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Skin Diseases, Vascular

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Vascular Diseases

Neoplasms, Vascular Tissue

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Lactitol

Slow-flow vascular malformations with identified causative variants in the phosphoinositide 3-kinase (PI3K) signalling pathway will receive alpelisib (provided by Novartis Pharmaceuticals), an oral alpha-specific PI3-kinase inhibitor for a total duration of 48 weeks as monotherapy, followed by 24 weeks of follow-up.

Fast-flow vascular malformations with identified causative variants in the RAS-MEK-ERK signalling pathway will receive mirdametinib (provided by SpringWorks Therapeutics, Inc.), an investigational oral MEK inhibitor for a total duration of 48 weeks as monotherapy, followed by 24 weeks of follow-up.

Alpelisib

Mirdametinib

Michelle de Silva, PhD

Tony Penington, MBBS, FRACS

Stephen Luen, MBChB, FRACP

Anthony Penington, MBBS, FRACS, MD(res), Grad Dip

Michelle de Silva, BSc(Hons), PhD, MGenCouns

Tony Penington, MBBS, FRACS.

Stephen Luen, MBChB, FRACP.

Lydia Pathmanathan, MBBS, FRACP.

Recent studies have demonstrated that growth of vascular malformations can be driven by genetic variants in one of 2 signalling pathways. Targeted drugs specific to these pathways have been developed and shown to be effective in treating cancer. This study will describe the effectiveness of (i) 48 weeks of alpelisib therapy for participants with slow-flow vascular malformations and a gene mutation in one of these signalling pathways (module 1) and (ii) 48 weeks of mirdametinib therapy for participants with fast-flow vascular malformations and a gene mutations in the other signalling pathway (module 2).

TARGET-VM is a modular open-label, signal seeking, phase II trial of targeted therapies for patients with vascular malformations. Patients with vascular malformations which are refractory to standard therapies, or in whom standard therapy is not appropriate, are potentially eligible for the clinical trial. Vascular malformations will be classified as slow-flow or fast-flow lesions using established clinical criteria. Genetic testing to identify causative variants in genes affecting the phosphoinositide 3-kinase (PI3K) signalling pathway for slow-flow vascular malformations or the Mitogen-Activated Protein Kinase (MAPK) signalling pathway for fast-flow vascular malformations must be performed using research protocols or commercial testing assays that are external to this clinical trial.

The study consists of individual modules, each evaluating the clinical efficacy of 48 weeks of targeted therapy. The treatment modules are:

1. Module 1 - Treatment for slow-flow vascular malformations Eligible patients with slow-flow vascular malformations with an identified causative variant in the PI3K signalling pathway will receive alpelisib, an oral alpha-specific PI3-kinase inhibitor for a total duration of 48 weeks as monotherapy (treatment period), followed by 24 weeks of follow-up (follow-up period).
2. Module 2 - Treatment for fast-flow vascular malformations Eligible patients with fast-flow vascular malformations with an identified causative variant in the MAPK signalling pathway will receive mirdametinib, an investigational oral MEK inhibitor for a total duration of 48 weeks as monotherapy (treatment period), followed by 24 weeks of follow-up (follow-up period).

TARGET-VM will be conducted only in Victoria, Australia.

i) Participants with slow-flow vascular malformations with an eligible gene mutation will receive 48 weeks of treatment with open-label alpelisib.

ii) Participants with fast-flow vascular malformations with an eligible gene mutation will receive 48 weeks of treatment with open-label mirdametinib

A Trial of Targeted Therapies for Patients With Slow-Flow or Fast-Flow Vascular Malformations

A Modular Open Label, Signal Seeking, Phase II Trial of Targeted Therapies for Patients With Slow-Flow or Fast-Flow Vascular Malformations (TARGET-VM)

From 6 months post analysis and article publication, the following will be made available long-term for use by future researchers from a recognised research institution whose proposed use of the data has been ethically reviewed and approved by an independent committee and who accept The Murdoch Children's Research Institute's (MCRI) conditions for access:

* Individual participant data that underlie the results reported in this article after de-identification
* Trial protocol, Statistical Analysis Plan, PICF The Sponsor-Investigator will be the long-term custodian after the archive period has finished.

Vascular malformations present with a range of different symptoms. Therefore, there is no single outcome measure that can capture the effectiveness of a systemic treatment across different patients. Thus for this study, an individualised primary outcome for each patient informed by their symptoms will be used, termed the Vascular Malformation Patient Specific Outcome Measure (VM-PSOM). The study "Outcome Committee" will define an individualised primary outcome for each patient informed by their symptoms and vascular malformation features prior to starting trial treatments. The VM-PSOM endpoint will therefore define a binary outcome for each patients (achieved or failed to reach the threshold improvement in the chosen measure).

