Advanced Solid Tumor, BRAF Gene Mutation, BRAF Gene Alteration, MEK Mutation, MEK Alteration, MAP2K1 Gene Mutation, MAP2K1 Gene Alteration, MAP2K2 Gene Mutation, MAP2K2 Gene Alteration
Conditions
Keywords
atypical BRAF, non-V600
Brief summary
This BVD-523-ABC study builds on the safety and clinical activity experience of previous studies that have evaluated ulixertinib as a novel targeted cancer treatment in cohorts of patients with specific genetic alterations and tumor histologies that result in aberrant MAPK pathway signaling. Early clinical data have demonstrated anti-tumor activity with ulixertinib treatment and have identified specific groups of patients for whom additional development is warranted.
Detailed description
This multi-center, phase II study will be conducted in two parts and assess the clinical benefit, safety, pharmacokinetics, and pharmacodynamics of ulixertinib (BVD-523) in patients with advanced malignancies. Part A (tumor histology agnostic) will be open label and enroll patients to one of six groups based on their tumor alteration. Targeted enrollment per group was 38 patients with a total targeted enrollment of 228 patients. Actual enrollment was total of 104 patients with 77 patients allocated to treatment. * Group 1: Patients with tumors, other than colorectal cancer (CRC), having a BRAF alteration that results in an amino acid change at positions G469, L485, or L597. * Group 2: Patients with tumors, other than CRC, having a defined Class 2 BRAF alteration (see Appendix 2 of protocol). * Group 3: Patients with tumors, other than CRC, having an atypical BRAF alteration (non V600) that is not specified in Group 1 or Group 2. * Group 4: Patients with CRC having any atypical BRAF alteration. * Group 5: Patients with tumors, other than CRC, harboring alterations in MEK1/2. * Group 6: Patients with CRC harboring alterations in MEK1/2. Part B (tumor histology specific) will randomly enroll patients with one of up to three specified tumor histologies to receive either ulixertinib or the physician's choice of treatment in a 2:1 ratio. Tumors must harbor a specified MEK or atypical BRAF alteration. If a patient progresses on physician's choice of treatment, crossover to the ulixertinib arm is permitted.The specific histologies to be included in this part will be selected based on available data and discussion with the clinical investigators, the medical monitor, and the sponsor. Total enrollment was targeted to approximately 80-100 patients per histology with up to three histologies included; however, the study was terminated prior to any patients enrolling in Part B.
Interventions
DRUGUlixertinib
Oral, 600 mg, twice daily, for 28-days in each treatment cycle
Physician's choice will be restricted to two approved (not off-label) treatments for each tumor histology (agents targeting BRAF or MEK kinases and experimental agents are not permitted as physician choice)).
Sponsors
BioMed Valley Discoveries, Inc
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients with a locally advanced or metastatic malignancy, that has progressed following systemic therapy for their disease, if available, or for which the patient is not a candidate or refuses. * Tumors harboring a MEK or atypical BRAF alteration. * Provide signed and dated informed consent prior to initiation of any study-related procedures that are not considered standard of care (SoC). * Male or female patients aged ≥18 years. * Patients must have measurable disease by RECIST version 1.1. * Eastern Cooperative Oncology Group (ECOG) performance status of 0 - 2. * Adequate renal function \[creatinine ≤1.5 times ULN (upper limit of normal)\] or a glomerular filtration rate (GFR) of ≥50 mL/min (using Cockcroft-Gault). * Adequate hepatic function \[total bilirubin ≤1.5 times ULN; AST (aspartate transaminase) and ALT (alanine transaminase) ≤3 times ULN or ≤5 times ULN if the elevation is due to liver involvement by tumor\]. * Adequate bone marrow function (hemoglobin ≥9.0 g/dL; platelets ≥100 x 109 cells/L; absolute neutrophil count ≥1.5 x 109 cells/L). * Adequate cardiac function: Left ventricular ejection fraction (LVEF) of \>50% as assessed by multi-gated acquisition (MUGA) or ultrasound/echocardiography (ECHO); and a corrected QT interval (QTc) \<480ms by the Fridericia method (QTcF). * Contraception - women: Negative pregnancy test for females of child-bearing potential; must be surgically sterile, postmenopausal (no menstrual cycle for at least 12 consecutive months), or compliant with a medically approved contraceptive regimen during and for 3 months after the last administration of study drug. Abstinence is not considered an adequate contraceptive regimen. * Contraception - men: Must be surgically sterile, or compliant with a medically approved contraceptive regimen during and for 3 months after the last administration of study drug. * Willing and able to participate in the trial and comply with all trial requirements. * Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational agent may be included after consultation with the medical monitor.
