Clinical Trials /

Paclitaxel + Carboplatin With AVB-S6-500 in Women With Stage III or IV Epithelial Ovarian, Primary Peritoneal, or Fallopian Tube Cancer Receiving Neoadjuvant Chemotherapy

NCT03607955

Description:

The receptor tyrosine kinase AXL is a pathway that plays a crucial role in metastasis and chemoresistance. Overexpression of AXL has been associated with metastasis, recurrence, and chemoresistance in various cancer including ovarian cancer[16, 17]}. Targeting AXL is an attractive approach because it is overexpressed among patients with epithelial ovarian cancer and strongly associated with advanced stages, high grade cancer and shorter median survival time. AVB-S6-500 is a potent AXL inhibitor by binding to the ligand Gas6. Pre-clinical studies found that AVB-S6-500 was efficacious in ovarian cancer xenograft tumor models. Interventions which would increase the proportion of patients achieving pCR in this patient population could impact survival favorably and are of interest for study.

Related Conditions:
  • Fallopian Tube Clear Cell Adenocarcinoma
  • Fallopian Tube Endometrioid Adenocarcinoma
  • Fallopian Tube Undifferentiated Carcinoma
  • High Grade Fallopian Tube Serous Adenocarcinoma
  • High Grade Ovarian Serous Adenocarcinoma
  • Ovarian Clear Cell Adenocarcinoma
  • Ovarian Endometrioid Adenocarcinoma
  • Ovarian Mixed Epithelial Tumor
  • Primary Peritoneal Carcinoma
  • Primary Peritoneal Clear Cell Carcinoma
  • Primary Peritoneal Endometrioid Adenocarcinoma
  • Primary Peritoneal Serous Adenocarcinoma
  • Primary Peritoneal Undifferentiated Carcinoma
  • Undifferentiated Ovarian Carcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Paclitaxel + Carboplatin With AVB-S6-500 in Women With Stage III or IV Epithelial Ovarian, Primary Peritoneal, or Fallopian Tube Cancer Receiving Neoadjuvant Chemotherapy
  • Official Title: Phase IB Study of Paclitaxel + Carboplatin With AVB-S6-500 in Women With Stage III or IV Epithelial Ovarian, Primary Peritoneal, or Fallopian Tube Cancer Receiving Neoadjuvant Chemotherapy

Clinical Trial IDs

  • ORG STUDY ID: 18-x211
  • NCT ID: NCT03607955

Conditions

  • Epithelial Ovarian Cancer
  • Primary Peritoneal Carcinoma
  • Fallopian Tube Cancer

Interventions

DrugSynonymsArms
AVB-S6-500AVB-S6-500 + Paclitaxel + Carboplatin
PaclitaxelTaxolAVB-S6-500 + Paclitaxel + Carboplatin
CarboplatinParaplatinAVB-S6-500 + Paclitaxel + Carboplatin

Purpose

The receptor tyrosine kinase AXL is a pathway that plays a crucial role in metastasis and chemoresistance. Overexpression of AXL has been associated with metastasis, recurrence, and chemoresistance in various cancer including ovarian cancer[16, 17]}. Targeting AXL is an attractive approach because it is overexpressed among patients with epithelial ovarian cancer and strongly associated with advanced stages, high grade cancer and shorter median survival time. AVB-S6-500 is a potent AXL inhibitor by binding to the ligand Gas6. Pre-clinical studies found that AVB-S6-500 was efficacious in ovarian cancer xenograft tumor models. Interventions which would increase the proportion of patients achieving pCR in this patient population could impact survival favorably and are of interest for study.

