Trial Title:
Avutometinib and Defactinib in Diffuse Gastric Cancer
NCT ID:
NCT06487221
Condition:
Gastric Cancer
Stomach Cancer
Conditions: Official terms:
Stomach Neoplasms
Study type:
Interventional
Study phase:
Phase 2
Overall status:
Recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Avutometinib
Description:
3.2mg orally
Arm group label:
Avutometinib & Defactinib
Other name:
VS6766
Intervention type:
Drug
Intervention name:
Defactinib
Description:
200 mg orally
Arm group label:
Avutometinib & Defactinib
Other name:
VS-6063
Summary:
The purpose of this study is to determine if the combination study treatment with
avutometinib and defactinib will prolong life in participants, is effective in decreasing
the size of the tumor(s), and if it is safe in subjects with diffuse-type stomach cancer.
Detailed description:
There are two main types of stomach cancer based on the appearance under the microscope:
intestinal-type and diffuse-type. Some stomach cancers also have a mix of intestinal-type
and diffuse-type (mixed type). The participants are being invited to take part in this
research study due to having been diagnosed with stomach cancer that has spread to other
parts of the body and/or cannot be surgically removed, has diffuse-type or mixed type
cells or has gene changes that are associated with diffuse-type stomach cancers (such as
mutations in the genes called CDH1 or RHOA), and have already been treated with
chemotherapy and the disease is now growing. Defactinib is an oral drug that inhibits the
protein focal adhesion kinase (FAK), which has been shown to promote growth of gastric
cancer. Avutometinib (also known as VS-6766) is an oral drug that blocks an important
signaling pathway in cancer cells known as the MAP kinase pathway. Avutometinib inhibits
two proteins in the MAPK kinase pathway, RAF and MEK. The purpose of this study is to
determine if the combination study treatment with defactinib and avutometinib is
effective in improving the length of time after the start of treatment in which a
participant is alive and their cancer does not grow or spread.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
1. Histologic or cytologic evidence of gastric/gastroesophageal junction carcinoma,
classified as diffuse type, poorly cohesive, signet ring cell, or mixed type.
Patients with known pathogenic CDH1 and/or RHOA mutations will be allowed regardless
of histology.
2. Prior therapy with at least one line of therapy for unresectable/metastatic disease,
which must include platinum and fluoropyrimidine.
3. ECOG performance status of 0 or 1
4. Age ≥ 18 years
5. Adequate organ function, defined by the following laboratory parameters:
a. Adequate hematologic function, including hemoglobin [Hb] ≥ 9.0 g/dL; platelets ≥
100,000/mm3; and absolute neutrophil count [ANC] ≥ 1500/mm3. If a red blood cell
transfusion or erythropoiesis-stimulating agent has been administered the Hb must
remain stable and ≥ 9 g/dL for at least 1 week prior to first dose of study
intervention.
(i) Subjects with Hgb ≥ 8.5 g/dL and <9.0 g/dL are eligible if there is no history
of significant cardiovascular risk features as per the investigator (i.e., prior
myocardial infarction) b. Adequate hepatic function: (i) total bilirubin ≤ 1.5 ×
upper limit of normal [ULN] for the institution; patients with Gilbert syndrome may
enroll if total bilirubin is < 3.0 mg/dL (51 μmol/L); (ii) alanine aminotransferase
(ALT) and aspartate aminotransferase (AST)
≤ 2.5 × ULN (or < 5 x ULN in patients with liver metastases). c. Adequate renal
function with creatinine clearance rate of ≥ 50 mL/min, as calculated by the
Cockcroft-Gault formula d. International normalized ratio (INR) ≤ 1.5 and partial
thromboplastin time (PTT) ≤ 1.5 x ULN in the absence of anticoagulation or
therapeutic levels in the presence of anticoagulation.
e. Albumin ≥ 3.0 g/dL (451 μmol/L). f. Creatine phosphokinase (CPK) ≤ 2.5 x ULN. g.
Adequate cardiac function with left ventricular ejection fraction ≥ 55% by
echocardiography (ECHO) or multiple-gated acquisition (MUGA) scan.
6. Disease that can be evaluated radiographically, which can be measurable disease or
non-measurable disease per RECIST 1.1. All radiology studies must be performed
within 28 days prior to start of study-directed therapy.
7. Tumor that is amenable to fresh biopsy, which may include malignant ascites that is
amenable for paracentesis.
8. Baseline QTc interval < 460 ms for females and ≤ 450 ms for males (average of
triplicate readings) using Fredericia's QT correction formula. NOTE: This criterion
does not apply to subjects with a right or left bundle branch block.
9. Adequate recovery from toxicities related to prior treatments to at least Grade 1 by
CTCAE v 5.0. Exceptions include alopecia and peripheral neuropathy grade ≤ 2.
Subjects with other toxicities that are stable on supportive therapy may be allowed
to participate with prior approval from the principal investigator.
