First in Human Trial of Topical VT30 in Pts With Venous/Lymphatic Malformations Assoc With PIK3CA or TEK Gene Mutations

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ClinicalTrials.gov Identifier: NCT04409145

Recruitment Status : Recruiting

First Posted : June 1, 2020

Last Update Posted : August 27, 2021

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Sponsor:

Information provided by (Responsible Party):

Venthera, Inc., a BridgeBio company

Study Description

Brief Summary:

VT30-101 is a 2-part first-in-human trial of topically administered VT30 to subjects with cutaneous venous malformations, lymphatic malformations, or mixed venolymphatic malformations associated with PIK3CA or TEK mutations.

Part 1 is a 4-week treatment, open-label, 4-sequence, escalating repeat-application cohort study, with intra-subject and inter-cohort dose escalation.

Part 2 is a 12-week treatment, randomized, placebo-controlled, double-blind, safety and exploratory efficacy study. Part 2 will be initiated only after the successful completion of Part 1 with results that demonstrate the general safety and tolerability of topically applied VT30. Up to 12 subjects who complete Part 1 may be enrolled into Part 2 of the study.

The primary objective is to evaluate the safety and tolerability of VT30. The study will also determine the dose and regimen of VT30 to be carried into Part 2 of the protocol. Other aims include documenting plasma drug levels of VT30 and VT10 and, on an exploratory basis, examining pharmacologic target engagement and change in potential efficacy readouts.

Condition or disease	Intervention/treatment	Phase
Venous Malformation Lymphatic Malformation Venolymphatic Malformation	Drug: VT30	Phase 1 Phase 2

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Detailed Description:

VT30-101 is designed as a Phase 1/2, first-in-human study of topically administered VT30 to subjects with cutaneous venous malformations (VMs), lymphatic malformations (LMs), or mixed venolymphatic malformations (VLMs) associated with phosphatidylinositol 3-kinase catalytic alpha polypeptide (PIK3CA) or tyrosine receptor kinase (TEK) mutations. Capillary involvement and/or extension of the lesion into subcutaneous tissues is permitted.

The study will occur in 2 parts, and in both study parts, subjects will participate in a Screening Period (up to 6 weeks) before beginning the indicated Treatment Period.

Part 1 will be an open-label, 4-sequence, escalating repeat-application study comprised of up to 4 cohorts (3 subjects per cohort, with 3 up to 6 in Cohort 4, or the final Part 1 cohort). In each cohort, subjects will be given topical VT30 for a 4-week Treatment Period. Subjects will begin treatment with the designated dose on Day 1. After 2 weeks, the Investigator will examine the treated surface area and determine if the formulation is tolerated such that the subject may apply the next dose strength of VT30 gel for the remaining duration of the Treatment Period.

Specifically, the following gel dose strengths (concentrations) are planned for Cohorts 1 through 3 in Part 1:

Cohort 1: initiate dosing with 0.12% (w/w) gel and progress to 0.6% (w/w) gel for the final 2 weeks of the Part 1 Treatment Period (if the lower dose is tolerated)
Cohort 2: initiate dosing with 0.6% (w/w) gel and progress to 1.2% (w/w) gel for the final 2 weeks of the Part 1 Treatment Period (if the lower dose is tolerated)
Cohort 3: initiate dosing with 1.2% (w/w) gel and progress to 2.3% (w/w) gel for the final 2 weeks of the Part 1 Treatment Period (if the lower dose is tolerated)

A Safety Review Committee (SRC), with sponsor, investigator and independent medical representation, will provide oversight and guidance for study conduct. After 3 subjects have been dosed for at least 21 days in any of the first three Part 1 cohorts, the SRC may request additional data, approve initiation of the subsequent cohort, or mandate that additional subjects to be enrolled at either the higher or lower dose within the cohort.

After 9 subjects in Cohorts 1 through 3 (3 subjects per cohort) have completed the 4-week Treatment Period, the SRC will determine if additional subjects should be assigned to Cohort 4 (or the final Part 1 cohort) to receive the MTD (maximum tolerated dose) or MFD (maximum feasible dose) strength of VT30. Subjects in Cohort 4 will receive the designated dose strength and regimen of VT30 for a full 4 weeks.

