Advanced Solid Tumors
Conditions
Brief summary
This open-label, multi-center Phase 1/2 study will assess the safety, pharmacokinetics, and pharmacodynamics of escalating doses of BVD-523 in patients with advanced malignancies. The study also seeks to demonstrate target modulation and early signs of clinical response in select patient populations.
Detailed description
The study is being performed to assess the safety and tolerability of BVD-523 In Part 1 of the study, an accelerated dose escalation plan will be used to establish dose limiting toxicities, maximum tolerated dose, and the recommended Phase 2 dose. In Part 2 of the study, additional patients with particular tumor types and/or cancers harboring specific genetic mutations will be recruited for treatment at the Recommended Phase 2 Dose. Patients may also be assessed pharmacodynamic measures in healthy or malignant tissues, using biomarker assays for phosphorylation, cytotoxic or cytostatic measures.
Interventions
DRUGBVD-523
Oral, multiple escalating doses, twice daily, for 21 days in each treatment cycle
Sponsors
BioMed Valley Discoveries, 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
* Patients with metastatic or advanced-stage malignant tumor. Patients may have received up to 2 prior lines of chemotherapy for their metastatic disease * ECOG score of 0 or 1 * Predicted life expectancy of ≥ 3 months * Adequate bone marrow, liver and renal function renal function * Adequate cardiac function * For women: Negative pregnancy test for females of child-bearing potential; must be surgically sterile, postmenopausal, or compliant with a contraceptive regimen during and for 3 months after the treatment period * For men: Must be surgically sterile, or compliant with a contraceptive regimen during and for 3 months after the treatment period * For Part 2 of the Study only, patients must have measurable disease by RECIST 1.1 and be in one of the the groups below. Patients in groups 1, 2, 4, 5 and 6 may not have been previously treated with BRAF and/or MEK inhibitors * Group 1: Patients with BRAF mutated cancer, except those with colorectal or non-small cell lung cancers * Group 2: Patients with BRAF mutated colorectal cancer * Group 3: Patients with BRAF mutated melanoma who have progressed on, or are refractory to BRAF and/or MEK inhibitors * Group 4: Patients with NRAS mutated melanoma * Group 5: Patients with MEK mutated cancer * Group 6: Patients with BRAF mutated non-small cell lung cancer * Group 7: Patients with ERK mutated cancer
Exclusion criteria
* Gastrointestinal condition which could impair absorption of study medication * Uncontrolled or severe intercurrent medical condition * Known uncontrolled brain metastases. Stable brain metastases either treated or being treated with a stable dose of steroids/anticonvulsants * Any cancer-directed therapy (chemotherapy, radiotherapy, hormonal therapy, biologic or immunotherapy, etc.) within 28 days or 5 half-lives, whichever is shorter * Major surgery within 4 weeks prior to first dose * Any use of an investigational drug within 28 days or 5 half-lives (whichever is shorter) prior to the first dose of BVD-523. * Pregnant or breast-feeding women * Any evidence of serious active infections * Any important medical illness or abnormal laboratory finding that would increase the risk of participating in this study * A history or current evidence/risk of retinal vein occlusion or central serous retinopathy * Concurrent therapy with any other investigational agent * Concomitant malignancies or previous malignancies with less than 2 years disease-free interval at the time of enrollment
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Determination of Recommended Phase 2 Dose (RP2D) of BVD-523 by Dose-limiting Toxicities (DLT). | As indicated by safety and tolerability during study conduct; ~42 months | DLT is defined as any BVD-523 related toxicity in the first 21 days of treatment that results in: 1. ≥Grade 4 hematologic toxicity for \>1 day; 2. Grade 3 hematologic toxicity with complications e.g., thrombocytopenia with bleeding; 3. ≥Grade 3 non-hematologic toxicity, except untreated nausea, vomiting, constipation, pain and rash (these become DLTs if the adverse event (AE) persists despite adequate treatment), a doubling of aspartate transaminase (AST)/alanine transaminase (ALT) in patients with grade 2 ALT/AST at baseline; 4. A treatment interruption exceeding 5 days (or an interruption exceeding 7 days for rash, despite adequate treatment) in Cycle 1 (or inability to begin Cycle 2 for \> 7 days) due to BVD-523-related toxicity. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Characterization of the Time Versus Plasma Concentration Profiles of BVD-523 and Selected Metabolites. | Samples will be collected on day 1 and day 15 of Cycle 1 | Data provided is for BVD-523. |
| Clinical Evidence of Tumor Response Assessed by Physical or Radiological Exam. | Patients will be evaluated at baseline & at periodic follow-up visits through the time their participation in the study is completion. The best responses presented occurred at different time points for each patient. | At enrollment, all study patients had metastatic or advanced-stage malignant tumor for which no curative therapy was known to exist. Patients entering Part 2 additionally had to have measurable disease by RECIST version 1.1. Data shown is best response. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Pharmacodynamic (PD) Response Measured as Percentage Enzyme Inhibition of RSK1 Ser 380 (pRSK) | Patients will be evaluated at baseline and on ~day 15 of Cycle 1 | RSK1, a member of the RSK serine/threonine kinase family, is a direct substrate of the MAP Kinases ERK1 & ERK2. RSK1 and ERK1/2 form an inactive complex in unstimulated cells. Upon activation of the mitogenic pathway, ERK1/2 phosphorylates Thr573, Thr359 and Ser363 on RSK1. Thr573 resides in the activation loop of the carboxy terminal kinase domain of RSK1 and once phosphorylated, enables RSK1 to autophosphorylate Ser380. Phosphorylation of Ser380 on RSK1 can therefore be used as a target biomarker for ERK1 and ERK2 activity. BVD-523 inhibits the activity of ERK. In this study, phosphorylation of RSK1 Ser 380 (pRSK) was used as a target biomarker for assessment of ERK inhibition by BVD-523 in human whole blood samples. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Dose-escalation 10mg b.i.d. Cohort Patients received 10mg oral doses of BVD 523 b.i.d. for 21 days (a Cycle). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion was noted. Treatment cycles occurred consecutively without interruption, except when necessary to manage AEs. All dose-escalation decisions were based on Cycle 1 safety data and doses were not escalated unless the patients receiving the highest current dose had been observed for at least 3 weeks. | 1 |
| Dose-escalation 20mg b.i.d. Cohort Patients received 20mg oral doses of BVD 523 b.i.d. for 21 days (a Cycle). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion was noted. Treatment cycles occurred consecutively without interruption, except when necessary to manage AEs. All dose-escalation decisions were based on Cycle 1 safety data and doses were not escalated unless the patients receiving the highest current dose had been observed for at least 3 weeks. | 1 |
| Dose-escalation 40mg b.i.d. Cohort Patients received 40mg oral doses of BVD 523 b.i.d. for 21 days (a Cycle). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion was noted. Treatment cycles occurred consecutively without interruption, except when necessary to manage AEs. All dose-escalation decisions were based on Cycle 1 safety data and doses were not escalated unless the patients receiving the highest current dose had been observed for at least 3 weeks. | 1 |
| Dose-escalation 75mg b.i.d. Cohort Patients received 75mg oral doses of BVD 523 b.i.d. for 21 days (a Cycle). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion was noted. Treatment cycles occurred consecutively without interruption, except when necessary to manage AEs. All dose-escalation decisions were based on Cycle 1 safety data and doses were not escalated unless the patients receiving the highest current dose had been observed for at least 3 weeks. | 1 |
| Dose-escalation 150mg b.i.d. Cohort Patients received 150mg oral doses of BVD 523 b.i.d. for 21 days (a Cycle). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion was noted. Treatment cycles occurred consecutively without interruption, except when necessary to manage AEs. All dose-escalation decisions were based on Cycle 1 safety data and doses were not escalated unless the patients receiving the highest current dose had been observed for at least 3 weeks. | 1 |
