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Active, not recruitingNCT02584478AL3818Updated Nov 8, 2023

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 3 interventional study of AL3818 and Paclitaxel in Endometrial Carcinoma, Ovarian Carcinoma and Fallopian Tube Carcinoma, sponsored by Advenchen Laboratories, LLC. Active, not recruiting at 41 sites in 6 countries. Open to female participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2023-11-08.

Sponsored by Advenchen Laboratories, LLC · Phase 3, Interventional, and Treatment

Phase
Phase 3
Study type
Interventional
Enrollment
294
Allocation
Randomized
Ages
18 Years and older
Sex
Female
01

Study 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.

Read the 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.

02

Conditions studied

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

Keywords

  • Dual receptor Tyrosine Kinase Inhibitor
  • Anti-angiogenic therapy
  • Combination Therapy
03

Who can participate

Ages eligible
18 Years and older
Sexes eligible
Female
Accepts healthy volunteers
No

Inclusion criteria

  1. Female ≥ 18 years of age

  2. Histologically proven diagnosis of:

    a. Endometrial and other uterine cancers with tumors of all histologies i. Recurrent Stage I to II endometrial and other uterine cancers, after at least one prior line of standard therapy, requiring further treatment with platinum-based chemotherapy ii. Advanced Stage III to IV endometrial and other uterine cancers requiring treatment with platinum-based chemotherapy

    b. Ovarian Cancer: Platinum-sensitive or platinum-resistant recurrent or metastatic ovarian, fallopian, or primary peritoneal cancer treated with at least one prior line of platinum-based chemotherapy and requiring further treatment.(Part 1/Phase Ib, Part 2/Phase 2a)

    Platinum-sensitive is defined as cancer progression ≥ 6 months after platinum- based chemotherapy. Platinum-resistant is defined as cancer progression \< 6 months after platinum-based chemotherapy.

    Histologic cell types eligible are endometrioid adenocarcinoma, serous adenocarcinoma, undifferentiated carcinoma, clear cell adenocarcinoma, mixed epithelial carcinoma, adenocarcinoma not otherwise specified.

    Phase III/Part 3:

(1) Platinum-resistant (progression within 6 months after last platinum-based chemotherapy) ovarian, fallopian, or primary peritoneal cancer that meets one of the following criteria: i. Subject has received at least two prior lines of systemic therapy including a bevacizumab-containing regimen as standard of care ii. Subject has received at least two prior lines of systemic therapy, has not received a prior bevacizumab-containing regimen and is not eligible for a bevacizumab containing regimen based on Investigator's assessment (2) Platinum-refractory (progression during first-line platinum-based chemotherapy) ovarian, fallopian, or primary peritoneal cancer after at least one prior line of systemic therapy (3) For groups 1-2 above: Subjects with positive deleterious or suspected deleterious, germline or somatic BRCA mutated status must have received a PARP inhibitor as a prior line of therapy.

c. Cervical cancer: recurrent or metastatic cervical cancer that is not amenable to curative treatment with surgery and/or radiation therapy after at least one prior line of standard therapy, requiring further treatment. Histologic cell types eligible are squamous cell carcinoma, adenosquamous carcinoma or adenocarcinoma

  1. Have measureable disease defined by RECIST 1.1 confirmed by CT or MRI scan within 28 days of enrollment.
  1. Life expectancy of ≥ 3 months at the time of enrollment.
  1. Able to take orally administered study medication.
  1. Have adequate baseline function and performance status within 28 days of enrollment:
  1. Bone marrow function: absolute neutrophil count (ANC) ≥ 1,500/mm3, platelets ≥ 100,000/mm3
  2. Renal function: creatinine ≤ 1.5 x institutional upper limit normal (ULN) or if creatinine is > 1.5 x ULN, creatinine clearance must be > 50 mL/min.
  3. Hepatic function: bilirubin ≤ 1.5 x ULN or ≤ 3.0 x ULN for subjects with Gilbert Syndrome; AST and ALT ≤ 3.0 × ULN.
  4. Coagulation profile: international normalized ratio (INR) is ≤ 1.5 and an aPTT or PTT \< 1.2 x ULN

  5. ECOG performance ≤ 2

    1. Women of child-bearing potential must agree to use contraceptive measures starting 1 week before C1D1 until 4 weeks after the last dose of study treatment and have a negative serum pregnancy test within 28 days of enrollment.
    1. Provide written informed consent and authorization permitting release of Protected Health Information.
    1. Ability and willingness to comply with the study protocol for the duration of the study and with follow-up procedures.

