Brain Metastases, Malignant Melanoma
Conditions
Keywords
Melanoma, CNS metastases, BRAF V600 mutation, E6201, Dabrafenib
Brief summary
This is a Phase 1 study of E6201 plus dabrafenib for the treatment of CNS metastases in BRAF V600-mutated metastatic melanoma. A total of up to N=28-34 subjects with melanoma metastasized to the CNS will be included.
Detailed description
Selected subjects will be: both males and females age ≥18 years; histologically confirmed melanoma with BRAF V600 mutation with CNS metastasis; archived tumor sample from the primary, recurrent or metastatic disease with documented BRAF mutation; recovered from all acute toxicities (≤ Grade 1) due to prior immunotherapy; determined to have adequate renal and hepatic function, and no known history of significant cardiac disease. Monotherapy Safety Run-in Phase: Following screening, a total of up to 4 subjects were enrolled. E6201 was administered by intravenous (IV) infusion over a 2-hour period at a dose of 320 mg/m\^2 twice weekly (Days 1, 4, 8, 11, 15 and 18) for three weeks, repeated every 28 days (1 cycle) until progression of disease, observation of unacceptable adverse events, intercurrent illness or changes in the subject's condition that prevents further study participation. Combination Safety Run-in Phase: Following screening, a total of 6-12 subjects are anticipated to establish the recommended doses of E6201 plus dabrafenib. E6201 will be administered by IV infusion over a 2-hour period twice weekly (Days 1, 4, 8, 11, 15 and 18) repeated every 28 days plus dabrafenib orally twice daily (=1 cycle). Dose Level 1: E6201 320 mg/m\^2 twice weekly plus dabrafenib 150 mg BID. Dose Level -1: E6201 240 mg/m\^2 twice weekly plus dabrafenib 150 mg BID. Dose Level -2: E6201 240 mg/m\^2 twice weekly plus dabrafenib 100 mg BID. Dose Level -3: E6201 160 mg/m\^2 twice weekly plus dabrafenib 100 mg BID Dose Level -4: E6201 160 mg/m\^2 twice weekly plus dabrafenib 75 mg BID. Dose Level -5: E6201 160 mg/m\^2 twice weekly plus dabrafenib 50 mg BID. A total of 6 subjects will be treated at the combined MTD doses for both drugs in the Combination Safety Run-in Phase before beginning the Expansion Phase. Expansion Phase: An additional cohort of up to N=18 subjects will be treated at the E6201 plus dabrafenib combined MTD. Subjects treated at the MTD in the Combination Safety Run-in Phase will count towards accrual in the Expansion Phase. CNS disease response will be assessed according to 2 methodologies: Response Evaluation Criteria in Solid Tumors (RECIST v. 1.1) and Response Assessment in Neuro-Oncology - Brain Metastases (RANO-BM). Non-CNS systemic disease will be assessed according to RECIST v. 1.1. Blood for hematology and serum chemistry determinations will be collected and ECGs will be taken during the study. Assessments will be obtained at Week 8 and every 8 weeks thereafter until documented progression of disease (PD). Subjects who demonstrate clinical benefit will be allowed to continue therapy with E6201 until progression of disease, observation of unacceptable adverse events, intercurrent illness or changes in the subject's condition that prevents further study participation.
Interventions
DRUGE6201
E6201 formulated in cyclodextrin for IV administration.
DRUGE6201 plus dabrafenib
E6201 formulated in cyclodextrin for IV administration. Dabrafenib capsules for oral administration.
