Metastatic Renal Cell Cancer
Conditions
Keywords
renal cell carcinoma, clear cell, renal cancer, metastatic renal cancer, Carcinoma, Renal Cell*/therapy, Humans, Kidney Neoplasms*/therapy
Brief summary
The purpose of this study is to determine the maximum tolerated dose of RX-0201, up to a target dose of 250 mg/m\^2/day, when given in combination with everolimus (Stage 1), and to assess the safety and efficacy of RX-0201 plus everolimus, in subjects with metastatic renal cell cancer (Stage 2).
Detailed description
This multi-center, open-label, randomized, parallel group study of RX-0201 in combination with everolimus, versus everolimus alone to treat subjects with advanced renal cell carcinoma will be conducted in 2 stages. Stage 1 will be an open-label, dose-escalation study of RX-0201 to identify a safe and tolerable dose of RX-0201 up to a target dose of 250 mg/m\^2/day when given in combination with everolimus. Stage 2 will be a randomized, open-label, 2-arm study of RX-0201 in combination with everolimus versus everolimus alone. Subjects will receive RX-0201, at the dose identified in Stage 1, in combination with everolimus or everolimus alone, for up to 8 cycles to determine safety and efficacy of the combination.
Interventions
DRUGRX-0201
RX-0201 will be administered in a dose up to 250mg/m\^2/day as a continuous infusion for a cycle of 21 days (14 days infused followed by 7 days off) for up to 8 cycles in Stage 1. In Stage 2, RX-0201 will be administered the dose determined in Stage 1 as a continuous infusion for a cycle of 21 days (14 days infused followed by 7 days off) for up to 8 cycles.
Sponsors
Rexahn Pharmaceuticals, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Males and females ≥ 18 years of age at screening * Histological or cytological diagnosis of renal cell cancer with a clear-cell component * Measurable or evaluable disease defined by Response Evaluation Criteria for Solid Tumors (RECIST) ver. 1.1 * Must have received at least one course of therapy with a VEGFR-targeting tyrosine kinase inhibitor (eg, sorafenib, sunitinib, axitinib, pazopanib or tivozanib) and progressed within 6 months of planned first dose of study treatment * ECOG performance status of 0,1 or 2 * Life expectancy \> 3 months * Provide written informed consent
Exclusion criteria
* Brain metastases or cranial epidural disease unless adequately treated with radiotherapy and/or surgery and stable for at least 3 months before planned first dose of study drug * Radiation therapy for bone metastasis within 2 weeks, any other external radiation therapy within 4 weeks before planned first dose of study drug. Systemic treatment with radionuclides within 6 weeks before planned first dose of study drug. Subjects with clinically relevant ongoing complications from prior radiation therapy are not eligible * Prior treatment with everolimus, or any other specific or selective TORC1/PI3K/AKT inhibitor (eg, temsirolimus) * Receipt of any type of small molecule kinase inhibitor (including investigational kinase inhibitor) within 2 weeks before planned first dose of study drug * Receipt of any type of anticancer antibody (including investigational antibody) within 4 weeks before planned first dose of study drug * Taking strong inducers or inhibitors of CYP450s for subjects receiving everolimus * Chronic treatment with corticosteroids or other immunosuppressive agents * Concomitant anticoagulation at therapeutic doses with oral anticoagulants or platelet inhibitors * Subjects with a known hypersensitivity to everolimus or other rapamycins (sirolimus, temsirolimus) or to its excipients * Major surgery within 2 months before planned first dose of study drug * Myocardial infarction within the previous 6 months before planned first dose of study drug * Active infection requiring parenteral antibiotics within 2 weeks before planned first dose of study drug * Diagnosis of another malignancy within 2 years before planned first dose of study drug, except for superficial skin cancers, or localized, low grade tumors * Prior or current history of hepatitis B, hepatitis C or human immunodeficiency virus * Sexually active fertile subjects (male and female) must agree to use medically accepted methods of contraception during the course of the study and for 30 days after the last dose of study treatment
