Trial Title:
A Study of Avutometinib and Defactinib in People With Thyroid Cancer
NCT ID:
NCT06007924
Condition:
Thyroid Cancer
Conditions: Official terms:
Thyroid Neoplasms
Thyroid Diseases
Conditions: Keywords:
Avutometinib
Defactinib
23-007
Study type:
Interventional
Study phase:
Phase 2
Overall status:
Recruiting
Study design:
Allocation:
Non-Randomized
Intervention model:
Parallel Assignment
Intervention model description:
This is a phase II clinical trial evaluating avutometinib in combination with defactinib
in radioiodine-refractory (RAIR), recurrent and/or metastatic differentiated thyroid
cancer (DTC) (Cohort A) and anaplastic thyroid cancer (ATC) (Cohort B) patients.
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Avutometinib
Description:
Avutometinib 3.2 mg twice weekly 3 weeks on/1 week off
Arm group label:
Anaplastic thyroid cancer (ATC)
Arm group label:
Radioiodine-refractory (RAIR), recurrent and/or metastatic differentiated thyroid cancer (DTC)
Intervention type:
Drug
Intervention name:
Defactinib
Description:
Defactinib 200 mg twice daily 3 weeks on/1 week off
Arm group label:
Anaplastic thyroid cancer (ATC)
Arm group label:
Radioiodine-refractory (RAIR), recurrent and/or metastatic differentiated thyroid cancer (DTC)
Summary:
The researchers are doing this study to find out if the combination of avutometinib and
defactinib is an effective treatment for RAF dimer-driven radioiodine-refractory
differentiated thyroid cancer or anaplastic thyroid cancer. The researchers will also
test whether avutometinib and defactinib is a safe treatment that causes few or mild side
effects.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
Cohort A will enroll RAIR, R/M DTC patients with RAF dimer-driven disease.
Cohort B will enroll ATC patients with RAF dimer-driven disease.
- Cohort A only: Patients must have pathologically or cytologically confirmed
differentiated thyroid cancer of follicular origin (including papillary thyroid
carcinoma, follicular thyroid carcinoma, hurthle cell carcinomas, poorly
differentiated thyroid carcinoma and their respective variants).
- Cohort B only: Patients must have anaplastic thyroid carcinoma.
- Confirmation in a CLIA certified laboratory that one of the patient's thyroid tumors
(primary tumor, recurrent tumor, or metastases) possess at least one of the
following genetic alterations: RAS mutation, NF1 mutation, RET rearrangement, NTRK
rearrangement, ALK rearrangement, Class 2 or 3 BRAF alterations (non-V600E/K
mutations or rearrangements).
- Cohort A only: Evidence of progressive disease (e.g. presence of new or growing
lesion(s) on radiologic imaging and/or new or worsening tumor-related symptoms)
within 14 months of study enrollment.
- Cohort A only: Patients must have recurrent or metastatic disease not amenable to
curative surgery or radiation.
- Patients with any number of prior therapies will be eligible.
- Patients must have RECIST v1.1 measurable disease.
- Age ≥ 18 years.
- ECOG performance status of 0 or 1.
- For Cohort A only: Patients must have not had recent treatment for thyroid cancer as
defined as:
- No prior RAI therapy is allowed <6 months prior to initiation of therapy on
this protocol. A diagnostic study using <10 mCi of RAI is not considered RAI
therapy
- No external beam radiation therapy <1 weeks prior to initiation of therapy on
this protocol.
- No chemotherapy or targeted therapy (e.g., tyrosine kinase inhibitor) is
allowed <4 weeks prior to the initiation of therapy on this protocol
- For Cohort A only: Patients must have RAI-refractory disease, defined as one of the
following:
- Total lifetime dose of radioiodine > 600 mCi
- A tumor that is not radioiodine-avid on a diagnostic radioiodine scan performed
- A radioiodine-avid metastatic lesion which progressed despite radioiodine
treatment given 6 months or more prior to study entry in the study. There are
no size limitations for the index lesions used to satisfy this entry criterion
- The presence of at least one fluorodeoxyglucose (FDG) avid lesion.
- Patients must be able to swallow and retain orally-administered pills without any
clinically significant gastrointestinal abnormalities that may alter absorption,
such as malabsorption syndrome or major resection of the stomach or bowels.
- 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.