Sponsors
University of Arizona
Spirita Oncology, LLC
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
4 subjects were treated in the E6201 Monotherapy Safety Run-in Phase. A total of 6-12 subjects are anticipated in the E6201 plus dabrafenib Combination Safety Run-in Phase. Once an MTD of the combination is determined, a total of 6 subjects will be treated at the combined MTD before the Expansion Phase will begin. In the Expansion Phase, an additional cohort of up to N=18 subjects will be treated at the combined E6201 plus dabrafenib MTD. Subjects treated at the MTD in the Combination Safety Run-in Phase will count towards accrual in the Expansion Phase.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Males and females ≥ 18 years of age * Histologically or cytologically confirmed BRAFV600-mutated melanoma * Documented metastasis of the primary tumor to the CNS * BRAF-mutation melanoma tumor status will be established prior to entry based on previous BRAF-gene analysis or MEK pathway mutation reports from a CLIA qualified laboratory. If a report is not available, the mutation analysis will be performed at Screening on archival tissue * Other metastatic melanoma systemic disease allowed * At least one measurable brain metastasis, 0.5 - 3.0 cm, as assessed by MRI ≤ 3 weeks prior to initiation of study treatment, provided neurological sequelae have resolved completely and at least one measurable metastasis with documented disease progression is present on MRI * Prior stereotactic radiosurgery and/or excision of up to 3 brain metastases is allowed \> 3 weeks before initiation of study treatment, provided neurological sequelae have resolved completely and at least one measurable metastasis with documented disease progression is present on MRI * One prior line of immunotherapy for metastatic disease is allowed, if ≥ 2 weeks has elapsed between the end of therapy and initiation of study treatment * Prior melanoma adjuvant immunotherapy is allowed, if ≥ 6 months has elapsed between the end of therapy and initiation of study treatment * Prior melanoma adjuvant BRAF/MEK inhibitor therapy is allowed, if ≥ 12 months has elapsed between the end of therapy and initiation of study treatment * Able to swallow and retain oral medication with no clinically significant gastrointestinal abnormalities that may alter absorption, such as malabsorption syndrome or major resection of the stomach or bowels (Combination Safety Run-in and Expansion Phases of the study only) * Asymptomatic or symptomatic CNS metastasis is allowed * Stable dose of corticosteroids for CNS metastasis for ≥ 7 days allowed * Patients with seizures due to CNS metastases must be controlled with stable anti-epileptic treatment for ≥ 14 days * Bisphosphonates and/or denosumab are allowed * Adequate performance status: Eastern Cooperative Oncology Group (ECOG) ≤ 2 * Life expectancy of ≥ 3 months * Adequate hematologic parameters without ongoing transfusional support: * Hemoglobin (Hb) ≥ 9 g/dL * Absolute neutrophil count (ANC) ≥ 1.0 x 10\^9 cells/L * Platelets ≥ 75 x 10\^9 cells/L * Adequate renal and hepatic function: * Creatinine ≤ 1.5 x the upper limit of normal (ULN), or calculated creatinine clearance ≥ 50 mL/minute x 1.73 m\^2 * Total bilirubin ≤ 2 times the upper limit of normal (ULN) unless due to Gilbert's disease * ALT/AST ≤ 2.5 times ULN, or \< 5 times ULN for subjects with liver metastases * Negative serum pregnancy test within 14 days prior to the first dose of study therapy for women of child-bearing potential (WCBP). Sexually active WCBP and male subjects must agree to use adequate methods to avoid pregnancy throughout the study and for 28 days after the completion of study treatment. * Ability to provide written informed consent
Exclusion criteria
* Urgent need of treatment to prevent acute neurologic deterioration, including urgent neurosurgery or radiotherapy * Symptoms of uncontrolled intracranial pressure * Symptomatic or untreated spinal cord compression * Prior treatment with any chemotherapeutic or investigational agent * Prior treatment with any BRAF and/or MEK inhibitor for metastatic disease * Prior treatment with \> 1 line of immunotherapy for metastatic disease * Serious cardiac condition within the last 6 months, such as uncontrolled arrhythmia, myocardial infarction, unstable angina or heart disease defined by the New York Heart Association (NYHA) Class III or Class IV * QT interval corrected for rate (QTc) \> 480 msec for on the ECG obtained at Screening using Fridericia method for QTc calculation * Active infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV) requiring systemic antiviral treatment within the last week prior to study treatment * Other active infection requiring IV antibiotic usage within the last week prior to study treatment * Any other medical intervention or other condition which, in the opinion of the Principal Investigator, could compromise adherence to study requirements or confound the interpretation of study results * Pregnant or breast-feeding
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Intracranial Disease Overall Response Rate by RANO-BM | At the end of Cycle 2 and every 2 cycles through 6 months following last dose of study drug (each cycle is 28 days) up to 1 year. | CNS disease response will be assessed by Response Assessment in Neuro-Oncology - Brain Metastases (RANO-BM) |
| Intracranial Disease Overall Response Rate by RECIST 1.1 | At the end of Cycle 2 and every 2 cycles through 6 months following last dose of study drug (each cycle is 28 days) up to 1 year. | CNS disease response will be assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Intracranial Disease Duration of Response | At the end of Cycle 2 and every 2 cycles through 6 months following last dose of study drug (each cycle is 28 days) up to 1 year. | Length of time from the first evidence of Objective Response (complete response or partial response) to the first evidence of progression |
| Systemic Disease Overall Response Rate (Other Than in the CNS) | At the end of Cycle 2 and every 2 cycles through 6 months following last dose of study drug (each cycle is 28 days) up to 1 year. | Systemic disease response will be assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1RECIST 1.1. |
| Progression-Free Survival | From Cycle 1 Day 1 through 6 months following the last dose of study drug (each cycle is 28 days) up to 1 year. | Length of time from the date of first administration of study drug to the first evidence of disease progression or death, whichever is earlier |
| Overall Survival | From Cycle 1 Day 1 through 6 months following the last dose of study drug or death, whichever is earlier (each cycle is 28 days) up to 1 year. | Length of time from the date of first administration of study drug to the date of death from any cause |
Countries
United States
Participant flow
Pre-assignment details
The study was terminated before any participants were enrolled in the Combination or Expansion Phases.
