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

A Phase 1 Study of E6201 Plus Dabrafenib for the Treatment of Central Nervous System Metastases (CNS) From BRAF V600-Mutated Metastatic Melanoma

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.

Study Overview

• Status: Terminated
• Conditions: Brain Metastases; Malignant Melanoma
• Intervention / Treatment: Drug: E6201; Drug: E6201 plus dabrafenib

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: Interventional
• Enrollment (Actual): 4
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Tucson, Arizona, United States, 85724
      • University of Arizona Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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.	Drug: E6201; E6201 formulated in cyclodextrin for IV administration.
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.	Drug: E6201 plus dabrafenib; E6201 formulated in cyclodextrin for IV administration. Dabrafenib capsules for oral administration.
Experimental: Expansion: E6201 Plus Dabrafenib; A total of up to N=18 will be treated at the E6201 plus dabrafenib combined MTD.	Drug: E6201 plus dabrafenib; E6201 formulated in cyclodextrin for IV administration. Dabrafenib capsules for oral administration.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Intracranial Disease Overall Response Rate by RANO-BM	CNS disease response will be assessed by Response Assessment in Neuro-Oncology - Brain Metastases (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.
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	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.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	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 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.	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.
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	From Cycle 1 Day 1 through 6 months following the last dose of study drug (each cycle is 28 days) up to 1 year.
Overall Survival	Length of time from the date of first administration of study drug to the date of death from any cause	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.

Collaborators and Investigators

• Sponsor: Spirita Oncology, LLC
• Collaborators: University of Arizona
• Investigators: Principal Investigator: Hani M Babiker, MD, University of Arizona

Publications and helpful links

Helpful Links

• Sponsor website

Study record dates

Study Major Dates

• Study Start (Actual): July 2, 2018
• Primary Completion (Actual): April 30, 2021
• Study Completion (Actual): October 11, 2021

Study Registration Dates

• First Submitted: October 30, 2017
• First Submitted That Met QC Criteria: November 1, 2017
• First Posted (Actual): November 6, 2017

Study Record Updates

• Last Update Posted (Actual): May 20, 2022
• Last Update Submitted That Met QC Criteria: March 5, 2022
• Last Verified: December 1, 2021

More Information

Terms related to this study

• Keywords: Melanoma; Dabrafenib; BRAF V600 mutation; CNS metastases; E6201
• Additional Relevant MeSH Terms: Pathologic Processes; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neoplastic Processes; Central Nervous System Neoplasms; Nervous System Neoplasms; Neuroendocrine Tumors; Nevi and Melanomas; Neoplasm Metastasis; Brain Neoplasms; Melanoma; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Dabrafenib
• Other Study ID Numbers: STX-101-02

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No