- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT06007924
A Study of Avutometinib and Defactinib in People With Thyroid Cancer
Phase II of Avutometinib (VS-6766) and Defactinib In RAF Dimer-Driven RAI-Refractory Differentiated and Anaplastic Thyroid Cancer Patients
Study Overview
Status
Conditions
Intervention / Treatment
Study Type
Enrollment (Estimated)
Phase
- Phase 2
Contacts and Locations
Study Contact
- Name: Alan Ho, MD, PhD
- Phone Number: 646-608-3774
- Email: hoa@mskcc.org
Study Contact Backup
- Name: David Pfister, MD
- Phone Number: 646-888-4237
Study Locations
-
-
New Jersey
-
Basking Ridge, New Jersey, United States, 07920
- Recruiting
- Memorial Sloan Kettering Basking Ridge (Limited Protocol Activities)
-
Contact:
- Alan Ho, MD. PhD
- Phone Number: 646-608-3774
-
Middletown, New Jersey, United States, 07748
- Recruiting
- Memorial Sloan Kettering Monmouth (Limited Protocol Activities)
-
Contact:
- Alan Ho, MD, PhD
- Phone Number: 646-608-3774
-
Montvale, New Jersey, United States, 07645
- Recruiting
- Memorial Sloan Kettering Bergen (Limited Protocol Activities)
-
Contact:
- Alan Ho, MD, PhD
- Phone Number: 646-608-3774
-
-
New York
-
Commack, New York, United States, 11725
- Recruiting
- Memorial Sloan Kettering Cancer Center Suffolk - Commack (Limited Protocol Activities)
-
Contact:
- Alan Ho, MD, PhD
- Phone Number: 646-608-3774
-
Harrison, New York, United States, 10604
- Recruiting
- Memorial Sloan Kettering Westchester (Limited Protocol Activities)
-
Contact:
- Alan Ho, MD, PhD
- Phone Number: 646-608-3774
-
New York, New York, United States, 10065
- Recruiting
- Memorial Sloan Kettering Cancer Center (All Protocol Activities)
-
Contact:
- Alan Ho, MD. PhD
- Phone Number: 646-608-3774
-
Principal Investigator:
- Alan Ho, MD, PhD
-
Contact:
- David Pfister, MD
- Phone Number: 646-888-4237
-
Rockville Centre, New York, United States, 11553
- Recruiting
- Memorial Sloan Kettering Nassau (Limited Protocol Activities)
-
Contact:
- Alan Ho, MD, PhD
- Phone Number: 646-608-3774
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
- Adult
- Older Adult
Accepts Healthy Volunteers
Description
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 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 <4weeks 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 brain metastases requiring steroids or other local interventions. Patients 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. Patients with new asymptomatic CNS metastases detected during the screening period must receive radiation therapy and/or surgery for CNS metastases. Following treatment, these patients may then be eligible if all other criteria are met.
- 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 palliative 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-druginteractions-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%2F1370&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
- Cohort A only: Symptomatic metastatic brain or leptomeningeal tumors (asymptomatic or treated metastatic brain or leptomeningeal tumors are allowed).
- 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 would 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
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Non-Randomized
- Interventional Model: Parallel Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Radioiodine-refractory (RAIR), recurrent and/or metastatic differentiated thyroid cancer (DTC)
Patients will be treated with avutometinib 3.2 mg twice weekly and defactinib 200 mg twice daily, both 3 weeks on/1 week off.
|
Avutometinib 3.2 mg twice weekly 3 weeks on/1 week off
Defactinib 200 mg twice daily 3 weeks on/1 week off
|
Experimental: Anaplastic thyroid cancer (ATC)
Patients will be treated with avutometinib 3.2 mg twice weekly and defactinib 200 mg twice daily, both 3 weeks on/1 week off.
|
Avutometinib 3.2 mg twice weekly 3 weeks on/1 week off
Defactinib 200 mg twice daily 3 weeks on/1 week off
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
overall response rate (ORR) cohort A
Time Frame: up to 2 years
|
Response and progression will be evaluated in this study using the new international criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1)
|
up to 2 years
|
overall response rate (ORR) cohort B
Time Frame: up to 2 years
|
Response and progression will be evaluated in this study using the new international criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1)
|
up to 2 years
|
Collaborators and Investigators
Collaborators
Investigators
- Principal Investigator: Alan Ho, MD, PhD, Memorial Sloan Kettering Cancer Center
Publications and helpful links
Helpful Links
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Estimated)
Study Completion (Estimated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
Other Study ID Numbers
- 23-007
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
IPD Plan Description
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
Clinical Trials on Thyroid Cancer
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National Cancer Institute (NCI)TerminatedInsular Thyroid Cancer | Recurrent Thyroid Cancer | Stage IV Follicular Thyroid Cancer | Stage IV Papillary Thyroid Cancer | Anaplastic Thyroid Cancer | Stage III Follicular Thyroid Cancer | Stage III Papillary Thyroid CancerUnited States
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University of WashingtonNational Cancer Institute (NCI); GlaxoSmithKline; National Comprehensive Cancer...CompletedRecurrent Thyroid Cancer | Stage IVA Follicular Thyroid Cancer | Stage IVA Papillary Thyroid Cancer | Stage IVB Follicular Thyroid Cancer | Stage IVB Papillary Thyroid Cancer | Stage IVC Follicular Thyroid Cancer | Stage IVC Papillary Thyroid CancerUnited States
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National Cancer Institute (NCI)CompletedRecurrent Thyroid Cancer | Stage IVA Follicular Thyroid Cancer | Stage IVA Papillary Thyroid Cancer | Stage IVB Follicular Thyroid Cancer | Stage IVB Papillary Thyroid Cancer | Stage IVC Follicular Thyroid Cancer | Stage IVC Papillary Thyroid CancerUnited States
-
University of PennsylvaniaCompletedMetastatic Medullary Thyroid Cancer | Metastatic Differentiated Thyroid Cancer | Metastatic Anaplastic Thyroid Cancer | Metastatic Poorly Differentiated Thyroid CancerUnited States
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National Cancer Institute (NCI)CompletedInsular Thyroid Cancer | Recurrent Thyroid Cancer | Stage II Follicular Thyroid Cancer | Stage II Papillary Thyroid Cancer | Stage IV Follicular Thyroid Cancer | Stage IV Papillary Thyroid CancerUnited States
-
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-
University of WashingtonNational Cancer Institute (NCI)CompletedRecurrent Thyroid Cancer | Thyroid Gland Medullary Carcinoma | Stage IVA Follicular Thyroid Cancer | Stage IVA Papillary Thyroid Cancer | Stage IVB Follicular Thyroid Cancer | Stage IVB Papillary Thyroid Cancer | Stage IVC Follicular Thyroid Cancer | Stage IVC Papillary Thyroid CancerUnited States
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H. Lee Moffitt Cancer Center and Research InstituteTerminatedThyroid Cancer, Medullary | Thyroid Cancer | Papillary Thyroid Cancer | Differentiated Thyroid Cancer | Poorly Differentiated Thyroid Gland Carcinoma | Follicular Thyroid CancerUnited States
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National Cancer Institute (NCI)CompletedRecurrent Thyroid Cancer | Stage IV Follicular Thyroid Cancer | Stage IV Papillary Thyroid CancerUnited States
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