Participants by arm
| Arm | Count |
|---|---|
| Monotherapy Safety Run-in: E6201 E6201 320 mg/m\^2 administered IV over 2 hours twice weekly on Days 1, 4, 8, 11, 15 and 18, repeated every 28 days (=1 cycle).
Dose reductions for toxicity are 240 mg/m\^2 (Dose Level -1) and 160 mg/m\^2 (Dose Level -2) twice weekly.
E6201: E6201 for Injection formulated in cyclodextrin for IV administration | 4 |
| Combination Safety Run-in: E6201 Plus Dabrafenib Dose Level 1: E6201 320 mg/m\^2 twice weekly plus dabrafenib 150 mg BID. Dose Level -1: E6201 240 mg/m\^2 twice weekly plus dabrafenib 150 mg BID. Dose Level -2: E6201 240 mg/m\^2 twice weekly plus dabrafenib 100 mg BID. Dose Level -3: E6201 160 mg/m\^2 twice weekly plus dabrafenib 100 mg BID Dose Level -4: E6201 160 mg/m\^2 twice weekly plus dabrafenib 75 mg BID. Dose Level -5: E6201 160 mg/m\^2 twice weekly plus dabrafenib 50 mg BID.
E6201 plus dabrafenib: E6201 for Injection formulated in cyclodextrin for IV administration plus oral dabrafenib capsules | 0 |
| Expansion: E6201 Plus Dabrafenib A total of up to N=18 will be treated at the E6201 plus dabrafenib combined MTD.
E6201 plus dabrafenib: E6201 for Injection formulated in cyclodextrin for IV administration plus oral dabrafenib capsules | 0 |
| Total | 4 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 | 0 |
| Overall Study | Death | 1 | 0 | 0 |
| Overall Study | Lack of Efficacy | 2 | 0 | 0 |
Baseline characteristics
| Characteristic | Monotherapy Safety Run-in: E6201 | Total |
|---|---|---|
| Age, Continuous | 51 years STANDARD_DEVIATION 14.7 | 51 years STANDARD_DEVIATION 14.7 |
| Eastern Cooperative Group (ECOG) Performance Status 0 | 1 Participants | 1 Participants |
| Eastern Cooperative Group (ECOG) Performance Status 1 | 2 Participants | 2 Participants |
| Eastern Cooperative Group (ECOG) Performance Status 2 | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants |
| Prior Cancer Therapies | 5.5 regimens | 5.5 regimens |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 4 Participants | 4 Participants |
| Region of Enrollment United States | 4 participants | 4 participants |
| Sex: Female, Male Female | 2 Participants | 2 Participants |
| Sex: Female, Male Male | 2 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 4 | 0 / 0 | 0 / 0 |
| other Total, other adverse events | 4 / 4 | 0 / 0 | 0 / 0 |
| serious Total, serious adverse events | 3 / 4 | 0 / 0 | 0 / 0 |
Outcome results
Primary
Intracranial Disease Overall Response Rate by RANO-BM
CNS disease response will be assessed by Response Assessment in Neuro-Oncology - Brain Metastases (RANO-BM)
Time frame: At the end of Cycle 2 and every 2 cycles through 6 months following last dose of study drug (each cycle is 28 days) up to 1 year.
