A Window of Opportunity Trial Evaluating the Oral TGF-beta Receptor I Inhibitor Vactosertib in Patients Undergoing Standard of Care Chemoradiotherapy for Locally Advanced Esophageal Adenocarcinoma
Overview
- Phase
- Phase 2
- Intervention
- Vactosertib
- Conditions
- Adenocarcinoma Esophagus
- Sponsor
- Sakti Chakrabarti
- Enrollment
- 25
- Locations
- 1
- Primary Endpoint
- Metabolic Response
- Status
- Recruiting
- Last Updated
- last year
Overview
Brief Summary
This interventional clinical trial aims to find ways of improving treatments for individuals with esophageal cancer. Laboratory-based studies show that using medicines that affect a protein called TGF-beta (TGFβ) can kill esophageal cancer cells in individuals who have localized esophageal adenocarcinoma and are being considered for standard-of-care chemoradiation prior to surgery. Participants of this study will take a pill called vactosertib for two weeks before starting standard of care chemoradiation. At the end of the two weeks of taking vactosertib, participants will have a Positron Emission Tomography Computer Assisted Tomography (PET CT) scan and undergo an endoscopy with a biopsy to determine if the vactosertib is working. After chemoradiation, participants will take vactosertib again for four weeks and then be considered for surgery.
Detailed Description
Esophageal adenocarcinoma (EAC) is an aggressive malignancy with limited effective treatment options. In localized EAC (clinical stages II and III), the standard of care is pre-operative concurrent chemoradiation (CRT) followed by surgical resection, which results in pathologic complete response (pCR) in approximately 20% of participants, but with high rates of post-operative recurrence. It was recently discovered that EACs are driven by signaling through TGFβ Receptor I (TGFβRI), and in vivo models of EAC show tumor reduction by targeting this pathway with a novel small molecule inhibitor of TGFβRI called vactosertib. In this study, participants who have locally advanced EAC will be treated with vactosertib before and after standard of care chemoradiation to take advantage of natural windows of opportunity during which participants are being planned for their standard of care treatments.
Investigators
Sakti Chakrabarti
Principal Investigator
Case Comprehensive Cancer Center
Eligibility Criteria
Inclusion Criteria
- •Subjects must have histologically or cytologically confirmed poorly differentiated or Grade 3 adenocarcinoma of the esophagus or gastroesophageal junction, clinical Stage II or III who are appropriate for concurrent chemoradiotherapy with carboplatin and paclitaxel or FOLFOX as per standard of care. Clinical staging appropriate:
- •cT2 N0 with high-risk lesions including lymphovascular invasion, tumors ≥ 3cm in size, or poorly differentiated histology, or
- •cT1b-cT2, N+, or
- •cT3-cT4a, any N
- •Subjects must be deemed a potential surgical candidate by a thoracic surgeon, surgical oncologist, or surgeon who is qualified to perform an esophagectomy.
- •Subjects must NOT have received prior chemotherapy, immunotherapy, or radiation therapy for management of this malignancy (prior ablations or localized therapies for Barrett's metaplasia are acceptable).
- •Age ≥18 years. Because no dosing or adverse event data are currently available on the use of vVactosertib in subjects ≤18 years of age, children are excluded from this study.
- •ECOG Performance status ≤2
- •Subjects must have normal organ and marrow function as defined below:
- •Serum total bilirubin \<2 mg/dl. If known Gilbert syndrome, total bilirubin must be \<3mg/dl
Exclusion Criteria
- •Subjects receiving any other investigational agents. Proton-beam radiation is acceptable, if it is considered standard of care in the opinion of the treating radiation oncologist.
- •Subjects with active malignancy within the past 3 years, except if locally curable cancers that have been apparently cured such as non-melanoma cutaneous malignancy, superficial bladder cancer, or carcinoma in situ of the breast or cervix.
- •History of allergic reactions to carboplatin, paclitaxel or fluorouracil, oxaliplatin, or vactosertib.
- •Subjects with contraindication to radiation therapy.
- •Subjects with contraindication to carboplatin and paclitaxel or FOLFOX chemotherapy as per standard of care.
- •Subjects with uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
- •Pregnant or breastfeeding women are excluded from this study because cytotoxic agents and radiation therapy have the potential for teratogenic or abortifacient effects. Because there is an unknown, but potential risk for adverse events in nursing infants secondary to treatment of the mother with chemotherapy, breastfeeding should be discontinued if the mother participates in the trial. These potential risks may also apply to other agents used in this study.
- •HIV-positive patients are ineligible because of the potential for pharmacokinetic interactions with chemotherapeutic agents and because of a potential risk of worsening HIV viral load in response to TGFβ signaling inhibition. In addition, these patients are at increased risk of lethal infections when treated with marrow suppressive therapy.
- •Chronic active untreated hepatitis B or C infection. (Assessments should include Hepatitis B Surface AB, Hepatitis B Surface AG, Hepatitis B Core AB - Total, Hepatitis B Core AB, IGM, Hepatitis C AB).
- •Treated viral hepatitis patients with undetectable viral load are excluded because there is an enhanced risk of reactivation of the virus. Apart from the potential reactivation risk, the hepatitis-induced liver damage may delay or even cause discontinuation of chemotherapy.
Arms & Interventions
Vactosertib + Chemoradiotherapy
Vactosertib orally, 200 mg twice daily for five days a week for 2 weeks, followed by standard of care chemoradiotherapy, followed by Vactosertib for 4 weeks after standard of care chemoradiotherapy
Intervention: Vactosertib
Vactosertib + Chemoradiotherapy
Vactosertib orally, 200 mg twice daily for five days a week for 2 weeks, followed by standard of care chemoradiotherapy, followed by Vactosertib for 4 weeks after standard of care chemoradiotherapy
Intervention: Standard of Care Chemotherapy
Vactosertib + Chemoradiotherapy
Vactosertib orally, 200 mg twice daily for five days a week for 2 weeks, followed by standard of care chemoradiotherapy, followed by Vactosertib for 4 weeks after standard of care chemoradiotherapy
Intervention: Concurrent Radiation
Outcomes
Primary Outcomes
Metabolic Response
Time Frame: At two weeks post treatment
Determine if two-week treatment with single agent vactosertib induces metabolic response by PET CT imaging in primary EAC tumors. This will be measured as the rate of tumors that have decreased FDG tracer uptake by \>= 35% SUV on PET CT after 2 week treatment with vactosertib.
Secondary Outcomes
- Pathological Response(At approximately 14 weeks from starting treatment)
- Correlate baseline expression(At approximately 14 weeks from starting treatment)
- Ability to take vactosertib before and after standard of care chemoradiation(At approximately 14 weeks from starting treatment)