BNC105P in Combination With Everolimus/Following Everolimus For Progressive Metastatic Clear Cell Renal Cell Carcinoma

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to determine whether BNC105P in combination with/following everolimus is effective in the treatment of progressive metastatic clear cell renal cell carcinoma following prior tyrosine kinase inhibitors.

Detailed Description
-----------------
OUTLINE: This is a multi-center study. Phase I: Patients will be accrued in the classic 3 patients per dose per cohort design, 21-day cycle Dose Level 1 Everolimus 10 mg BNC105P 4.2 mg/m2 Dose Level 2 Everolimus 10 mg BNC105P 8.4 mg/m2 Dose Level 3 Everolimus 10 mg BNC105P 12.6 mg/m2 Dose Level 4 Everolimus 10 mg BNC105P 16 mg/m2 Phase II: Patients will be randomized 1:1 to Arm A or Arm B Combination Arm A: Everolimus 10 mg + BNC105P MTD (from Phase 1 study) 21 day cycle Sequential Arm B: Everolimus 10 mg 21 day cycle Patients to receive BNC105P monotherapy at 16 mg/m2 following progression or intolerable toxicity on everolimus therapy. Karnofsky Performance Score (KPS) ≥70 within 7 days prior to registration for protocol therapy. Life Expectancy: Not specified Hematopoietic: White blood cell count (WBC) > 3.5 K/mm3 Hemoglobin (Hgb) > 8.5 g/dL Platelets > 100 K/mm3 Absolute neutrophil count (ANC) > 1.5 K/mm3 Hepatic: Total Bilirubin < 1.25 x ULN Aminotransferase (AST and ALT) < 2.5 x ULN Renal: Serum Creatinine < 2.5 x ULN (upper limit normal) Cardiovascular: 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.

Official Title
-----------------
Phase I/II Study of BNC105P in Combination With Everolimus or Following Everolimus For Progressive Metastatic Clear Cell Renal Cell Carcinoma Following Prior Tyrosine Kinase Inhibitors

Conditions
-----------------
Renal Cell Carcinoma

Intervention / Treatment
-----------------
* Drug: Everolimus
* Drug: BNC105P


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Histological or cytological proof of component (any percent) of clear cell RCC (renal cell carcinoma). Metastatic or locally advanced unresectable RCC. NOTE: Prior nephrectomy is not mandatory. Progressive disease after 1-2 prior VEGF-directed tyrosine kinase inhibitors (TKIs). Measurable disease according to RECIST and obtained by imaging within 30 days prior to registration for protocol therapy. Written informed consent and HIPAA authorization for release of personal health information. Age > 18 years at the time of consent. 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 4 weeks after treatment discontinuation. Females of childbearing potential must have a negative pregnancy test within 7 days prior to registration for protocol therapy. Exclusion Criteria: 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 ≥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, AE must be resolved back to baseline. 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. With the exception of Bevacizumab treatment, which must be completed 30 days prior to registration for protocol therapy. Prior radiation therapy to < 25% of the bone marrow [see bone marrow radiation chart in the study procedure manual (SPM)] allowed if completed within 30 days prior to registration for protocol therapy. Corrected QT interval (QTc) ≤ 450 msec at least 7 days prior to registration for protocol therapy. No clinically significant infections as judged by the treating investigator. No liver disease such as cirrhosis, chronic active hepatitis or chronic persistent hepatitis. No collecting duct, medullary or sarcomatoid histology. 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. No use of full dose, therapeutic anti-coagulation with warfarin or related anti-coagulants or unfractionated or low molecular weight heparins. No uncontrolled hypertension (BP >150/100mmHg despite full doses of 1 anti-hypertensive medication). No thrombotic event within 6 months (deep vein thrombosis, pulmonary embolism) of registration for protocol therapy. No grade 2 or greater peripheral neuropathy.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Combination Arm A: Everolimus + BNC105P<br>Combination Arm A: Everolimus 10 mg, BNC105P MTD (from Phase 1 study) 21 day cycle | Drug: Everolimus<br>* Everolimus 10 mg. Taken orally, every evening, 1 hr before or 2 hrs after meals<br>Drug: BNC105P<br>* BNC105P, up to 16 mg/m^2<br>|
| Active Comparator: Sequential Arm B:Everolimus followed by BNC105P Monotherapy<br>Sequential Arm B: Everolimus 10 mg, 21 day cycle Patients to receive BNC105P monotherapy at 16 mg/m2 following progression or intolerable toxicity on everolimus therapy. | Drug: Everolimus<br>* Everolimus 10 mg. Taken orally, every evening, 1 hr before or 2 hrs after meals<br>Drug: BNC105P<br>* BNC105P, up to 16 mg/m^2<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase I: Maximum Tolerated Dose of BNC105P in Combination With Everolimus. | Phase I | Until disease progression or unacceptable toxicity, up to 24 cycles or 24 months | 
| Phase I: Toxicities of BNC105P in Combination With Everolimus. | Determine the toxicities of BNC105P in combination with everolimus. Drug-related treatment emergent adverse events by CTCAE grade 2 or greater are reported | Until disease progression or unacceptable toxicity, up to 24 cycles or 24 months | 
| Phase II: 6-month Progression Free Survival (PFS) With the Addition of BNC105P to Everolimus. | Improvement in 6-month PFS with the addition of BNC105P to everolimus. Progression is defined using RECIST criteria as at least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase I: Response Rate of BNC105P in Combination With Everolimus. | Number of objective responses per RECIST criteria. Complete Response (CR): Disappearance of all target lesions. Partial Response (PR): At least a 30% decrease in the sum of the LD of target lesions, taking as reference the baseline sum LD. Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started. | Until disease progression or unacceptable toxicity, up to 24 cycles or 24 months | 
| Geometric Mean Half-life of BNC105 and BNC105P in Combination With Everolimus. | Determine the PK Profile for BN105P in combination with everolimus by calculating the geometric mean half-life of BNC105P | 12 months | 
| Phase II: Response Rate With Combination Therapy Compared to Everolimus Alone | Objective response is defined as a confirmed CR or PR per RECIST criteria. Complete Response (CR): Disappearance of all target lesions. Partial Response (PR): At least a 30% decrease in the sum of the LD of target lesions, taking as reference the baseline sum LD. Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started. | 12 months | 
| Phase II: Progression Free Survival (PFS) With BNC105P Alone in Patients After Progressing on Everolimus. | Median time to progression for arm P participants who crossed over to BNC105P monotherapy after progression. Progression is defined per RECIST criteria as at least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions | 12 months | 
| Phase II: Adverse Events of Everolimus and BNC105P When Administered as a Combination or Sequential Regimen. | Determine adverse events of everolimus and BNC105P when administered as a combination or sequential regimen. Total number of serious and non-serious adverse events for Arm A and Arm B are summarized. Complete adverse event information is supplied in the Adverse Events reporting section. | 12 months | 
| Phase II: Overall Survival | Determine overall survival probability, up to a maximum of 5 years from registration for protocol therapy. | 60 months | 
| Exploratory Objective: Correlation of PFS With Biomarkers | Exploratory analysis of serum biomarkers were undertaken to generate a potential signature for response. The correlation with 6 month progression free survival P value for four plasma biomarkers is reported. | 6 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
BNC105P, Metastatic Kidney Cancer