Acute Myelogenous Leukemia, Myelodysplastic Syndrome
Conditions
Brief summary
This study is being performed to assess the safety, tolerability, and preliminary clinical effects of BVD-523 given orally, twice daily for 21-day cycles, in patients with Acute Myelogenous Leukemia (AML) or Myelodysplastic Syndrome (MDS).
Detailed description
The study is being performed to assess the safety and tolerability of BVD-523 given orally, twice daily for 21-day cycles. Part 1 of the study will establish dose limiting toxicities (DLT), maximum tolerated dose (MTD), and the recommended Phase 2 dose (RP2D). 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 (RP2D). 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 100 Years
Healthy volunteers
No
Inclusion criteria
* Have either of the following diagnoses: 1. Morphologically confirmed acute myeloid leukemia (AML), except acute promyelocytic leukemia (APL), including leukemia secondary to prior therapy or antecedent hematologic disorder (e.g., MDS or myeloproliferative disorders), who have failed to achieve CR or who have relapsed after prior therapy and are not candidates for potentially curative therapy 2. Intermediate-2 or High-grade risk MDS (including chronic myelomonocytic leukemia (CMML)) * Have received at least one prior therapy. Patients who are over age 65 and have not received therapy for AML are also eligible, if they are not candidates for induction chemotherapy * ECOG performance status of 0 to 2 * Predicted life expectancy of ≥ 3 months * Adequate liver, renal and cardiac function For Group 1 in Part 2 of the Study ONLY: • Positive for RAS mutation at a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory prior to study entry
Exclusion criteria
* Concomitant malignancies except carcinoma in situ, basal or squamous cell skin carcinoma; low grade prostate cancer treated with prostatectomy more than 10 years ago; early stage melanoma treated with complete surgical excision more than 5 years ago; carcinoma in situ of cervix treated with cone procedure more than 8 years ago * Gastrointestinal condition which could impair absorption of study medication * Uncontrolled or severe intercurrent medical condition * Patients with rapidly increasing peripheral blood blast counts * Known uncontrolled central nervous system involvement * Any cancer-directed therapy within 28 days or 5 half-lives, whichever is shorter * Any concurrent or prior use of an investigational drug (including MEK inhibitors) within previous 28 days or 5 half-lives, whichever is shorter * Received chemotherapy regimens with delayed toxicity within the last four weeks (six weeks for prior nitrosourea or mitomycin C). Received chemotherapy regimens given continuously or on a weekly basis with limited potential for delayed toxicity within the last two weeks. * Ongoing anticoagulant therapy that cannot be held if necessary to permit bone marrow sampling. * Major surgery within 4 weeks prior to first dose * 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 drugs known to be strong inhibitors of CYP1A2, CYP2D6, and CYP3A4, or strong inducers of CYP3A4
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Dose Limiting Toxicities | In the first 21 days of treatment | DLT defined using CTCAE v.4.03. All toxicities were considered to be related to BVD523 if not definitively explained by underlying disease, intercurrent illness, or con meds. |
