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 | Unknown Phase 3 DMC

• 1 other identifier: AL3818-US-002
• Study Type: interventional
• Target: 294
• Locations: 6 countries
• Sites: 41

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.

Conditions

Endometrial Carcinoma; Ovarian Carcinoma; Fallopian Tube Carcinoma; Primary Peritoneal Carcinoma; Cervical Carcinoma

Keywords

Dual receptor Tyrosine Kinase Inhibitor; Anti-angiogenic therapy; Combination Therapy

Outcome Measures

Primary Outcomes (3)

• Recommended Phase 2 Dose (RP2D) - Part 1 (Phase 1b)

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

  Cycle 1 (21-days)

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

  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)

  12 months

• Measure the Progression Free Survival (PFS)- Part 3 ( Phase 3)

  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).

  12 Months

Secondary Outcomes (7)

• 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)

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

  12 Months

• 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.

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

  Cycle 1 Day 1 up to 5 years

• Objective Response Rate- Part 3 ( Phase 3)

  12 Months

Other Outcomes (1)

• Toxicity as assessed by CTCAE (v4.3) - Part 2 (Phase 2a)

  12 Months

Study Arms (4)

Phase 3 -Active Treatment Arm

EXPERIMENTAL

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

Drug: AL3818; Drug: Paclitaxel; Drug: Pegylated Liposomal Doxorubicin (PLD); Drug: Topotecan

Phase 3-Control Treatment Arm

OTHER

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

Drug: Paclitaxel; Drug: Pegylated Liposomal Doxorubicin (PLD); Drug: Topotecan

Phase 1b: AL3818 plus carboplatin and paclitaxel

EXPERIMENTAL

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.

Drug: Carboplatin; Drug: Paclitaxel; Drug: AL3818

Phase 2a: AL3818 plus carboplatin and paclitaxel

EXPERIMENTAL

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.

Drug: Carboplatin; Drug: Paclitaxel; Drug: AL3818

Interventions

AL3818 DRUG

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

Also known as: Anlotinib Hydrochloride, Anlotinib, Catequentinib

Phase 3 -Active Treatment Arm

Paclitaxel DRUG

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

Phase 3 -Active Treatment Arm; Phase 3-Control Treatment Arm

Pegylated Liposomal Doxorubicin (PLD) DRUG

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

Phase 3 -Active Treatment Arm; Phase 3-Control Treatment Arm

Topotecan DRUG

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

Also known as: Daily Topotecan

Phase 3 -Active Treatment Arm; Phase 3-Control Treatment Arm

Carboplatin DRUG

AUC 5/6 on Day 1 of each 21-Day cycles

Also known as: Paraplatin

Phase 1b: AL3818 plus carboplatin and paclitaxel; Phase 2a: AL3818 plus carboplatin and paclitaxel

Eligibility Criteria

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

You may not qualify if:

• Serious, non-healing wound, ulcer or bone fracture.
• 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).
• (Intentionally left blank)
• Active bleeding or pathologic conditions that carry high risk of bleeding, such as known bleeding disorder, coagulopathy, or tumor involving major vessels.
• 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.
• 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.
• 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.
• Women who are pregnant or nursing.
• (Intentionally left blank)
• Clinically significant, uncontrolled hypokalemia, hypomagnesaemia, and/or hypocalcaemia.
• Hemoptysis within 3 months prior to enrollment.
• Acute or chronic liver disease, active hepatitis A or B with known cirrhosis or liver dysfunction.
• Cytotoxic chemotherapy, immunotherapy, or radiotherapy within 28 days (42 days in cases of mitomycin C, nitrosourea, lomustine) prior to enrollment.
• 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.