| Dose-escalation 300mg b.i.d. Cohort Patients received 300mg oral doses of BVD 523 b.i.d. for 21 days (a Cycle). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion was noted. Treatment cycles occurred consecutively without interruption, except when necessary to manage AEs. All dose-escalation decisions were based on Cycle 1 safety data and doses were not escalated unless the patients receiving the highest current dose had been observed for at least 3 weeks. | 4 |
| Dose-escalation 600mg b.i.d. Cohort Patients received 600mg oral doses of BVD 523 b.i.d. for 21 days (a Cycle). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion was noted. Treatment cycles occurred consecutively without interruption, except when necessary to manage AEs. All dose-escalation decisions were based on Cycle 1 safety data and doses were not escalated unless the patients receiving the highest current dose had been observed for at least 3 weeks. | 7 |
| Dose-escalation 750mg b.i.d. Cohort Patients received 750mg oral doses of BVD 523 b.i.d. for 21 days (a Cycle). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion was noted. Treatment cycles occurred consecutively without interruption, except when necessary to manage AEs. All dose-escalation decisions were based on Cycle 1 safety data and doses were not escalated unless the patients receiving the highest current dose had been observed for at least 3 weeks. | 4 |
| Dose-escalation 900mg b.i.d. Cohort Patients received 900mg oral doses of BVD 523 b.i.d. for 21 days (a Cycle). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion was noted. Treatment cycles occurred consecutively without interruption, except when necessary to manage AEs. All dose-escalation decisions were based on Cycle 1 safety data and doses were not escalated unless the patients receiving the highest current dose had been observed for at least 3 weeks. | 7 |
| Cohort-expansion Group 1 Patients with BRAF mutated cancer, except those with colorectal or non-small cell lung cancers, not previously treated with BRAF and/or MEK inhibitors. Patients received 600mg oral doses of BVD 523 b.i.d. for 21 days (a Cycle). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or another withdrawal criterion was met. Treatment cycles occurred consecutively without interruption except when necessary to manage AEs. | 24 |
| Cohort-expansion Group 2 Patients with BRAF mutated colorectal cancer, not previously treated with BRAF and/or MEK inhibitors. Patients received 600mg oral doses of BVD 523 b.i.d. for 21 days (a Cycle). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or another withdrawal criterion was met. Treatment cycles occurred consecutively without interruption except when necessary to manage AEs. | 17 |
| Cohort-expansion Group 3 Patients with BRAF mutated melanoma who had progressed or were refractory to BRAF and/or MEK inhibitors. Patients received 600mg oral doses of BVD 523 b.i.d. for 21 days (a Cycle). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or another withdrawal criterion was met. Treatment cycles occurred consecutively without interruption except when necessary to manage AEs. | 21 |
| Cohort-expansion Group 4 Patients with NRAS mutated melanoma, not previously treated with BRAF and/or MEK inhibitors. Patients received 600mg oral doses of BVD 523 b.i.d. for 21 days (a Cycle). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or another withdrawal criterion was met. Treatment cycles occurred consecutively without interruption except when necessary to manage AEs. | 22 |
| Cohort-expansion Group 5 Patients with MEK mutated cancer, not previously treated with BRAF and/or MEK inhibitors. Patients received 600mg oral doses of BVD 523 b.i.d. for 21 days (a Cycle). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or another withdrawal criterion was met. Treatment cycles occurred consecutively without interruption except when necessary to manage AEs. | 8 |
| Cohort-expansion Group 6 Patients with BRAF mutated non-small cell lung cancer, not previously treated with BRAF and/or MEK inhibitors. Patients received 600mg oral doses of BVD 523 b.i.d. for 21 days (a Cycle). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or another withdrawal criterion was met. Treatment cycles occurred consecutively without interruption except when necessary to manage AEs. | 16 |
| Total | 135 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 | FG010 | FG011 | FG012 | FG013 | FG014 | FG015 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Death | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 1 | 0 | 1 | 0 |
| Overall Study | Disease Progression | 1 | 0 | 1 | 1 | 1 | 4 | 7 | 4 | 6 | 15 | 15 | 15 | 15 | 4 | 11 | 0 |
| Overall Study | Enrolled, but not treated | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Other - as entered by PI in eCRF | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 1 | 2 | 1 | 1 | 1 | 0 |
| Overall Study | Patient Condition Changed | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 4 | 0 | 1 | 0 | 1 | 0 | 0 |
| Overall Study | Unacceptable Toxicity | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 0 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 3 | 1 | 1 | 5 | 2 | 3 | 0 |
Baseline characteristics
| Characteristic | Total | Dose-escalation 20mg b.i.d. Cohort | Dose-escalation 40mg b.i.d. Cohort | Dose-escalation 75mg b.i.d. Cohort | Dose-escalation 150mg b.i.d. Cohort | Dose-escalation 300mg b.i.d. Cohort | Dose-escalation 600mg b.i.d. Cohort | Dose-escalation 750mg b.i.d. Cohort | Dose-escalation 900mg b.i.d. Cohort | Dose-escalation 10mg b.i.d. Cohort | Cohort-expansion Group 1 | Cohort-expansion Group 2 | Cohort-expansion Group 3 | Cohort-expansion Group 4 | Cohort-expansion Group 5 | Cohort-expansion Group 6 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 63 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 4 Participants | 4 Participants | 1 Participants | 1 Participants | 1 Participants | 12 Participants | 10 Participants | 5 Participants | 11 Participants | 2 Participants | 10 Participants |
| Age, Categorical Between 18 and 65 years | 72 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 3 Participants | 3 Participants | 6 Participants | 0 Participants | 12 Participants | 7 Participants | 16 Participants | 11 Participants | 6 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 3 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 121 Participants | 1 Participants | 1 Participants | 1 Participants | 1 Participants | 4 Participants | 7 Participants | 4 Participants | 7 Participants | 1 Participants | 19 Participants | 15 Participants | 21 Participants | 16 Participants | 8 Participants | 15 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 11 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 5 Participants | 2 Participants | 0 Participants | 3 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 6 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 2 Participants | 1 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 6 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 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 | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 6 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 1 Participants | 3 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 117 Participants | 1 Participants | 1 Participants | 1 Participants | 1 Participants | 3 Participants | 7 Participants | 4 Participants | 5 Participants | 1 Participants | 19 Participants | 15 Participants | 20 Participants | 18 Participants | 6 Participants | 15 Participants |
| Region of Enrollment United States | 135 participants | 1 participants | 1 participants | 1 participants | 1 participants | 4 participants | 7 participants | 4 participants | 7 participants | 1 participants | 24 participants | 17 participants | 21 participants | 22 participants | 8 participants | 16 participants |
| Sex: Female, Male Female | 52 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 5 Participants | 1 Participants | 5 Participants | 1 Participants | 8 Participants | 7 Participants | 9 Participants | 5 Participants | 1 Participants | 9 Participants |
| Sex: Female, Male Male | 83 Participants | 1 Participants | 1 Participants | 1 Participants | 1 Participants | 3 Participants | 2 Participants | 3 Participants | 2 Participants | 0 Participants | 16 Participants | 10 Participants | 12 Participants | 17 Participants | 7 Participants | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 1 | 0 / 1 | 0 / 1 | 0 / 1 | 0 / 1 | 0 / 4 | 0 / 7 | 0 / 4 | 0 / 7 | 3 / 108 |
| other Total, other adverse events | 1 / 1 | 1 / 1 | 1 / 1 | 1 / 1 | 1 / 1 | 4 / 4 | 7 / 7 | 4 / 4 | 7 / 7 | 107 / 108 |
| serious Total, serious adverse events | 0 / 1 | 1 / 1 | 1 / 1 | 1 / 1 | 1 / 1 | 2 / 4 | 2 / 7 | 1 / 4 | 5 / 7 | 57 / 108 |
Outcome results
Primary
Determination of Recommended Phase 2 Dose (RP2D) of BVD-523 by Dose-limiting Toxicities (DLT).
