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)
- Conditions
- Fallopian Tube CarcinomaCervical CarcinomaEndometrial CarcinomaOvarian CarcinomaPrimary Peritoneal Carcinoma
- Interventions
- Registration Number
- NCT02584478
- Lead Sponsor
- Advenchen Laboratories, LLC
- 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.
- Detailed Description
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.
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- Female
- Target Recruitment
- 294
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Phase 3 -Active Treatment Arm AL3818 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 Phase 3 -Active Treatment Arm Pegylated Liposomal Doxorubicin (PLD) 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 Phase 3 -Active Treatment Arm Topotecan 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 Phase 3-Control Treatment Arm 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: AL3818 plus carboplatin and paclitaxel Carboplatin 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 1b: AL3818 plus carboplatin and paclitaxel Paclitaxel 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 1b: AL3818 plus carboplatin and paclitaxel AL3818 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: AL3818 plus carboplatin and paclitaxel Carboplatin 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. Phase 2a: AL3818 plus carboplatin and paclitaxel Paclitaxel 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. Phase 2a: AL3818 plus carboplatin and paclitaxel AL3818 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. Phase 3-Control Treatment Arm Pegylated Liposomal Doxorubicin (PLD) 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 3 -Active Treatment Arm Paclitaxel 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 Phase 3-Control Treatment Arm Paclitaxel 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
- Primary Outcome Measures
Name Time Method Measure the Progression Free Survival (PFS)- Part 3 ( Phase 3) 12 Months 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).
Recommended Phase 2 Dose (RP2D) - Part 1 (Phase 1b) Cycle 1 (21-days) Determine the Recommended Phase 2 Dose (RP2D) via evaluation of dose limiting toxicity (DLT) events.
Objective Response Rates (ORR) - Part 2 (Phase 2a) 12 months 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)
- Secondary Outcome Measures
Name Time Method Number of Participants with Adverse Events as a measure of safety and toxicity of 21-Day cycles of AL3818 as measured by incidence and severity of treatment-related adverse events (TRAE) - Part 1 (Phase 1b) Cycle 1 (Day 21) 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).
Clinical Benefit Rate (CBR) - Part 2 (Phase 2a) 12 Months 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).
Duration Of Response - Part 3 ( Phase 3) 12 Months To evaluate the efficacy between the Active Arm and Control Arm as measured by the secondary endpoints of duration of response (DOR)
Overall Survival - Part 3 ( Phase 3) 12 Months To evaluate the efficacy between the Active Arm and Control Arm as measured by the endpoints of Overall survival
Objective Response Rate- Part 3 ( Phase 3) 12 Months To evaluate the efficacy between the Active Arm and Control Arm as measured by the secondary endpoints of objective response rate (ORR). (OS).
Progression-Free Survival (PFS) - 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. 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 (OS) - Part 2 (Phase 2a) Cycle 1 Day 1 up to 5 years Overall survival is defined as the date the study treatment was initiated to the date of death from any cause. Kaplan-Meier analysis
Trial Locations
- Locations (41)
The First Hospital of China Medical University
🇨🇳Shenyang, Shenyang, China
Obstetrics&Gynecology Hospital of Fudan University
🇨🇳Shanghai, Yangpu District, China
Chongqing University Cancer Hospital
🇨🇳Chongqing, China
Agostino Gemelli University Hospital Rome
🇮🇹Rome, Italy
Baptist Health Lexington Oncology Research
🇺🇸Lexington, Kentucky, United States
University of Miami Sylvester Comprehensive Cancer Center
🇺🇸Miami, Florida, United States
AHN West Penn Hospital
🇺🇸Pittsburgh, Pennsylvania, United States
Jilin Cancer Hospital
🇨🇳Changchun, Jilin, China
The Oncology Institute of Hope and Innovation
🇺🇸Long Beach, California, United States
University of Wisconsin Madison
🇺🇸Madison, Wisconsin, United States
Henan Cancer Hospital
🇨🇳Hefei, Henan, China
UTSW
🇺🇸Dallas, Texas, United States
Beijing Cancer Hospital
🇨🇳Beijing, China
Zhongda Hospital Southeast University
🇨🇳Chongqing, Sichuan, China
Tianjin Central Hospital of Gynecology Obstetrics
🇨🇳Tianjin, Tianjin, China
National Cancer Institute IRCCS "G. Pascale" Foundation
🇮🇹Naples, Campania, Italy
Weifang People's Hospital
🇨🇳Weifang, China
Complex Structure Gynecology Oncology National Cancer Institute of Milan
🇮🇹Milan, Italy
Operative Unit of Oncology
🇮🇹Ravenna, Italy
Severance Hospital
🇰🇷Seoul,, Korea, Republic of
Campus Bio Medico University Hospital Foundation
🇮🇹Rome, Italy
Hospital Universitario Reina Sofía
🇪🇸Córdoba, Andalucía, Spain
ICO Badalona
🇪🇸Badalona, Catalunya, Spain
Hospital Regional Universitario de Málaga
🇪🇸Malaga, Andalucía, Spain
Korea University Guro Hospital
🇰🇷Seoul, Korea, Republic of
Hospital Clínic de Barcelona
🇪🇸Barcelona, Spain
Hospital Universitario Ramón y Cajal
🇪🇸Madrid, Spain
Hospital Clínico San Carlos
🇪🇸Madrid, Spain
HCU Virgen Arrixaca
🇪🇸Murcia, Spain
The Royal Marsden NHS Foundation Trust
🇬🇧London, United Kingdom
The Christie NHS Foundation Trust
🇬🇧Manchester, United Kingdom
Cannizzaro Emergency Hospital
🇮🇹Catania, Italy
Seoul National University Hospital
🇰🇷Seoul, Korea, Republic of
Hospital Universitari Vall d'Hebrón
🇪🇸Barcelona, Catalunya, Spain
Washington University
🇺🇸Saint Louis, Missouri, United States
University Hospital of Bologna-IRCCS
🇮🇹Bologna, Emilia-Romagna, Italy
Samsung Medical Center
🇰🇷Seoul, Korea, Republic of
Hospital Clínico Universitario de Valencia
🇪🇸Valencia, Comunidad Valenciana, Spain
Romagnolo Institute For the Study of Tumors "Dino Amadori"
🇮🇹Meldola (FC), Forlì-Cesena, Italy
Cambridge University Hospitals NHS Foundation Trust
🇬🇧Cambridge, Cambridgeshire, United Kingdom
Montefiore Medical Center
🇺🇸Bronx, New York, United States