Trial Title:
A Phase 2 Study of Avutometinib (VS-6766) Plus Defactinib
NCT ID:
NCT05512208
Condition:
Endometrioid Cancer
Mucinous Ovarian Cancer
High Grade Serous Ovarian Cancer
Cervical Cancer
Solid Tumor
Conditions: Official terms:
Ovarian Neoplasms
Carcinoma, Ovarian Epithelial
Conditions: Keywords:
Avutometinib
defactinib
VS-6766
Study type:
Interventional
Study phase:
Phase 2
Overall status:
Recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Intervention model description:
A single-stage exploratory, Phase 2, multicenter, parallel cohort, open label study
designed to evaluate efficacy and safety of VS-6766 + defactinib.
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Avutometinib (VS-6766) + defactinib
Description:
Avutometinib (VS-6766): will be administered at 3.2 mg orally twice a week Defactinib:
will be administered at 200 mg orally twice a day (BID).
Treatment will be for 3 weeks, followed by a 1-week rest period, in each 4-week (28 day)
cycle.
Arm group label:
Avutometinib (VS-6766) + Defactinib
Summary:
The purpose of this research is to test the effectiveness and safety of the study drugs
(VS-6766 and defactinib), and see what effects (good and bad) these drugs have on the
patients with endometrioid cancer, mucinous ovarian cancer, high-grade serous ovarian
cancer, or cervical cancer.
Detailed description:
This is a single-stage exploratory, Phase 2, multicenter, parallel cohort, open label
study designed to evaluate efficacy and safety of VS-6766 + defactinib.
Enrolled study patients will receive the study drugs (VS-6766 and defactinib) to take
orally based on the study procedures. Patients will follow the study procedures and
attend all the study visits where various procedures including physical examinations,
vitals, assessing the size of the patient's tumor, and examination of urine and blood may
take place. Additional visits may be done to assess any other side effects a patient's
experiences.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
1. Female subjects ≥ 18 years of age.
2. Histologically proven gynecological cancers with mutated RAS, BRAF (type I, II,
and/or III), NF-1 loss of function, and/or RAS activation.
1. Mutational status will be taken from the previous next-gen sequencing (NGS) or
molecular testing results and reviewed by the Principal Investigator prior to
the start of treatment.
2. Adequate pathology material (as defined in the lab manual) must be available
prior to treatment assignment to be used for confirmation.
3. Tumor with known RAS mutation, BRAF (type I, II, and/or III) mutation, NF-1 and/or
RAS activation status determined from previous NGS or molecular testing. Adequate
archival tumor tissue less than 5 years old or fresh biopsy tissue samples (as
defined in the lab manual) must be available.
4. Progression (radiographic or clinical) or recurrence of gynecological cancer after
at least one prior systemic therapy for metastatic disease. Below are additional
prior treatments that are allowed once the requirement of prior platinum therapy is
satisfied.
a. Prior systemic therapy for metastatic disease (FIGO stage II-IV) may consist of
chemotherapy administered as single agent or a platinum or another chemotherapy
doublet with or without bevacizumab, with or without maintenance therapy or
radiation therapy; and/or hormonal therapy.
5. Measurable disease according to RECIST 1.1.
6. An Eastern Cooperative Group (ECOG) performance status ≤ 1.
7. Must have adequate organ function defined by the following laboratory parameters:
1. 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 has been administered the Hb must remain stable and ≥9 g/dL
for at least 1 week prior to first dose of study therapy.
2. Adequate hepatic function: (i) total bilirubin ≤1.5 × upper limit of normal
[ULN] for the institution; subjects with Gilbert syndrome may enroll if total
bilirubin is <3.0 mg/dL (51 μmole/L) upon discussion with the Principal
Investigator (PI). (ii) alanine aminotransferase (ALT) and alanine
aminotransferase (AST) ≤2.5 × ULN (or <5x ULN in subjects with liver
metastases).
3. Adequate renal function with creatinine clearance rate of ≥50 mL/min as
calculated by the Cockcroft-Gault formula or serum creatinine of ≤ 1.5 x ULN.
4. 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.
5. Albumin ≥3.0 g/dL (451 μmole/L).
6. Creatine phosphokinase (CPK) ≤2.5 x ULN.
7. Adequate cardiac function with left ventricular ejection fraction ≥ 50% by
echocardiography (ECHO) or multiple-gated acquisition (MUGA) scan.
8. Baseline QTc interval < 460 ms (average of triplicate readings) (CTCAE Grade1) 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
a. 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 by the Sponsor.