DLT is defined as any BVD-523 related toxicity in the first 21 days of treatment that results in: 1. ≥Grade 4 hematologic toxicity for \>1 day; 2. Grade 3 hematologic toxicity with complications e.g., thrombocytopenia with bleeding; 3. ≥Grade 3 non-hematologic toxicity, except untreated nausea, vomiting, constipation, pain and rash (these become DLTs if the adverse event (AE) persists despite adequate treatment), a doubling of aspartate transaminase (AST)/alanine transaminase (ALT) in patients with grade 2 ALT/AST at baseline; 4. A treatment interruption exceeding 5 days (or an interruption exceeding 7 days for rash, despite adequate treatment) in Cycle 1 (or inability to begin Cycle 2 for \> 7 days) due to BVD-523-related toxicity.
Time frame: As indicated by safety and tolerability during study conduct; ~42 months
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Dose-escalation 10mg b.i.d. Cohort | Determination of Recommended Phase 2 Dose (RP2D) of BVD-523 by Dose-limiting Toxicities (DLT). | Grade 3 Hematologic Toxicity with Complications | Yes | 0 Participants |
| Dose-escalation 10mg b.i.d. Cohort | Determination of Recommended Phase 2 Dose (RP2D) of BVD-523 by Dose-limiting Toxicities (DLT). | ≥Grade 3 Non-Hematologic Toxicity | No | 1 Participants |
| Dose-escalation 10mg b.i.d. Cohort | Determination of Recommended Phase 2 Dose (RP2D) of BVD-523 by Dose-limiting Toxicities (DLT). | Any DLT | No | 1 Participants |
| Dose-escalation 10mg b.i.d. Cohort | Determination of Recommended Phase 2 Dose (RP2D) of BVD-523 by Dose-limiting Toxicities (DLT). | Any DLT | Yes | 0 Participants |
| Dose-escalation 10mg b.i.d. Cohort | Determination of Recommended Phase 2 Dose (RP2D) of BVD-523 by Dose-limiting Toxicities (DLT). | ≥Grade 3 Non-Hematologic Toxicity | Yes | 0 Participants |
| Dose-escalation 10mg b.i.d. Cohort | Determination of Recommended Phase 2 Dose (RP2D) of BVD-523 by Dose-limiting Toxicities (DLT). | Grade 3 Hematologic Toxicity with Complications | No | 1 Participants |
| Dose-escalation 20mg b.i.d. Cohort | Determination of Recommended Phase 2 Dose (RP2D) of BVD-523 by Dose-limiting Toxicities (DLT). | ≥Grade 3 Non-Hematologic Toxicity | No | 1 Participants |
| Dose-escalation 20mg b.i.d. Cohort | Determination of Recommended Phase 2 Dose (RP2D) of BVD-523 by Dose-limiting Toxicities (DLT). | ≥Grade 3 Non-Hematologic Toxicity | Yes | 0 Participants |
| Dose-escalation 20mg b.i.d. Cohort | Determination of Recommended Phase 2 Dose (RP2D) of BVD-523 by Dose-limiting Toxicities (DLT). | Any DLT | No | 1 Participants |
| Dose-escalation 20mg b.i.d. Cohort | Determination of Recommended Phase 2 Dose (RP2D) of BVD-523 by Dose-limiting Toxicities (DLT). | Grade 3 Hematologic Toxicity with Complications | No | 1 Participants |
| Dose-escalation 20mg b.i.d. Cohort | Determination of Recommended Phase 2 Dose (RP2D) of BVD-523 by Dose-limiting Toxicities (DLT). | Grade 3 Hematologic Toxicity with Complications | Yes | 0 Participants |
| Dose-escalation 20mg b.i.d. Cohort | Determination of Recommended Phase 2 Dose (RP2D) of BVD-523 by Dose-limiting Toxicities (DLT). | Any DLT | Yes | 0 Participants |
| Dose-escalation 40mg b.i.d. Cohort | Determination of Recommended Phase 2 Dose (RP2D) of BVD-523 by Dose-limiting Toxicities (DLT). | Grade 3 Hematologic Toxicity with Complications | Yes | 0 Participants |
| Dose-escalation 40mg b.i.d. Cohort | Determination of Recommended Phase 2 Dose (RP2D) of BVD-523 by Dose-limiting Toxicities (DLT). | ≥Grade 3 Non-Hematologic Toxicity | Yes | 0 Participants |
| Dose-escalation 40mg b.i.d. Cohort | Determination of Recommended Phase 2 Dose (RP2D) of BVD-523 by Dose-limiting Toxicities (DLT). | ≥Grade 3 Non-Hematologic Toxicity | No | 1 Participants |
| Dose-escalation 40mg b.i.d. Cohort | Determination of Recommended Phase 2 Dose (RP2D) of BVD-523 by Dose-limiting Toxicities (DLT). | Grade 3 Hematologic Toxicity with Complications | No | 1 Participants |
| Dose-escalation 40mg b.i.d. Cohort | Determination of Recommended Phase 2 Dose (RP2D) of BVD-523 by Dose-limiting Toxicities (DLT). | Any DLT | Yes | 0 Participants |
| Dose-escalation 40mg b.i.d. Cohort | Determination of Recommended Phase 2 Dose (RP2D) of BVD-523 by Dose-limiting Toxicities (DLT). | Any DLT | No | 1 Participants |
| Dose-escalation 75mg b.i.d. Cohort | Determination of Recommended Phase 2 Dose (RP2D) of BVD-523 by Dose-limiting Toxicities (DLT). | Any DLT | No | 1 Participants |
| Dose-escalation 75mg b.i.d. Cohort | Determination of Recommended Phase 2 Dose (RP2D) of BVD-523 by Dose-limiting Toxicities (DLT). | Any DLT | Yes | 0 Participants |
| Dose-escalation 75mg b.i.d. Cohort | Determination of Recommended Phase 2 Dose (RP2D) of BVD-523 by Dose-limiting Toxicities (DLT). | Grade 3 Hematologic Toxicity with Complications | Yes | 0 Participants |
| Dose-escalation 75mg b.i.d. Cohort | Determination of Recommended Phase 2 Dose (RP2D) of BVD-523 by Dose-limiting Toxicities (DLT). | Grade 3 Hematologic Toxicity with Complications | No | 1 Participants |
| Dose-escalation 75mg b.i.d. Cohort | Determination of Recommended Phase 2 Dose (RP2D) of BVD-523 by Dose-limiting Toxicities (DLT). | ≥Grade 3 Non-Hematologic Toxicity | Yes | 0 Participants |
| Dose-escalation 75mg b.i.d. Cohort | Determination of Recommended Phase 2 Dose (RP2D) of BVD-523 by Dose-limiting Toxicities (DLT). | ≥Grade 3 Non-Hematologic Toxicity | No | 1 Participants |
| Dose-escalation 150mg b.i.d. Cohort | Determination of Recommended Phase 2 Dose (RP2D) of BVD-523 by Dose-limiting Toxicities (DLT). | Any DLT | Yes | 0 Participants |