Exclusion criteria

Exclusion Criteria

  1. Serious, non-healing wound, ulcer or bone fracture.
  2. 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).
  3. (Intentionally left blank)
  4. Active bleeding or pathologic conditions that carry high risk of bleeding, such as known bleeding disorder, coagulopathy, or tumor involving major vessels.

  5. 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.

  6. 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.
  7. 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.
  8. Women who are pregnant or nursing.
  9. (Intentionally left blank)
  10. Clinically significant, uncontrolled hypokalemia, hypomagnesaemia, and/or hypocalcaemia.
  11. Hemoptysis within 3 months prior to enrollment.
  12. Acute or chronic liver disease, active hepatitis A or B with known cirrhosis or liver dysfunction.
  13. Cytotoxic chemotherapy, immunotherapy, or radiotherapy within 28 days (42 days in cases of mitomycin C, nitrosourea, lomustine) prior to enrollment.
  14. 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.
  15. Known history of human immunodeficiency virus infection (HIV).
  16. Active bacterial infections requiring systemic antibiotics (excluding uncomplicated urinary tract infection).
  17. 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 prior to enrollment or whose previous cancer treatment contraindicates this protocol therapy.
  18. History of non-malignant gastrointestinal bleeding, gastric stress ulcerations, or peptic ulcer disease within the past 3-months prior to enrollment that in the opinion of the investigator may place the subject 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 of enrollment.
  21. Pre-existing uncontrolled hypertension as documented by two baseline blood pressure readings taken at least five minutes apart, defined as systolic BP >160 mm Hg or diastolic BP > 90 mm Hg pressure.
  22. QTc > 470 msec on screening ECG per Fridericia's formula.
  23. History of or existing risk factors for Torsades de pointes (TdP) (e.g., heart failure, hypokalemia, family history of Long QT Syndrome).
  24. Concurrent use of concomitant medications that prolong the QT/QTc interval.
  25. Baseline echocardiogram (within 56 days of enrollment) with left ventricular ejection fraction (LVEF) \< 50%.
  26. 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.
  27. History of pancreatitis; history of renal disease that includes histologically confirmed glomerulonephritis, biopsy proven tubulointerstitial nephritis, crystal nephropathy or other renal insufficiencies.
  28. Treatment with an investigational agent within 28 days of enrollment.
  29. Known recreational substance abuse.
  30. Anticoagulation therapy with warfarin. Subjects treated with heparin, low molecular weight heparin, or any other anticoagulant may be included provided the subject has been on a stable therapeutic dose of the anticoagulant for at least 14 days prior to enrollment.
  31. Known hypersensitivity to AL3818 or components of the formulation.
04

Study design

Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomized
Intervention model
Parallel assignment
Masking
None (open label)
Enrollment
294 participants (actual)

Study arms

  • Experimental
    Phase 3 -Active Treatment Arm

    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

  • Other
    Phase 3-Control Treatment Arm

    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

  • Experimental
    Phase 1b: AL3818 plus carboplatin and 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.

    Drug: Carboplatin · Drug: Paclitaxel · Drug: AL3818

  • Experimental
    Phase 2a: AL3818 plus carboplatin and 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.

    Drug: Carboplatin · Drug: Paclitaxel · Drug: AL3818

Interventions

  • DrugAL3818

    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

  • DrugPaclitaxel

    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

  • DrugPegylated Liposomal Doxorubicin (PLD)

    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

  • DrugTopotecan

    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

  • DrugTopotecan

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

    Also known as: Weekly Topotecan

  • DrugCarboplatin

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

    Also known as: Paraplatin

  • DrugPaclitaxel

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

    Also known as: Taxol

  • DrugAL3818

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

05

What researchers measure

Primary outcomes

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

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

    Time frame: Cycle 1 (21-days)

  2. 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)

    Time frame: 12 months

  3. 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).

    Time frame: 12 Months

Secondary outcomes

  1. 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)

    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).

    Time frame: Cycle 1 (Day 21)

  2. Clinical Benefit Rate (CBR) - 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. Measured as CR+PR+SD (SD ≥ 16 weeks from inclusion).

