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

• Sponsor: Spirita Oncology, LLC (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT03332589
• Collaborator: University of Arizona (Other)
• Enrollment: 4
• Location: 1
• Arms: 3
• Actual Duration (Months): 39.3
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Malignant Melanoma; Brain Metastases	Drug: E6201; Drug: E6201 plus dabrafenib	Phase 1

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 Design

• Study Type: Interventional
• Actual Enrollment: 4 participants
• 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.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
• Official Title: A Phase 1 Study of E6201 Plus Dabrafenib for the Treatment of Central Nervous System Metastases (CNS) From BRAF V600-Mutated Metastatic Melanoma
• Actual Study Start Date: Jul 2, 2018
• Actual Primary Completion Date: Apr 30, 2021
• Actual Study Completion Date: Oct 11, 2021

Arms and Interventions

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.

Outcome Measures

Primary Outcome Measures

1. 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)

2. 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 Outcome Measures

1. 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

2. 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.

3. 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

4. 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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Arizona Cancer Center	Tucson	Arizona	United States	85724

Sponsors and Collaborators

• Spirita Oncology, LLC
• University of Arizona

Investigators

• Principal Investigator: Hani M Babiker, MD, University of Arizona

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Dec 31, 2019

More Information

Additional Information:

• Sponsor website

Publications

None provided.

• Responsible Party: Spirita Oncology, LLC
• ClinicalTrials.gov Identifier: NCT03332589
• Other Study ID Numbers: STX-101-02
• First Posted: Nov 6, 2017
• Last Update Posted: May 20, 2022
• Last Verified: Dec 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Spirita Oncology, LLC: Melanoma; CNS metastases; BRAF V600 mutation; E6201; Dabrafenib
• Additional relevant MeSH terms: Melanoma; Neoplasm Metastasis; Neoplasms, Second Primary; Brain Neoplasms; Dabrafenib

Study Results

Participant Flow

Pre-assignment Detail	The study was terminated before any participants were enrolled in the Combination or Expansion Phases.

Arm/Group Title	Monotherapy Safety Run-in: E6201	Combination Safety Run-in: E6201 Plus Dabrafenib	Expansion: E6201 Plus Dabrafenib
Arm/Group Description	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	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	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
Period Title: Overall Study
STARTED	4	0	0
COMPLETED	0	0	0
NOT COMPLETED	4	0	0

Baseline Characteristics

Arm/Group Title	Monotherapy Safety Run-in: E6201	Combination Safety Run-in: E6201 Plus Dabrafenib	Expansion: E6201 Plus Dabrafenib	Total
Arm/Group Description	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	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	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	Total of all reporting groups
Overall Participants	4	0	0	4
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	51 (14.7)	51 (14.7)
Sex: Female, Male (Count of Participants)
Female	2 50%	2 Infinity
Male	2 50%	2 Infinity
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 25%	1 Infinity
Not Hispanic or Latino	3 75%	3 Infinity
Unknown or Not Reported	0 0%	0 NaN
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 NaN
Asian	0 0%	0 NaN
Native Hawaiian or Other Pacific Islander	0 0%	0 NaN
Black or African American	0 0%	0 NaN
White	4 100%	4 Infinity
More than one race	0 0%	0 NaN
Unknown or Not Reported	0 0%	0 NaN
Region of Enrollment (participants) [Number]
United States	4 100%	4 Infinity
Eastern Cooperative Group (ECOG) Performance Status (Count of Participants)
0	1 25%	1 Infinity
1	2 50%	2 Infinity
2	1 25%	1 Infinity
Prior Cancer Therapies (regimens) [Median (Full Range) ]
Median (Full Range) [regimens]	5.5	5.5

Outcome Measures

1. Primary Outcome

Title	Intracranial Disease Overall Response Rate by RANO-BM
Description	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.