| Dose-escalation 150mg b.i.d. Cohort | Determination of Recommended Phase 2 Dose (RP2D) of BVD-523 by Dose-limiting Toxicities (DLT). | ≥Grade 3 Non-Hematologic Toxicity | Yes | 0 Participants |
| Dose-escalation 150mg b.i.d. Cohort | Determination of Recommended Phase 2 Dose (RP2D) of BVD-523 by Dose-limiting Toxicities (DLT). | Grade 3 Hematologic Toxicity with Complications | Yes | 0 Participants |
| Dose-escalation 150mg b.i.d. Cohort | Determination of Recommended Phase 2 Dose (RP2D) of BVD-523 by Dose-limiting Toxicities (DLT). | Grade 3 Hematologic Toxicity with Complications | No | 1 Participants |
| Dose-escalation 150mg b.i.d. Cohort | Determination of Recommended Phase 2 Dose (RP2D) of BVD-523 by Dose-limiting Toxicities (DLT). | ≥Grade 3 Non-Hematologic Toxicity | No | 1 Participants |
| Dose-escalation 150mg b.i.d. Cohort | Determination of Recommended Phase 2 Dose (RP2D) of BVD-523 by Dose-limiting Toxicities (DLT). | Any DLT | No | 1 Participants |
| Dose-escalation 300mg b.i.d. Cohort | Determination of Recommended Phase 2 Dose (RP2D) of BVD-523 by Dose-limiting Toxicities (DLT). | Grade 3 Hematologic Toxicity with Complications | No | 4 Participants |
| Dose-escalation 300mg b.i.d. Cohort | Determination of Recommended Phase 2 Dose (RP2D) of BVD-523 by Dose-limiting Toxicities (DLT). | Any DLT | Yes | 0 Participants |
| Dose-escalation 300mg b.i.d. Cohort | Determination of Recommended Phase 2 Dose (RP2D) of BVD-523 by Dose-limiting Toxicities (DLT). | ≥Grade 3 Non-Hematologic Toxicity | Yes | 0 Participants |
| Dose-escalation 300mg b.i.d. Cohort | Determination of Recommended Phase 2 Dose (RP2D) of BVD-523 by Dose-limiting Toxicities (DLT). | ≥Grade 3 Non-Hematologic Toxicity | No | 4 Participants |
| Dose-escalation 300mg b.i.d. Cohort | Determination of Recommended Phase 2 Dose (RP2D) of BVD-523 by Dose-limiting Toxicities (DLT). | Grade 3 Hematologic Toxicity with Complications | Yes | 0 Participants |
| Dose-escalation 300mg b.i.d. Cohort | Determination of Recommended Phase 2 Dose (RP2D) of BVD-523 by Dose-limiting Toxicities (DLT). | Any DLT | No | 4 Participants |
| Dose-escalation 600mg b.i.d. Cohort | Determination of Recommended Phase 2 Dose (RP2D) of BVD-523 by Dose-limiting Toxicities (DLT). | Grade 3 Hematologic Toxicity with Complications | Yes | 0 Participants |
| Dose-escalation 600mg b.i.d. Cohort | Determination of Recommended Phase 2 Dose (RP2D) of BVD-523 by Dose-limiting Toxicities (DLT). | Any DLT | No | 6 Participants |
| Dose-escalation 600mg b.i.d. Cohort | Determination of Recommended Phase 2 Dose (RP2D) of BVD-523 by Dose-limiting Toxicities (DLT). | ≥Grade 3 Non-Hematologic Toxicity | No | 6 Participants |
| Dose-escalation 600mg b.i.d. Cohort | Determination of Recommended Phase 2 Dose (RP2D) of BVD-523 by Dose-limiting Toxicities (DLT). | Grade 3 Hematologic Toxicity with Complications | No | 7 Participants |
| Dose-escalation 600mg b.i.d. Cohort | Determination of Recommended Phase 2 Dose (RP2D) of BVD-523 by Dose-limiting Toxicities (DLT). | ≥Grade 3 Non-Hematologic Toxicity | Yes | 1 Participants |
| Dose-escalation 600mg b.i.d. Cohort | Determination of Recommended Phase 2 Dose (RP2D) of BVD-523 by Dose-limiting Toxicities (DLT). | Any DLT | Yes | 1 Participants |
| Dose-escalation 750mg b.i.d. Cohort | Determination of Recommended Phase 2 Dose (RP2D) of BVD-523 by Dose-limiting Toxicities (DLT). | ≥Grade 3 Non-Hematologic Toxicity | Yes | 2 Participants |
| Dose-escalation 750mg b.i.d. Cohort | Determination of Recommended Phase 2 Dose (RP2D) of BVD-523 by Dose-limiting Toxicities (DLT). | Grade 3 Hematologic Toxicity with Complications | No | 3 Participants |
| Dose-escalation 750mg b.i.d. Cohort | Determination of Recommended Phase 2 Dose (RP2D) of BVD-523 by Dose-limiting Toxicities (DLT). | Grade 3 Hematologic Toxicity with Complications | Yes | 1 Participants |
| Dose-escalation 750mg b.i.d. Cohort | Determination of Recommended Phase 2 Dose (RP2D) of BVD-523 by Dose-limiting Toxicities (DLT). | Any DLT | No | 2 Participants |
| Dose-escalation 750mg b.i.d. Cohort | Determination of Recommended Phase 2 Dose (RP2D) of BVD-523 by Dose-limiting Toxicities (DLT). | ≥Grade 3 Non-Hematologic Toxicity | No | 2 Participants |
| Dose-escalation 750mg b.i.d. Cohort | Determination of Recommended Phase 2 Dose (RP2D) of BVD-523 by Dose-limiting Toxicities (DLT). | Any DLT | Yes | 2 Participants |
| Dose-escalation 900mg b.i.d. Cohort | Determination of Recommended Phase 2 Dose (RP2D) of BVD-523 by Dose-limiting Toxicities (DLT). | ≥Grade 3 Non-Hematologic Toxicity | No | 5 Participants |
| Dose-escalation 900mg b.i.d. Cohort | Determination of Recommended Phase 2 Dose (RP2D) of BVD-523 by Dose-limiting Toxicities (DLT). | ≥Grade 3 Non-Hematologic Toxicity | Yes | 2 Participants |
| Dose-escalation 900mg b.i.d. Cohort | Determination of Recommended Phase 2 Dose (RP2D) of BVD-523 by Dose-limiting Toxicities (DLT). | Any DLT | Yes | 2 Participants |
| Dose-escalation 900mg b.i.d. Cohort | Determination of Recommended Phase 2 Dose (RP2D) of BVD-523 by Dose-limiting Toxicities (DLT). | Grade 3 Hematologic Toxicity with Complications | No | 5 Participants |
| Dose-escalation 900mg b.i.d. Cohort | Determination of Recommended Phase 2 Dose (RP2D) of BVD-523 by Dose-limiting Toxicities (DLT). | Grade 3 Hematologic Toxicity with Complications | Yes | 2 Participants |
| Dose-escalation 900mg b.i.d. Cohort | Determination of Recommended Phase 2 Dose (RP2D) of BVD-523 by Dose-limiting Toxicities (DLT). | Any DLT | No | 5 Participants |
Secondary
Characterization of the Time Versus Plasma Concentration Profiles of BVD-523 and Selected Metabolites.