Population: The analysis population was the per-protocol set (PPS). The PPS included all participants in the full analysis set (FAS) who had a valid baseline and one or more post-treatment assessments for a specific measure. No participants were enrolled in the Combination Safety Run-In or Expansion Phases of the study.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Monotherapy Safety Run-in: E6201 | Intracranial Disease Overall Response Rate by RANO-BM | Progressive Disease | 1 Participants |
| Monotherapy Safety Run-in: E6201 | Intracranial Disease Overall Response Rate by RANO-BM | Stable Disease | 2 Participants |
| Monotherapy Safety Run-in: E6201 | Intracranial Disease Overall Response Rate by RANO-BM | Complete Response | 0 Participants |
| Monotherapy Safety Run-in: E6201 | Intracranial Disease Overall Response Rate by RANO-BM | Partial Response | 0 Participants |
| Monotherapy Safety Run-in: E6201 | Intracranial Disease Overall Response Rate by RANO-BM | Not Evaluable | 1 Participants |
| Combination Safety Run-in: E6201 Plus Dabrafenib | Intracranial Disease Overall Response Rate by RANO-BM | Stable Disease | 0 Participants |
| Combination Safety Run-in: E6201 Plus Dabrafenib | Intracranial Disease Overall Response Rate by RANO-BM | Complete Response | 0 Participants |
| Combination Safety Run-in: E6201 Plus Dabrafenib | Intracranial Disease Overall Response Rate by RANO-BM | Partial Response | 0 Participants |
| Combination Safety Run-in: E6201 Plus Dabrafenib | Intracranial Disease Overall Response Rate by RANO-BM | Progressive Disease | 0 Participants |
| Combination Safety Run-in: E6201 Plus Dabrafenib | Intracranial Disease Overall Response Rate by RANO-BM | Not Evaluable | 0 Participants |
| Expansion: E6201 Plus Dabrafenib | Intracranial Disease Overall Response Rate by RANO-BM | Not Evaluable | 0 Participants |
| Expansion: E6201 Plus Dabrafenib | Intracranial Disease Overall Response Rate by RANO-BM | Progressive Disease | 0 Participants |
| Expansion: E6201 Plus Dabrafenib | Intracranial Disease Overall Response Rate by RANO-BM | Complete Response | 0 Participants |
| Expansion: E6201 Plus Dabrafenib | Intracranial Disease Overall Response Rate by RANO-BM | Stable Disease | 0 Participants |
| Expansion: E6201 Plus Dabrafenib | Intracranial Disease Overall Response Rate by RANO-BM | Partial Response | 0 Participants |
Primary
Intracranial Disease Overall Response Rate by RECIST 1.1
CNS disease response will be assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
Time frame: At the end of Cycle 2 and every 2 cycles through 6 months following last dose of study drug (each cycle is 28 days) up to 1 year.
Population: The analysis population was the per-protocol set (PPS). The PPS included all participants in the full analysis set (FAS) who had a valid baseline and one or more post-treatment assessments for a specific measure. No participants were enrolled in the Combination Safety Run-In or Expansion phases of the study.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Monotherapy Safety Run-in: E6201 | Intracranial Disease Overall Response Rate by RECIST 1.1 | Progressive Disease | 1 Participants |
| Monotherapy Safety Run-in: E6201 | Intracranial Disease Overall Response Rate by RECIST 1.1 | Stable Disease | 2 Participants |
| Monotherapy Safety Run-in: E6201 | Intracranial Disease Overall Response Rate by RECIST 1.1 | Complete Response | 0 Participants |
| Monotherapy Safety Run-in: E6201 | Intracranial Disease Overall Response Rate by RECIST 1.1 | Partial Response | 0 Participants |
| Monotherapy Safety Run-in: E6201 | Intracranial Disease Overall Response Rate by RECIST 1.1 | Not Evaluable | 1 Participants |
| Combination Safety Run-in: E6201 Plus Dabrafenib | Intracranial Disease Overall Response Rate by RECIST 1.1 | Stable Disease | 0 Participants |
| Combination Safety Run-in: E6201 Plus Dabrafenib | Intracranial Disease Overall Response Rate by RECIST 1.1 | Complete Response | 0 Participants |
| Combination Safety Run-in: E6201 Plus Dabrafenib | Intracranial Disease Overall Response Rate by RECIST 1.1 | Partial Response | 0 Participants |
| Combination Safety Run-in: E6201 Plus Dabrafenib | Intracranial Disease Overall Response Rate by RECIST 1.1 | Progressive Disease | 0 Participants |
| Combination Safety Run-in: E6201 Plus Dabrafenib | Intracranial Disease Overall Response Rate by RECIST 1.1 | Not Evaluable | 0 Participants |
| Expansion: E6201 Plus Dabrafenib | Intracranial Disease Overall Response Rate by RECIST 1.1 | Not Evaluable | 0 Participants |
| Expansion: E6201 Plus Dabrafenib | Intracranial Disease Overall Response Rate by RECIST 1.1 | Progressive Disease | 0 Participants |
| Expansion: E6201 Plus Dabrafenib | Intracranial Disease Overall Response Rate by RECIST 1.1 | Complete Response | 0 Participants |
| Expansion: E6201 Plus Dabrafenib | Intracranial Disease Overall Response Rate by RECIST 1.1 | Stable Disease | 0 Participants |
| Expansion: E6201 Plus Dabrafenib | Intracranial Disease Overall Response Rate by RECIST 1.1 | Partial Response | 0 Participants |
Secondary
Intracranial Disease Duration of Response
Length of time from the first evidence of Objective Response (complete response or partial response) to the first evidence of progression
Time frame: At the end of Cycle 2 and every 2 cycles through 6 months following last dose of study drug (each cycle is 28 days) up to 1 year.