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Dose-limiting Toxicities (DLTs) (Stage 1) | after 1 cycle (3 weeks) of treatment with RX-0201 and everolimus | Incidence of adverse events and clinical laboratory abnormalities defined as dose-limiting toxicities |
| Progression Free Survival (Stage 2) | 4 months of treatment with RX-0201 and everolimus | Median PFS. Progression determined by RECIST v1.1 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Best Overall Response as Determined by RECIST v1.1. | Baseline and at weeks 6, 12, 18, and 24 | Best overall response as determined by RECIST v1.1. Not Evaluable included the subjects who had completed at least one treatment cycle but no overall response evaluation. Not Done included the subjects who dropped out from the study without completing any treatment cycle and overall response evaluation. The best overall response for each subject from all post-baseline time point overall responses was used. The best overall response was the best response recorded from the start of the treatment until disease progression/recurrence, or occurrence of intolerable toxicity, whatever came first. |
| Incidence of Adverse Events, Changes in Clinical Laboratory Tests and Vital Signs Over Time (Stage 1 and Stage 2) | up to 24 weeks of treatment with RX-0201 plus everolimus and at least 30 days of safety follow up | safety of RX-0201 was evaluated through reporting using the grading system in the CTCAE version 4.03 for adverse events and laboratory abnormalities. All statistical methods for safety were descriptive in nature. |
| Steady State Concentration (Css) of RX-0201 (Stage 1) | predose, 1, 2, 3, 4, 6, and 24 hours after start of Cycle 1 RX-0201 infusion, and then immediately prior to the end of Cycle 1 infusion (Day 15), 1, 2, 3, 4, 6, and 24 hours after infusion is stopped | Css of RX-0201 at the beginning and end of the 14 day continuous infusion |
Other
| Measure | Time frame | Description |
|---|---|---|
| Biomarker Concentrations in Blood | Baseline and at weeks 6, 12, 18, and 24 | Exploratory analysis of AKT pathway biomarkers, tumor apoptosis biomarkers and other biomarkers in blood or tumor samples |
| RX-0201 Concentration in the Blood (Stage 2 Only) | After 2 weeks of treatment | Exploratory analysis of plasma concentrations of RX-0201 at the end of infusion |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 125 mg/m^2/Day RX-0201 + Everolimus (Stage 1) RX-0201 was administered as 125 mg/m\^2/day as a continuous infusion for a cycle of 21 days (14 days infused followed by 7 days off) for up to 8 cycles in Stage 1.
10 mg everolimus was taken daily for a cycle of 21 days | 3 |
| 200 mg/m^2/Day RX-0201 + Everolimus (Stage 1) RX-0201 was administered as 200 mg/m\^2/day as a continuous infusion for a cycle of 21 days (14 days infused followed by 7 days off) for up to 8 cycles in Stage 1.
10 mg everolimus was taken daily for a cycle of 21 days | 4 |
| 250 mg/m^2/Day RX-0201 + Everolimus (Stage 1) RX-0201 was administered as 250 mg/m\^2/day as a continuous infusion for a cycle of 21 days (14 days infused followed by 7 days off) for up to 8 cycles in Stage 1.
10 mg everolimus was taken daily for a cycle of 21 days | 3 |
| 250 mg/m^2/Day RX-0201 + Everolimus (Stage 2) RX-0201 was administered as 250 mg/m\^2/day as a continuous infusion for a cycle of 21 days (14 days infused followed by 7 days off) for up to 8 cycles in Stage 2 after the determination of MTD in Stage 1.
10 mg everolimus was taken daily for a cycle of 21 days | 11 |
| Total | 21 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 0 | 2 |
| Overall Study | Physician Decision | 0 | 0 | 1 | 1 |
| Overall Study | Progressive disease | 0 | 0 | 0 | 2 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 0 | 2 |
Baseline characteristics
| Characteristic | Total | 250 mg/m^2/Day RX-0201 + Everolimus (Stage 2) | 250 mg/m^2/Day RX-0201 + Everolimus (Stage 1) | 200 mg/m^2/Day RX-0201 + Everolimus (Stage 1) | 125 mg/m^2/Day RX-0201 + Everolimus (Stage 1) |
