKGROUND

• Byron SA, Loch DC, Pollock PM. Fibroblast growth factor receptor inhibition synergizes with Paclitaxel and Doxorubicin in endometrial cancer cells. Int J Gynecol Cancer. 2012 Nov;22(9):1517-26. doi: 10.1097/IGC.0b013e31826f6806.

  PMID: 23060048 BACKGROUND

• Gorringe KL, Jacobs S, Thompson ER, Sridhar A, Qiu W, Choong DY, Campbell IG. High-resolution single nucleotide polymorphism array analysis of epithelial ovarian cancer reveals numerous microdeletions and amplifications. Clin Cancer Res. 2007 Aug 15;13(16):4731-9. doi: 10.1158/1078-0432.CCR-07-0502.

  PMID: 17699850 BACKGROUND

• Christensen C, Lauridsen JB, Berezin V, Bock E, Kiselyov VV. The neural cell adhesion molecule binds to fibroblast growth factor receptor 2. FEBS Lett. 2006 Jun 12;580(14):3386-90. doi: 10.1016/j.febslet.2006.05.008. Epub 2006 May 11.

  PMID: 16709412 BACKGROUND

• Byron SA, Gartside MG, Wellens CL, Goodfellow PJ, Birrer MJ, Campbell IG, Pollock PM. FGFR2 mutations are rare across histologic subtypes of ovarian cancer. Gynecol Oncol. 2010 Apr;117(1):125-9. doi: 10.1016/j.ygyno.2009.12.002. Epub 2010 Jan 27.

  PMID: 20106510 BACKGROUND

• Taniguchi F, Itamochi H, Harada T, Terakawa N. Fibroblast growth factor receptor 2 expression may be involved in transformation of ovarian endometrioma to clear cell carcinoma of the ovary. Int J Gynecol Cancer. 2013 Jun;23(5):791-6. doi: 10.1097/IGC.0b013e31828f38c4.

  PMID: 23640291 BACKGROUND

• Tsang TY, Mohapatral G, Itamochi H, Mok SC, and Birrer MJ., Abstract 1528: Identification of FGFR3 as a potential therapeutic target gene for human clear cell ovarian cancer by global genomic analysis. Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA

  BACKGROUND

• Kawase R, Ishiwata T, Matsuda Y, Onda M, Kudo M, Takeshita T, Naito Z. Expression of fibroblast growth factor receptor 2 IIIc in human uterine cervical intraepithelial neoplasia and cervical cancer. Int J Oncol. 2010 Feb;36(2):331-40.

  PMID: 20043066 BACKGROUND

MeSH Terms

Conditions

Endometrial Neoplasms; Ovarian Neoplasms; Uterine Cervical Neoplasms

Interventions

anlotinib

Condition Hierarchy (Ancestors)

Uterine Neoplasms; Genital Neoplasms, Female; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Uterine Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases; Endocrine Gland Neoplasms; Ovarian Diseases; Adnexal Diseases; Endocrine System Diseases; Gonadal Disorders; Uterine Cervical Diseases

Study Officials

• Clinical Director

  Advenchen Laboratories, LLC

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 26, 2014
• First Posted: September 24, 2015
• Study Start: November 1, 2015
• Primary Completion: February 14, 2017
• Study Completion: May 30, 2017
• Last Updated: June 19, 2019

Record last verified: 2019-06

Locations

US (2)