Population: There were no Objective Responses during the study. Thus, Duration of Response could not be calculated.
Secondary
Overall Survival
Length of time from the date of first administration of study drug to the date of death from any cause
Time frame: From Cycle 1 Day 1 through 6 months following the last dose of study drug or death, whichever is earlier (each cycle is 28 days) up to 1 year.
Population: The analysis population was the per-protocol set (PPS). The PPS included all participants in the full analysis set (FAS) who had a valid baseline and one or more post-treatment assessments for a specific measure. No subjects were enrolled in the Combination Safety Run-In or Expansion Phases of the study.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Monotherapy Safety Run-in: E6201 | Overall Survival | NA months |
Secondary
Progression-Free Survival
Length of time from the date of first administration of study drug to the first evidence of disease progression or death, whichever is earlier
Time frame: From Cycle 1 Day 1 through 6 months following the last dose of study drug (each cycle is 28 days) up to 1 year.
Population: The analysis population was the per-protocol set (PPS). The PPS included all participants in the full analysis set (FAS) who had a valid baseline and one or more post-treatment assessments for a specific measure. No subjects were enrolled in the Combination Safety Run-In or Expansion Phases of the study.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Monotherapy Safety Run-in: E6201 | Progression-Free Survival | NA months |
Secondary
Systemic Disease Overall Response Rate (Other Than in the CNS)
Systemic disease response will be assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1RECIST 1.1.
Time frame: At the end of Cycle 2 and every 2 cycles through 6 months following last dose of study drug (each cycle is 28 days) up to 1 year.
Population: The analysis population was the per-protocol set (PPS). The PPS included all participants in the full analysis set (FAS) who had a valid baseline and one or more post-treatment assessments for a specific measure. No subjects were enrolled in the Combination Safety Run-In or Expansion Phases of the study.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Monotherapy Safety Run-in: E6201 | Systemic Disease Overall Response Rate (Other Than in the CNS) | Progressive Disease | 0 Participants |
| Monotherapy Safety Run-in: E6201 | Systemic Disease Overall Response Rate (Other Than in the CNS) | Partial Response | 0 Participants |
| Monotherapy Safety Run-in: E6201 | Systemic Disease Overall Response Rate (Other Than in the CNS) | Not Evaluable | 1 Participants |
| Monotherapy Safety Run-in: E6201 | Systemic Disease Overall Response Rate (Other Than in the CNS) | Complete Response | 0 Participants |
| Monotherapy Safety Run-in: E6201 | Systemic Disease Overall Response Rate (Other Than in the CNS) | Stable Disease | 3 Participants |
| Combination Safety Run-in: E6201 Plus Dabrafenib | Systemic Disease Overall Response Rate (Other Than in the CNS) | Complete Response | 0 Participants |
| Combination Safety Run-in: E6201 Plus Dabrafenib | Systemic Disease Overall Response Rate (Other Than in the CNS) | Progressive Disease | 0 Participants |
| Combination Safety Run-in: E6201 Plus Dabrafenib | Systemic Disease Overall Response Rate (Other Than in the CNS) | Stable Disease | 0 Participants |
| Combination Safety Run-in: E6201 Plus Dabrafenib | Systemic Disease Overall Response Rate (Other Than in the CNS) | Not Evaluable | 0 Participants |
| Combination Safety Run-in: E6201 Plus Dabrafenib | Systemic Disease Overall Response Rate (Other Than in the CNS) | Partial Response | 0 Participants |
| Expansion: E6201 Plus Dabrafenib | Systemic Disease Overall Response Rate (Other Than in the CNS) | Not Evaluable | 0 Participants |
| Expansion: E6201 Plus Dabrafenib | Systemic Disease Overall Response Rate (Other Than in the CNS) | Partial Response | 0 Participants |
| Expansion: E6201 Plus Dabrafenib | Systemic Disease Overall Response Rate (Other Than in the CNS) | Stable Disease | 0 Participants |
| Expansion: E6201 Plus Dabrafenib | Systemic Disease Overall Response Rate (Other Than in the CNS) | Progressive Disease | 0 Participants |
| Expansion: E6201 Plus Dabrafenib | Systemic Disease Overall Response Rate (Other Than in the CNS) | Complete Response | 0 Participants |