| Steady-state Plasma Concentration of BVD-523 and Selected Metabolites Over 12 Hours | Samples will be collected on or about Day 22 of the protocol | The PK population consisted of patients who received at least one dose of BVD-523 and had evaluable PK data in plasma. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Evidence of Cancer Response in Bone Marrow Biopsies | Until patient discontinuation; ~24 months on average | Assessments were made via bone marrow biopsies using the International Working Group 2003 and 2006 criteria for AML or MDS, respectively. Bone marrow assessments (aspiration or biopsy, cytogenetics) were collected prior to therapy on Day 1 and Day 22, every 2 cycles thereafter, as well as at the final study visit if discontinuation was not due to disease progression. Some patients were unable to have bone marrow assessments taken at any or all of the time points. Shown is best response across all time points. Less than partial remission/response (\<PR), partial remission/response (PR), complete remission/response with incomplete platelet recovery (CRp), or complete remission/response (CR). |
| Duration of Disease Control in Patients That Respond | Until patient discontinuation; ~24 months on average | Assessments were made via bone marrow biopsies using the International Working Group 2003 and 2006 criteria for AML or MDS, respectively. Progression-free survival (PFS) and duration of response (DOR) of AML or MDS patients was assessed in patients treated with BVD-523 that achieved complete remission/response (CR) or complete remission/response with incomplete platelet recovery (CRp). \<PR = less than partial remission/response. Shown is the duration (number of days) of CR or CRp response for the 2 patients in part 2 that obtained this level of response. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Pharmacodynamic Results of Inhibition (%) of Molecular Target (ERK Pathway) Assessed by Blood and Tissue Analyses. | Patients will be evaluated at baseline and on or about Day 22 of the protocol | Multiple biomarkers intended to demonstrate inhibition of the molecular target, and mechanism of action were investigated from blood and/or bone marrow aspirate samples. Phosphorylation of ERK enzyme substrate proteins (e.g. RSK1 and RSK2 genes) were measured. Additional biomarkers, including PBMCs and/or DNA sequence analysis, were identified and measured as appropriate. Measurements were by ELISA. The pharmacodynamics (PD) population was defined as all patients who received at least one dose of study drug and had sufficient, valid PD samples to estimate key parameters for at least one of the days of sampling. |
Countries
United States
Participant flow
Recruitment details
Up to 6 study centers were to enroll up to 20 AML or MDS patients for Part 1 (dose-escalation) and 40 evaluable patients (≤ 20 RAS mutant positive AML or MDS patients and ≤ 20 RAS mutant negative AML or MDS patients) for Part 2 (cohort expansion). The last patient completed in May 2017.
Participants by arm
| Arm | Count |
|---|---|
| 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 21 days (1 cycle). | 5 |
| 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 21 days (1 cycle). | 6 |
| 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 21 days (1 cycle). | 7 |
| Cohort-expansion RAS(+) Group 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. | 14 |
| Cohort-expansion RAS(-) Group 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 |
| Total | 53 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 0 | 1 | 0 |
| Overall Study | Alternative Treatment | 0 | 0 | 0 | 1 | 0 |
| Overall Study | At Least 3 Drug Interruptions | 0 | 0 | 1 | 1 | 1 |
| Overall Study | Death | 1 | 1 | 1 | 1 | 1 |
| Overall Study | Disease Progression | 1 | 3 | 2 | 8 | 11 |
| Overall Study | Lack of Efficacy | 0 | 0 | 0 | 0 | 3 |
| Overall Study | Lost to Follow-up | 1 | 0 | 0 | 0 | 0 |
