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.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
AVB-S6-500 is supplied by Aravive Biologics
Commercially available
Commercially available
-For patients scheduled to undergo a diagnostic laparoscopy for tissue diagnosis prior to neoadjuvant chemotherapy, a tissue biopsy section from the ovary or an intra-abdominal implant will be performed
-Standard of care procedure but research specimens will be collected
* Standard of Care * Research tissue samples will be collected
-Before initiation of neoadjuvant chemotherapy and at the time of interval debulking surgery either pre-operatively, intraoperatively, or post-operatively.
-A total of 25-100ml of ascites will be collected prior to chemotherapy treatment, if available.
Maximum tolerated dose (MTD) of AVB-S6-500 in combination with and following conventional chemotherapy and maintenance
* 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.
Time frame: Completion of the enrollment and treatment of all patients (estimated to be approximately 26 months)
Dose limiting toxicities (DLTs) of AVB-S6-500 in combination with and following conventional chemotherapy and maintenance
-Hematologic DLT any of the following that occur during the 1st cycle (C) that are possibly (pos), probably (prob), or definitely (def) related to the study treatment: * Grade (Gr.) 4 neutropenia or thrombocytopenia \> 7 day * Febrile neutropenia w/ temp \> 38.5 °C * Gr. 4 anemia or Gr. 4 thrombocytopenia which requires transfusion therapy on more than 2 occasions in 7 days * Gr. thrombocytopenia w/ bleeding Non-hematologic DLT is any pos, prob, or def related Gr. 3 or grade 4 non-hematologic toxicity that occurs during C1 with the following exceptions: * Gr. 3/4 nausea/vomiting/anorexia that returns to Gr. 1 prior to the start of C2 * Gr. 3 nausea/vomiting or diarrhea \< 72 hours with adequate antiemetic and other supportive care starting with C2 * Gr. 3 triglycerides will only be considered a DLT for patients who have grade 3 in spite of appropriate lipid lowering drug therapy * Gr. 3 rash (patients who have received 2 weeks of supportive care treatment w/ no improvement)
Time frame: Through completion of 1st cycle for all patients (estimated to be 13 months)
Tolerability of the combination at the MTD of AVB-S6-500 assessed in combination with standard neoadjuvant chemotherapy as measured by treatment discontinuation
Time frame: Through completion of treatment (estimated to be 14 months)
Tolerability of the combination at the MTD of AVB-S6-500 assessed in combination with standard neoadjuvant chemotherapy as measured by number of dose interruption/reductions
Time frame: Through completion of treatment (estimated to be 14 months)
Tolerability of the combination at the MTD of AVB-S6-500 assessed in combination with standard neoadjuvant chemotherapy as measured by use of supportive therapies
Time frame: Through completion of treatment (estimated to be 14 months)
Tolerability of the combination at the MTD of AVB-S6-500 assessed in combination with standard neoadjuvant chemotherapy as measured by number of hospital admissions
Time frame: Through completion of treatment (estimated to be 14 months)
Tolerability of the combination at the MTD of AVB-S6-500 assessed in combination with standard neoadjuvant chemotherapy as measured by number of deaths
Time frame: Through completion of treatment (estimated to be 14 months)
Objective clinical response (cOR) of AVB-S6-500 in combination with and following conventional chemotherapy and maintenance
-cOR = clinical response seen at the time of surgery with no visible disease
Time frame: At the time of interval debulking (approximately 9-12 weeks)
Pathological complete response (pCR) at the time of interval debulking surgery of AVB-S6-500 in combination with and following conventional chemotherapy and maintenance
-pCR = pathological response seen by the pathology at the time of surgery with treatment effect and no disease seen microscopically
Time frame: At the time of interval debulking (approximately 9-12 weeks)
Progression-free survival (PFS) at 1 year after debulking surgery of AVB-S6-500 in combination with and following conventional chemotherapy and maintenance
* 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).
Time frame: 1 year after debulking surgery (approximately 64 weeks)
Progression-free survival (PFS) at 2 years after debulking surgery of AVB-S6-500 in combination with and following conventional chemotherapy and maintenance
* 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).
Time frame: 2 years after debulking surgery (approximately 116 weeks)
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Overall survival (OS) by long-term follow-up of AVB-S6-500 in combination with and following conventional chemotherapy and maintenance
-OS is defined as the time from the date of treatment to the date of death, censored at the last follow-up otherwise.
Time frame: 5 years after completion of treatment (approximately 74 months)