Trial Arms

NameTypeDescriptionInterventions
AVB-S6-500 + Paclitaxel + CarboplatinExperimentalPaclitaxel will be given intravenously at a dose of 175 mg/m^2 on an outpatient basis over 3 hours on Day 1 of each 21-day cycle Carboplatin will be given intravenously at a dose of AUC 6 over 30 minutes on Day 1 of each cycle of chemotherapy AVB-S6-500 will be given at doses based on the dose escalation schema The investigators will continue dosing AVB-S6-500 until 1 week prior to surgery and continuing after surgery. Maintenance dosing q2 weeks will begin with Cycle 7A/7B and be given every 2 weeks for 12 months through Cycle 19 (total of 13 maintenance cycles).
  • AVB-S6-500
  • Paclitaxel
  • Carboplatin

Eligibility Criteria

        Inclusion Criteria:

          -  Histologic diagnosis of epithelial ovarian, fallopian tube, or primary peritoneal
             cancer per pre-treatment biopsies by laparoscopy or interventional radiology or
             CT-guided core biopsy.

          -  Patients with the following histologic epithelial cell types are eligible:

               -  High grade serous adenocarcinoma

               -  Endometrioid adenocarcinoma

               -  Undifferentiated carcinoma

               -  Clear cell adenocarcinoma

               -  Mixed epithelia carcinoma

               -  Adenocarcinoma not otherwise specified (NOS)

          -  Disease must be considered "bulky" by the clinician (unresectable via primary
             debulking surgery) and in need of neoadjuvant chemotherapy prior to debulking surgery.
             This assessment of unresectability can be made via imaging or laparoscopic scoring.

          -  Must have pre-treatment tumor tissue available or agree to tissue collection from
             IR-guided biopsy.

          -  Any hormonal therapy directed at the malignant tumor must be discontinued at least one
             week prior to registration. Continuation of hormone replacement therapy is permitted.

          -  At least 18 years of age.

          -  Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2

          -  Normal bone marrow and organ function as defined below:

               -  Absolute neutrophil count ≥ 1,500/mcl

               -  Platelets ≥ 100,000/mcl

               -  Hemoglobin ≥ 9.0 g/dL

               -  Total bilirubin ≤ 1.5 x IULN

               -  AST(SGOT)/ALT(SGPT) ≤ 2.5 x IULN (unless liver metastases are present in which
                  case AST/ALT must be ≤ 5.0 x IULN)

               -  Serum creatinine < 2.0 mg/dL or < 177 µmol/L OR calculated or measured creatinine
                  clearance ≥ 40 mL/min (using Cockcroft-Gault equation)

               -  INR ≤ 1.5 x IULN

               -  aPTT ≤ 1.5 x IULN

          -  Women of childbearing potential must agree to use adequate contraception (hormonal or
             barrier method of birth control, abstinence) prior to study entry and for the duration
             of study participation. Should a woman become pregnant or suspect she is pregnant
             while participating in this study, she must inform her treating physician immediately.

          -  Ability to understand and willingness to sign an IRB approved written informed consent
             document (or that of legally authorized representative, if applicable).

        Exclusion Criteria:

          -  Any prior treatment with AVB-S6-500 or standard of care drugs (cisplatin, carboplatin,
             paclitaxel).

          -  A history of other malignancy ≤ 3 years previous with the exception of basal cell or
             squamous cell carcinoma of the skin which were treated with local resection only.
             Patients with concomitant endometrial cancer diagnosed at the time of the ovarian
             cancer are allowed to participate if the endometrial cancer is FIGO stage IB or less.

          -  Currently receiving any other (non-study) cytotoxic chemotherapy.

          -  Currently receiving any other investigational agents or has received an
             investigational agent within 4 weeks of start of study treatment.

          -  Known brain metastases. Patients with known brain metastases must be excluded from
             this clinical trial because of their poor prognosis and because they often develop
             progressive neurologic dysfunction that would confound the evaluation of neurologic
             and other adverse events.

          -  A history of allergic reactions attributed to compounds of similar chemical or
             biologic composition to AVB-S6-500 or other agents used in the study.

          -  Abnormal gastrointestinal function (nausea or vomiting). This includes GI obstruction
             or bleeding or signs/symptoms thereof within 3 months of study enrollment. Patients
             with a history of abdominal fistula will be considered eligible if the fistula was
             surgically repaired or has healed, there has been no evidence of fistula for at least
             6 months, and patient is deemed to be at low risk of recurrent fistula.