Data provided is for BVD-523.
Time frame: Samples will be collected on day 1 and day 15 of Cycle 1
Population: Day 1 - Dose-escalation 10mg b.i.d. patient was not calculable. Cohort-expansion numbers do not include those patients that were dose reduced and/or were not at a steady state with 600mg b.i.d. for the Day 15 draw.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dose-escalation 10mg b.i.d. Cohort | Characterization of the Time Versus Plasma Concentration Profiles of BVD-523 and Selected Metabolites. | Cmax Day 1 | NA ng/mL | — |
| Dose-escalation 10mg b.i.d. Cohort | Characterization of the Time Versus Plasma Concentration Profiles of BVD-523 and Selected Metabolites. | Cmax Day 15 | 45.7 ng/mL | — |
| Dose-escalation 20mg b.i.d. Cohort | Characterization of the Time Versus Plasma Concentration Profiles of BVD-523 and Selected Metabolites. | Cmax Day 1 | 14.9 ng/mL | — |
| Dose-escalation 20mg b.i.d. Cohort | Characterization of the Time Versus Plasma Concentration Profiles of BVD-523 and Selected Metabolites. | Cmax Day 15 | 15.8 ng/mL | — |
| Dose-escalation 40mg b.i.d. Cohort | Characterization of the Time Versus Plasma Concentration Profiles of BVD-523 and Selected Metabolites. | Cmax Day 1 | 100 ng/mL | — |
| Dose-escalation 40mg b.i.d. Cohort | Characterization of the Time Versus Plasma Concentration Profiles of BVD-523 and Selected Metabolites. | Cmax Day 15 | 191 ng/mL | — |
| Dose-escalation 75mg b.i.d. Cohort | Characterization of the Time Versus Plasma Concentration Profiles of BVD-523 and Selected Metabolites. | Cmax Day 1 | 133 ng/mL | — |
| Dose-escalation 75mg b.i.d. Cohort | Characterization of the Time Versus Plasma Concentration Profiles of BVD-523 and Selected Metabolites. | Cmax Day 15 | 326 ng/mL | — |
| Dose-escalation 150mg b.i.d. Cohort | Characterization of the Time Versus Plasma Concentration Profiles of BVD-523 and Selected Metabolites. | Cmax Day 15 | 459 ng/mL | — |
| Dose-escalation 150mg b.i.d. Cohort | Characterization of the Time Versus Plasma Concentration Profiles of BVD-523 and Selected Metabolites. | Cmax Day 1 | 216 ng/mL | — |
| Dose-escalation 300mg b.i.d. Cohort | Characterization of the Time Versus Plasma Concentration Profiles of BVD-523 and Selected Metabolites. | Cmax Day 15 | 586 ng/mL | Standard Deviation 257 |
| Dose-escalation 300mg b.i.d. Cohort | Characterization of the Time Versus Plasma Concentration Profiles of BVD-523 and Selected Metabolites. | Cmax Day 1 | 765 ng/mL | Standard Deviation 234 |
| Dose-escalation 600mg b.i.d. Cohort | Characterization of the Time Versus Plasma Concentration Profiles of BVD-523 and Selected Metabolites. | Cmax Day 1 | 1110 ng/mL | Standard Deviation 589 |
| Dose-escalation 600mg b.i.d. Cohort | Characterization of the Time Versus Plasma Concentration Profiles of BVD-523 and Selected Metabolites. | Cmax Day 15 | 3090 ng/mL | Standard Deviation 1570 |
| Dose-escalation 750mg b.i.d. Cohort | Characterization of the Time Versus Plasma Concentration Profiles of BVD-523 and Selected Metabolites. | Cmax Day 1 | 1450 ng/mL | Standard Deviation 539 |
| Dose-escalation 750mg b.i.d. Cohort | Characterization of the Time Versus Plasma Concentration Profiles of BVD-523 and Selected Metabolites. | Cmax Day 15 | 2290 ng/mL | Standard Deviation 1790 |
| Dose-escalation 900mg b.i.d. Cohort | Characterization of the Time Versus Plasma Concentration Profiles of BVD-523 and Selected Metabolites. | Cmax Day 1 | 1430 ng/mL | Standard Deviation 1010 |
| Dose-escalation 900mg b.i.d. Cohort | Characterization of the Time Versus Plasma Concentration Profiles of BVD-523 and Selected Metabolites. | Cmax Day 15 | 1730 ng/mL | Standard Deviation 401 |
| Cohort-expansion Group 1 | Characterization of the Time Versus Plasma Concentration Profiles of BVD-523 and Selected Metabolites. | Cmax Day 15 | 2440 ng/mL | Standard Deviation 900 |
| Cohort-expansion Group 1 | Characterization of the Time Versus Plasma Concentration Profiles of BVD-523 and Selected Metabolites. | Cmax Day 1 | 1180 ng/mL | Standard Deviation 501 |
| Cohort-expansion Group 2 | Characterization of the Time Versus Plasma Concentration Profiles of BVD-523 and Selected Metabolites. | Cmax Day 1 | 1260 ng/mL | Standard Deviation 474 |
| Cohort-expansion Group 2 | Characterization of the Time Versus Plasma Concentration Profiles of BVD-523 and Selected Metabolites. | Cmax Day 15 | 1890 ng/mL | Standard Deviation 953 |
| Cohort-expansion Group 3 | Characterization of the Time Versus Plasma Concentration Profiles of BVD-523 and Selected Metabolites. | Cmax Day 15 | 2340 ng/mL | Standard Deviation 962 |
| Cohort-expansion Group 3 | Characterization of the Time Versus Plasma Concentration Profiles of BVD-523 and Selected Metabolites. | Cmax Day 1 | 1190 ng/mL | Standard Deviation 467 |
| Cohort-expansion Group 4 | Characterization of the Time Versus Plasma Concentration Profiles of BVD-523 and Selected Metabolites. | Cmax Day 15 | 1890 ng/mL | Standard Deviation 1060 |
| Cohort-expansion Group 4 | Characterization of the Time Versus Plasma Concentration Profiles of BVD-523 and Selected Metabolites. | Cmax Day 1 | 1230 ng/mL | Standard Deviation 840 |
| Cohort-expansion Group 5 | Characterization of the Time Versus Plasma Concentration Profiles of BVD-523 and Selected Metabolites. | Cmax Day 1 | 1140 ng/mL | Standard Deviation 423 |
| Cohort-expansion Group 5 | Characterization of the Time Versus Plasma Concentration Profiles of BVD-523 and Selected Metabolites. | Cmax Day 15 | 2050 ng/mL | Standard Deviation 1570 |
| Cohort-expansion Group 6 | Characterization of the Time Versus Plasma Concentration Profiles of BVD-523 and Selected Metabolites. | Cmax Day 15 | 2680 ng/mL | Standard Deviation 1520 |
| Cohort-expansion Group 6 | Characterization of the Time Versus Plasma Concentration Profiles of BVD-523 and Selected Metabolites. | Cmax Day 1 | 1560 ng/mL | Standard Deviation 885 |
Secondary
Clinical Evidence of Tumor Response Assessed by Physical or Radiological Exam.