VM-PSOM response at the 168 day follow-up visit assessment compared with the 48 week (end-of-treatment) VM-PSOM.

Objective response rate by volumetric MRI assessment comparing 48 week (end-of-treatment) MRI with baseline MRI. MRI scan will only be performed in patients where their vascular malformation is feasibly evaluable by MRI scan. Objective response is defined as ≥ 20% reduction from index date in the sum of measurable target lesion volume by volumetric analysis on MRI.

The mean scores in the OVAMA (Outcome measures for VAscular MAlformations) questionnaire will be calculated and analysed at specified time points. This is a set of questions developed specifically to measure symptom burden from vascular malformations. These questions are open-ended to allow the subject to describe how they feel. The questions are more tightly structured to allow comparison of answers to other people with vascular malformations. The questions have been designed in a way to determine if symptoms are getting better over time.

The mean scores in the OVAMA (Outcome measures for VAscular MAlformations) questionnaire will be calculated and analysed at specified time points.

Peter MacCallum Cancer Centre, Australia

Royal Children's Hospital

Murdoch Childrens Research Institute

Oral, 600 mg, twice daily, for 28-days in each treatment cycle

Physician's choice will be restricted to two approved (not off-label) treatments for each tumor histology (agents targeting BRAF or MEK kinases and experimental agents are not permitted as physician choice). If a patient progresses on physician's choice of treatment, crossover to the ulixertinib arm is permitted.

Ulixertinib

Physician's choice will be restricted to two approved (not off-label) treatments for each tumor histology (agents targeting BRAF or MEK kinases and experimental agents are not permitted as physician choice)).

Physician's Choice

This BVD-523-ABC study builds on the safety and clinical activity experience of previous studies that have evaluated ulixertinib as a novel targeted cancer treatment in cohorts of patients with specific genetic alterations and tumor histologies that result in aberrant MAPK pathway signaling. Early clinical data have demonstrated anti-tumor activity with ulixertinib treatment and have identified specific groups of patients for whom additional development is warranted.

This multi-center, phase II study will be conducted in two parts and assess the clinical benefit, safety, pharmacokinetics, and pharmacodynamics of ulixertinib (BVD-523) in patients with advanced malignancies.

Part A (tumor histology agnostic) will be open label and enroll patients to one of six groups based on their tumor alteration.

* Group 1: Patients with tumors, other than colorectal cancer (CRC), having a BRAF alteration that results in an amino acid change at positions G469, L485, or L597.
* Group 2: Patients with tumors, other than CRC, having a defined Class 2 BRAF alteration (see Appendix 2 of protocol).
* Group 3: Patients with tumors, other than CRC, having an atypical BRAF alteration (non V600) that is not specified in Group 1 or Group 2.
* Group 4: Patients with CRC having any atypical BRAF alteration.
* Group 5: Patients with tumors, other than CRC, harboring alterations in MEK1/2.
* Group 6: Patients with CRC harboring alterations in MEK1/2.

Part B (tumor histology specific) will randomly enroll patients with one of up to three specified tumor histologies to receive either ulixertinib or the physician's choice of treatment in a 2:1 ratio. Tumors must harbor a specified MEK or atypical BRAF alteration. If a patient progresses on physician's choice of treatment, crossover to the ulixertinib arm is permitted.The specific histologies to be included in this part will be selected based on available data and discussion with the clinical investigators, the medical monitor, and the sponsor.

Study of Ulixertinib for Patients With Advanced Malignancies Harboring MEK or Atypical BRAF Alterations

A Two-Part, Phase II, Multi-center Study of the ERK Inhibitor Ulixertinib (BVD-523) for Patients With Advanced Malignancies Harboring MEK or Atypical BRAF Alterations

ORR will be defined as the percentage of patients achieving a Best Overall Response (BOR) of confirmed Complete Response (CR) and/or Partial Response (PR). Patients will be evaluated at baseline \& at periodic follow-up visits through the time their participation in the study is complete.The best responses will occur at different time points for each patient.

PFS will be defined as time from first day of study drug to disease progression as adjudicated by the independent review committee or death. Patients with no event will be censored at the last available tumor assessment.

Time from first response to disease progression (DP) or death; assessed until DP, death, or initiation of subsequent anticancer therapy. Patients with no event will be censored at the last available tumor assessment.

PFS will be defined as time from first day of study drug to disease progression or death. Patients with no event will be censored at the last available tumor assessment. This analysis will be based on investigator assessment.

OS will be defined as time from first day of study drug to death. Patients with no event will be censored at the last date the patient is known to be alive.

Single time point taken prior to taking study drug (trough) at steady state. Steady state is defined as patients who have received at least 5 days, or 10 consecutive doses, of study drug.

