Renal Cell Carcinoma
Conditions
Keywords
Metastatic Kidney Cancer, BNC105P
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.
Interventions
DRUGEverolimus
Everolimus 10 mg. Taken orally, every evening, 1 hr before or 2 hrs after meals
DRUGBNC105P
BNC105P, up to 16 mg/m\^2
Sponsors
Bionomics Limited
Hoosier Cancer Research Network
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase I: Maximum Tolerated Dose of BNC105P in Combination With Everolimus. | Until disease progression or unacceptable toxicity, up to 24 cycles or 24 months | Phase I |
| Phase I: Toxicities of BNC105P in Combination With Everolimus. | Until disease progression or unacceptable toxicity, up to 24 cycles or 24 months | Determine the toxicities of BNC105P in combination with everolimus. Drug-related treatment emergent adverse events by CTCAE grade 2 or greater are reported |
| Phase II: 6-month Progression Free Survival (PFS) With the Addition of BNC105P to Everolimus. | 6 months | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase II: Progression Free Survival (PFS) With BNC105P Alone in Patients After Progressing on Everolimus. | 12 months | 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 |
| Phase II: Adverse Events of Everolimus and BNC105P When Administered as a Combination or Sequential Regimen. | 12 months | 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. |
| Phase I: Response Rate of BNC105P in Combination With Everolimus. | Until disease progression or unacceptable toxicity, up to 24 cycles or 24 months | 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. |
| Exploratory Objective: Correlation of PFS With Biomarkers | 6 months | 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. |
| Phase II: Overall Survival | 60 months | Determine overall survival probability, up to a maximum of 5 years from registration for protocol therapy. |
| Geometric Mean Half-life of BNC105 and BNC105P in Combination With Everolimus. | 12 months | Determine the PK Profile for BN105P in combination with everolimus by calculating the geometric mean half-life of BNC105P |
| Phase II: Response Rate With Combination Therapy Compared to Everolimus Alone | 12 months | 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. |
Countries
Australia, Singapore, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Phase I Participants Participants in the phase I dose escalation portion of the study. | 15 |
| Phase II: Arm A Phase II Participants, Arm A
Everolimus + BNC105P | 69 |
| Phase II: Arm B Participants Phase II: Arm B Participants
Everolimus only, followed by BNC105P monotherapy | 69 |
| Total | 153 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Phase I | Symptomatic Deterioration before Treatme | 3 | 0 | 0 |
| Phase II | Determined Ineligible per protocol | 0 | 1 | 0 |
| Phase II | Not Evaluable per protocol | 0 | 0 | 2 |
Baseline characteristics
| Characteristic | Phase I Participants | Total | Phase II: Arm B Participants | Phase II: Arm A |
|---|---|---|---|---|
| Age, Continuous | 58 years STANDARD_DEVIATION 9 | 62 years STANDARD_DEVIATION 9 | 63 years STANDARD_DEVIATION 9 | 62 years STANDARD_DEVIATION 9 |
| Initial Karnovksy Performance Score (KPS) KPS 100 | 0 Participants | 54 Participants | 25 Participants | 29 Participants |
| Initial Karnovksy Performance Score (KPS) KPS 70 | 4 Participants | 13 Participants | 5 Participants | 4 Participants |
| Initial Karnovksy Performance Score (KPS) KPS 80 | 2 Participants | 30 Participants | 15 Participants | 13 Participants |
| Initial Karnovksy Performance Score (KPS) KPS 90 | 9 Participants | 56 Participants | 24 Participants | 23 Participants |
| Memorial Sloan Kettering Cancer Center Risk Group (MSKCC MSKCC Risk Group - Good | 3 Participants | 36 Participants | 16 Participants | 17 Participants |
| Memorial Sloan Kettering Cancer Center Risk Group (MSKCC MSKCC Risk Group - Intermediate | 11 Participants | 103 Participants | 47 Participants | 45 Participants |
| Memorial Sloan Kettering Cancer Center Risk Group (MSKCC MSKCC Risk Group - Poor | 1 Participants | 14 Participants | 6 Participants | 7 Participants |
| Metastatic Site Bone | 8 Participants | 53 Participants | 24 Participants | 21 Participants |
| Metastatic Site Brain | 2 Participants | 10 Participants | 5 Participants | 3 Participants |
| Metastatic Site Liver | 6 Participants | 32 Participants | 13 Participants | 13 Participants |
