A Phase II Study of BVD-523 in Metastatic Uveal Melanoma

• Sponsor: Dana-Farber Cancer Institute (Other)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT03417739
• Collaborator: BioMed Valley Discoveries, Inc (Industry)
• Enrollment: 13
• Locations: 2
• Arm: 1
• Anticipated Duration (Months): 89.2
• Patients Per Site: 6.5
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This research study is studying a targeted therapy called BVD-523 as a possible treatment for advanced uveal melanoma.

Condition or Disease	Intervention/Treatment	Phase
Uveal Melanoma	Drug: BVD-523	Phase 2

Detailed Description

This research study is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of an investigational drug to learn whether the drug works in treating a specific disease. "Investigational" means that the drug is being studied.

The FDA (the U.S. Food and Drug Administration) has not approved BVD-523 as a treatment for any disease.

BVD-523 has been tested in patients with solid tumors to determine the highest dose of BVD-523 that can be safely given to patients.

In this research study, the investigators are evaluating the role of BVD-523 in the treatment of patients with uveal melanoma. Genetic changes within metastatic uveal melanoma activate proteins in the MAPK protein signaling pathway which leads to tumor growth. In the laboratory BVD-523 works against one of these proteins called ERK to decrease tumor growth. In this study, the investigators are testing BVD-523 to see if it works to treat metastatic uveal melanoma.

Study Design

• Study Type: Interventional
• Actual Enrollment: 13 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Study of BVD-523 in Metastatic Uveal Melanoma
• Actual Study Start Date: Mar 26, 2018
• Actual Primary Completion Date: May 5, 2020
• Anticipated Study Completion Date: Aug 31, 2025

Arms and Interventions

Arm	Intervention/Treatment
Experimental: BVD-523 BVD-523 is administered at the RP2D of 600mgs taken twice daily orally for 28 consecutive days (1 cycle). Planned does may modified based on toxicity.	Drug: BVD-523; ERK1 and ERK2 inhibitor; Other Names: Ulixertinib

Outcome Measures

Primary Outcome Measures

1. Overall Response Rate [up to 52 weeks]

   Overall Response Rate (ORR) was defined as the proportion of participants achieving complete response (CR) or partial response (PR) based on RECIST 1.1 criteria on treatment. Per RECIST 1.1 for target lesions: CR is complete disappearance of all target lesions and PR is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. PR or better overall response assumes at a minimum incomplete response/stable disease (SD) for the evaluation of non-target lesions and absence of new lesions.

Secondary Outcome Measures

1. Disease Control Rate [up to 52 weeks]

   A combination of patients who experience complete response, partial response and stable disease on CT or other form of imaging

2. Median Overall Survival [Participant survival information will be collected every 4 weeks from the date of last dose of study drug until the participant's death or until the participant is lost to follow-up, or until study closure. Median follow-up was 6 months.]

   OS based on the Kaplan-Meier method is defined as the time from study entry to death or censored at date last known alive.

3. Median Time to Tumor Progression [Between the dates of the start of trial treatment and first documentation of progressive disease. In the absence of documented progressive disease, follow-up will be censored at date of last disease assessment. up to 52 weeks]

   Time from enrollment on study until the tumor is progressing by RECIST v1.0 as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions

4. To Evaluate the Pharmacodynamics of ERK Inhibition on BVD-523 With a Comparison of Pre- and On-treatment Biopsies. [Tumor biopsies are obtained 7-28 days prior to the first treatment and 12-16 days following the initial treatment in order to facilitate ERK signaling analysis, mutation analysis, sequencing, and cell line development.]

   MAPK pathway inhibition will be analyzed in pre-treatment and post-treatment samples to understand the effect of ERK inhibition by BVD-523

5. To Better Understand the Genetic Variability of Uveal Melanoma Through Whole Exome Sequencing [Tumor biopsies are obtained 7-28 days prior to the first treatment and 12-16 days following the initial treatment in order to facilitate ERK signaling analysis, mutation analysis, sequencing, and cell line development.]

   DNA sequencing will occur in tissue samples from patients treated on study to gain a better understanding of the genetic variability observed in uveal melanoma

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Participants must have histologically or cytologically confirmed stage IV uveal melanoma

• Participants must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as ≥20 mm with conventional techniques or as ≥10 mm with spiral CT scan, MRI, or calipers by clinical exam. See Section 11 for the evaluation of measurable disease.

• Patients can have received any number of prior therapies for treatment of their uveal melanoma excluding prior treatment with an ERK inhibitor. Patients who have received prior MEK inhibition or other MAPK targeted agents will be allowed on study.

• Age ≥ 18 years of age.

• ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A)

• Life expectancy of greater than 6 months

• Participants must have normal organ and marrow function as defined below:

• leukocytes ≥3,000/mcL

• hemoglobin ≥9.0 g/dL

• absolute neutrophil count ≥1,500/mcL

• platelets ≥100,000/mcL

• total bilirubin ≤1.5 × institutional upper limit of normal AST(SGOT)/ALT(SGPT) ≤2.5 × institutional upper limit of normal, unless there is known liver involvement in which case ≤5.0 × institutional upper limit of normal

• creatinine within normal institutional limits OR

• creatinine clearance ≥60 mL/min/1.73 m2 for participants with creatinine levels above institutional normal.

• Participants must have adequate cardiac function, e.g. left ventricular ejection fraction (LVEF) of >50% as assessed by multi-gated acquisition (MUGA) or ultrasound/echocardiography (ECHO); corrected QT interval (QTc) <470ms.

• Presence of metastatic disease that would be amenable to the required biopsies. Ideally pre and post biopsies should be from the same lesion and otherwise from lesions in the same organ. If not possible, then biopsy of the lesions in different organs will be permitted.

• The effects of BVD-523 on the developing human fetus are unknown. For this reason and because ERK inhibitors could potentially be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and 4 months after completion of BVD-523 administration. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of BVD-523 administration.

• Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

• Participants who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C), small molecule targeted therapy (i.e. - kinase inhibitors) within 3 weeks or the last dose of antibody therapy within 4 weeks prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier.

• Participants who are receiving any other investigational agents.

• Major surgery within 4 weeks of the first dose of BVD-523. Tumor embolization procedure or ablation procedure within 2 weeks of first dose of BVD-523.

• Participants with known brain metastases or evidence of leptomeningeal involvement are eligible only if these lesions are treated and both clinically and radiographically stable for at least four weeks. Patients are eligible if they are being treated with a stable dosage of steroids/anticonvulsants, requiring no dose increase for 4 weeks.

• History of allergic reactions attributed to compounds of similar chemical or biologic composition to BVD-523.

• Participants receiving any medications or substances that are known to be strong inhibitors of CYP1A2, CYP2D6, and CYP3A4 or strong inducers of CYP3A4 are ineligible. Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated list such as http://medicine.iupui.edu/clinpharm/ddis/table.aspx; medical reference texts such as the Physicians' Desk Reference may also provide this information. As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product.

• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.

• Pregnant women are excluded from this study because BVD-523 is an ERK with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with BVD-523 breastfeeding should be discontinued if the mother is treated with BVD-523.

• Gastrointestinal (GI) condition which could impair absorption of study medication or inability to ingest study medication.

• A history of current evidence/risk of retinal vein occlusion (RVO) or central serous retinopathy (CSR)

• Concomitant malignancies or previous malignancies with less than 2 years of disease-free interval at the time of enrollment (except non-melanoma skin cancer, cervical cancer in situ, prostate cancer with undetectable PSA). Other concurrent malignancies must be discussed with the medical monitor prior to enrollment.

• Patients with melanoma of cutaneous, mucosal or acral-lentiginous origin or of unknown primary.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Massachusetts General Hospital	Boston	Massachusetts	United States	02214
2	Dana Farber Cancer Institute	Boston	Massachusetts	United States	02215

Sponsors and Collaborators

• Dana-Farber Cancer Institute
• BioMed Valley Discoveries, Inc

Investigators

• Principal Investigator: Elizabeth Buchbinder, MD, Dana-Farber Cancer Institute

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jan 23, 2019

More Information

Publications

None provided.

• Responsible Party: Elizabeth Buchbinder, Principal Investigator, Dana-Farber Cancer Institute
• ClinicalTrials.gov Identifier: NCT03417739
• Other Study ID Numbers: 17-526
• First Posted: Jan 31, 2018
• Last Update Posted: Nov 23, 2021
• Last Verified: Nov 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 Elizabeth Buchbinder, Principal Investigator, Dana-Farber Cancer Institute: Uveal Melanoma
• Additional relevant MeSH terms: Melanoma; Uveal Neoplasms

Study Results

Participant Flow

Arm/Group Title	BVD-523
Arm/Group Description	BVD-523 is administered at the RP2D of 600mgs taken twice daily orally for 28 consecutive days (1 cycle). Planned does may modified based on toxicity.
Period Title: Overall Study
STARTED	13
COMPLETED	13
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	BVD-523
Arm/Group Description	BVD-523 is administered at the RP2D of 600mgs taken twice daily orally for 28 consecutive days (1 cycle). Planned does may modified based on toxicity.
Overall Participants	13
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	63.1 (10.1)
Sex: Female, Male (Count of Participants)
Female	9 69.2%
Male	4 30.8%
Race/Ethnicity, Customized (Count of Participants)
Asian	1 7.7%
White	12 92.3%
Region of Enrollment (Count of Participants)
United States	13 100%

Outcome Measures

1. Primary Outcome

Title	Overall Response Rate
Description	Overall Response Rate (ORR) was defined as the proportion of participants achieving complete response (CR) or partial response (PR) based on RECIST 1.1 criteria on treatment. Per RECIST 1.1 for target lesions: CR is complete disappearance of all target lesions and PR is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. PR or better overall response assumes at a minimum incomplete response/stable disease (SD) for the evaluation of non-target lesions and absence of new lesions.
Time Frame	up to 52 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	BVD-523
Arm/Group Description	BVD-523 is administered at the RP2D of 600mgs taken twice daily orally for 28 consecutive days (1 cycle). Planned does may modified based on toxicity.
Measure Participants	13
Number (95% Confidence Interval) [percentage of participants]	0 0%

2. Secondary Outcome

Title	Disease Control Rate
Description	A combination of patients who experience complete response, partial response and stable disease on CT or other form of imaging
Time Frame	up to 52 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	BVD-523
Arm/Group Description	BVD-523 is administered at the RP2D of 600mgs taken twice daily orally for 28 consecutive days (1 cycle). Planned does may modified based on toxicity.
Measure Participants	13
Number [percentage of participants]	0 0%

3. Secondary Outcome

Title	Median Overall Survival
Description	OS based on the Kaplan-Meier method is defined as the time from study entry to death or censored at date last known alive.
Time Frame	Participant survival information will be collected every 4 weeks from the date of last dose of study drug until the participant's death or until the participant is lost to follow-up, or until study closure. Median follow-up was 6 months.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	BVD-523
Arm/Group Description	BVD-523 is administered at the RP2D of 600mgs taken twice daily orally for 28 consecutive days (1 cycle). Planned does may modified based on toxicity.
Measure Participants	13
Median (90% Confidence Interval) [Months]	6.9

4. Secondary Outcome

Title	Median Time to Tumor Progression
Description	Time from enrollment on study until the tumor is progressing by RECIST v1.0 as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions
Time Frame	Between the dates of the start of trial treatment and first documentation of progressive disease. In the absence of documented progressive disease, follow-up will be censored at date of last disease assessment. up to 52 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	BVD-523
Arm/Group Description	BVD-523 is administered at the RP2D of 600mgs taken twice daily orally for 28 consecutive days (1 cycle). Planned does may modified based on toxicity.
Measure Participants	13
Median (90% Confidence Interval) [months]	2

5. Secondary Outcome

Title	To Evaluate the Pharmacodynamics of ERK Inhibition on BVD-523 With a Comparison of Pre- and On-treatment Biopsies.
Description	MAPK pathway inhibition will be analyzed in pre-treatment and post-treatment samples to understand the effect of ERK inhibition by BVD-523
Time Frame	Tumor biopsies are obtained 7-28 days prior to the first treatment and 12-16 days following the initial treatment in order to facilitate ERK signaling analysis, mutation analysis, sequencing, and cell line development.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

