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

Neoplasms

Skin and Connective Tissue Diseases

All Conditions

Rare Diseases

Melanoma

Glioma

Part A will evaluate the safety of NST-628 with advanced solid tumors and determine the recommended dose for expansion of NST-628.

Part B will evaluate the objective tumor response rate in subjects with advanced solid tumors harboring specified genetic alterations receiving NST-628 and evaluate the safety of NST-628 in subjects with advanced solid tumors in cohorts defined below:

i. Melanoma Cohorts

1. Activating NRAS mutations
2. Select BRAF alterations

ii. Non-Melanoma Cohorts:

1. Solid tumors with NRAS activating mutations
2. Solid tumors with KRAS activating mutations
3. Solid tumors with select BRAF alterations
4. Glioma with BRAF alterations

NST-628 is a small molecule non-covalent pan-RAF/MEK dual molecular glue targeting RAF and MEK nodes of MAPK pathway.

NST-628

Ann Marie Kennedy

Brianna Flores

Andrea Vandross, MD

Erica Torres

Naga Cheedella, MD

Blake Patterson

Mohamad Salkeni, MD

Shiena Lemin

Charlotte Lemech, MD

Jia (Jenny) Liu, MD

Sarah McLennan

Victoria Atkinson, MD

Scott McGregor

Omar Faruque, MD

Meggan O'Riley

Ganessan Kichenadasse, MD

This is a two-part Phase 1, open label, multi-center, single arm, non-randomized, multiple dose, safety, pharmacokinetic (PK) and preliminary efficacy study of single agent NST-628 in adult patients with MAPK pathway mutated/dependent advanced solid tumors who have exhausted standard treatment options.

The study includes two parts, a dose escalation part (Part A) followed by a dose expansion part (Part B). Part A will estimate the maximum tolerated dose (MTD) in dose escalation cohorts in patients with advanced solid tumors for whom no standard therapy is available in order to establish the recommended dose for expansion (RDE). Successive cohorts of subjects will receive escalating doses of NST-628 orally once daily in 28-day cycles.

Bayesian Optimal Interval (BOIN) method will be used for dose escalation.

Once MTD is reached or dose escalation is stopped prior to reaching MTD and provisional RDE selected, the provisional RDE level will be expanded. If warranted by dose/toxicity/anti-tumor activity observations, additional, lower dose level(s) may also be expanded.

Part B of the study will include up to 6 cohorts of approximately up to 30 subjects each with select MAPK pathway mutant solid tumors enrolled at the RDE in order to explore benefit from treatment as suggested by preclinical findings and will better define the safety profile of NST-628 at the RDE. Additional safety information gathered in Part B may be used to modify the dose recommended for future studies.

The end of the study is the last visit of the last subject.

A Study to Investigate the Safety and Efficacy of NST-628 Oral Tablets in Subjects With Solid Tumors

A Phase I, Open Label Single-arm Two-part Study to Investigate Safety, Pharmacokinetics, and Preliminary Efficacy of Pan-RAF/MEK Glue NST-628 Oral Tablets in Subject With Solid Tumors Harboring Genetic Alterations in the MAPK Pathway and With Other Solid Tumors

Objective response per RECIST v. 1.1 or other response assessment tool standard for a given tumor type.

PFS defined as the time to first occurrence of disease progression per RECIST v1.1 (or other response assessment tool standard for a given tumor type) or death

Overall survival (OS) defined as the time to death

Nested Therapeutics, Inc

Digestive System Diseases

Gland and Hormone Related Diseases

Respiratory Tract (Lung and Bronchial) Diseases

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Esophageal Neoplasms

Carcinoma

Cholangiocarcinoma

Pancreatic Neoplasms

Carcinoma, Non-Small-Cell Lung

Thyroid Neoplasms

Thyroid Diseases

Stomach Neoplasms

Glioblastoma

Head and Neck Neoplasms

Lung Neoplasms

Carcinoma, Hepatocellular

Ovarian Neoplasms

Carcinoma, Ovarian Epithelial

Urinary Bladder Neoplasms

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Nerve Tissue

Adenocarcinoma

Neoplasms, Glandular and Epithelial

Astrocytoma

Neoplasms, Neuroepithelial

Esophageal Cancer

Pancreatic Cancer

Ovarian Cancer

Bile Duct Cancer

Stomach Cancer

Ovarian Epithelial Cancer

Small Intestine Cancer

Neuroepithelioma

Ulixertinib (BVD-523) is an oral, first-in-class ERK1/2 inhibitor

Ulixertinib (BVD-523)

xCures Clinical Operations

Louis B Nabors, MD

Marshall Schreeder, MD

Jose Galeas, MD

David Palchak, MD

Richard M Green, MD

Michael Demeure, MD

Naveed Wagle, MD

Benjamin A Weinberg, MD

Jennifer E. Tseng, MD

Joshua Lukenbill, DO

Jon Olson, MD

Philip L. Brooks, MD

Mohammad Mobayed, MD

Nathan B. Green, DO

Seth Cohen, MD

Carl J. Minniti Jr., MD

Bonni Guerin, MD

MInsig Choi, MD

Manish Bhandari, MD

Rex Mowat, MD

Suresh Nair, MD

Elena G Chiorean, MD

The objective of this expanded access program is to provide ulixertinib (BVD-523) for compassionate use in advanced cancer patients with MAPK pathway-altered solid tumor(s), including but not limited to KRAS, NRAS, HRAS, BRAF, MEK, and ERK mutations who have incomplete response to or have exhausted available therapies.

Ulixertinib is available for treatment as monotherapy or in combination with other clinically tolerable agent(s), conditionally approved by the drug manufacturer.

Expanded Access to Ulixertinib (BVD-523) in Patients With Advanced MAPK Pathway-Altered Malignancies

Cancer Commons

xCures

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
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 Study to Investigate the Safety and Efficacy of NST-628 Oral Tablets in Subjects With Solid Tumors	NCT06326411	Oncology MEK Mutation RAF Gene Mutati... Ras (KRAS or NR... Melanoma NSCLC Glioma Solid Tumor, Ad... MAPK Pathway Ge...	NST-628	18 Years -	Nested Therapeutics, Inc
Expanded Access to Ulixertinib (BVD-523) in Patients With Advanced MAPK Pathway-Altered Malignancies	NCT04566393	Pancreatic Canc... Small Bowel Can... Colorectal Canc... Melanoma Non Small Cell ... Thyroid Cancer Bladder Cancer Head and Neck C... Gastric Cancer Esophageal Canc... Cholangiocarcin... Ovarian Cancer Hepatocellular ... Glioblastoma MAPK Gene Mutat... KRAS Activating... BRAF Gene Mutat... NRAS Gene Mutat... HRAS Gene Mutat... MEK Mutation ERK Mutation	Ulixertinib (BV...	12 Years -	xCures
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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