Sponsors & Collaborators

• Advenchen Laboratories, LLC: lead

Study Sites (41)

The Oncology Institute of Hope and Innovation

Long Beach, California, 90805, United States

Location

University of Miami Sylvester Comprehensive Cancer Center

Miami, Florida, 33136, United States

Location

Baptist Health Lexington Oncology Research

Lexington, Kentucky, 40503, United States

Location

Washington University

St Louis, Missouri, 63130, United States

Location

Montefiore Medical Center

The Bronx, New York, 10467, United States

Location

AHN West Penn Hospital

Pittsburgh, Pennsylvania, 15224, United States

Location

UTSW

Dallas, Texas, 75390, United States

Location

University of Wisconsin Madison

Madison, Wisconsin, 53792, United States

Location

Henan Cancer Hospital

Hefei, Henan, China

Location

Jilin Cancer Hospital

Changchun, Jilin, China

Location

The First Hospital of China Medical University

Shenyang, Shenyang, 110001, China

Location

Zhongda Hospital Southeast University

Chongqing, Sichuan, China

Location

Tianjin Central Hospital of Gynecology Obstetrics

Tianjin, Tianjin Municipality, China

Location

Obstetrics&Gynecology Hospital of Fudan University

Shanghai, Yangpu District, China

Location

Beijing Cancer Hospital

Beijing, China

Location

Chongqing University Cancer Hospital

Chongqing, China

Location

Weifang People's Hospital

Weifang, China

Location

National Cancer Institute IRCCS "G. Pascale" Foundation

Naples, Campania, Italy

Location

University Hospital of Bologna-IRCCS

Bologna, Emilia-Romagna, Italy

Location

Romagnolo Institute For the Study of Tumors "Dino Amadori"

Meldola (FC), Forlì-Cesena, 47014, Italy

Location

Cannizzaro Emergency Hospital

Catania, Italy

Location

Complex Structure Gynecology Oncology National Cancer Institute of Milan

Milan, Italy

Location

Operative Unit of Oncology

Ravenna, 44266, Italy

Location

Agostino Gemelli University Hospital Rome

Rome, Italy

Location

Campus Bio Medico University Hospital Foundation

Rome, Italy

Location

Samsung Medical Center

Seoul, 05351, South Korea

Location

Korea University Guro Hospital

Seoul, South Korea

Location

Seoul National University Hospital

Seoul, South Korea

Location

Severance Hospital

Seoul, South Korea

Location

Hospital Universitario Reina Sofía

Córdoba, Andalusia, Spain

Location

Hospital Regional Universitario de Málaga

Málaga, Andalusia, 29011, Spain

Location

ICO Badalona

Badalona, Catalonia, 08916, Spain

Location

Hospital Universitari Vall d'Hebrón

Barcelona, Catalonia, 08035, Spain

Location

Hospital Clínico Universitario de Valencia

Valencia, Valencia, Spain

Location

Hospital Clínic de Barcelona

Barcelona, Spain

Location

Hospital Universitario Ramón y Cajal

Madrid, 28034, Spain

Location

Hospital Clínico San Carlos

Madrid, Spain

Location

HCU Virgen Arrixaca

Murcia, 30120, Spain

Location

Cambridge University Hospitals NHS Foundation Trust

Cambridge, Cambridgeshire, United Kingdom

Location

The Royal Marsden NHS Foundation Trust

London, United Kingdom

Location

The Christie NHS Foundation Trust

Manchester, United Kingdom

Location

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MeSH Terms

Conditions

Endometrial Neoplasms; Ovarian Neoplasms; Fallopian Tube Neoplasms; Uterine Cervical Neoplasms

Interventions

anlotinib; Paclitaxel; liposomal doxorubicin; Topotecan; Carboplatin

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; Fallopian Tube Diseases; Uterine Cervical Diseases

Intervention Hierarchy (Ancestors)

Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Diterpenes; Terpenes; Camptothecin; Alkaloids; Heterocyclic Compounds; Coordination Complexes

Study Officials

• Clinical Director

  Advenchen Laboratories, LLC

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: 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).

Study Record Dates

• First Submitted: August 28, 2015
• First Posted: October 22, 2015
• Study Start: December 1, 2015
• Primary Completion: October 1, 2024
• Study Completion: December 1, 2024
• Last Updated: November 8, 2023

Record last verified: 2023-11

Locations

IT (8); US (8); KR (4); CN (9); ES (9); GB (3)