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

• Phase I: To determine maximum tolerated dose and toxicities of BNC105P in combination with everolimus. [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]
• Phase II: Improvement in 6-month PFS with the addition of BNC105P to everolimus. [ Time Frame: 12 months ] [ Designated as safety issue: No ]

• Phase I: To determine the response rate of BNC105P in combination with everolimus. [ Time Frame: 12 months ] [ Designated as safety issue: No ]
• Phase I: To evaluate the pharmacokinetic (PK) profile for BNC105P in combination with everolimus [ Time Frame: 12 months ] [ Designated as safety issue: No ]
• Phase II: To determine response rate with combination therapy compared to everolimus alone [ Time Frame: 12 months ] [ Designated as safety issue: No ]
• Phase II: To determine PFS with BNC105P alone in patients progressing on everolimus. [ Time Frame: 12 months ] [ Designated as safety issue: No ]
• Phase II: To evaluate the adverse events of the everolimus and BNC105P when administered as a combination or sequential regimen. [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]
• Phase II: To determine the overall survival, up to a maximum of 5 years from registration for protocol therapy. [ Time Frame: 60 months ] [ Designated as safety issue: No ]
• Exploratory Objective: To determine the correlation of PFS with biomarkers [ Time Frame: 24 months ] [ Designated as safety issue: No ]

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.

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.

• Drug: Everolimus
  Everolimus 10 mg. Taken orally, every evening, 1 hr before or 2 hrs after meals
• Drug: BNC105P
  MTD as determined by Phase I portion
• Drug: Everolimus
  Everolimus 10 mg. Taken orally, every evening, 1 hr before or 2 hrs after meals
• Drug: BNC105P
  Patients to receive BNC105P monotherapy - 16 mg/m2 following progression on everolimus therapy.

• Active Comparator: Combination Arm A: Everolimus + BNC105P
  Combination Arm A: Everolimus 10 mg, BNC105P MTD (from Phase 1 study) 21 day cycle
  Interventions:

  • Drug: Everolimus
  • Drug: BNC105P
• Active Comparator: Sequential Arm B: Everolimus Alone

  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.

  Interventions:

  • Drug: Everolimus
  • Drug: BNC105P

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.