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Phase 3: AL3818 8 mg once daily in combination with one background chemotherapy in 21-day cycles. Platinum resistant recurrent or metastatic ovarian, fallopian, or primary peritoneal cancer subjects will be enrolled into one of the following three background chemotherapy groups:

* Weekly paclitaxel (default choice; if the subject is ineligible for paclitaxel, the investigator will select from PLD or topotecan)
* Pegylated liposomal doxorubicin (PLD)
* Topotecan

Control Treatment Arm: Background chemotherapy treatment alone. Platinum resistant recurrent or metastatic ovarian, fallopian, or primary peritoneal cancer subjects will be enrolled into one of the following three background chemotherapy groups:

* Weekly paclitaxel (default choice; if the subject is ineligible for paclitaxel, the investigator will select from PLD or topotecan)
* Pegylated liposomal doxorubicin (PLD)
* Topotecan

Phase 1b: Sequential deescalating dosing evaluation to determine the recommended Phase II dose (RP2D). For 21-day treatment cycles, cohort 1 (3 subjects) will be administered carboplatin (AUC 5/6 over 30 minutes) and paclitaxel (175mg/m2 over 3 hours) intravenously on Day 1. AL3818 is orally administered daily starting on Day 8 until Day 21 (14 days) at an initial dose of 12 mg/day.

Phase 2a: subjects will receive chemotherapy and oral AL3818 for 6 cycles (18 weeks, 21-day cycles of treatment) followed by continuous maintenance treatment of oral AL3818 for up to 12 months. Subjects will be administered carboplatin (AUC 5/6 over 30 minutes) and paclitaxel (175mg/m2 over 3 hours) intravenously on Day 1. AL3818 is orally administered daily starting on Day 8 until Day 21 (14 days) at the RP2D found in Phase 1b.

Taken daily from Day 8 to Day 21 (14 days),administered orally combination with one background chemotherapy in 21-day cycles.

AL3818

Weekly single agent Paclitaxel will be administered on Day 1, 8, and 15 of each 21-day cycle. Suggested dose: 80 mg/m\^2 intravenously or local standard.

Paclitaxel may also be administered once weekly with a 1-week break every 3 weeks in lieu of every week

Single agent Pegylated Liposomal Doxorubicin (PLD) administered every 4 weeks on the following cycle days corresponding with AL3818 cycles until maximum cumulative dose per local standard reached.

Suggested dose: 40 mg/m\^2 intravenously or local standard

Pegylated Liposomal Doxorubicin (PLD)

Daily Topotecan on Days 1-5 of each 21-day cycle Suggested dose: 1.25 mg/m2 intravenously or local standard OR Weekly Topotecan with a 1 week break every 3 weeks. Suggested dose: 4 mg/m2 intravenously or local standard

Weekly Topotecan with a 1 week break every 3 weeks Suggested dose: 4 mg/m2 intravenously or local standard

175mg/m2 IV over 3 hours on Day 1 of each 21-Day cycle

Taken daily from Day 8 to Day 21 (14 days). Administered orally.

Clinical Director

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.

Overall duration of the study will be approximately 42 months. Part 1 and 2 of this study are not randomized and have no concurrent controls. AL3818 and chemotherapy will be administered in an open-label fashion. Phase III/Part 3 is unblinded and randomized. Within each one of the three background chemotherapy groups, subjects will be randomized at a 1:1 ratio stratified by prior angiogenesis inhibitors mainly Avastin use status (Yes or No) and number of prior treatment (≤3 or \>3) to receive AL3818 plus background chemotherapy (Active Arm) or background chemotherapy alone (Control Arm).

Phase 1/2a/3 Evaluation of Adding AL3818 to Standard Platinum-Based Chemotherapy in Subjects With Recurrent or Metastatic Endometrial, Ovarian, Fallopian, Primary Peritoneal or Cervical Carcinoma (AL3818-US-002)

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

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)

Determine the Recommended Phase 2 Dose (RP2D) via evaluation of dose limiting toxicity (DLT) events.

Evaluated by Response Evaluation Criteria In Solid Tumors (RECIST, v1.1) criteria after three complete 21-day cycles in the first 9 cycles then once every 6 cycles for up to 12 months. ORR is measured by the number of complete (CR) and partial responses (PR)

To evaluate the efficacy between the Active Arm (AL3818 in combination with background chemotherapy) and Control Arm (background chemotherapy alone arm) as measured by the primary endpoint of Progression Free Survival (PFS).