| Overall Study | Need for Hydroxyurea | 2 | 0 | 0 | 0 | 0 |
| Overall Study | Patient Condition Changed | 0 | 0 | 2 | 0 | 1 |
| Overall Study | Physician Decision | 0 | 1 | 0 | 1 | 0 |
| Overall Study | Screened for Other Protocol | 0 | 1 | 0 | 0 | 0 |
| Overall Study | Unacceptable Toxicity | 0 | 0 | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 1 | 1 | 3 |
Baseline characteristics
| Characteristic | Dose-escalation 300mg b.i.d. Cohort | Total | Cohort-expansion RAS(-) Group | Cohort-expansion RAS(+) Group | Dose-escalation 750mg b.i.d. Cohort | Dose-escalation 600mg b.i.d. Cohort |
|---|---|---|---|---|---|---|
| Age, Continuous | 71.6 years STANDARD_DEVIATION 9.21 | 66.8 years STANDARD_DEVIATION 14.62 | 66.0 years STANDARD_DEVIATION 15.66 | 70.6 years STANDARD_DEVIATION 10.08 | 65.6 years STANDARD_DEVIATION 18.11 | 58.7 years STANDARD_DEVIATION 19.18 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 7 Participants | 1 Participants | 4 Participants | 2 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 5 Participants | 46 Participants | 20 Participants | 10 Participants | 5 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 3 Participants | 1 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 3 Participants | 2 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 3 Participants | 0 Participants | 0 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 3 Participants | 1 Participants | 2 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 5 Participants | 41 Participants | 17 Participants | 11 Participants | 4 Participants | 4 Participants |
| Region of Enrollment United States | 5 participants | 53 participants | 21 participants | 14 participants | 7 participants | 6 participants |
| Sex: Female, Male Female | 2 Participants | 20 Participants | 8 Participants | 5 Participants | 4 Participants | 1 Participants |
| Sex: Female, Male Male | 3 Participants | 33 Participants | 13 Participants | 9 Participants | 3 Participants | 5 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 |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 4 / 5 | 2 / 6 | 4 / 7 | 2 / 14 | 4 / 21 |
| other Total, other adverse events | 2 / 5 | 1 / 6 | 6 / 7 | 9 / 14 | 11 / 21 |
| serious Total, serious adverse events | 5 / 5 | 4 / 6 | 6 / 7 | 10 / 14 | 18 / 21 |
Outcome results
Primary
Number of Patients With Dose Limiting Toxicities
DLT defined using CTCAE v.4.03. All toxicities were considered to be related to BVD523 if not definitively explained by underlying disease, intercurrent illness, or con meds.
Time frame: In the first 21 days of treatment
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Dose-escalation 300mg b.i.d. Cohort | Number of Patients With Dose Limiting Toxicities | Any BVD-523-related DLTs? | Yes | 0 Participants |
| Dose-escalation 300mg b.i.d. Cohort | Number of Patients With Dose Limiting Toxicities | Related tox causing tx delay >4 days (rash >7days) | No | 5 Participants |
| Dose-escalation 300mg b.i.d. Cohort | Number of Patients With Dose Limiting Toxicities | Any BVD-523-related DLTs? | No | 5 Participants |
| Dose-escalation 300mg b.i.d. Cohort | Number of Patients With Dose Limiting Toxicities | Related tox causing tx delay >4 days (rash >7days) | Yes | 0 Participants |
| Dose-escalation 600mg b.i.d. Cohort | Number of Patients With Dose Limiting Toxicities | Related tox causing tx delay >4 days (rash >7days) | No | 6 Participants |
| Dose-escalation 600mg b.i.d. Cohort | Number of Patients With Dose Limiting Toxicities | Any BVD-523-related DLTs? | Yes | 0 Participants |
| Dose-escalation 600mg b.i.d. Cohort | Number of Patients With Dose Limiting Toxicities | Any BVD-523-related DLTs? | No | 6 Participants |
| Dose-escalation 600mg b.i.d. Cohort | Number of Patients With Dose Limiting Toxicities | Related tox causing tx delay >4 days (rash >7days) | Yes | 0 Participants |
| Dose-escalation 750mg b.i.d. Cohort | Number of Patients With Dose Limiting Toxicities | Any BVD-523-related DLTs? | No | 5 Participants |
| Dose-escalation 750mg b.i.d. Cohort | Number of Patients With Dose Limiting Toxicities | Related tox causing tx delay >4 days (rash >7days) | No | 5 Participants |
| Dose-escalation 750mg b.i.d. Cohort | Number of Patients With Dose Limiting Toxicities | Related tox causing tx delay >4 days (rash >7days) | Yes | 2 Participants |
| Dose-escalation 750mg b.i.d. Cohort | Number of Patients With Dose Limiting Toxicities | Any BVD-523-related DLTs? | Yes | 2 Participants |
| Cohort-expansion RAS(+) Group | Number of Patients With Dose Limiting Toxicities | Related tox causing tx delay >4 days (rash >7days) | Yes | 0 Participants |
| Cohort-expansion RAS(+) Group | Number of Patients With Dose Limiting Toxicities | Any BVD-523-related DLTs? | Yes | 0 Participants |
| Cohort-expansion RAS(+) Group | Number of Patients With Dose Limiting Toxicities | Any BVD-523-related DLTs? | No | 14 Participants |
| Cohort-expansion RAS(+) Group | Number of Patients With Dose Limiting Toxicities | Related tox causing tx delay >4 days (rash >7days) | No | 14 Participants |
| Cohort-expansion RAS(-) Group | Number of Patients With Dose Limiting Toxicities | Related tox causing tx delay >4 days (rash >7days) | No | 21 Participants |
| Cohort-expansion RAS(-) Group | Number of Patients With Dose Limiting Toxicities | Any BVD-523-related DLTs? | No | 21 Participants |
| Cohort-expansion RAS(-) Group | Number of Patients With Dose Limiting Toxicities | Any BVD-523-related DLTs? | Yes | 0 Participants |
| Cohort-expansion RAS(-) Group | Number of Patients With Dose Limiting Toxicities | Related tox causing tx delay >4 days (rash >7days) | Yes | 0 Participants |
Comparison: In Part 1, 2 patients experienced DLTs in the 750 mg b.i.d. treatment group (2/7; 29%). There were no dose-limiting toxicities in the 600 mg b.i.d. group or 300 mg b.i.d. group. Therefore, based on these results, 600 mg b.i.d. was selected as the MTD dose (and RP2D dose) which was used as the treatment dose in Part 2 of the study.
Primary
Steady-state Plasma Concentration of BVD-523 and Selected Metabolites Over 12 Hours
The PK population consisted of patients who received at least one dose of BVD-523 and had evaluable PK data in plasma.
Time frame: Samples will be collected on or about Day 22 of the protocol
Population: The cohort-expansion patients were not separated by RAS status for the purposes of this assessment. Two patients in the cohort expansion had to have their dose reduced to 300mg BID and were analyzed separately (Cmax 1000 \& 1340 ng/mL on Day 22). 00 = not calculated (only 1 evaluable patient).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dose-escalation 300mg b.i.d. Cohort | Steady-state Plasma Concentration of BVD-523 and Selected Metabolites Over 12 Hours | 8 hr | 480 ng/mL | Standard Deviation 301 |
| Dose-escalation 300mg b.i.d. Cohort | Steady-state Plasma Concentration of BVD-523 and Selected Metabolites Over 12 Hours | 12 hr | 528 ng/mL | Standard Deviation 364 |
| Dose-escalation 300mg b.i.d. Cohort | Steady-state Plasma Concentration of BVD-523 and Selected Metabolites Over 12 Hours | 0.5 hr | 428 ng/mL | Standard Deviation 193 |
| Dose-escalation 300mg b.i.d. Cohort | Steady-state Plasma Concentration of BVD-523 and Selected Metabolites Over 12 Hours | 1 hr | 506 ng/mL | Standard Deviation 159 |