Following the completion of Cohort 4 in Part 1, the SRC will determine whether to authorize initiation of Part 2 and will confirm the dose level and regimen to be administered in Part 2.

Part 2 will be a randomized, placebo-controlled, double-blind study containing 36 subjects assigned in a 2:1 ratio to receive either VT30 or placebo. Up to 12 subjects who complete Part 1 may enroll in Part 2, provided they meet all Part 2-specific inclusion criteria with no applicable exclusions.

After the first 12 subjects in Part 2 have completed 4 weeks of treatment, the SRC will conduct a review of blinded safety data to confirm no revisions or changes are needed to the protocol. Subsequent reviews may also be conducted to ensure continued acceptable safety and tolerability.

After subjects complete their designated Treatment Period (in Part 1 or Part 2), they will participate in a 4-week post treatment Follow-up Period.

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	51 participants
Allocation:	N/A
Intervention Model:	Single Group Assignment
Intervention Model Description:	Part 1: Open-label, 4-sequence, escalating repeat-application cohort study, with intra-subject and inter-cohort dose escalation to determine safety and tolerability, and maximum feasible dose/maximum tolerable dose Part 2: Randomized, placebo-controlled, double-blind, safety and exploratory efficacy study
Masking:	None (Open Label)
Masking Description:	Part 1: Open label Part 2: Double blind
Primary Purpose:	Treatment
Official Title:	Open-Label, Intra Subject, Dose Escalation (Part 1) Followed by Randomized, Double Blind, Placebo Controlled (Part 2) Trial of Topical VT30 in Pts With Venous, Lymphatic or Mixed Malformations Associated With PIK3CA or TEK Genetic Mutations
Actual Study Start Date :	October 1, 2020
Estimated Primary Completion Date :	June 2022
Estimated Study Completion Date :	June 2022

Resource links provided by the National Library of Medicine

Genetic and Rare Diseases Information Center resources: Lymphatic Malformations

U.S. FDA Resources

Arms and Interventions

Arm	Intervention/treatment
Experimental: VT30 VT30 is a PI3K-inhibitor prodrug, formulated as a topical gel and dispensed from a metered dose pump; administration is once or twice daily, applied to target-treatment area(s) on the skin. One pump action dispenses 250 µL of gel, intended to treat an area of 140 cm2.	Drug: VT30 VT30 gel is intended as a topical treatment of cutaneous VMs, LMs, or VLMs that driven by inappropriate PI3K activation. In the skin, VT30 is rapidly metabolized to VT10, an active drug form, and is intended to sufficiently permeate the stratum corneum and achieve target engagement. It is expected that VT30 will lead to amelioration of the signs and symptoms of cutaneous VMs, LMs and/or VLMs.

Arm

Intervention/treatment

Experimental: VT30

VT30 is a PI3K-inhibitor prodrug, formulated as a topical gel and dispensed from a metered dose pump; administration is once or twice daily, applied to target-treatment area(s) on the skin. One pump action dispenses 250 µL of gel, intended to treat an area of 140 cm2.

Drug: VT30

VT30 gel is intended as a topical treatment of cutaneous VMs, LMs, or VLMs that driven by inappropriate PI3K activation. In the skin, VT30 is rapidly metabolized to VT10, an active drug form, and is intended to sufficiently permeate the stratum corneum and achieve target engagement. It is expected that VT30 will lead to amelioration of the signs and symptoms of cutaneous VMs, LMs and/or VLMs.