- Patients must have tissue from the primary tumor or metastases available for
correlative studies. Either a paraffin block or at least 20 unstained slides are
acceptable (30 unstained slides would be ideal). (If less than twenty unstained
slides are available and a paraffin bloc is not available, the patient may be able
to participate at the discretion of the investigator).
- Patients must agree to undergo two research biopsies of (a) malignant lesion(s).
Tumor tissue obtained prior to study consent or treatment as part of standard of
care can also be submitted in lieu of performance of the first pre-treatment biopsy
if the Principal Investigator deems it to be of sufficient
quantity/quality/timeliness. Patients may also be exempt from biopsy if 1) the
investigator or person performing the biopsy judges that no tumor is accessible for
biopsy, 2) the investigator or person performing the biopsy feels that the biopsy
poses too great of a risk to the patient (including if conduct of the biopsy will
result in an unacceptable delay in therapy), or 3) the patient cannot be safely
removed from anti-coagulation therapy (if the anti-coagulation therapy needs to be
temporarily held for the biopsy procedure). If the only tumor accessible for biopsy
is also the only lesion that can be used for RECIST v1.1 response evaluation, then
the patient may be exempt from biopsy. If the investigator deems a second research
biopsy to be high risk after a patient has completed the first research biopsy, the
patient may be exempt from the second biopsy. Biopsies of lesions that are in
proximity to any vital neurovascular structures that can be considered high risk
procedures will not be biopsied.
- Baseline QTc interval < 460 ms for women and ≤450 ms for men using Frederica's QT
correction formula. NOTE: This criterion does not apply to patients with a right or
left bundle branch block.
- Adequate cardiac function wit left ventricular ejection fraction >50% by
echocardiography (ECHO) or multiple-gated acquisition (MUGA) scan.
- Screening laboratory values must meet the following criteria:
- WBC ≥ 2000/μL
- Neutrophils ≥ 1000/μL
- Platelets ≥ 100 x10^3 /μL
- Hemoglobin > 9.0 g/dL
- AST/ALT ≤ 2.5 x ULN (of < 5x ULN in patients with liver metastases)
- Total Bilirubin ≤ 1.5 x ULN (except subjects with Gilbert Syndrome, who can
have total bilirubin < 3.0 mg/dL)
- 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.
- Albumin ≥ 3.0 g/dL (451 μmole/L)
- Creatine phosphokinase (CPK) ≤ 2.5 x ULN
- Serum creatinine ≤ 1.5 x ULN or creatinine clearance (CrCl) ≥ 50 mL/min (if
using the Cockcroft-Gault formula below)
- Female CrCl = (140 - age in years) x weight in kg x 0.85 72 x serum creatinine
in mg/dL
- Male CrCl = (140 - age in years) x weight in kg x 1.00 72 x serum creatinine in
mg/dL
Exclusion Criteria:
- Symptomatic untreated brain or leptomeningeal metastases Note: Patients with
asymptomatic or treated brain or leptomeningeal metastases are allowed. Participants
with symptomatic brain or leptomeningeal metastases after surgical and/org radiation
therapy may be allowed with Principal Investigator approval.
- Prior therapy with a MEK 1/2 inhibitor or an inhibitor that targets Class II/Class
III BRAF alterations or a FAK inhibitor (with the exception of patients who received
these therapies for a defined period of time to enhance radioiodine activity).
- Patient who have had systemic investigational anti-cancer therapy within 4 weeks of
the first dose of study therapy.
- Major surgery within 4 weeks (excluding placement of vascular access), minor surgery
within 2 weeks, or radiotherapy within 1 week of the first dose of study drug.
- Treatment with warfarin. Patients on warfarin for deep vein thrombosis/pulmonary
embolism should be converted to low-molecular-weight heparin (LMWH) or direct oral
anticoagulants (DOACs).
- Concomitant use of strong inhibitors and inducers of CYP3A4 (see Appendix 1 in
Section 18). Patients should refrain from consumption of grapefruit, grapefruit
juice and St. John's Wort, and other medications (with or without prescriptions),
supplements, herbal remedies or foods that are strong inhibitors or inducers of
CYP3A4 during treatment
- Concomitant use of strong CYP2C9 inhibtors or inducers. For additional guidance see
https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drugintera
ctions-table-substrates-inhibitors-and-inducers
- Concomitant use of strong P-glycoprotein(P-gp) inhibitors or inducers. For
additional guidance see
https://www.uptodate.com/contents/image/print?imageKey=EM%2F73326&topicKey=HEME%2F13
70&source=outlinelink
- Patients with history of glaucoma, history of retinal vein occlusion (RVO),
predisposing factors for RVO, including uncontrolled hypertension, uncontrolled
diabetes.