    Time frame: 12 Months

  3. Progression-Free Survival (PFS) - 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. Kaplan-Meier analysis

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

  4. Overall Survival (OS) - Part 2 (Phase 2a)

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

    Time frame: Cycle 1 Day 1 up to 5 years

  5. Objective Response Rate- Part 3 ( Phase 3)

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

    Time frame: 12 Months

  6. Duration Of Response - Part 3 ( Phase 3)

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

    Time frame: 12 Months

  7. Overall Survival - Part 3 ( Phase 3)

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

    Time frame: 12 Months

Other outcomes

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

    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)

    Time frame: 12 Months

06

Study locations

41 sites
  • The Oncology Institute of Hope and Innovation
    Long Beach, California 90805, United States
  • University of Miami Sylvester Comprehensive Cancer Center
    Miami, Florida 33136, United States
  • Baptist Health Lexington Oncology Research
    Lexington, Kentucky 40503, United States
  • Washington University
    Saint Louis, Missouri 63130, United States
  • Montefiore Medical Center
    Bronx, New York 10467, United States
  • AHN West Penn Hospital
    Pittsburgh, Pennsylvania 15224, United States
  • UTSW
    Dallas, Texas 75390, United States
  • University of Wisconsin Madison
    Madison, Wisconsin 53792, United States
  • Henan Cancer Hospital
    Hefei, Henan, China
  • Jilin Cancer Hospital
    Changchun, Jilin, China
  • The First Hospital of China Medical University
    Shenyang, Shenyang 110001, China
  • Zhongda Hospital Southeast University
    Chongqing, Sichuan, China
  • Tianjin Central Hospital of Gynecology Obstetrics
    Tianjin, Tianjin, China
  • Obstetrics&Gynecology Hospital of Fudan University
    Shanghai, Yangpu District, China
  • Beijing Cancer Hospital
    Beijing, China
  • Chongqing University Cancer Hospital
    Chongqing, China
  • Weifang People's Hospital
    Weifang, China
  • National Cancer Institute IRCCS "G. Pascale" Foundation
    Naples, Campania, Italy
  • University Hospital of Bologna-IRCCS
    Bologna, Emilia-Romagna, Italy
  • Romagnolo Institute For the Study of Tumors "Dino Amadori"
    Meldola (FC), Forlì-Cesena 47014, Italy
  • Cannizzaro Emergency Hospital
    Catania, Italy
  • Complex Structure Gynecology Oncology National Cancer Institute of Milan
    Milan, Italy
  • Operative Unit of Oncology
    Ravenna, 44266, Italy
  • Agostino Gemelli University Hospital Rome
    Rome, Italy
  • Campus Bio Medico University Hospital Foundation
    Rome, Italy
  • Severance Hospital
    Seoul,, Korea, Republic of
  • Samsung Medical Center
    Seoul, 05351, Korea, Republic of
  • Korea University Guro Hospital
    Seoul, Korea, Republic of
  • Seoul National University Hospital
    Seoul, Korea, Republic of
  • Hospital Universitario Reina Sofía
    Córdoba, Andalucía, Spain
  • Hospital Regional Universitario de Málaga
    Malaga, Andalucía 29011, Spain
  • ICO Badalona
    Badalona, Catalunya 08916, Spain
  • Hospital Universitari Vall d'Hebrón
    Barcelona, Catalunya 08035, Spain
  • Hospital Clínico Universitario de Valencia
    Valencia, Comunidad Valenciana, Spain
  • Hospital Clínic de Barcelona
    Barcelona, Spain
  • Hospital Universitario Ramón y Cajal
    Madrid, 28034, Spain
  • Hospital Clínico San Carlos
    Madrid, Spain
  • HCU Virgen Arrixaca
    Murcia, 30120, Spain
  • Cambridge University Hospitals NHS Foundation Trust
    Cambridge, Cambridgeshire, United Kingdom
  • The Royal Marsden NHS Foundation Trust
    London, United Kingdom
  • The Christie NHS Foundation Trust
    Manchester, United Kingdom
07

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08

Registry details

Key details

Study ID
NCT02584478
Lead sponsor
Advenchen Laboratories, LLC
Responsible party
Sponsor
First posted
Oct 22, 2015
Start date
Dec 2015
Primary completion
Oct 2024 (estimated)
Completion
Dec 2024 (estimated)
Last update
Nov 8, 2023

Study contacts

Clinical Director
study director · Advenchen Laboratories, LLC

Oversight

Data monitoring committee
Yes
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