| Dose-escalation 300mg b.i.d. Cohort | Steady-state Plasma Concentration of BVD-523 and Selected Metabolites Over 12 Hours | 4 hr | 1150 ng/mL | Standard Deviation 555 |
| Dose-escalation 300mg b.i.d. Cohort | Steady-state Plasma Concentration of BVD-523 and Selected Metabolites Over 12 Hours | 2 hr | 1300 ng/mL | Standard Deviation 1090 |
| Dose-escalation 300mg b.i.d. Cohort | Steady-state Plasma Concentration of BVD-523 and Selected Metabolites Over 12 Hours | 6 hr | 728 ng/mL | Standard Deviation 435 |
| Dose-escalation 300mg b.i.d. Cohort | Steady-state Plasma Concentration of BVD-523 and Selected Metabolites Over 12 Hours | 0 hr (predose) | 455 ng/mL | Standard Deviation 212 |
| Dose-escalation 600mg b.i.d. Cohort | Steady-state Plasma Concentration of BVD-523 and Selected Metabolites Over 12 Hours | 2 hr | 1760 ng/mL | Standard Deviation 0 |
| Dose-escalation 600mg b.i.d. Cohort | Steady-state Plasma Concentration of BVD-523 and Selected Metabolites Over 12 Hours | 8 hr | 1100 ng/mL | Standard Deviation 0 |
| Dose-escalation 600mg b.i.d. Cohort | Steady-state Plasma Concentration of BVD-523 and Selected Metabolites Over 12 Hours | 1 hr | 1590 ng/mL | Standard Deviation 0 |
| Dose-escalation 600mg b.i.d. Cohort | Steady-state Plasma Concentration of BVD-523 and Selected Metabolites Over 12 Hours | 0 hr (predose) | 1860 ng/mL | Standard Deviation 0 |
| Dose-escalation 600mg b.i.d. Cohort | Steady-state Plasma Concentration of BVD-523 and Selected Metabolites Over 12 Hours | 6 hr | 1510 ng/mL | Standard Deviation 0 |
| Dose-escalation 600mg b.i.d. Cohort | Steady-state Plasma Concentration of BVD-523 and Selected Metabolites Over 12 Hours | 12 hr | 902 ng/mL | Standard Deviation 0 |
| Dose-escalation 600mg b.i.d. Cohort | Steady-state Plasma Concentration of BVD-523 and Selected Metabolites Over 12 Hours | 0.5 hr | 1670 ng/mL | Standard Deviation 0 |
| Dose-escalation 600mg b.i.d. Cohort | Steady-state Plasma Concentration of BVD-523 and Selected Metabolites Over 12 Hours | 4 hr | 1520 ng/mL | Standard Deviation 0 |
| Dose-escalation 750mg b.i.d. Cohort | Steady-state Plasma Concentration of BVD-523 and Selected Metabolites Over 12 Hours | 0 hr (predose) | 2080 ng/mL | Standard Deviation 1310 |
| Dose-escalation 750mg b.i.d. Cohort | Steady-state Plasma Concentration of BVD-523 and Selected Metabolites Over 12 Hours | 0.5 hr | 2020 ng/mL | Standard Deviation 1240 |
| Dose-escalation 750mg b.i.d. Cohort | Steady-state Plasma Concentration of BVD-523 and Selected Metabolites Over 12 Hours | 4 hr | 2670 ng/mL | Standard Deviation 1490 |
| Dose-escalation 750mg b.i.d. Cohort | Steady-state Plasma Concentration of BVD-523 and Selected Metabolites Over 12 Hours | 2 hr | 2220 ng/mL | Standard Deviation 1500 |
| Dose-escalation 750mg b.i.d. Cohort | Steady-state Plasma Concentration of BVD-523 and Selected Metabolites Over 12 Hours | 1 hr | 2130 ng/mL | Standard Deviation 693 |
| Dose-escalation 750mg b.i.d. Cohort | Steady-state Plasma Concentration of BVD-523 and Selected Metabolites Over 12 Hours | 6 hr | 2360 ng/mL | Standard Deviation 1510 |
| Dose-escalation 750mg b.i.d. Cohort | Steady-state Plasma Concentration of BVD-523 and Selected Metabolites Over 12 Hours | 8 hr | 1870 ng/mL | Standard Deviation 1150 |
| Dose-escalation 750mg b.i.d. Cohort | Steady-state Plasma Concentration of BVD-523 and Selected Metabolites Over 12 Hours | 12 hr | 1650 ng/mL | Standard Deviation 1070 |
| Cohort-expansion RAS(+) Group | Steady-state Plasma Concentration of BVD-523 and Selected Metabolites Over 12 Hours | 12 hr | 974 ng/mL | Standard Deviation 567 |