OS will be defined time from first day of study drug to death. Patients with no event will be censored at the last date the patient is known to be alive.

Time from first response to disease progression or death; assessed until DP, death, or initiation of subsequent anticancer therapy. Patients with no event will be censored at the last available tumor assessment.

BioMed Valley Discoveries, Inc

Digestive System Diseases

Adenocarcinoma

Colorectal Neoplasms

Intestinal Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Colonic Diseases

Intestinal Diseases

Rectal Diseases

Carcinoma

Neoplasms, Glandular and Epithelial

Antineoplastic Agents

Antibodies

Antibodies, Monoclonal

Immunoglobulins

Trametinib

Panitumumab

Antineoplastic Agents, Immunological

Immunoglobulins, Intravenous

Immunologic Factors

Protein Kinase Inhibitors

Enzyme Inhibitors

Patients with EGFR ectodomain mutation receive panitumumab IV over 30-90 minutes on day 1. Cycles repeat every 14 days in the absence of disease progression or unacceptable toxicity. Patients with disease progression may crossover to Cohort 2.

Patients with KRAS, NRAS, or BRAF mutation receive trametinib PO QD on days 1-14 and panitumumab as in Cohort 1. Cycles repeat every 14 days in the absence of disease progression or unacceptable toxicity.

Patients without EGFR ectodomain, KRAS, NRAS, or BRAF mutation receive panitumumab as in Cohort 1. Cycles repeat every 14 days in the absence of disease progression or unacceptable toxicity. Patients with disease progression may crossover to Cohort 2.

Laboratory Biomarker Analysis

Christine Parseghian

This phase II clinical trial studies how well panitumumab with or without trametinib works in treating patients with stage IV colorectal cancer. Immunotherapy with monoclonal antibodies, such as panitumumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving panitumumab with or without trametinib may work better in treating patients with stage IV colorectal cancer.

PRIMARY OBJECTIVES:

I. To evaluate the anti-tumor efficacy of panitumumab monotherapy in patients who were initially KRAS/NRAS/BRAF wild-type at baseline who have progressed on prior anti-EGFR therapy and subsequently have detectable EGFR ectodomain mutation post-progression in circulating free tumor deoxyribonucleic acid (DNA).

II. To evaluate the anti-tumor efficacy of panitumumab and trametinib combination therapy in patients who were initially KRAS/NRAS/BRAF wild-type at baseline who have progressed on prior anti-EGFR therapy and subsequently have detectable levels of KRAS, NRAS, and/or BRAF mutation post-progression in circulating free tumor DNA.

III. To evaluate the anti-tumor efficacy of panitumumab monotherapy in patients who were initially KRAS/NRAS/BRAF wild-type at baseline who have progressed on prior anti-EGFR therapy and subsequently do not have detectable KRAS, NRAS, BRAF, or EGFR ectodomain mutation post-progression in circulating free tumor DNA.

SECONDARY OBJECTIVES:

I. To evaluate the toxicities of panitumumab and trametinib combination therapy.

II. To evaluate the anti-tumor efficacy of panitumumab and trametinib combination therapy in patients who were initially KRAS/NRAS/BRAF wild-type at baseline who progressed on prior anti-EGFR therapy, developed detectable EGFR ectodomain mutations, and progress through retreatment with panitumumab.

III. To evaluate the anti-tumor efficacy of panitumumab and trametinib combination therapy in patients who were initially KRAS/NRAS/BRAF wild-type at baseline who progressed on prior anti-EGFR therapy, did not develop detectable mutations in KRAS, NRAS, BRAF, or EGFR ectodomain, and progress through retreatment with panitumumab.

IV. To evaluate clinical outcomes with panitumumab monotherapy in patients who were initially KRAS/NRAS/BRAF wild-type at baseline who have progressed on prior anti-EGFR therapy and subsequently have detectable EGFR ectodomain mutation post-progression in circulating free tumor DNA.

V. To evaluate clinical outcomes with panitumumab and trametinib combination therapy in patients who were initially KRAS/NRAS/BRAF wild-type at baseline who have progressed on prior anti-EGFR therapy and subsequently have detectable levels of KRAS, NRAS, and/or BRAF mutation post-progression in circulating free tumor DNA.

VI. To evaluate clinical outcomes with panitumumab monotherapy in patients who were initially KRAS/NRAS/BRAF wild-type at baseline who have progressed on prior anti-EGFR therapy and subsequently do not have detectable KRAS, NRAS, BRAF, or EGFR ectodomain mutation post-progression in circulating free tumor DNA.

VII. To study the biological basis of development of primary and secondary resistance to anti-EGFR antibodies and MEK inhibitors.