Outcome Measure Data

Analysis Population Description

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/Group Title	Monotherapy Safety Run-in: E6201	Combination Safety Run-in: E6201 Plus Dabrafenib	Expansion: E6201 Plus Dabrafenib
Arm/Group Description	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	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	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
Measure Participants	4	0	0
Complete Response	0 0%	0 NaN	0 NaN
Partial Response	0 0%	0 NaN	0 NaN
Stable Disease	2 50%	0 NaN	0 NaN
Progressive Disease	1 25%	0 NaN	0 NaN
Not Evaluable	1 25%	0 NaN	0 NaN

2. Primary Outcome

Title	Intracranial Disease Overall Response Rate by RECIST 1.1
Description	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.

Outcome Measure Data

Analysis Population Description

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/Group Title	Monotherapy Safety Run-in: E6201	Combination Safety Run-in: E6201 Plus Dabrafenib	Expansion: E6201 Plus Dabrafenib
Arm/Group Description	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	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	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
Measure Participants	4	0	0
Complete Response	0 0%	0 NaN	0 NaN
Partial Response	0 0%	0 NaN	0 NaN
Stable Disease	2 50%	0 NaN	0 NaN
Progressive Disease	1 25%	0 NaN	0 NaN
Not Evaluable	1 25%	0 NaN	0 NaN

3. Secondary Outcome

Title	Intracranial Disease Duration of Response
Description	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.

Outcome Measure Data

Analysis Population Description

There were no Objective Responses during the study. Thus, Duration of Response could not be calculated.

Arm/Group Title	Monotherapy Safety Run-in: E6201	Combination Safety Run-in: E6201 Plus Dabrafenib	Expansion: E6201 Plus Dabrafenib
Arm/Group Description	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	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	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
Measure Participants	0	0	0

4. Secondary Outcome

Title	Systemic Disease Overall Response Rate (Other Than in the CNS)
Description	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.

Outcome Measure Data

Analysis Population Description

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/Group Title	Monotherapy Safety Run-in: E6201	Combination Safety Run-in: E6201 Plus Dabrafenib	Expansion: E6201 Plus Dabrafenib
Arm/Group Description	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	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	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
Measure Participants	4	0	0
Complete Response	0 0%	0 NaN	0 NaN
Partial Response	0 0%	0 NaN	0 NaN
Stable Disease	3 75%	0 NaN	0 NaN
Progressive Disease	0 0%	0 NaN	0 NaN
Not Evaluable	1 25%	0 NaN	0 NaN

5. Secondary Outcome

Title	Progression-Free Survival
Description	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.

Outcome Measure Data

Analysis Population Description

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/Group Title	Monotherapy Safety Run-in: E6201	Combination Safety Run-in: E6201 Plus Dabrafenib	Expansion: E6201 Plus Dabrafenib
Arm/Group Description	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	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	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
Measure Participants	1	0	0
Median (Standard Deviation) [months]	NA

6. Secondary Outcome

Title	Overall Survival
Description	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.

Outcome Measure Data

Analysis Population Description

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/Group Title	Monotherapy Safety Run-in: E6201	Combination Safety Run-in: E6201 Plus Dabrafenib	Expansion: E6201 Plus Dabrafenib
Arm/Group Description	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	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	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
Measure Participants	1	0	0
Median (Standard Deviation) [months]	NA