|---|---|---|---|---|---|
| Age, Continuous | 62.8 years STANDARD_DEVIATION 7.87 | 63.9 years STANDARD_DEVIATION 6.3 | 61.0 years STANDARD_DEVIATION 15.87 | 62.0 years STANDARD_DEVIATION 12.83 | 62.7 years STANDARD_DEVIATION 10.79 |
| ECOG ECOG = 0 | 9 Participants | 6 Participants | 1 Participants | 1 Participants | 1 Participants |
| ECOG ECOG = 1 | 11 Participants | 5 Participants | 1 Participants | 3 Participants | 2 Participants |
| ECOG ECOG = 2 | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 1 Participants | 1 Participants | 1 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 18 Participants | 10 Participants | 2 Participants | 3 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 2 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 14 Participants | 8 Participants | 2 Participants | 1 Participants | 3 Participants |
| Sex: Female, Male Female | 7 Participants | 4 Participants | 1 Participants | 2 Participants | 0 Participants |
| Sex: Female, Male Male | 14 Participants | 7 Participants | 2 Participants | 2 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 0 / 4 | 0 / 3 | 0 / 11 |
| other Total, other adverse events | 3 / 3 | 4 / 4 | 3 / 3 | 11 / 11 |
| serious Total, serious adverse events | 2 / 3 | 1 / 4 | 2 / 3 | 4 / 11 |
Outcome results
Primary
Incidence of Dose-limiting Toxicities (DLTs) (Stage 1)
Incidence of adverse events and clinical laboratory abnormalities defined as dose-limiting toxicities
Time frame: after 1 cycle (3 weeks) of treatment with RX-0201 and everolimus
Population: DLTs were only applicable to Stage 1.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 125 mg/m^2/Day RX-0201 + Everolimus (Stage 1) | Incidence of Dose-limiting Toxicities (DLTs) (Stage 1) | 0 Participants |
| 200 mg/m^2/Day RX-0201 + Everolimus (Stage 1) | Incidence of Dose-limiting Toxicities (DLTs) (Stage 1) | 0 Participants |
| 250 mg/m^2/Day RX-0201 + Everolimus (Stage 1) | Incidence of Dose-limiting Toxicities (DLTs) (Stage 1) | 0 Participants |
Primary
Progression Free Survival (Stage 2)
Median PFS. Progression determined by RECIST v1.1
Time frame: 4 months of treatment with RX-0201 and everolimus
Population: Progression Free Survival (PFS) was determined only in the Stage 2 population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 125 mg/m^2/Day RX-0201 + Everolimus (Stage 1) | Progression Free Survival (Stage 2) | NA days |
Secondary
Best Overall Response as Determined by RECIST v1.1.
Best overall response as determined by RECIST v1.1. Not Evaluable included the subjects who had completed at least one treatment cycle but no overall response evaluation. Not Done included the subjects who dropped out from the study without completing any treatment cycle and overall response evaluation. The best overall response for each subject from all post-baseline time point overall responses was used. The best overall response was the best response recorded from the start of the treatment until disease progression/recurrence, or occurrence of intolerable toxicity, whatever came first.
Time frame: Baseline and at weeks 6, 12, 18, and 24
Population: All enrolled subjects with subjects analyzed according to the treatment assigned at enrollment/ randomization.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| 125 mg/m^2/Day RX-0201 + Everolimus (Stage 1) | Best Overall Response as Determined by RECIST v1.1. | Complete Response (CR) | 0 Participants |
| 125 mg/m^2/Day RX-0201 + Everolimus (Stage 1) | Best Overall Response as Determined by RECIST v1.1. | Partial Response (PR) | 0 Participants |
| 125 mg/m^2/Day RX-0201 + Everolimus (Stage 1) | Best Overall Response as Determined by RECIST v1.1. | Stable Disease (SD) | 2 Participants |
| 125 mg/m^2/Day RX-0201 + Everolimus (Stage 1) | Best Overall Response as Determined by RECIST v1.1. | Progressive Disease (PD) | 0 Participants |
| 125 mg/m^2/Day RX-0201 + Everolimus (Stage 1) | Best Overall Response as Determined by RECIST v1.1. | Not Evaluable (NE) | 0 Participants |
| 125 mg/m^2/Day RX-0201 + Everolimus (Stage 1) | Best Overall Response as Determined by RECIST v1.1. | Not Done (ND) | 1 Participants |