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).

Evaluated by Response Evaluation Criteria In Solid Tumors (RECIST, v1.1) criteria after three complete 21-day cycles in the first 9 cycles then once every 6 cycles for up to 12 months. Measured as CR+PR+SD (SD ≥ 16 weeks from inclusion).

Evaluated by Response Evaluation Criteria In Solid Tumors (RECIST, v1.1) criteria after three complete 21-day cycles in the first 9 cycles then once every 6 cycles for up to 12 months. Kaplan-Meier analysis

Overall survival is defined as the date the study treatment was initiated to the date of death from any cause. Kaplan-Meier analysis

To evaluate the efficacy between the Active Arm and Control Arm as measured by the secondary endpoints of objective response rate (ORR). (OS).

To evaluate the efficacy between the Active Arm and Control Arm as measured by the secondary endpoints of duration of response (DOR)

To evaluate the efficacy between the Active Arm and Control Arm as measured by the endpoints of Overall survival

Advenchen Laboratories, LLC

Uterine Cervical Neoplasms

Uterine Cervical Diseases

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).

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.

This is a Phase 1b/2a study to evaluate the safety, pharmacokinetics and efficacy of 21-day cycles of AL3818 therapy. The study is divided into two parts. Part 1 (Phase 1b) will evaluate the dose limiting toxicity (DLT) and general safety during the first 21-day cycle of Al3818 therapy and to reevaluate the MTD. It will include a sequential evaluation of 3 subjects per cohort in a 3+3 design with up to 18 subjects in total. Cohort 1 will initiate at a dose of 12 mg/day of AL3818, for cycles of 14 days of 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. All subjects will be allowed continuation of therapy with repeat cycles of 21-days if they are tolerating AL3818 and have stable disease or better. 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) will evaluate the safety and preliminary efficacy of repeated 21-day cycles of AL3818. It will include up to 45 additional subjects with metastatic endometrial cancer, ovarian cancer refractory to platinum therapy or cervical cancer refractory to standard therapy. 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 off).

All subjects in Part 1 and Part 2 of this study will be permitted to continue therapy with only safety monitoring and bimonthly assessments for progression, if AL3818 is well tolerated and the subject has stable disease or better.

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

A Phase 1/2a Evaluation of the Safety, Pharmacokinetics and Efficacy of AL3818, a Dual Receptor Tyrosine Kinase Inhibitor, in Subjects With Recurrent or Metastatic Endometrial, Ovarian or Cervical Cancer (AL3818-US-001)

For participation in Phase 2a: FGFr amplification (or mutation) status of each subject will be determined by analyses of archived tissue or new biopsy (if archived tissue is unavailable) and correlate with response

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.

Reevaluation of the MTD determined by DLT events

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

Evaluated by Response Evaluation Criteria In Solid Tumors (RECIST, v1.1) criteria after three complete 21-day cycles. Measured as CR+PR+SD (SD ≥ 16 weeks from inclusion)

Evaluated by Response Evaluation Criteria In Solid Tumors (RECIST, v1.1) criteria after three complete 21-day cycles for up to 12 months. Kaplan-Meier analysis

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Phase 1/2a/3 Evaluation of Adding AL3818 to Standard Platinum-Based Chemotherapy in Subjects With Recurrent or Metastatic Endometrial, Ovarian, Fallopian, Primary Peritoneal or Cervical Carcinoma (AL3818-US-002)	NCT02584478	Endometrial Car... Ovarian Carcino... Fallopian Tube ... Primary Periton... Cervical Carcin...	AL3818 Paclitaxel Pegylated Lipos... Topotecan Topotecan Carboplatin Paclitaxel AL3818	18 Years -	Advenchen Laboratories, LLC
Phase 1/2a Evaluation of AL3818 in Subjects With Recurrent or Metastatic Endometrial, Ovarian or Cervical Cancer (AL3818-US-001)	NCT02558348	Endometrial Can... Ovarian Cancer Cervical Cancer	AL3818	18 Years -	Advenchen Laboratories, LLC

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