Working…
COVID-19 is an emerging, rapidly evolving situation.
Get the latest public health information from CDC: https://www.coronavirus.gov.

Get the latest research information from NIH: https://www.nih.gov/coronavirus.
ClinicalTrials.gov
ClinicalTrials.gov Menu

E6201 Plus Dabrafenib for the Treatment of Metastatic Melanoma Central Nervous System Metastases (CNS)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03332589
Recruitment Status : Recruiting
First Posted : November 6, 2017
Last Update Posted : May 1, 2020
Sponsor:
Collaborator:
University of Arizona
Information provided by (Responsible Party):
Spirita Oncology, LLC

Tracking Information
First Submitted Date  ICMJE October 30, 2017
First Posted Date  ICMJE November 6, 2017
Last Update Posted Date May 1, 2020
Actual Study Start Date  ICMJE July 2, 2018
Estimated Primary Completion Date January 1, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 13, 2018)
  • Intracranial disease overall response rate by 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) ]
    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 [ 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) ]
    CNS disease response will be assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
Original Primary Outcome Measures  ICMJE
 (submitted: November 1, 2017)
Overall rate of response of brain metastases [ Time Frame: Time to progression will be calculated from the date of first treatment (C1D1) to the date of first evidence of progression of CNS disease, measured after every two cycles (56 days). ]
Response of CNS metastases due to metastatic melanoma with a BRAF or MEK mutation who have relapsed or progressed from initial or systemic disease
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: November 13, 2018)
  • Intracranial disease duration of response [ 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) ]
    Length of time from the first evidence of objective response to the first evidence of progression
  • Systemic disease overall response rate (other than in the CNS) [ 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) ]
    Systemic disease response will be assessed by RECIST 1.1.
  • Progression-Free Survival [ Time Frame: From Cycle 1 Day 1 through 6 months following the last dose of study drug (each cycle is 28 days) ]
    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 [ 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) ]
    Length of time from the date of first administration of study drug to the date of death from any cause
  • Safety of E6201 in this patient population [ 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) ]
    Safety assessed through the monitoring of adverse events (AEs) and serious adverse events (SAEs).
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE E6201 Plus Dabrafenib for the Treatment of Metastatic Melanoma Central Nervous System Metastases (CNS)
Official Title  ICMJE A Phase 1 Study of E6201 Plus Dabrafenib for the Treatment of Central Nervous System Metastases (CNS) From BRAF V600-Mutated Metastatic Melanoma
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Single Group Assignment
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.
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Malignant Melanoma
  • Brain Metastases
Intervention  ICMJE
  • Drug: E6201
    E6201 for Injection formulated in cyclodextrin for IV administration
  • Drug: E6201 plus dabrafenib
    E6201 for Injection formulated in cyclodextrin for IV administration plus oral dabrafenib capsules
Study Arms  ICMJE
  • Experimental: 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.

    Intervention: Drug: E6201
  • Experimental: 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.
    Intervention: Drug: E6201 plus dabrafenib
  • Experimental: Expansion: E6201 Plus Dabrafenib
    A total of up to N=18 will be treated at the E6201 plus dabrafenib combined MTD.
    Intervention: Drug: E6201 plus dabrafenib
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: November 1, 2017)
24
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE June 30, 2021
Estimated Primary Completion Date January 1, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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 metastais, 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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Linda J Paradiso, DVM +1 (713) 898-8965 linda.paradiso@spiritaoncology.com
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03332589
Other Study ID Numbers  ICMJE STX-101-02
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Spirita Oncology, LLC
Study Sponsor  ICMJE Spirita Oncology, LLC
Collaborators  ICMJE University of Arizona
Investigators  ICMJE
Principal Investigator: Hani M Babiker, MD University of Arizona
PRS Account Spirita Oncology, LLC
Verification Date April 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP