Neoplasms

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Dabrafenib

Protein Kinase Inhibitors

Enzyme Inhibitors

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.

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 up to N=18 will be treated at the E6201 plus dabrafenib combined MTD.

E6201 formulated in cyclodextrin for IV administration.

E6201

E6201 formulated in cyclodextrin for IV administration. Dabrafenib capsules for oral administration.

E6201 plus dabrafenib

Hani M Babiker, MD

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.

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.

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.

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

CNS disease response will be assessed by Response Assessment in Neuro-Oncology - Brain Metastases (RANO-BM)

CNS disease response will be assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1

Length of time from the first evidence of Objective Response (complete response or partial response) to the first evidence of progression

Systemic disease response will be assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1RECIST 1.1.

Length of time from the date of first administration of study drug to the first evidence of disease progression or death, whichever is earlier

Length of time from the date of first administration of study drug to the date of death from any cause

University of Arizona

Spirita Oncology, LLC

Adverse events were reported for all study participants who were administered at least one dose of study medication.

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

Monotherapy Safety Run-in: E6201

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

Combination Safety Run-in: 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

Expansion: E6201 Plus Dabrafenib

Total

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

ECOG Performance Status:

0 = Fully active, able to carry on all pre-disease performance without restriction

1. = Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work

   = Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and about more than 50% of waking hours
2. = Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours

Eastern Cooperative Group (ECOG) Performance Status

Prior Cancer Therapies

No subjects were enrolled in the Combination Safety Run-In or Expansion Phases of the study.

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

Chief Development Officer

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.

Intracranial Disease Overall Response Rate by RANO-BM

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.

Intracranial Disease Overall Response Rate by RECIST 1.1

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

Intracranial Disease Duration of Response

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.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
E6201 Plus Dabrafenib for the Treatment of Metastatic Melanoma Central Nervous System Metastases (CNS)	NCT03332589	Malignant Melan... Brain Metastase...	E6201 E6201 plus dabr...	18 Years -	Spirita Oncology, LLC
E6201 Plus Dabrafenib for the Treatment of Metastatic Melanoma Central Nervous System Metastases (CNS)	NCT03332589	Malignant Melan... Brain Metastase...	E6201 E6201 plus dabr...	18 Years -	Spirita Oncology, LLC

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