Adverse Events

Time Frame	Adverse event data and all-cause mortality data were collected for each subject from C1D1 to 6 months after the last dose of study drug up to 1 year.
Adverse Event Reporting Description	Adverse events were reported for all study participants who were administered at least one dose of study medication.
Arm/Group Title	Monotherapy Safety Run-in: E6201		Combination Safety Run-in: E6201 Plus Dabrafenib		Expansion: E6201 Plus Dabrafenib
Arm/Group Description	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		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		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
All Cause Mortality
	Monotherapy Safety Run-in: E6201		Combination Safety Run-in: E6201 Plus Dabrafenib		Expansion: E6201 Plus Dabrafenib
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/4 (25%)		0/0 (NaN)		0/0 (NaN)
Serious Adverse Events
	Monotherapy Safety Run-in: E6201		Combination Safety Run-in: E6201 Plus Dabrafenib		Expansion: E6201 Plus Dabrafenib
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/4 (75%)		0/0 (NaN)		0/0 (NaN)
Gastrointestinal disorders
Abdominal pain	1/4 (25%)	1	0/0 (NaN)	0	0/0 (NaN)	0
Infections and infestations
Sepsis	1/4 (25%)	1	0/0 (NaN)	0	0/0 (NaN)	0
Psychiatric disorders
Confusional state	1/4 (25%)	1	0/0 (NaN)	0	0/0 (NaN)	0
Respiratory, thoracic and mediastinal disorders
Hypoxia	1/4 (25%)	1	0/0 (NaN)	0	0/0 (NaN)	0
Other (Not Including Serious) Adverse Events
	Monotherapy Safety Run-in: E6201		Combination Safety Run-in: E6201 Plus Dabrafenib		Expansion: E6201 Plus Dabrafenib
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/4 (100%)		0/0 (NaN)		0/0 (NaN)
Blood and lymphatic system disorders
Thrombocytopenia	1/4 (25%)	1	0/0 (NaN)	0	0/0 (NaN)	0
Cardiac disorders
Tachycardia	1/4 (25%)	1	0/0 (NaN)	0	0/0 (NaN)	0
Eye disorders
Blurred vision	1/4 (25%)	1	0/0 (NaN)	0	0/0 (NaN)	0
Gastrointestinal disorders
Abdominal distension	1/4 (25%)	1	0/0 (NaN)	0	0/0 (NaN)	0
Abdominal pain	1/4 (25%)	1	0/0 (NaN)	0	0/0 (NaN)	0
General disorders
Fatigue	1/4 (25%)	1	0/0 (NaN)	0	0/0 (NaN)	0
Gait disturbance	1/4 (25%)	1	0/0 (NaN)	0	0/0 (NaN)	0
Hepatobiliary disorders
Hyperbilirubinaemia	1/4 (25%)	1	0/0 (NaN)	0	0/0 (NaN)	0
Infections and infestations
Respiratory tract infection	1/4 (25%)	1	0/0 (NaN)	0	0/0 (NaN)	0
Rhinitis	1/4 (25%)	1	0/0 (NaN)	0	0/0 (NaN)	0
Sepsis	2/4 (50%)	2	0/0 (NaN)	0	0/0 (NaN)	0
Metabolism and nutrition disorders
Hypokalaemia	3/4 (75%)	3	0/0 (NaN)	0	0/0 (NaN)	0
Nervous system disorders
Dizziness	1/4 (25%)	1	0/0 (NaN)	0	0/0 (NaN)	0
Neuropathy peripheral	1/4 (25%)	1	0/0 (NaN)	0	0/0 (NaN)	0
Seizure	1/4 (25%)	1	0/0 (NaN)	0	0/0 (NaN)	0
Vasogenic cerebral oedema	1/4 (25%)	1	0/0 (NaN)	0	0/0 (NaN)	0
Psychiatric disorders
Confusional state	1/4 (25%)	1	0/0 (NaN)	0	0/0 (NaN)	0
Renal and urinary disorders
Urinary hesitation	1/4 (25%)	1	0/0 (NaN)	0	0/0 (NaN)	0
Respiratory, thoracic and mediastinal disorders
Allergic rhinitis	1/4 (25%)	1	0/0 (NaN)	0	0/0 (NaN)	0
Hypoxia	1/4 (25%)	1	0/0 (NaN)	0	0/0 (NaN)	0
Oropharyngeal pain	1/4 (25%)	1	0/0 (NaN)	0	0/0 (NaN)	0
Pulmonary embolism	1/4 (25%)	1	0/0 (NaN)	0	0/0 (NaN)	0
Vascular disorders
Oedema peripheral	1/4 (25%)	1	0/0 (NaN)	0	0/0 (NaN)	0

Limitations/Caveats

Due to the departure of the study PI from the institution, the study was terminated early.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.