Ulixertinib (BVD-523) and Hydroxychloroquine in Patients W Advanced MAPK-Mutated Gastrointestinal Adenocarcinomas

NCT04145297 | Completed Phase 1 DMC FDA Drug

• 1 other identifier: HCI127114
• Study Type: interventional
• Target: 16
• Locations: 1 country
• Sites: 1

Brief Summary

Open-label dose escalation of Ulixertinib combined with fixed dose of hydroxychloroquine.

Conditions

Gastrointestinal Neoplasms

Outcome Measures

Primary Outcomes (1)

• Recommended phase 2 dose of ulixertinib in combination with a fixed dose of hydroxychloroquine in subjects with advanced, RAS, non-V600 BRAF, ERK or MEK mutated gastrointestinal malignancies

  The incidence of DLTs during the defined DLT period

  the day of the first dose, cycle one day one, to cycle one day 28 (Cycle=28 days)

Secondary Outcomes (2)

• Safety and tolerability of ulixertinib and hydroxychloroquine in the study population: adverse events (AEs) and serious adverse events (SAEs)

  Any patient who has taken at least one dose of both ulixertinib and hydroxychloroquine will be evaluable for toxicity. Assessment will be completed through safety follow-up visit at 60 days after the end of treatment visit.

• Efficacy of ulixertinib and hydroxychloroquine in the study population: Objective response rate (PR and CR)

  Patients will be evaluable for response once they have completed the first cycle of treatment and completed the C2D1 CT Scan.Assessment will be completed through safety follow-up visit at 60 days after the end of treatment visit.

Study Arms (1)

Treatment: all patients

EXPERIMENTAL

Hydroxychloroquine will be provided as 200 mg tablets and will be self-administered by mouth twice daily. Ulixertinib will be provided as 150 mg capsules and will be self-administered twice daily by mouth at the assigned dose level. Both medications will be administered in 28-day cycles

Drug: Ulixertinib; Drug: Hydroxychloroquine

Interventions

Ulixertinib DRUG

Ulixertinib will be provided as 150 mg capsules and will be self-administered twice daily by mouth at the assigned dose level. Ulixertinib Dose Level 0 300 mg PO BID, Dose Level 1 (starting dose) 450 mg PO BID, Dose Level 2 600 mg PO BID, Medication will be administered in 28-day cycles

Also known as: BVD-523

Treatment: all patients

Hydroxychloroquine DRUG

Hydroxychloroquine will be provided as 200 mg tablets and will be self-administered by mouth twice daily. Fixed Dose 600mg POBID. Medication will be administered in 28-day cycles

Treatment: all patients

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male or female subject aged ≥ 18 years.
• Subject with histologically confirmed MAPK-mutated GI malignancies: KRAS, NRAS, HRAS, BRAFnon-V600, MEK, and ERK.
• Subject is willing to provide a baseline biopsy.
• Prior lines of therapy:
• For patients with cholangiocarcinoma: subject must have progressed during or after one line of therapy.
• For patients with pancreatic adenocarcinoma: the subject must have progressed during or after one line of therapy.
• For patients with colorectal carcinoma: the subject must have progressed during or after two lines of therapy.
• For patients with stomach or esophageal carcinoma: the subject must have progressed during or after two lines of therapy.
• Subject must have measurable disease by RECIST 1.1 criteria by CT or MRI.
• ECOG Performance Status ≤ 1.
• Adequate organ function as defined as:
• Hematologic:
• Absolute neutrophil count (ANC) ≥ 1500/mm3
• Platelet count ≥ 100,000/mm3
• Hemoglobin ≥ 10 g/dL

You may not qualify if:

• Subject has received systemic antineoplastic therapy (including unconjugated therapeutic antibodies and toxin immunoconjugates) or any investigational therapy ≤ 14 days or within 5 half-lives prior to starting study treatment, whichever is shorter.
• Subject has received radiotherapy ≤ 14 days prior to the first dose of study treatment. Localized radiation therapy for the treatment of symptomatic bone metastasis is allowed during that timeframe.
• Subjects who have undergone major surgery ≤ 3 weeks prior to starting study drug or who have not fully recovered from major surgery.
• Presence of peritoneal carcinomatosis (PC).
• Diagnosis of any other malignancy within 2 years prior to study enrollment, except for adequately treated basal cell or squamous cell skin cancer, carcinoma in situ of the breast, bladder or of the cervix, and low-grade (Gleason 6 or below) prostate cancer on surveillance with no plans for treatment intervention (eg, surgery, radiation, or castration) or prostate cancer that has been adequately treated with prostatectomy or radiotherapy and currently with no evidence of disease or symptoms is allowed.
• Known brain metastases or cranial epidural disease.
• Note: Brain metastases or cranial epidural disease adequately treated with radiotherapy and/or surgery and stable for at least 4 weeks before the first dose of study treatment will be allowed on trial. Subjects must be neurologically asymptomatic and without corticosteroid treatment at the time of first dose of study treatment.
• History or current evidence of retinal vein occlusion (RVO) or current risk factors for RVO (e.g. uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or hypercoagulability syndromes).
• Current evidence of uncontrolled, significant intercurrent illness including, but not limited to, the following conditions:
• Cardiovascular disorders:
• Congestive heart failure New York Heart Association Class 3 or 4, unstable angina pectoris, serious cardiac arrhythmias.
• Stroke (including transient ischemic attack \[TIA\]), myocardial infarction (MI), or other ischemic events, or thromboembolic event (eg, deep venous thrombosis, pulmonary embolism) within 3 months before first dose.
• QTc prolongation defined as a QTcF \> 500 ms.
• History of seizures
• Impairment of gastrointestinal function or gastrointestinal disease (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection under the judgment of the PI may impair absorption of study drugs).

Sponsors & Collaborators

• University of Utah: lead
• BioMed Valley Discoveries, Inc: collaborator

Study Sites (1)

Huntsman Cancer Institute

Salt Lake City, Utah, 84112, United States

Location

MeSH Terms

Conditions

Gastrointestinal Neoplasms

Interventions

ulixertinib; Hydroxychloroquine

Condition Hierarchy (Ancestors)

Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases

Intervention Hierarchy (Ancestors)

Chloroquine; Aminoquinolines; Quinolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Open-label dose escalation of Ulixertinib combined with fixed dose of hydroxychloroquine.

Study Record Dates

• First Submitted: October 28, 2019
• First Posted: October 30, 2019
• Study Start: March 17, 2020
• Primary Completion: June 10, 2022
• Study Completion: August 18, 2022
• Last Updated: November 18, 2024

Record last verified: 2024-11

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)