| Cohort-expansion RAS(+) Group | Steady-state Plasma Concentration of BVD-523 and Selected Metabolites Over 12 Hours | 4 hr | 1800 ng/mL | Standard Deviation 914 |
| Cohort-expansion RAS(+) Group | Steady-state Plasma Concentration of BVD-523 and Selected Metabolites Over 12 Hours | 0 hr (predose) | 1540 ng/mL | Standard Deviation 800 |
| Cohort-expansion RAS(+) Group | Steady-state Plasma Concentration of BVD-523 and Selected Metabolites Over 12 Hours | 0.5 hr | 1280 ng/mL | Standard Deviation 767 |
| Cohort-expansion RAS(+) Group | Steady-state Plasma Concentration of BVD-523 and Selected Metabolites Over 12 Hours | 1 hr | 1440 ng/mL | Standard Deviation 698 |
| Cohort-expansion RAS(+) Group | Steady-state Plasma Concentration of BVD-523 and Selected Metabolites Over 12 Hours | 6 hr | 1400 ng/mL | Standard Deviation 741 |
| Cohort-expansion RAS(+) Group | Steady-state Plasma Concentration of BVD-523 and Selected Metabolites Over 12 Hours | 8 hr | 1140 ng/mL | Standard Deviation 623 |
| Cohort-expansion RAS(+) Group | Steady-state Plasma Concentration of BVD-523 and Selected Metabolites Over 12 Hours | 2 hr | 1790 ng/mL | Standard Deviation 776 |
Secondary
Clinical Evidence of Cancer Response in Bone Marrow Biopsies
Assessments were made via bone marrow biopsies using the International Working Group 2003 and 2006 criteria for AML or MDS, respectively. Bone marrow assessments (aspiration or biopsy, cytogenetics) were collected prior to therapy on Day 1 and Day 22, every 2 cycles thereafter, as well as at the final study visit if discontinuation was not due to disease progression. Some patients were unable to have bone marrow assessments taken at any or all of the time points. Shown is best response across all time points. Less than partial remission/response (\<PR), partial remission/response (PR), complete remission/response with incomplete platelet recovery (CRp), or complete remission/response (CR).
Time frame: Until patient discontinuation; ~24 months on average
| Arm | Measure | Category | Value (COUNT_OF_UNITS) |
|---|---|---|---|
| Dose-escalation 300mg b.i.d. Cohort | Clinical Evidence of Cancer Response in Bone Marrow Biopsies | < PR | 20 Response(s) |
| Dose-escalation 300mg b.i.d. Cohort | Clinical Evidence of Cancer Response in Bone Marrow Biopsies | PR | 0 Response(s) |
| Dose-escalation 300mg b.i.d. Cohort | Clinical Evidence of Cancer Response in Bone Marrow Biopsies | CRp | 0 Response(s) |
| Dose-escalation 300mg b.i.d. Cohort | Clinical Evidence of Cancer Response in Bone Marrow Biopsies | CR | 0 Response(s) |
| Dose-escalation 600mg b.i.d. Cohort | Clinical Evidence of Cancer Response in Bone Marrow Biopsies | CR | 1 Response(s) |
| Dose-escalation 600mg b.i.d. Cohort | Clinical Evidence of Cancer Response in Bone Marrow Biopsies | < PR | 22 Response(s) |
| Dose-escalation 600mg b.i.d. Cohort | Clinical Evidence of Cancer Response in Bone Marrow Biopsies | CRp | 2 Response(s) |
| Dose-escalation 600mg b.i.d. Cohort | Clinical Evidence of Cancer Response in Bone Marrow Biopsies | PR | 1 Response(s) |
Secondary
Duration of Disease Control in Patients That Respond
Assessments were made via bone marrow biopsies using the International Working Group 2003 and 2006 criteria for AML or MDS, respectively. Progression-free survival (PFS) and duration of response (DOR) of AML or MDS patients was assessed in patients treated with BVD-523 that achieved complete remission/response (CR) or complete remission/response with incomplete platelet recovery (CRp). \<PR = less than partial remission/response. Shown is the duration (number of days) of CR or CRp response for the 2 patients in part 2 that obtained this level of response.