At enrollment, all study patients had metastatic or advanced-stage malignant tumor for which no curative therapy was known to exist. Patients entering Part 2 additionally had to have measurable disease by RECIST version 1.1. Data shown is best response.
Time frame: Patients will be evaluated at baseline & at periodic follow-up visits through the time their participation in the study is completion. The best responses presented occurred at different time points for each patient.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Dose-escalation 10mg b.i.d. Cohort | Clinical Evidence of Tumor Response Assessed by Physical or Radiological Exam. | Stable Disease | 1 Participants |
| Dose-escalation 10mg b.i.d. Cohort | Clinical Evidence of Tumor Response Assessed by Physical or Radiological Exam. | Partial Response | 0 Participants |
| Dose-escalation 10mg b.i.d. Cohort | Clinical Evidence of Tumor Response Assessed by Physical or Radiological Exam. | Complete Response | 0 Participants |
| Dose-escalation 10mg b.i.d. Cohort | Clinical Evidence of Tumor Response Assessed by Physical or Radiological Exam. | Progressive Disease | 0 Participants |
| Dose-escalation 20mg b.i.d. Cohort | Clinical Evidence of Tumor Response Assessed by Physical or Radiological Exam. | Partial Response | 0 Participants |
| Dose-escalation 20mg b.i.d. Cohort | Clinical Evidence of Tumor Response Assessed by Physical or Radiological Exam. | Progressive Disease | 0 Participants |
| Dose-escalation 20mg b.i.d. Cohort | Clinical Evidence of Tumor Response Assessed by Physical or Radiological Exam. | Complete Response | 0 Participants |
| Dose-escalation 20mg b.i.d. Cohort | Clinical Evidence of Tumor Response Assessed by Physical or Radiological Exam. | Stable Disease | 1 Participants |
| Dose-escalation 40mg b.i.d. Cohort | Clinical Evidence of Tumor Response Assessed by Physical or Radiological Exam. | Stable Disease | 0 Participants |
| Dose-escalation 40mg b.i.d. Cohort | Clinical Evidence of Tumor Response Assessed by Physical or Radiological Exam. | Progressive Disease | 1 Participants |
| Dose-escalation 40mg b.i.d. Cohort | Clinical Evidence of Tumor Response Assessed by Physical or Radiological Exam. | Complete Response | 0 Participants |
| Dose-escalation 40mg b.i.d. Cohort | Clinical Evidence of Tumor Response Assessed by Physical or Radiological Exam. | Partial Response | 0 Participants |
| Dose-escalation 75mg b.i.d. Cohort | Clinical Evidence of Tumor Response Assessed by Physical or Radiological Exam. | Partial Response | 0 Participants |
| Dose-escalation 75mg b.i.d. Cohort | Clinical Evidence of Tumor Response Assessed by Physical or Radiological Exam. | Complete Response | 0 Participants |
| Dose-escalation 75mg b.i.d. Cohort | Clinical Evidence of Tumor Response Assessed by Physical or Radiological Exam. | Progressive Disease | 0 Participants |
| Dose-escalation 75mg b.i.d. Cohort | Clinical Evidence of Tumor Response Assessed by Physical or Radiological Exam. | Stable Disease | 1 Participants |
| Dose-escalation 150mg b.i.d. Cohort | Clinical Evidence of Tumor Response Assessed by Physical or Radiological Exam. | Progressive Disease | 0 Participants |
| Dose-escalation 150mg b.i.d. Cohort | Clinical Evidence of Tumor Response Assessed by Physical or Radiological Exam. | Stable Disease | 1 Participants |
| Dose-escalation 150mg b.i.d. Cohort | Clinical Evidence of Tumor Response Assessed by Physical or Radiological Exam. | Complete Response | 0 Participants |
| Dose-escalation 150mg b.i.d. Cohort | Clinical Evidence of Tumor Response Assessed by Physical or Radiological Exam. | Partial Response | 0 Participants |
| Dose-escalation 300mg b.i.d. Cohort | Clinical Evidence of Tumor Response Assessed by Physical or Radiological Exam. | Stable Disease | 2 Participants |
| Dose-escalation 300mg b.i.d. Cohort | Clinical Evidence of Tumor Response Assessed by Physical or Radiological Exam. | Partial Response | 0 Participants |
| Dose-escalation 300mg b.i.d. Cohort | Clinical Evidence of Tumor Response Assessed by Physical or Radiological Exam. | Progressive Disease | 2 Participants |
| Dose-escalation 300mg b.i.d. Cohort | Clinical Evidence of Tumor Response Assessed by Physical or Radiological Exam. | Complete Response | 0 Participants |
| Dose-escalation 600mg b.i.d. Cohort | Clinical Evidence of Tumor Response Assessed by Physical or Radiological Exam. | Progressive Disease | 1 Participants |
| Dose-escalation 600mg b.i.d. Cohort | Clinical Evidence of Tumor Response Assessed by Physical or Radiological Exam. | Complete Response | 0 Participants |
| Dose-escalation 600mg b.i.d. Cohort | Clinical Evidence of Tumor Response Assessed by Physical or Radiological Exam. | Partial Response | 1 Participants |
| Dose-escalation 600mg b.i.d. Cohort | Clinical Evidence of Tumor Response Assessed by Physical or Radiological Exam. | Stable Disease | 5 Participants |
| Dose-escalation 750mg b.i.d. Cohort | Clinical Evidence of Tumor Response Assessed by Physical or Radiological Exam. | Stable Disease | 0 Participants |
| Dose-escalation 750mg b.i.d. Cohort | Clinical Evidence of Tumor Response Assessed by Physical or Radiological Exam. | Partial Response | 1 Participants |