| Metastatic Site Lung | 13 Participants | 124 Participants | 54 Participants | 57 Participants |
| Number of Prior Therapies 1 Prior Therapy | 0 Participants | 27 Participants | 13 Participants | 14 Participants |
| Number of Prior Therapies 2 Prior Therapies | 0 Participants | 42 Participants | 18 Participants | 24 Participants |
| Number of Prior Therapies 3 Prior Therapies | 3 Participants | 28 Participants | 15 Participants | 10 Participants |
| Number of Prior Therapies >=4 Prior Therapies | 12 Participants | 56 Participants | 23 Participants | 21 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 10 Participants | 5 Participants | 5 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 8 Participants | 4 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 13 Participants | 133 Participants | 59 Participants | 61 Participants |
| Sex: Female, Male Female | 6 Participants | 39 Participants | 13 Participants | 20 Participants |
| Sex: Female, Male Male | 9 Participants | 114 Participants | 56 Participants | 49 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 15 / 15 | 70 / 70 | 69 / 69 |
| serious Total, serious adverse events | 9 / 15 | 22 / 70 | 31 / 69 |
Outcome results
Primary
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
Time frame: 6 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I Participants | Phase II: 6-month Progression Free Survival (PFS) With the Addition of BNC105P to Everolimus. | .3382 probability of 6MPFS |
| Sequential Arm B:Everolimus Followed by BNC105P Monotherapy | Phase II: 6-month Progression Free Survival (PFS) With the Addition of BNC105P to Everolimus. | .3030 probability of 6MPFS |
p-value: 0.6625Chi-squared
Primary
Phase I: Maximum Tolerated Dose of BNC105P in Combination With Everolimus.
Phase I
Time frame: Until disease progression or unacceptable toxicity, up to 24 cycles or 24 months
Population: 12 participants completed at least one cycle of combination therapy and were evaluable.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I Participants | Phase I: Maximum Tolerated Dose of BNC105P in Combination With Everolimus. | 16 mg/m^2 |
Primary
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
Time frame: Until disease progression or unacceptable toxicity, up to 24 cycles or 24 months
Population: 12 participants who completed at least one cycle of combination therapy.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase I Participants | Phase I: Toxicities of BNC105P in Combination With Everolimus. | Mucositis (oral) Grade 2 | 2 participants |
| Phase I Participants | Phase I: Toxicities of BNC105P in Combination With Everolimus. | Dyspepsia Grade 2 | 1 participants |
| Phase I Participants | Phase I: Toxicities of BNC105P in Combination With Everolimus. | AST-SGOT Grade 2 | 1 participants |
| Phase I Participants | Phase I: Toxicities of BNC105P in Combination With Everolimus. | Cough Grade 2 | 1 participants |
| Phase I Participants | Phase I: Toxicities of BNC105P in Combination With Everolimus. | Hemoglobin Grade 2 | 4 participants |
| Phase I Participants | Phase I: Toxicities of BNC105P in Combination With Everolimus. | Hemoglobin Grade 3 | 1 participants |
| Phase I Participants | Phase I: Toxicities of BNC105P in Combination With Everolimus. | Hypomagnesia Grade 2 | 1 participants |
| Phase I Participants | Phase I: Toxicities of BNC105P in Combination With Everolimus. | Low Platelets Grade 2 | 1 participants |
| Phase I Participants | Phase I: Toxicities of BNC105P in Combination With Everolimus. | Weight Loss Grade 2 | 1 participants |
| Phase I Participants | Phase I: Toxicities of BNC105P in Combination With Everolimus. | Fatigue Grade 2 | 2 participants |
| Phase I Participants | Phase I: Toxicities of BNC105P in Combination With Everolimus. | Left ventricular systolic dysfunction Grade 2 | 1 participants |
| Phase I Participants | Phase I: Toxicities of BNC105P in Combination With Everolimus. | Nail Infection Grade 2 | 1 participants |
| Phase I Participants | Phase I: Toxicities of BNC105P in Combination With Everolimus. | Diaphoresis Grade 2 | 1 participants |
| Phase I Participants | Phase I: Toxicities of BNC105P in Combination With Everolimus. | Pericardial effusion Grade 3 | 1 participants |
| Phase I Participants | Phase I: Toxicities of BNC105P in Combination With Everolimus. | Pleural effusion Grade 2 | 1 participants |
Secondary
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.