- Patients with a history of retinal pathology or evidence of visible retinal
pathology that is considered a risk factor for RVO, such as an intraocular pressure
> 21 mmHg
- Treatment-refractory hypertension defined as a blood pressure of systolic >140 mmHg
and/or diastolic >90 mmHg which cannot be controlled by anti-hypertensive therapy.
- Patients with active hepatitis B infection (HBV surface antigen positive).
- Subject is known to be positive for Human Immunodeficiency Virus (HIV) or active
Hepatitis C Virus (HCV). Testing for HIV or Hepatitis C prior to initiation of the
study drug is not required. If a patient has a known history of treated HCV, then a
viral load is required to confirm clearance of infection.
- Known severe acute respiratory syndrome coronavirus 2 SARS-Cov2 infection (clinical
symptoms) ≤28 days prior to first dose of study therapy.
- History of rhabdomyolysis.
- 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.
- Subjects with the inability to swallow oral medications or impaired gastrointestinal
absorption due to gastrectomy or active inflammatory bowel disease
- Any other medical condition (e.g., cardiac, gastrointestinal, pulmonary,
psychiatric, neurological, genetic, etc.) that in the opinion of the Investigator
places the patient at unacceptably high risk for toxicity.
- Patients who are pregnant or breastfeeding.
- Patients with hypersensitivity to mannitol, magnesium stearate, HPMC (hydroxypropyl
methylcellulose) shells
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
Memorial Sloan Kettering Basking Ridge (Limited Protocol Activities)
Address:
City:
Basking Ridge
Zip:
07920
Country:
United States
Status:
Recruiting
Contact:
Last name:
Alan Ho, MD. PhD
Phone:
646-608-3774
Facility:
Name:
Memorial Sloan Kettering Monmouth (Limited Protocol Activities)
Address:
City:
Middletown
Zip:
07748
Country:
United States
Status:
Recruiting
Contact:
Last name:
Alan Ho, MD, PhD
Phone:
646-608-3774
Facility:
Name:
Memorial Sloan Kettering Bergen (Limited Protocol Activities)
Address:
City:
Montvale
Zip:
07645
Country:
United States
Status:
Recruiting
Contact:
Last name:
Alan Ho, MD, PhD
Phone:
646-608-3774
Facility:
Name:
Memorial Sloan Kettering Cancer Center Suffolk - Commack (Limited Protocol Activities)
Address:
City:
Commack
Zip:
11725
Country:
United States
Status:
Recruiting
Contact:
Last name:
Alan Ho, MD, PhD
Phone:
646-608-3774
Facility:
Name:
Memorial Sloan Kettering Westchester (Limited Protocol Activities)
Address:
City:
Harrison
Zip:
10604
Country:
United States
Status:
Recruiting
Contact:
Last name:
Alan Ho, MD, PhD
Phone:
646-608-3774
Facility:
Name:
Memorial Sloan Kettering Cancer Center (All Protocol Activities)
Address:
City:
New York
Zip:
10065
Country:
United States
Status:
Recruiting
Contact:
Last name:
Alan Ho, MD. PhD
Phone:
646-608-3774
Contact backup:
Last name:
David Pfister, MD
Phone:
646-888-4237
Investigator:
Last name:
Alan Ho, MD, PhD
Email:
Principal Investigator
Facility:
Name:
Memorial Sloan Kettering Nassau (Limited Protocol Activities)
Address:
City:
Rockville Centre
Zip:
11553
Country:
United States
Status:
Recruiting
Contact:
Last name:
Alan Ho, MD, PhD
Phone:
646-608-3774
Start date:
August 16, 2023
Completion date:
August 16, 2027
Lead sponsor:
Agency:
Memorial Sloan Kettering Cancer Center
Agency class:
Other
Collaborator:
Agency:
Verastem, Inc.
Agency class:
Industry
Source:
Memorial Sloan Kettering Cancer Center
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06007924
http://www.mskcc.org/mskcc/html/44.cfm