| 200 mg/m^2/Day RX-0201 + Everolimus (Stage 1) | Best Overall Response as Determined by RECIST v1.1. | Not Done (ND) | 1 Participants |
| 200 mg/m^2/Day RX-0201 + Everolimus (Stage 1) | Best Overall Response as Determined by RECIST v1.1. | Progressive Disease (PD) | 2 Participants |
| 200 mg/m^2/Day RX-0201 + Everolimus (Stage 1) | Best Overall Response as Determined by RECIST v1.1. | Complete Response (CR) | 0 Participants |
| 200 mg/m^2/Day RX-0201 + Everolimus (Stage 1) | Best Overall Response as Determined by RECIST v1.1. | Stable Disease (SD) | 1 Participants |
| 200 mg/m^2/Day RX-0201 + Everolimus (Stage 1) | Best Overall Response as Determined by RECIST v1.1. | Partial Response (PR) | 0 Participants |
| 200 mg/m^2/Day RX-0201 + Everolimus (Stage 1) | Best Overall Response as Determined by RECIST v1.1. | Not Evaluable (NE) | 0 Participants |
| 250 mg/m^2/Day RX-0201 + Everolimus (Stage 1) | Best Overall Response as Determined by RECIST v1.1. | Partial Response (PR) | 0 Participants |
| 250 mg/m^2/Day RX-0201 + Everolimus (Stage 1) | Best Overall Response as Determined by RECIST v1.1. | Stable Disease (SD) | 1 Participants |
| 250 mg/m^2/Day RX-0201 + Everolimus (Stage 1) | Best Overall Response as Determined by RECIST v1.1. | Progressive Disease (PD) | 0 Participants |
| 250 mg/m^2/Day RX-0201 + Everolimus (Stage 1) | Best Overall Response as Determined by RECIST v1.1. | Not Done (ND) | 2 Participants |
| 250 mg/m^2/Day RX-0201 + Everolimus (Stage 1) | Best Overall Response as Determined by RECIST v1.1. | Not Evaluable (NE) | 1 Participants |
| 250 mg/m^2/Day RX-0201 + Everolimus (Stage 1) | Best Overall Response as Determined by RECIST v1.1. | Complete Response (CR) | 0 Participants |
| RX-0201 Plus Everolimus (Stage 2) | Best Overall Response as Determined by RECIST v1.1. | Not Evaluable (NE) | 0 Participants |
| RX-0201 Plus Everolimus (Stage 2) | Best Overall Response as Determined by RECIST v1.1. | Not Done (ND) | 3 Participants |
| RX-0201 Plus Everolimus (Stage 2) | Best Overall Response as Determined by RECIST v1.1. | Partial Response (PR) | 0 Participants |
| RX-0201 Plus Everolimus (Stage 2) | Best Overall Response as Determined by RECIST v1.1. | Progressive Disease (PD) | 1 Participants |
| RX-0201 Plus Everolimus (Stage 2) | Best Overall Response as Determined by RECIST v1.1. | Complete Response (CR) | 0 Participants |
| RX-0201 Plus Everolimus (Stage 2) | Best Overall Response as Determined by RECIST v1.1. | Stable Disease (SD) | 7 Participants |
Secondary
Incidence of Adverse Events, Changes in Clinical Laboratory Tests and Vital Signs Over Time (Stage 1 and Stage 2)
safety of RX-0201 was evaluated through reporting using the grading system in the CTCAE version 4.03 for adverse events and laboratory abnormalities. All statistical methods for safety were descriptive in nature.
Time frame: up to 24 weeks of treatment with RX-0201 plus everolimus and at least 30 days of safety follow up
Secondary
Steady State Concentration (Css) of RX-0201 (Stage 1)
Css of RX-0201 at the beginning and end of the 14 day continuous infusion
Time frame: predose, 1, 2, 3, 4, 6, and 24 hours after start of Cycle 1 RX-0201 infusion, and then immediately prior to the end of Cycle 1 infusion (Day 15), 1, 2, 3, 4, 6, and 24 hours after infusion is stopped
Population: Stage 1 subjects who had sufficient PK samples for analysis
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 125 mg/m^2/Day RX-0201 + Everolimus (Stage 1) | Steady State Concentration (Css) of RX-0201 (Stage 1) | 1626 ng/ml | Standard Deviation 1107.2 |
| 200 mg/m^2/Day RX-0201 + Everolimus (Stage 1) | Steady State Concentration (Css) of RX-0201 (Stage 1) | 3283 ng/ml | — |
| 250 mg/m^2/Day RX-0201 + Everolimus (Stage 1) | Steady State Concentration (Css) of RX-0201 (Stage 1) | 5147 ng/ml | — |
Other Pre-specified
Biomarker Concentrations in Blood
Exploratory analysis of AKT pathway biomarkers, tumor apoptosis biomarkers and other biomarkers in blood or tumor samples
Time frame: Baseline and at weeks 6, 12, 18, and 24
Other Pre-specified
RX-0201 Concentration in the Blood (Stage 2 Only)
Exploratory analysis of plasma concentrations of RX-0201 at the end of infusion
Time frame: After 2 weeks of treatment