Clinical Trials /

Phase 1/2a 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

Description:

This trial is a Phase 1b/2a trial designed to evaluate the safety and efficacy of adding oral AL3818 to standard platinum-based chemotherapy concurrently and continued as a maintenance therapy for up to 12 months.

Related Conditions:
  • Cervical Adenocarcinoma
  • Cervical Adenosquamous Carcinoma
  • Cervical Squamous Cell Carcinoma
  • Endometrial Carcinoma
  • Fallopian Tube Adenocarcinoma
  • Fallopian Tube Undifferentiated Carcinoma
  • Malignant Ovarian Mixed Epithelial Tumor
  • Malignant Uterine Neoplasm
  • Ovarian Adenocarcinoma
  • Primary Peritoneal Carcinoma
  • Primary Peritoneal Undifferentiated Carcinoma
  • Undifferentiated Ovarian Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Phase 1/2a 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)
  • Official Title: A Phase 1/2a Evaluation of the Safety and Efficacy of Adding AL3818, 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 (AL3818-US-002)

Clinical Trial IDs

  • ORG STUDY ID: AL3818-US-002
  • NCT ID: NCT02584478

Conditions

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

Interventions

DrugSynonymsArms
AL3818Anlotinib HydrochlorideAL3818 plus carboplatin and paclitaxel
CarboplatinParaplatinAL3818 plus carboplatin and paclitaxel
PaclitaxelTaxolAL3818 plus carboplatin and paclitaxel

Purpose

This trial is a Phase 1b/2a trial designed to evaluate the safety and efficacy of adding oral AL3818 to standard platinum-based chemotherapy concurrently and continued as a maintenance therapy for up to 12 months.

Detailed Description

      This trial is a Phase 1b/2a trial designed to evaluate the safety and efficacy of adding
      oral AL3818 to standard platinum-based chemotherapy such as carboplatin plus paclitaxel,
      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.

      This study will be 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). 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.
    

Trial Arms

NameTypeDescriptionInterventions
AL3818 plus carboplatin and paclitaxelExperimentalPhase 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.
  • AL3818
  • Carboplatin
  • Paclitaxel

Eligibility Criteria

        Inclusion Criteria:

          -  Female ≥ 18 years

          -  Previously histologically proven diagnosis of

             a. Endometrial Cancer: recurrent or persistent endometrial carcinoma refractory to
             conventional therapy or established treatments with the following histologic
             epithelial cell types i. 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 b. Ovarian Cancer: recurrent or persistent
             ovarian or primary peritoneal cancer refractory to established treatments with the
             following histologic epithelial cell types i. Endometrioid adenocarcinoma, serous
             adenocarcinoma, undifferentiated carcinoma, clear cell adenocarcinoma, mixed
             epithelial carcinoma, adenocarcinoma not otherwise specified.

             c. Cervical cancer: squamous cell carcinoma of the cervix refractory to conventional
             therapy or established treatments with the following histologic epithelial cell
             types: i. Squamous cell carcinoma, adenosquamous carcinoma or adenocarcinoma
             Measurable disease defined as at least one lesion that can be accurately measured in
             at least one dimension (longest dimension to be recorded). Each lesion must be ≥ 20mm
             when measured by conventional techniques, including palpation, plain x-ray, CT, and
             MRI or ≥ 10mm when measured by spiral CT.

          -  Life expectancy ≥ 3 months

          -  Able to take orally administered study medication

          -  Must sign approved informed consent and authorization permitting release of personal
             health information.

          -  Patient must have adequate:

               1. Bone marrow function: absolute neutrophil count (ANC) ≥ 1,500/mm^3, equivalent
                  to Common Toxicity Criteria (CTC) grade 1, platelets ≥ 100,000/mm^3

               2. Renal function: creatinine ≤ 1.5 x institutional upper limit normal (ULN), CTC
                  grade 1. Note: If creatinine is > 1.5 x ULN, creatinine clearance must be > 50
                  mL/min.