Time frame: 6 months
Population: Analysis was pre-specified to look at the correlation irrespective of arm.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase I Participants | Exploratory Objective: Correlation of PFS With Biomarkers | Serum Amyloid P-Component (SAP) | 0.0184 Correlation with PFS P Value |
| Phase I Participants | Exploratory Objective: Correlation of PFS With Biomarkers | Sex Hormone-Binding Globulin (SHBG) | 0.0063 Correlation with PFS P Value |
| Phase I Participants | Exploratory Objective: Correlation of PFS With Biomarkers | Matrix Metalloproteinase-9 (MMP-9) | 0.0421 Correlation with PFS P Value |
| Phase I Participants | Exploratory Objective: Correlation of PFS With Biomarkers | Stem Cell Factor (SCF) | 0.0291 Correlation with PFS P Value |
Secondary
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
Time frame: 12 months
Population: 14 participants has sufficient data collected for the analysis of this objective
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Phase I Participants | Geometric Mean Half-life of BNC105 and BNC105P in Combination With Everolimus. | Half-life of BNC105 | .32 hours |
| Phase I Participants | Geometric Mean Half-life of BNC105 and BNC105P in Combination With Everolimus. | Half-life of BNC105P | .08 hours |
Secondary
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.
Time frame: 12 months
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase I Participants | Phase II: Adverse Events of Everolimus and BNC105P When Administered as a Combination or Sequential Regimen. | Non-Serious Adverse Events | 1419 number of adverse events |
| Phase I Participants | Phase II: Adverse Events of Everolimus and BNC105P When Administered as a Combination or Sequential Regimen. | Serious Adverse Events | 39 number of adverse events |
| Sequential Arm B:Everolimus Followed by BNC105P Monotherapy | Phase II: Adverse Events of Everolimus and BNC105P When Administered as a Combination or Sequential Regimen. | Non-Serious Adverse Events | 1654 number of adverse events |
| Sequential Arm B:Everolimus Followed by BNC105P Monotherapy | Phase II: Adverse Events of Everolimus and BNC105P When Administered as a Combination or Sequential Regimen. | Serious Adverse Events | 50 number of adverse events |
Secondary
Phase II: Overall Survival
Determine overall survival probability, up to a maximum of 5 years from registration for protocol therapy.
Time frame: 60 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I Participants | Phase II: Overall Survival | .15 probability of OS at 60 months. |
| Sequential Arm B:Everolimus Followed by BNC105P Monotherapy | Phase II: Overall Survival | .21 probability of OS at 60 months. |
Secondary
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
Time frame: 12 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase I Participants | Phase II: Progression Free Survival (PFS) With BNC105P Alone in Patients After Progressing on Everolimus. | 1.8 months |
Secondary
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.
Time frame: 12 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase I Participants | Phase II: Response Rate With Combination Therapy Compared to Everolimus Alone | 1 Participants |
| Sequential Arm B:Everolimus Followed by BNC105P Monotherapy | Phase II: Response Rate With Combination Therapy Compared to Everolimus Alone | 1 Participants |
Secondary
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.
Time frame: Until disease progression or unacceptable toxicity, up to 24 cycles or 24 months
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase I Participants | Phase I: Response Rate of BNC105P in Combination With Everolimus. | CR | 0 Participants |
| Phase I Participants | Phase I: Response Rate of BNC105P in Combination With Everolimus. | PR | 0 Participants |
| Phase I Participants | Phase I: Response Rate of BNC105P in Combination With Everolimus. | SD | 8 Participants |
| Phase I Participants | Phase I: Response Rate of BNC105P in Combination With Everolimus. | PD | 4 Participants |
| Phase I Participants | Phase I: Response Rate of BNC105P in Combination With Everolimus. | Unknown | 3 Participants |