None listed
Conditions
Brief summary
Bionomics has discovered and is developing BNC105P as a Vascular Disrupting Agent (VDA). VDAs are a novel class of agents that target endothelial cells and pericytes of the already established tumor vasculature, leading to an occlusion (blockage) of tumor blood vessels, thus starving tumors of oxygen and other required nutrients. The disruption of blood vessels that feed tumors represents a promising therapeutic strategy for treating cancer. In addition, BNC105P has a direct anti-proliferative effect on cancer cells. BNC105P is the phosphate ester of BNC105, a small molecule Tubulin Polymerization Inhibitor (TPI), and which has displayed a strong efficacy in renal, breast and colon tumor models and other tumor types. Clinical studies undertaken to date have shown BNC105P, administered as a 10 minute IV infusion on Days 1 and 8 of a repeating 21-day cycle, is tolerated at 16 mg/m2. Upon exposure to hypoxia (a low oxygen environment induced by disruption of tumor blood flow), renal tumors have been shown to upregulate an intracellular signaling pathway termed the ‘mTOR’ pathway, as a survival response. The combined blockade of tumor blood flow (via the use of BNC105P) and the blockade of the mTOR pathway (via the targeted mTOR inhibitor Everolimus) is the underlying rationale behind this trial. This dual blockade may result in improved clinical outcomes for RCC patients who have progressed on other available agents. The randomized phase II component of this trial will compare everolimus alone (a current standard of care) with everolimus plus BNC105P. Progression Free Survival (PFS) at 6 months is the primary endpoint. The study has been powered to detect an improvement in 6-month PFS from 36% for everolimus to 60% with the combination group. Additionally, patients progressing on everolimus alone will be offered BNC105P (a sequential approach), which will provide an opportunity to evaluate the activity of monotherapy with BNC105P alone.
Interventions
Arm A: Everolimus 10mg Daily, BNC105P 16mg/m2 infusion on Day 1 and Day 8 of a 21 day cycle (combination arm). Drugs used on Arm A are given simultaneously: everolimus by oral administration daily, BNC105P by IV administration (on days 1 and 8 of a repeating 21 day cycle).
Arm B: This is a sequential Arm. Arm B subjects are administered Everolimus at 10mg per day by oral administration until disease progression or unacceptable toxicity is observed (then Everolimus is ceased). Once this occurs,
Arm A: Everolimus 10mg Daily, BNC105P 16mg/m2 infusion on Day 1 and Day 8 of a 21 day cycle (combination arm). Drugs used on Arm A are given simultaneously: everolimus by oral administration daily, BNC105P by IV administration (on days 1 and 8 of a repeating 21 day cycle). Arm B: This is a sequential Arm. Arm B subjects are administered Everolimus at 10mg per day by oral administration until disease progression or unacceptable toxicity is observed (then Everolimus is ceased). Once this occurs, patients have the option to enter BNC105P only portion of Arm B. BNC105P given by IV administration at 16mg/m2 (on days 1 and 8 of a repeating 21 day cycle).
Sponsors
Bionomics Pty Ltd
Study design
Allocation
Randomised controlled trial
Intervention model
Parallel
Primary purpose
Treatment
Masking
Open (masking not used)
Eligibility
Sex/Gender
All
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Written informed consent and HIPAA authorization for release of personal health information. NOTE: HIPAA authorization may be included in the informed consent orobtained separately. Age > or equal to 18 years at the time of consent. Karnofsky Performance Score (KPS) > or equal to 70 within 7 days prior to registration for protocol therapy. Females of childbearing potential and males must be willing to use an effective method of contraception (hormonal or barrier method of birth control; abstinence) from the time consent is signed until 8 weeks after treatment discontinuation. Females of childbearing potential must have a negative pregnancy test within 7 days prior to registration for protocol therapy. NOTE: Females are considered not of child bearing potential if they are surgically sterile (they have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are postmenopausal. Females must not be breastfeeding. Histological or cytological proof of component (any percent) of clear cell RCC (renal cell carcinoma). NOTE: No component of collecting duct or medullary histology is allowed. Up to 30% sarcomatoid histology will be permitted. Metastatic or locally advanced unresectable RCC. NOTE: Prior nephrectomy is not mandatory Progressive disease after 1-2 prior VEGF-directed tyrosine kinase inhibitors (TKIs). NOTE: Patients who did not tolerate a VEGF-directed TKI may also be considered for entry to the trial. The Sponsor is to be consulted in such cases. Prior treatment with more than 2 VEGF-directed TKIs will be permitted in the phase I component of the study. Measurable disease according to RECIST and obtained by imaging within 30 days prior to registration for protocol therapy. Prior cancer treatment must be completed at least 14 days prior to registration for protocol therapy and the patient must have recovered from the acute toxic effects of the regimen. At least 30 days must have elapsed prior to registration following major surgery (opening of a body cavity – chest, abdomen or cranium), or at least 7 days prior to registration for minor surgery. Prior radiation therapy to <25% of the bone marrow [see bone marrow radiation chart in the study procedure manual (SPM)] allowed if completed within 14 days prior to registration for protocol therapy. Corrected QT interval (QTc) < or equal to 450 msec within 7 days prior to registration for protocol therapy. NOTE: if (QTc) is >450 and < or equal to 500 msec, subject to local cardiology review and approval, the patient may be enrolled if the QTc elevation is deemed clinically insignificant. NOTE: Laboratory values must be obtained within 7 days prior to registration for protocol therapy. White blood cell count (WBC) >or equal to 3.5 K/ mm3 Hemoglobin (Hgb) > or equal to 8.5 g/dL Platelets > or equal to 100 K/ mm3 Absolute neutrophil count (ANC) > or equal to 1.5 K/ mm3 Serum Creatinine <2.5 x ULN (upper limit normal) Total Bilirubin < and equal to 1.25 x ULN Aminotransferase (AST and ALT) < or equal to 2.5 × ULN INR <1.5 ULN
Exclusion criteria
No clinically significant infections as judged by the treating investigator No liver disease such as cirrhosis, chronic active hepatitis or chronic persistent hepatitis No prior treatment with temsirolimus or everolimus in the phase II component of the study NOTE: Prior treatment with these agents is permitted in the phase I component of the study. In those cases where everolimus is being used immediately prior to study entry, a washout period will not be required. No use of full dose, therapeutic anti-coagulation with warfarin or related anti-coagulants or unfractionated or low molecular weight heparins. NOTE: Low dose warfarin for catheter prophylaxis or acetylsalicylic acid < equal to 325 mg/day is acceptable. No uncontrolled hypertension, BP >150/100mmHg despite use of antihypertensive medication(s). No thrombotic event within 6 months (deep vein thrombosis, pulmonary embolism) of registration for protocol therapy. No significant cardiovascular events within 6 months (CVA, CAD, peripheral arterial obstruction, arrhythmias, cardiac dysfunction) of registration for protocol therapy No history of clinical CHF or LVEF <50% by Echo (or MUGA) within 30 days prior to registration for protocol therapy. No grade 2 or greater peripheral neuropathy. No active brain metastases. Patients with neurological symptoms must undergo a head CT scan or brain MRI to exclude brain metastasis within 30 days prior to registration on protocol therapy. NOTE: A patient with prior brain metastasis are eligible if they have completed their radiation treatment for brain metastasis > or equal to 30 days prior to registration for protocol therapy, are off steroids, and are asymptomatic. No other currently active malignancy. No treatment with any investigational agent within 14 days prior to registration for protocol therapy. NOTE: If treated with investigational agent within 14 days prior to registration patients AE must be resolved back to baseline.
Outcome results
None listed