6. Secondary Outcome

Title	To Better Understand the Genetic Variability of Uveal Melanoma Through Whole Exome Sequencing
Description	DNA sequencing will occur in tissue samples from patients treated on study to gain a better understanding of the genetic variability observed in uveal melanoma
Time Frame	Tumor biopsies are obtained 7-28 days prior to the first treatment and 12-16 days following the initial treatment in order to facilitate ERK signaling analysis, mutation analysis, sequencing, and cell line development.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	AE data collected at day 1 of each cycle, and day 15 of cycle 1, days 22 to 28 of cycle 2. Also during off treatment follow-up. AE will be collected every 4 weeks from the date of last dose of study drug until the participant's death or until the participant is lost to follow-up, or until study closure up to one year.
Adverse Event Reporting Description	Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.
Arm/Group Title	BVD-523
Arm/Group Description	BVD-523 is administered at the RP2D of 600mgs taken twice daily orally for 28 consecutive days (1 cycle). Planned does may modified based on toxicity. BVD-523: ERK1 and ERK2 inhibitor
All Cause Mortality
	BVD-523
	Affected / at Risk (%)	# Events
Total	0/13 (0%)
Serious Adverse Events
	BVD-523
	Affected / at Risk (%)	# Events
Total	5/13 (38.5%)
Blood and lymphatic system disorders
Anemia	1/13 (7.7%)
Investigations
Alanine aminotransferase increased	2/13 (15.4%)
Aspartate aminotransferase increased	2/13 (15.4%)
Serum amylase increased	1/13 (7.7%)
Metabolism and nutrition disorders
Hyponatremia	1/13 (7.7%)
Skin and subcutaneous tissue disorders
Pruritus	1/13 (7.7%)
Rash maculo-papular	1/13 (7.7%)
Other (Not Including Serious) Adverse Events
	BVD-523
	Affected / at Risk (%)	# Events
Total	13/13 (100%)
Blood and lymphatic system disorders
Anemia	1/13 (7.7%)
Blood and lymphatic system disorders - Other, specify	1/13 (7.7%)
Lymph node pain	1/13 (7.7%)
Cardiac disorders
Palpitations	1/13 (7.7%)
Supraventricular tachycardia	1/13 (7.7%)
Eye disorders
Blurred vision	1/13 (7.7%)
Eye disorders - Other, specify	2/13 (15.4%)
Gastrointestinal disorders
Abdominal distension	1/13 (7.7%)
Abdominal pain	6/13 (46.2%)
Anal ulcer	1/13 (7.7%)
Ascites	1/13 (7.7%)
Constipation	3/13 (23.1%)
Diarrhea	10/13 (76.9%)
Esophageal stenosis	1/13 (7.7%)
Gastrointestinal disorders - Other, specify	3/13 (23.1%)
Gingival pain	1/13 (7.7%)
Hemorrhoids	1/13 (7.7%)
Mucositis oral	1/13 (7.7%)
Nausea	8/13 (61.5%)
Rectal ulcer	1/13 (7.7%)
Stomach pain	1/13 (7.7%)
Vomiting	2/13 (15.4%)
General disorders
Chills	1/13 (7.7%)
Edema limbs	4/13 (30.8%)
Fatigue	7/13 (53.8%)
Fever	3/13 (23.1%)
Gait disturbance	1/13 (7.7%)
General disorders and administration site conditions - Other, specify	3/13 (23.1%)
Non-cardiac chest pain	1/13 (7.7%)
Pain	1/13 (7.7%)
Infections and infestations
Urinary tract infection	1/13 (7.7%)
Injury, poisoning and procedural complications
Bruising	1/13 (7.7%)
Fracture	2/13 (15.4%)
Investigations
Alanine aminotransferase increased	2/13 (15.4%)
Alkaline phosphatase increased	1/13 (7.7%)
Aspartate aminotransferase increased	2/13 (15.4%)
Blood bilirubin increased	1/13 (7.7%)
CPK increased	1/13 (7.7%)
Creatinine increased	3/13 (23.1%)
Platelet count decreased	1/13 (7.7%)
Serum amylase increased	1/13 (7.7%)
Weight loss	1/13 (7.7%)
White blood cell decreased	1/13 (7.7%)
Metabolism and nutrition disorders
Anorexia	7/13 (53.8%)
Dehydration	3/13 (23.1%)
Hypoalbuminemia	4/13 (30.8%)
Hypocalcemia	1/13 (7.7%)
Hypokalemia	1/13 (7.7%)
Hypomagnesemia	1/13 (7.7%)
Hyponatremia	2/13 (15.4%)
Musculoskeletal and connective tissue disorders
Generalized muscle weakness	1/13 (7.7%)
Musculoskeletal and connective tissue disorder - Other, specify	1/13 (7.7%)
Pain in extremity	1/13 (7.7%)
Nervous system disorders
Dizziness	3/13 (23.1%)
Dysgeusia	1/13 (7.7%)
Tremor	1/13 (7.7%)
Psychiatric disorders
Agitation	1/13 (7.7%)
Anxiety	2/13 (15.4%)
Confusion	1/13 (7.7%)
Depression	1/13 (7.7%)
Renal and urinary disorders
Hematuria	3/13 (23.1%)
Urine discoloration	1/13 (7.7%)
Reproductive system and breast disorders
Vaginal inflammation	1/13 (7.7%)
Respiratory, thoracic and mediastinal disorders
Cough	3/13 (23.1%)
Dyspnea	3/13 (23.1%)
Hypoxia	1/13 (7.7%)
Skin and subcutaneous tissue disorders
Alopecia	2/13 (15.4%)
Dry skin	1/13 (7.7%)
Pruritus	5/13 (38.5%)
Rash acneiform	7/13 (53.8%)
Rash maculo-papular	4/13 (30.8%)
Skin and subcutaneous tissue disorders - Other, specify	3/13 (23.1%)
Vascular disorders
Hot flashes	1/13 (7.7%)
Hypotension	2/13 (15.4%)
Thromboembolic event	1/13 (7.7%)
Vascular disorders - Other, specify	1/13 (7.7%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE 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.