10. The effects of the study drugs on the developing human fetus are unknown. For this
reason, women of child-bearing potential and men must agree to use adequate
contraception (see Section 7.6 for Contraception Guidance) prior to study entry and
for the duration of study participation. 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 3 months after the last dose of the study drug.
11. Ability to understand and the willingness to sign a written informed consent
document.
Exclusion Criteria:
1. Systemic anti-cancer therapy within 3 weeks of the first dose of study therapy, or
within 5 half-lives of the previous drug, whichever is shorter.
2. Patients currently receiving any other investigational agent.
3. Subjects may not have had a history of malignancy other that esophagogastric cancer
within two years prior to screening, with the exception of those with a negligible
risk of metastasis or death (e.g., 5-year overall survival >90%) such as adequately
treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, localized
prostate cancer, ductal carcinoma in situ, or stage I uterine cancer.
4. Major surgery within 4 weeks or palliative radiotherapy within 1 week of the first
dose of study therapy.
5. Treatment with warfarin. Subjects on warfarin for DVT/PE can be converted to low-
molecular-weight heparin (LMWH).
6. History of treatment with a direct and specific inhibitor of FAK, MEK, or KRAS.
7. Patients who had exposure to medications (with or without prescriptions),
supplements, herbal remedies, or foods with potential for drug-drug interactions
with avutometinib and/or defactinib within 14 days prior to the first dose of study
intervention and during the course of therapy, including:
1. Strong CYP3A4 inhibitors or inducers.
2. Strong CYP2C9 inhibitors or inducers.
3. Strong P-glycoprotein (P-gp) inhibitors or inducers
4. Strong breast cancer resistance protein (BCRP) inhibitors or inducers
8. Symptomatic brain metastases requiring steroids or other local interventions.
Subjects with previously diagnosed brain metastases are eligible if they have
completed their treatment and have recovered from the acute effects of radiation
therapy or surgery prior to study entry, have discontinued corticosteroid treatment
for these metastases for at least 4 weeks prior to first dose of study therapy, and
are neurologically stable.
9. Known hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) infection that
is active and/or requires therapy. HIV patients on combination antiretroviral
therapy are ineligible because of the potential for pharmacokinetic interactions
with the investigational agents.
10. Active skin disorder that has required systemic therapy within the past 1 year.
11. History of rhabdomyolysis.
12. Concurrent ocular disorders including the following:
1. Patients with history of glaucoma, history of retinal vein occlusion (RVO),
predisposing factors for RVO, including uncontrolled hypertension, uncontrolled
diabetes.
2. Patients with history of retinal pathology or evidence of visible retinal
pathology that is considered a risk factor for RVO, intraocular pressure > 21
mm Hg as measured by tonometry, or other significant ocular pathology, such as
anatomical abnormalities that increase the risk for RVO.
3. Patients with active or chronic, visually significant corneal disorders, other
active ocular conditions requiring ongoing therapy or clinically significant
corneal disease that prevents adequate monitoring of drug-induced keratopathy.
Examples of visually significant corneal disorders include corneal
degeneration, active or recurrent keratitis, and other forms of serious ocular
surface inflammatory conditions. Visually significant corneal disorders do NOT
include dry eyes, blepharitis, and uncomplicated corneal erosions.
13. Concurrent congestive heart failure, prior history of class III/IV cardiac disease
(New York Heart Association [NYHA]), myocardial infarction within the last 6 months,
unstable arrhythmias, unstable angina or severe obstructive pulmonary disease.
14. Inability to swallow oral medications.
15. History of hypersensitivity to any of the inactive ingredients
(hydroxylpropylmethylcellulose, mannitol, magnesium stearate) of the investigational
product.
16. Female subjects who are pregnant or breastfeeding. Pregnant women are excluded from
this study because the risk for teratogenic or abortifacient effects with the
investigational agents is unknown. Because there is an unknown but potential risk
for adverse events in nursing infants secondary to treatment of the mother,
breastfeeding should be discontinued if the mother is treated with the
investigational agents.
17. Any other medical condition (e.g., cardiac, gastrointestinal, pulmonary,
psychiatric, neurological, genetic, etc.) that in the opinion of the investigator
would place the subject at unacceptably high risk for toxicity.
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
Columbia University Irving Medical Center
Address:
City:
New York
Zip:
10032
Country:
United States
Status:
Recruiting
Contact:
Last name:
Research Nurse Navigator
Phone:
212-342-5162
Email:
cancerclinicaltrials@cumc.columbia.edu
Investigator:
Last name:
Ryan Moy, MD, PhD
Email:
Principal Investigator
Start date:
October 28, 2024
Completion date:
May 30, 2029
Lead sponsor:
Agency:
Ryan H. Moy, MD, PhD
Agency class:
Other
Collaborator:
Agency:
Verastem Oncology
Agency class:
Other
Source:
Columbia University
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06487221