10. Females with reproductive potential and their male partners agree to use highly
effective method of contraceptive (per recommendations in Section 13.4) during the
trial and for 3 months following the last dose of study drug.
Exclusion Criteria:
1. Systemic anti-cancer therapy within 4 weeks of the first dose of study therapy.
2. Prior MEKi or RAFi exposure.
3. Low grade serous ovarian cancer (LGSOC).
4. History of prior malignancy with recurrence <3 years from the time of enrollment.
Subjects with basal cell carcinoma of the skin, superficial bladder cancer, squamous
cell carcinoma of the skin, and in situ cervical cancer that has undergone
potentially curative therapy with no evidence of disease recurrence for ≥1 year
since completion of the appropriate therapy may be included. Subjects with other
malignancies associated with very low risk of metastasis or death may be included
upon discussion with the PI.
5. Subjects who are deemed in the opinion of their treating physician to be appropriate
candidates for a debulking surgery. These subjects should preferentially receive
surgery prior to consideration of trial therapy.
6. Major surgery within 4 weeks (excluding placement of vascular access), minor surgery
within 2 weeks, or palliative radiotherapy within 1 week (7 days) of the first dose
of study therapy.
7. Treatment with warfarin. Subjects on warfarin for DVT/PE can be converted to
low-molecular weight heparin (LMWH) or direct oral anticoagulants (DOACs).
8. Exposure to strong CYP2C9 and CYP3A4 inhibitors or inducers within 14 days prior to
the first dose and during the course of therapy. See Table 14 and Table 15 for
representative lists of CYP inhibitors and inducers. For additional guidance, see
https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drugintera
ctions-table-substrates-inhibitors-and-inducers.
9. Exposure to P-glycoprotein (P-gp) inhibitors or inducers within 14 days prior to the
first dose and during the course of the study. See Table 16 for a representative
list of P-gp inhibitors and inducers.
10. Symptomatic brain metastases requiring steroids or other interventions. These
metastases may manifest as altered mental status, persistent headaches, persistent
nausea, focal weakness or numbness, and seizures. 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
2 weeks prior to first dose of study therapy, and are neurologically stable, with no
evidence of interim progression. Subjects with new asymptomatic CNS metastases
detected during the screening period must receive radiation therapy and/or surgery
for CNS metastases. Following treatment, these subjects may then be eligible if all
other criteria are met.
11. Known SARS-Cov2 infection (clinical symptoms) ≤28 days prior to first dose of study
therapy.
12. Known hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) infection that
is active and/or requires therapy.
13. Active skin disorder that has required systemic therapy within the past year.
14. History of rhabdomyolysis.
15. Concurrent ocular disorders:
1. Subjects with history of glaucoma, history of retinal vein occlusion (RVO),
predisposing factors for RVO, including uncontrolled hypertension, uncontrolled
diabetes.
2. Subject 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. Subjects with a history of corneal erosion (instability of corneal epithelium),
corneal degeneration, active or recurrent keratitis, and other forms of serious
ocular surface inflammatory conditions.
16. 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.
17. Subjects with the inability to swallow oral medications or impaired gastrointestinal
absorption due to gastrectomy or active inflammatory bowel disease.
18. Subjects with a history of hypersensitivity to any of the inactive ingredients
(hydroxypropylmethylcellulose, mannitol, magnesium stearate) of the investigational
product.
19. Female subjects who are pregnant or breastfeeding.
20. 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:
Female
Minimum age:
18 Years
Maximum age:
99 Years
Healthy volunteers:
No
Locations:
Facility:
Name:
University of New Mexico Comprehensive Cancer Center
Address:
City:
Albuquerque
Zip:
87131
Country:
United States
Status:
Recruiting
Contact:
Last name:
Colleen C McCormick, MD
Phone:
505-925-0460
Email:
CCMcCormick@salud.unm.edu
Contact backup:
Last name:
Ellen Wojcik, MBA-HCM
Email:
ewojcik@salud.unm.edu
Investigator:
Last name:
Colleen C McCormick, MD
Email:
Principal Investigator
Facility:
Name:
Stephenson Cancer Center
Address:
City:
Oklahoma City
Zip:
73117
Country:
United States
Status:
Recruiting
Contact:
Last name:
SCC IIT Office
Phone:
405-271-8777
Email:
SCC-IIT-Office@ouhsc.edu
Start date:
February 6, 2023
Completion date:
December 2029
Lead sponsor:
Agency:
University of Oklahoma
Agency class:
Other
Collaborator:
Agency:
Verastem, Inc.
Agency class:
Industry
Source:
University of Oklahoma
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05512208