          -  Significant cardiac disease history including:

               -  Clinically significant atrial or ventricular arrhythmias requiring treatment

               -  Medically controlled congestive heart failure

               -  Significant angina or clinically and/or electrocardiographically documented
                  myocardial infarction within the past year

               -  Clinically significant valvular disease

          -  Non-healing wound, ulcer, or bone fracture.

          -  Receiving treatment for active autoimmune disease. "Active" refers to any condition
             currently requiring therapy.

          -  Received prior radiotherapy to any portion of the abdominal cavity or pelvis. Prior
             radiation for localized cancer of the breast, head and neck, or skin is permitted,
             provided that it was completed more than 3 years prior to registration and the patient
             remains free of recurrent or metastatic disease.

          -  Received prior chemotherapy for any abdominal or pelvic tumor. Prior adjuvant
             chemotherapy for localized breast cancer is permitted, provided that was completed
             more than 3 years prior to registration and the patient remains free of recurrent or
             metastatic disease.

          -  Known active hepatitis; ongoing systemic bacterial, fungal, or viral infection; known
             HIV infection or AIDS-related illness.

          -  History or evidence upon physical examination of CNS disease, including primary brain
             tumor, seizures not controlled with standard medical therapy, or history of CVA, TIA,
             or subarachnoid hemorrhage within 6 months of the first date of treatment on this
             study.

          -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active
             infection, symptomatic congestive heart failure, unstable angina pectoris, or cardiac
             arrhythmia.

          -  History of major surgical procedure within 21 days prior to start of study treatment.

          -  Pregnant and/or breastfeeding. Women of childbearing potential must have a negative
             pregnancy test within 14 days of study entry.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum tolerated dose (MTD) of AVB-S6-500 in combination with and following conventional chemotherapy and maintenance
Time Frame:Completion of the enrollment and treatment of all patients (estimated to be approximately 26 months)
Safety Issue:
Description:The study will employ the Bayesian optimal interval design (BOIN) to find the MTD. Select as the MTD the dose for which the isotonic estimate of the toxicity rate is closest to the target toxicity rate. If there are ties, select the higher dose level when the isotonic estimate is lower than the target toxicity rate and select the lower dose level when the isotonic estimate is greater than or equal to the target toxicity rate.

Secondary Outcome Measures

Measure:Objective clinical response (cOR) of AVB-S6-500 in combination with and following conventional chemotherapy and maintenance
Time Frame:At the time of interval debulking (approximately 9-12 weeks)
Safety Issue:
Description:-cOR = clinical response seen at the time of surgery with no visible disease
Measure:Pathological complete response (pCR) at the time of interval debulking surgery of AVB-S6-500 in combination with and following conventional chemotherapy and maintenance
Time Frame:At the time of interval debulking (approximately 9-12 weeks)
Safety Issue:
Description:-pCR = pathological response seen by the pathology at the time of surgery with treatment effect and no disease seen microscopically
Measure:Progression-free survival (PFS) at 1 year after debulking surgery of AVB-S6-500 in combination with and following conventional chemotherapy and maintenance
Time Frame:1 year after debulking surgery (approximately 64 weeks)
Safety Issue:
Description:PFS is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first. Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progressions).
Measure:Progression-free survival (PFS) at 2 years after debulking surgery of AVB-S6-500 in combination with and following conventional chemotherapy and maintenance
Time Frame:2 years after debulking surgery (approximately 116 weeks)
Safety Issue:
Description:PFS is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first. Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progressions).
Measure:Overall survival (OS) by long-term follow-up of AVB-S6-500 in combination with and following conventional chemotherapy and maintenance
Time Frame:5 years after completion of treatment (approximately 74 months)
Safety Issue:
Description:-OS is defined as the time from the date of treatment to the date of death, censored at the last follow-up otherwise.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Washington University School of Medicine

Last Updated

September 23, 2019