Outcome Measures

Primary Outcome Measures :

Evaluation of safety and tolerability [ Time Frame: From pre-treatment to 4 weeks of treatment ]
Composite of adverse events and changes in physical exam findings, vital signs, lab tests, and electrocardiogram evaluations

Secondary Outcome Measures :

Maximum feasible dose / maximum tolerable dose [ Time Frame: From pre-treatment to 4 weeks ]
The MTD or MFD strength will be determined based on results from Part 1, and will inform the dose strength to be used in Part 2
Tissue and serum drug levels [ Time Frame: From pre-treatment to 4 weeks ]
Plasma levels of VT30 and VT10 will be assessed following topical administration of VT30 to determine level of systemic exposure

Other Outcome Measures:

Maximum tissue concentration of study drug [ Time Frame: From pre-treatment to 4 weeks ]
As assessed by treated lesion tissue levels of phosphoproteins, as an indicator of local target engagement
Changes in Pain [ Time Frame: From pre-treatment to 4 weeks ]
Assessed by subjects' self-reporting their pain, related to the treated lesion, on a Numerical Rating Scale
Changes in lesion [ Time Frame: From pre-treatment to 4 weeks ]
Assessed by change in appearance of the treated lesion
Changes in management of lesion bleeding, oozing, or discharge [ Time Frame: From pre-treatment to 4 weeks ]
Assessed by subject-reported difficulty managing bleeding, oozing, or discharge from the treated lesion

Eligibility Criteria

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Ages Eligible for Study:	18 Years to 60 Years (Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Have signed the current approved informed consent form
Have a clinically or phenotypically defined VM, LM, or mixed VLM affecting the skin
Lesion genotyping confirms either PIK3CA or TEK mutations, known to be pathogenic
Agrees to use contraception if of childbearing potential
Be willing and able to comply with the protocol and be available for the entire study
Be at least 18 to 60 years of age
Lesion must be amenable to defining a contiguous study treatment area of 140 cm2

Exclusion Criteria:

Lesion to be treated is on the face or involves mucosa
Presence of ulcerations on the target-treatment lesion
Known systemic hypersensitivity to the VT30 drug substance, its inactive ingredients, or the vehicle
Uncontrolled diabetes mellitus
Hyperlipidemia that is poorly controlled on current treatment
Pregnant or nursing, planning to become pregnant, or planning to father a child during the study
History of malignancy except successfully treated nonmetastatic cutaneous squamous cell or basal cell carcinoma and/or localized carcinoma in situ of the cervix
Major surgery within 8 weeks of Screening, or a surgical, laser or other procedure involving the target lesion within 8 weeks of Screening, or planned to occur during the study
Any other medical or personal condition that, in the opinion of the Investigator, may potentially compromise the safety or compliance of the subject, or may preclude the subject's successful completion of the clinical study
Medically significant infection (eg, cellulitis or abscess, or a systemic infection) within 8 weeks of Screening
Ongoing therapy with another topical treatment or any medication that inhibits PI3K, Akt pathway, or the mTOR pathway, or in the opinion of the Investigator, the subject requires systemic therapy for their vascular malformation condition
Use of a biologic or systemic immunosuppressive agent within 3 months of Screening
Systemic use of corticosteroids, within 30 days of Screening
Treatment with a small molecule investigational product within 30 days of Screening, or with any investigational biologic products within 3 months of Screening
Positive for hepatitis C antibody, hepatitis B surface antigen, hepatitis B core antibody, or human immunodeficiency virus
Alanine transaminase or aspartate transaminase laboratory values in excess of 1.5X the upper limit of normal at Screening
Hemoglobin A1c is >8%
Any other clinically significant laboratory or testing abnormality that, in the opinion of the Investigator, might confound the study, interfere with the subject's ability to complete the study, or represent a meaningful safety risk upon study enrollment

Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04409145

Contacts

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Contact: Lisa Pugliese	650-825-4080	lp@venthera.com