| Dose-escalation 750mg b.i.d. Cohort | Clinical Evidence of Tumor Response Assessed by Physical or Radiological Exam. | Complete Response | 0 Participants |
| Dose-escalation 750mg b.i.d. Cohort | Clinical Evidence of Tumor Response Assessed by Physical or Radiological Exam. | Progressive Disease | 3 Participants |
| Dose-escalation 900mg b.i.d. Cohort | Clinical Evidence of Tumor Response Assessed by Physical or Radiological Exam. | Stable Disease | 4 Participants |
| Dose-escalation 900mg b.i.d. Cohort | Clinical Evidence of Tumor Response Assessed by Physical or Radiological Exam. | Complete Response | 0 Participants |
| Dose-escalation 900mg b.i.d. Cohort | Clinical Evidence of Tumor Response Assessed by Physical or Radiological Exam. | Partial Response | 1 Participants |
| Dose-escalation 900mg b.i.d. Cohort | Clinical Evidence of Tumor Response Assessed by Physical or Radiological Exam. | Progressive Disease | 2 Participants |
| Cohort-expansion Group 1 | Clinical Evidence of Tumor Response Assessed by Physical or Radiological Exam. | Complete Response | 0 Participants |
| Cohort-expansion Group 1 | Clinical Evidence of Tumor Response Assessed by Physical or Radiological Exam. | Progressive Disease | 4 Participants |
| Cohort-expansion Group 1 | Clinical Evidence of Tumor Response Assessed by Physical or Radiological Exam. | Partial Response | 4 Participants |
| Cohort-expansion Group 1 | Clinical Evidence of Tumor Response Assessed by Physical or Radiological Exam. | Stable Disease | 14 Participants |
| Cohort-expansion Group 2 | Clinical Evidence of Tumor Response Assessed by Physical or Radiological Exam. | Partial Response | 0 Participants |
| Cohort-expansion Group 2 | Clinical Evidence of Tumor Response Assessed by Physical or Radiological Exam. | Progressive Disease | 5 Participants |
| Cohort-expansion Group 2 | Clinical Evidence of Tumor Response Assessed by Physical or Radiological Exam. | Complete Response | 0 Participants |
| Cohort-expansion Group 2 | Clinical Evidence of Tumor Response Assessed by Physical or Radiological Exam. | Stable Disease | 8 Participants |
| Cohort-expansion Group 3 | Clinical Evidence of Tumor Response Assessed by Physical or Radiological Exam. | Partial Response | 1 Participants |
| Cohort-expansion Group 3 | Clinical Evidence of Tumor Response Assessed by Physical or Radiological Exam. | Progressive Disease | 8 Participants |
| Cohort-expansion Group 3 | Clinical Evidence of Tumor Response Assessed by Physical or Radiological Exam. | Complete Response | 0 Participants |
| Cohort-expansion Group 3 | Clinical Evidence of Tumor Response Assessed by Physical or Radiological Exam. | Stable Disease | 6 Participants |
| Cohort-expansion Group 4 | Clinical Evidence of Tumor Response Assessed by Physical or Radiological Exam. | Stable Disease | 7 Participants |
| Cohort-expansion Group 4 | Clinical Evidence of Tumor Response Assessed by Physical or Radiological Exam. | Complete Response | 0 Participants |
| Cohort-expansion Group 4 | Clinical Evidence of Tumor Response Assessed by Physical or Radiological Exam. | Progressive Disease | 9 Participants |
| Cohort-expansion Group 4 | Clinical Evidence of Tumor Response Assessed by Physical or Radiological Exam. | Partial Response | 3 Participants |
| Cohort-expansion Group 5 | Clinical Evidence of Tumor Response Assessed by Physical or Radiological Exam. | Progressive Disease | 3 Participants |
| Cohort-expansion Group 5 | Clinical Evidence of Tumor Response Assessed by Physical or Radiological Exam. | Complete Response | 0 Participants |
| Cohort-expansion Group 5 | Clinical Evidence of Tumor Response Assessed by Physical or Radiological Exam. | Partial Response | 0 Participants |
| Cohort-expansion Group 5 | Clinical Evidence of Tumor Response Assessed by Physical or Radiological Exam. | Stable Disease | 2 Participants |
| Cohort-expansion Group 6 | Clinical Evidence of Tumor Response Assessed by Physical or Radiological Exam. | Stable Disease | 9 Participants |
| Cohort-expansion Group 6 | Clinical Evidence of Tumor Response Assessed by Physical or Radiological Exam. | Partial Response | 3 Participants |
| Cohort-expansion Group 6 | Clinical Evidence of Tumor Response Assessed by Physical or Radiological Exam. | Complete Response | 0 Participants |
| Cohort-expansion Group 6 | Clinical Evidence of Tumor Response Assessed by Physical or Radiological Exam. | Progressive Disease | 2 Participants |
Other Pre-specified
Pharmacodynamic (PD) Response Measured as Percentage Enzyme Inhibition of RSK1 Ser 380 (pRSK)
RSK1, a member of the RSK serine/threonine kinase family, is a direct substrate of the MAP Kinases ERK1 & ERK2. RSK1 and ERK1/2 form an inactive complex in unstimulated cells. Upon activation of the mitogenic pathway, ERK1/2 phosphorylates Thr573, Thr359 and Ser363 on RSK1. Thr573 resides in the activation loop of the carboxy terminal kinase domain of RSK1 and once phosphorylated, enables RSK1 to autophosphorylate Ser380. Phosphorylation of Ser380 on RSK1 can therefore be used as a target biomarker for ERK1 and ERK2 activity. BVD-523 inhibits the activity of ERK. In this study, phosphorylation of RSK1 Ser 380 (pRSK) was used as a target biomarker for assessment of ERK inhibition by BVD-523 in human whole blood samples.