               3. Hepatic function: bilirubin ≤ 1.5 x ULN (CTC grade 1) or ≤ 3.0 x ULN for
                  subjects with Gilbert Syndrome; AST and ALT ≤ 3.0 ×ULN.

               4. Coagulation profile: PT such that international normalized ratio (INR) is ≤ 1.55
                  (or an in-range INR, usually between 2 and 3, if a patient is on a stable dose
                  of therapeutic warfarin or low molecular weight heparin) and a PTT < 1.2 times
                  control.

               5. ECOG performance ≤ 2

          -  Patient of child-bearing potential must agree to use contraceptive measures starting
             1 week before the administration of the first dose of AL3818 until 4 weeks after
             discontinuing study drug and have a negative serum pregnancy test prior to study
             entry and cannot be lactating.

          -  Ability and willingness to comply with the study protocol for the duration of the
             study and with follow-up procedures.

        Exclusion Criteria:

          -  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.

             a. 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 hours to
             allow participation in the study.

          -  Patients with clinically significant cardiovascular disease including 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, Serious cardiac arrhythmia requiring medication, Grade II or greater
             peripheral vascular disease.

          -  Patients who are pregnant or nursing.

          -  Women of childbearing potential who are unable to use contraceptive measures during
             study therapy and for at least 3 months after completion of AL3818 therapy.

          -  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 .

          -  Known history of human immunodeficiency virus infection (HIV).

          -  Subjects with active bacterial infections (other than uncomplicated urinary tract
             infection) and/or receiving systemic antibiotics.

          -  Patients with 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 or whose previous cancer treatment contraindicates this protocol therapy.

          -  History of non-malignant GI bleeding, gastric stress ulcerations, or peptic ulcer
             disease within the past 3-months that in the opinion of the investigator may place
             the patient at risk of side effects on an anti-angiogenesis product.

          -  History of significant vascular disease (e.g. aortic aneurysm, aortic dissection).

          -  Intra-abdominal abscess within the last 3 months.

          -  Pre-existing uncontrolled hypertension as documented by 2 baseline BP readings taken
             at least one hour apart, defined as systolic bloodpressure (BP) >160 mm Hg or
             diastolic BP > 90 mm Hg pressure.

          -  QTcF>470 msec on screening ECG.

          -  A history of additional risk factors for TdP (e.g., heart failure, hypokalemia,
             family history of Long QT Syndrome).

          -  The use of concomitant medications that prolong the QT/QTc interval. Baseline
             echocardiogram (within 2 months) with left ventricular ejection fraction (LVEF) <
             50%.

          -  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.

          -  History of pancreatitis and/or renal disease or pancreatitis that includes
             histologically confirmed glomerulonephritis, biopsy proven tubulointerstitial
             nephritis, crystal nephropathy, or other renal insufficiencies.

          -  Treatment with an investigational agent within the longest time frame of either 5
             half- lives or 30 days of initiating study drug.

          -  Known recreational substance abuse.

          -  Known hypersensitivity to AL3818 or components of the formulation.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Recommended Phase 2 Dose (RP2D) - Part 1 (Phase 1b)
Time Frame:Cycle 1 (21-days)
Safety Issue:
Description:Determine the Recommended Phase 2 Dose (RP2D) via evaluation of dose limiting toxicity (DLT) events.

Secondary Outcome Measures

Measure: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)
Time Frame:Cycle 1 (Day 21)
Safety Issue:
Description: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).
Measure:Clinical Benefit Rate (CBR) - Part 2 (Phase 2a)
Time Frame:12 Months
Safety Issue:
Description: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).
Measure:Progression-Free Survival (PFS) - Part 2 (Phase 2a)
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.
Safety Issue:
Description: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
Measure:Overall Survival (OS) - Part 2 (Phase 2a)
Time Frame:Cycle 1 Day 1 up to 5 years
Safety Issue:
Description:Overall survival is defined as the date the study treatment was initiated to the date of death from any cause. Kaplan-Meier analysis

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Advenchen Laboratories, LLC

Trial Keywords

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

Last Updated

July 11, 2016