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
  • Ovarian Undifferentiated Carcinoma
  • Primary Peritoneal Carcinoma
  • Primary Peritoneal Undifferentiated 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 Critera

          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.

             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. c. Cervical cancer: recurrent or metastatic
             cervical cancer that is not amenable to curative treatment with surgery and/or
             radiation therapy and has not been previously treated with chemotherapy for
             recurrence.

             Histologic cell types eligible are squamous cell carcinoma, adenosquamous carcinoma or
             adenocarcinoma

          3. Have measureable disease defined by RECIST 1.1 confirmed by CT or MRI scan within 28
             days of enrollment.

          4. Life expectancy of ≥ 3 months at the time of enrollment.

          5. Able to take orally administered study medication.

          6. 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

          7. 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.

          8. Provide written informed consent and authorization permitting release of Protected
             Health Information.

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

        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.
      
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

June 17, 2019