Time frame: Patients will be evaluated at baseline and on ~day 15 of Cycle 1
Population: The protocol was amended to stop collecting PD samples unless the patient consented to a tumor biopsy. Therefore, some patients did not have PD samples collected or did not consent to optional research tests involving collection of tumor tissue and blood/plasma samples.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dose-escalation 10mg b.i.d. Cohort | Pharmacodynamic (PD) Response Measured as Percentage Enzyme Inhibition of RSK1 Ser 380 (pRSK) | Cycle 1, Day 1; pre-dose | 0.000 Enzyme inhibition (%) | Standard Deviation 0 |
| Dose-escalation 10mg b.i.d. Cohort | Pharmacodynamic (PD) Response Measured as Percentage Enzyme Inhibition of RSK1 Ser 380 (pRSK) | Cycle 1, Day 1; 4 hours post-dose | 82.162 Enzyme inhibition (%) | Standard Deviation 27.3012 |
| Dose-escalation 10mg b.i.d. Cohort | Pharmacodynamic (PD) Response Measured as Percentage Enzyme Inhibition of RSK1 Ser 380 (pRSK) | Cycle 1, Day 15; pre-dose | 94.607 Enzyme inhibition (%) | Standard Deviation 9.9291 |
| Dose-escalation 10mg b.i.d. Cohort | Pharmacodynamic (PD) Response Measured as Percentage Enzyme Inhibition of RSK1 Ser 380 (pRSK) | Cycle 1, Day 15; 4 hours post-dose | 91.419 Enzyme inhibition (%) | Standard Deviation 13.9282 |
| Dose-escalation 20mg b.i.d. Cohort | Pharmacodynamic (PD) Response Measured as Percentage Enzyme Inhibition of RSK1 Ser 380 (pRSK) | Cycle 1, Day 15; pre-dose | 66.667 Enzyme inhibition (%) | Standard Deviation 57.735 |
| Dose-escalation 20mg b.i.d. Cohort | Pharmacodynamic (PD) Response Measured as Percentage Enzyme Inhibition of RSK1 Ser 380 (pRSK) | Cycle 1, Day 1; 4 hours post-dose | 69.989 Enzyme inhibition (%) | Standard Deviation 36.9362 |
| Dose-escalation 20mg b.i.d. Cohort | Pharmacodynamic (PD) Response Measured as Percentage Enzyme Inhibition of RSK1 Ser 380 (pRSK) | Cycle 1, Day 1; pre-dose | 0.000 Enzyme inhibition (%) | Standard Deviation 0 |
| Dose-escalation 20mg b.i.d. Cohort | Pharmacodynamic (PD) Response Measured as Percentage Enzyme Inhibition of RSK1 Ser 380 (pRSK) | Cycle 1, Day 15; 4 hours post-dose | 56.554 Enzyme inhibition (%) | Standard Deviation 51.2962 |
| Dose-escalation 40mg b.i.d. Cohort | Pharmacodynamic (PD) Response Measured as Percentage Enzyme Inhibition of RSK1 Ser 380 (pRSK) | Cycle 1, Day 15; 4 hours post-dose | 87.624 Enzyme inhibition (%) | Standard Deviation 26.0916 |
| Dose-escalation 40mg b.i.d. Cohort | Pharmacodynamic (PD) Response Measured as Percentage Enzyme Inhibition of RSK1 Ser 380 (pRSK) | Cycle 1, Day 15; pre-dose | 78.679 Enzyme inhibition (%) | Standard Deviation 37.6286 |
| Dose-escalation 40mg b.i.d. Cohort | Pharmacodynamic (PD) Response Measured as Percentage Enzyme Inhibition of RSK1 Ser 380 (pRSK) | Cycle 1, Day 1; 4 hours post-dose | 87.563 Enzyme inhibition (%) | Standard Deviation 26.8634 |
| Dose-escalation 40mg b.i.d. Cohort | Pharmacodynamic (PD) Response Measured as Percentage Enzyme Inhibition of RSK1 Ser 380 (pRSK) | Cycle 1, Day 1; pre-dose | 0.000 Enzyme inhibition (%) | Standard Deviation 0 |
| Dose-escalation 75mg b.i.d. Cohort | Pharmacodynamic (PD) Response Measured as Percentage Enzyme Inhibition of RSK1 Ser 380 (pRSK) | Cycle 1, Day 1; pre-dose | 0.000 Enzyme inhibition (%) | Standard Deviation 0 |
| Dose-escalation 75mg b.i.d. Cohort | Pharmacodynamic (PD) Response Measured as Percentage Enzyme Inhibition of RSK1 Ser 380 (pRSK) | Cycle 1, Day 15; 4 hours post-dose | 98.902 Enzyme inhibition (%) | Standard Deviation 3.4722 |
| Dose-escalation 75mg b.i.d. Cohort | Pharmacodynamic (PD) Response Measured as Percentage Enzyme Inhibition of RSK1 Ser 380 (pRSK) | Cycle 1, Day 1; 4 hours post-dose | 96.868 Enzyme inhibition (%) | Standard Deviation 5.8054 |
| Dose-escalation 75mg b.i.d. Cohort | Pharmacodynamic (PD) Response Measured as Percentage Enzyme Inhibition of RSK1 Ser 380 (pRSK) | Cycle 1, Day 15; pre-dose | 91.955 Enzyme inhibition (%) | Standard Deviation 21.5915 |
| Dose-escalation 150mg b.i.d. Cohort | Pharmacodynamic (PD) Response Measured as Percentage Enzyme Inhibition of RSK1 Ser 380 (pRSK) | Cycle 1, Day 15; pre-dose | 89.050 Enzyme inhibition (%) | Standard Deviation 18.966 |
| Dose-escalation 150mg b.i.d. Cohort | Pharmacodynamic (PD) Response Measured as Percentage Enzyme Inhibition of RSK1 Ser 380 (pRSK) | Cycle 1, Day 15; 4 hours post-dose | 92.640 Enzyme inhibition (%) | Standard Deviation 12.7479 |
| Dose-escalation 150mg b.i.d. Cohort | Pharmacodynamic (PD) Response Measured as Percentage Enzyme Inhibition of RSK1 Ser 380 (pRSK) | Cycle 1, Day 1; 4 hours post-dose | 93.910 Enzyme inhibition (%) | Standard Deviation 12.18 |
| Dose-escalation 150mg b.i.d. Cohort | Pharmacodynamic (PD) Response Measured as Percentage Enzyme Inhibition of RSK1 Ser 380 (pRSK) | Cycle 1, Day 1; pre-dose | 0.000 Enzyme inhibition (%) | Standard Deviation 0 |
| Dose-escalation 300mg b.i.d. Cohort | Pharmacodynamic (PD) Response Measured as Percentage Enzyme Inhibition of RSK1 Ser 380 (pRSK) | Cycle 1, Day 1; 4 hours post-dose | 80.214 Enzyme inhibition (%) | Standard Deviation 28.9393 |
| Dose-escalation 300mg b.i.d. Cohort | Pharmacodynamic (PD) Response Measured as Percentage Enzyme Inhibition of RSK1 Ser 380 (pRSK) | Cycle 1, Day 15; pre-dose | 99.447 Enzyme inhibition (%) | Standard Deviation 1.4627 |
| Dose-escalation 300mg b.i.d. Cohort | Pharmacodynamic (PD) Response Measured as Percentage Enzyme Inhibition of RSK1 Ser 380 (pRSK) | Cycle 1, Day 15; 4 hours post-dose | 85.329 Enzyme inhibition (%) | Standard Deviation 27.2781 |
| Dose-escalation 300mg b.i.d. Cohort | Pharmacodynamic (PD) Response Measured as Percentage Enzyme Inhibition of RSK1 Ser 380 (pRSK) | Cycle 1, Day 1; pre-dose | 0.000 Enzyme inhibition (%) | Standard Deviation 0 |