Exclusion criteria
* Gastrointestinal (GI) condition that could impair absorption of study medication (specific cases e.g., remote history of GI surgery, may be enrolled after discussion with the medical monitor) or inability to ingest 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, with no dose change in the previous 4 weeks, can be allowed. * Having received any cancer-directed therapy (chemotherapy, hormonal therapy, biologic or immunotherapy, etc.) within 28 days or 5 half-lives (whichever is shorter) prior to the first dose of study drug. Patients previously treated with radiotherapy must have recovered from the acute toxicities associated with such treatment. * 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 study drug. A minimum of 10 days between termination of the prior investigational drug and administration of study drug is required. In addition, any drug-related toxicity except alopecia should have recovered to Grade 1 or less. * Prior therapy with any ERK inhibitor (e.g. LY3214996, LTT462). * Groups 1-4: Prior therapy with any BRAF and/or MEK inhibitor (e.g. encorafenib, dabrafenib, vemurafenib, binimetinib, trametinib, cobimetinib) is excluded. Prior BRAF and/or MEK inhibitor therapy is permitted for Groups 5 and 6. * For Part B, agents targeting BRAF or MEK kinases and experimental agents are not permitted as physician's choice * Pregnant or breast-feeding women. * Any evidence of serious active infections. Patients are allowed to enroll if they have been fever-free for at least 48 hours and are on an active treatment that is not prohibited in Appendix 1 of the protocol. * Any important medical illness or abnormal laboratory finding that would increase the risk of participating in this study (based on the investigator's judgment). * A history or current evidence/risk of retinal vein occlusion (RVO) or central serous retinopathy (CSR). * Concurrent therapy with any other investigational agent. * Concurrent therapy with drugs known to be strong inhibitors or inducers of CYP1A2, CYP2D6, and CYP3A4.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part A: Overall Response Rate (ORR) According to RECIST 1.1 | Up to 25 months | ORR will be defined as the percentage of patients achieving a Best Overall Response (BOR) of confirmed Complete Response (CR) and/or Partial Response (PR). Patients will be evaluated at baseline & at periodic follow-up visits through the time their participation in the study is complete.The best responses will occur at different time points for each patient. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part A: Progression Free Survival (PFS) According to RECIST 1.1 | 18 months | PFS will be defined as time from first day of study drug to disease progression or death. Patients with no event will be censored at the last available tumor assessment. This analysis will be based on investigator assessment. |
| Part A: Overall Survival (OS) According to RECIST 1.1 | 18 months | OS will be defined as time from first day of study drug to death. Patients with no event will be censored at the last date the patient is known to be alive. |
| Part A: Pharmacokinetic Concentration of BVD-523 at Steady State | Single time point drawn at Visit 4/approximately day 15 (or whenever the patient reaches steady state). | Single time point taken prior to taking study drug (trough) at steady state. Steady state is defined as patients who have received at least 5 days, or 10 consecutive doses, of study drug. |
Countries
United States
Participant flow
Recruitment details
The study was conducted at 24 clinical sites in the USA. Enrollment took place between January 2021 and December 2022.
Participants by arm
| Arm | Count |
|---|---|
| Part A: Ulixertinib Oral, 600 mg, twice daily, for 28-days in each treatment cycle
Ulixertinib: Oral, 600 mg, twice daily, for 28-days in each treatment cycle | 77 |
| Total | 77 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Allocated to Treatment | Adverse Event | 6 | 0 | 0 |
| Allocated to Treatment | Death | 4 | 0 | 0 |
| Allocated to Treatment | Other | 5 | 0 | 0 |
| Allocated to Treatment | Physician Decision | 4 | 0 | 0 |
| Allocated to Treatment | Progressive Disease | 51 | 0 | 0 |
| Allocated to Treatment | Withdrawal by Subject | 7 | 0 | 0 |
| Assessed for Eligibility | Adverse Event | 1 | 0 | 0 |
| Assessed for Eligibility | Death | 1 | 0 | 0 |
| Assessed for Eligibility | Physician Decision | 1 | 0 | 0 |
| Assessed for Eligibility | Screen Failure | 24 | 0 | 0 |
Baseline characteristics
| Characteristic | Part A: Ulixertinib |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 28 Participants |
| Age, Categorical Between 18 and 65 years | 49 Participants |
| Age, Continuous | 59.9 years STANDARD_DEVIATION 12.03 |
| ECOG Performance at Baseline ECOG 0 | 23 Participants |
| ECOG Performance at Baseline ECOG 1 | 50 Participants |
| ECOG Performance at Baseline ECOG 2 | 4 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 73 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 70 Participants |
| Region of Enrollment United States | 77 participants |
| Sex: Female, Male Female | 38 Participants |
| Sex: Female, Male Male | 39 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 52 / 104 |
| other Total, other adverse events | 76 / 77 |
| serious Total, serious adverse events | 41 / 77 |
Outcome results
Primary
Part A: Overall Response Rate (ORR) According to RECIST 1.1
ORR will be defined as the percentage of patients achieving a Best Overall Response (BOR) of confirmed Complete Response (CR) and/or Partial Response (PR). Patients will be evaluated at baseline & at periodic follow-up visits through the time their participation in the study is complete.The best responses will occur at different time points for each patient.
Time frame: Up to 25 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A: Ulixertinib | Part A: Overall Response Rate (ORR) According to RECIST 1.1 | 0 Participants |
Secondary
Part A: Overall Survival (OS) According to RECIST 1.1
OS will be defined as time from first day of study drug to death. Patients with no event will be censored at the last date the patient is known to be alive.
Time frame: 18 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A: Ulixertinib | Part A: Overall Survival (OS) According to RECIST 1.1 | 5.2 months |
Secondary
Part A: Pharmacokinetic Concentration of BVD-523 at Steady State
Single time point taken prior to taking study drug (trough) at steady state. Steady state is defined as patients who have received at least 5 days, or 10 consecutive doses, of study drug.
Time frame: Single time point drawn at Visit 4/approximately day 15 (or whenever the patient reaches steady state).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A: Ulixertinib | Part A: Pharmacokinetic Concentration of BVD-523 at Steady State | 1136.39 ng/mL | Standard Deviation 689.538 |
Secondary
Part A: Progression Free Survival (PFS) According to RECIST 1.1
PFS will be defined as time from first day of study drug to disease progression or death. Patients with no event will be censored at the last available tumor assessment. This analysis will be based on investigator assessment.
Time frame: 18 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A: Ulixertinib | Part A: Progression Free Survival (PFS) According to RECIST 1.1 | 1.5 months |