Locations

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United States, Arizona
Phoenix Children's Hospital	Recruiting
Phoenix, Arizona, United States, 85016
Contact: Kellie Badger, RN 602-933-2053 kbadger@phoenixchildrens.com
Principal Investigator: Harper Price, MD
United States, Arkansas
Arkansas Children's Hospital/UAMS	Recruiting
Little Rock, Arkansas, United States, 72202
Contact: D'Ann Pierce 501-364-4440 piercecarold@uams.edu
Principal Investigator: Shelley Crary,, MD
United States, California
Stanford University Medical Center	Recruiting
Palo Alto, California, United States, 94304
Contact: Elidia Tafoya, RN 650-724-1982 etafoya@stanford.edu
Principal Investigator: Joyce Teng, MD
Dermatology Cosmetic Laser Medical Associates of La Jolla	Recruiting
San Diego, California, United States, 92121
Contact: Leslie Aguilar 858-657-1004 laguilar@clderm.com
Principal Investigator: - Mitchel Goldman, MD
United States, Colorado
Children's Hospital of Colorado	Recruiting
Aurora, Colorado, United States, 80045
Contact: Wendy Moore, BSN 720-777-6353 Wendy.moore2@childrenscolorado.org
Principal Investigator: Taizo Nakano, MD
United States, Indiana
Indiana University Health (Riley Children's Hospital and University Hospital)	Recruiting
Indianapolis, Indiana, United States, 46202
Contact: Flossy Lincoln, RN 317-274-8750 fnjinimb@iupui.edu
Principal Investigator: Anita Haggstrom,, MD
United States, Minnesota
Mayo Clinic	Recruiting
Rochester, Minnesota, United States, 55905
Contact: Alison Gilbertson 507-422-6964 Langer.alison@mayo.edu
Principal Investigator: Megha Tollefson, MD Tollefson, MD
United States, North Carolina
Duke University	Recruiting
Raleigh, North Carolina, United States, 27513
Contact: Hai Hai Huang, RN 919-684-3401 h.hai@duke.edu
Principal Investigator: Kristy Pahl, MD
United States, Ohio
Cincinnatti Children's Hospital	Recruiting
Cincinnati, Ohio, United States, 45229
Contact: Megan Metcalf, RN 513-803-2606 Megan.Metcalf@cchmc.org
Principal Investigator: Adrienne Hammill, MD
University Hospitals- Cleveland Medical Center	Recruiting
Cleveland, Ohio, United States, 44106
Contact: Amanda Rivera, RN 216-844-4908 Amanda.Rivera@UHhospitals.org
Principal Investigator: Irina Pateva, MD
United States, Pennsylvania
Children's Hospital of Philadelphia	Recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: Meghan Martin, MS, CCRP 215-590-6625 KILLENM1@chop.edu
Contact: Bede Nriagu, MBBS, MPH 800-879-2467 NRIAGUB@chop.edu
Principal Investigator: Kristin Snyder, MD
United States, Texas
Texas Children's Hospital	Recruiting
Houston, Texas, United States, 77030
Contact: Stanley Oseghale, RN 832-822-3565 sxosegha@texaschildrens.org
Principal Investigator: Denise Metry, MD
Texas Dermatology and Laser Specialists	Recruiting
San Antonio, Texas, United States, 78218
Contact: Jenna Encina Encina 210-852-2779 jenna@texasdls.com
Principal Investigator: John Browning, MD
United States, Virginia
University of Virginia Department of Dermatology	Recruiting
Charlottesville, Virginia, United States, 44106
Contact: Ashton Leone, RN 434-243-5737 AML7Q@virginia.edu
Principal Investigator: Richard Flowers, MF
United States, Wisconsin
University of Wisconsin-Madison	Recruiting
Madison, Wisconsin, United States, 53715
Contact: Christina Sheehan 608-287-2006 csheehan@dermatology.wisc.edu
Principal Investigator: Beth Ann Drolet

Sponsors and Collaborators

Venthera, Inc., a BridgeBio company

Investigators

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Study Director:	Ken Truitt, MD	Venthera, Inc., a BridgeBio company

More Information

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Responsible Party:	Venthera, Inc., a BridgeBio company
ClinicalTrials.gov Identifier:	NCT04409145
Other Study ID Numbers:	VT30-101
First Posted:	June 1, 2020 Key Record Dates
Last Update Posted:	August 27, 2021
Last Verified:	July 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	No

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Studies a U.S. FDA-regulated Drug Product:	Yes
Studies a U.S. FDA-regulated Device Product:	No

Additional relevant MeSH terms:

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Lymphangioma Lymphatic Abnormalities Congenital Abnormalities Lymphatic Vessel Tumors	Neoplasms by Histologic Type Neoplasms Lymphatic Diseases

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