Time frame: Until patient discontinuation; ~24 months on average
Population: Part 1: \<PR for all data points. Part 2: One patient had a CRp at 2 visits. One patient had a CR.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dose-escalation 300mg b.i.d. Cohort | Duration of Disease Control in Patients That Respond | 64 Days |
| Dose-escalation 600mg b.i.d. Cohort | Duration of Disease Control in Patients That Respond | 5 Days |
Other Pre-specified
Pharmacodynamic Results of Inhibition (%) of Molecular Target (ERK Pathway) Assessed by Blood and Tissue Analyses.
Multiple biomarkers intended to demonstrate inhibition of the molecular target, and mechanism of action were investigated from blood and/or bone marrow aspirate samples. Phosphorylation of ERK enzyme substrate proteins (e.g. RSK1 and RSK2 genes) were measured. Additional biomarkers, including PBMCs and/or DNA sequence analysis, were identified and measured as appropriate. Measurements were by ELISA. The pharmacodynamics (PD) population was defined as all patients who received at least one dose of study drug and had sufficient, valid PD samples to estimate key parameters for at least one of the days of sampling.
Time frame: Patients will be evaluated at baseline and on or about Day 22 of the protocol
Population: Data was not collected/reported for patient at time point or patient did not start a second cycle.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dose-escalation 300mg b.i.d. Cohort | Pharmacodynamic Results of Inhibition (%) of Molecular Target (ERK Pathway) Assessed by Blood and Tissue Analyses. | Baseline (Cycle 1, Day 1) Pre-Dose | 0.0 Percent (%) Inhibition | Standard Deviation 0 |
| Dose-escalation 300mg b.i.d. Cohort | Pharmacodynamic Results of Inhibition (%) of Molecular Target (ERK Pathway) Assessed by Blood and Tissue Analyses. | Baseline (Cycle 1, Day 1) 4 Hours Post-Dose | 78.1 Percent (%) Inhibition | Standard Deviation 30.86 |
| Dose-escalation 300mg b.i.d. Cohort | Pharmacodynamic Results of Inhibition (%) of Molecular Target (ERK Pathway) Assessed by Blood and Tissue Analyses. | Cycle 2, Day 1 Pre-Dose | 73.6 Percent (%) Inhibition | Standard Deviation 33.55 |
| Dose-escalation 300mg b.i.d. Cohort | Pharmacodynamic Results of Inhibition (%) of Molecular Target (ERK Pathway) Assessed by Blood and Tissue Analyses. | Cycle 2, Day 1 - 4 Hours Post-Dose | 75.9 Percent (%) Inhibition | Standard Deviation 32.75 |
| Dose-escalation 600mg b.i.d. Cohort | Pharmacodynamic Results of Inhibition (%) of Molecular Target (ERK Pathway) Assessed by Blood and Tissue Analyses. | Cycle 2, Day 1 - 4 Hours Post-Dose | 83.0 Percent (%) Inhibition | Standard Deviation 41.82 |
| Dose-escalation 600mg b.i.d. Cohort | Pharmacodynamic Results of Inhibition (%) of Molecular Target (ERK Pathway) Assessed by Blood and Tissue Analyses. | Baseline (Cycle 1, Day 1) Pre-Dose | 0.0 Percent (%) Inhibition | Standard Deviation 0 |
| Dose-escalation 600mg b.i.d. Cohort | Pharmacodynamic Results of Inhibition (%) of Molecular Target (ERK Pathway) Assessed by Blood and Tissue Analyses. | Cycle 2, Day 1 Pre-Dose | 71.5 Percent (%) Inhibition | Standard Deviation 58.36 |
| Dose-escalation 600mg b.i.d. Cohort | Pharmacodynamic Results of Inhibition (%) of Molecular Target (ERK Pathway) Assessed by Blood and Tissue Analyses. | Baseline (Cycle 1, Day 1) 4 Hours Post-Dose | 56.9 Percent (%) Inhibition | Standard Deviation 177.46 |