OUTLINE: Patients are assigned to 1 of 3 cohorts.

COHORT 1: Patients with EGFR ectodomain mutation receive panitumumab intravenously (IV) over 30-90 minutes on day 1. Cycles repeat every 14 days in the absence of disease progression or unacceptable toxicity. Patients with disease progression may crossover to Cohort 2.

COHORT 2: Patients with KRAS, NRAS, or BRAF mutation receive trametinib orally (PO) once daily (QD) on days 1-14 and panitumumab as in Cohort 1. Cycles repeat every 14 days in the absence of disease progression or unacceptable toxicity.

COHORT 3: Patients without EGFR ectodomain, KRAS, NRAS, or BRAF mutation receive panitumumab as in Cohort 1. Cycles repeat every 14 days in the absence of disease progression or unacceptable toxicity. Patients with disease progression may crossover to Cohort 2.

After completion of study treatment, patients are followed up for 4 weeks and then every 3 months for 24 months.

Panitumumab With or Without Trametinib in Treating Patients With Stage IV Colorectal Cancer

A Phase II Enrichment Study of Panitumumab as a Single Agent or in Combination With Trametinib in Anti-EGFR-Refractory Stage IV Colorectal Cancer Patients

Will be evaluated along with the exact 95% confidence interval.

The incidence rates will be estimated, along with the exact 95% confidence intervals.

The probability of PFS will be estimated using the method of Kaplan and Meier. The two-sided log-rank test will be used to assess the differences between groups.

The probability of OS will be estimated using the method of Kaplan and Meier. The two-sided log-rank test will be used to assess the differences between groups.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
A Trial of Targeted Therapies for Patients With Slow-Flow or Fast-Flow Vascular Malformations	NCT05983159	Slow-Flow Vascu... Fast-Flow Vascu... Vascular Malfor... Venous Malforma... Lymphatic Malfo... Lymphatic Malfo... Lymphangioma Arteriovenous M... Venous Malforma... Cystic Hygroma Vascular Anomal... Vascular Anomal... PI3K Gene Mutat... MAP2K1 Gene Mut... PIK3CA-related ... Arteriovenous M... KRAS G12C KRAS G12D	Alpelisib Mirdametinib	2 Years -	Murdoch Childrens Research Institute
Study of Ulixertinib for Patients With Advanced Malignancies Harboring MEK or Atypical BRAF Alterations	NCT04488003	Advanced Solid ... BRAF Gene Mutat... BRAF Gene Alter... MEK Mutation MEK Alteration MAP2K1 Gene Mut... MAP2K1 Gene Alt... MAP2K2 Gene Mut... MAP2K2 Gene Alt...	Ulixertinib Physician's Cho...	18 Years -	BioMed Valley Discoveries, Inc
A Trial of Targeted Therapies for Patients With Slow-Flow or Fast-Flow Vascular Malformations	NCT05983159	Slow-Flow Vascu... Fast-Flow Vascu... Vascular Malfor... Venous Malforma... Lymphatic Malfo... Lymphatic Malfo... Lymphangioma Arteriovenous M... Venous Malforma... Cystic Hygroma Vascular Anomal... Vascular Anomal... PI3K Gene Mutat... MAP2K1 Gene Mut... PIK3CA-related ... Arteriovenous M... KRAS G12C KRAS G12D	Alpelisib Mirdametinib	2 Years -	Murdoch Childrens Research Institute
Panitumumab With or Without Trametinib in Treating Patients With Stage IV Colorectal Cancer	NCT03087071	EGFR NP_005219.... KRAS Gene Mutat... MAP2K1 Gene Mut... Metastatic Colo... Refractory Colo... Stage IV Colore... Stage IVA Color... Stage IVB Color...	Laboratory Biom... Panitumumab Trametinib	18 Years -	M.D. Anderson Cancer Center
Panitumumab With or Without Trametinib in Treating Patients With Stage IV Colorectal Cancer	NCT03087071	EGFR NP_005219.... KRAS Gene Mutat... MAP2K1 Gene Mut... Metastatic Colo... Refractory Colo... Stage IV Colore... Stage IVA Color... Stage IVB Color...	Laboratory Biom... Panitumumab Trametinib	18 Years -	M.D. Anderson Cancer Center
Study of Ulixertinib for Patients With Advanced Malignancies Harboring MEK or Atypical BRAF Alterations	NCT04488003	Advanced Solid ... BRAF Gene Mutat... BRAF Gene Alter... MEK Mutation MEK Alteration MAP2K1 Gene Mut... MAP2K1 Gene Alt... MAP2K2 Gene Mut... MAP2K2 Gene Alt...	Ulixertinib Physician's Cho...	18 Years -	BioMed Valley Discoveries, Inc

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