Clinical Trials/NCT05999812

NCT05999812

Active, not recruiting

Phase 2

Phase II Single-arm, Single-center Clinical Trial of All-trans-retinoic Acid, Bevacizumab and Atezolizumab in Refractory Microsatellite Stable Colorectal Cancer

University of Texas Southwestern Medical Center1 site in 1 country22 target enrollmentDecember 19, 2023

ConditionsColorectal Cancer

Interventionsall trans Retinoic Acid Atezolizumab Bevacizumab

Drugsall trans Retinoic Acid Atezolizumab Bevacizumab

Overview

Phase: Phase 2
Intervention: all trans Retinoic Acid
Conditions: Colorectal Cancer
Sponsor: University of Texas Southwestern Medical Center
Enrollment: 22
Locations: 1
Primary Endpoint: Objective Response Rate of of ATRA, bevacizumab and atezolizumab combination
Status: Active, not recruiting
Last Updated: 11 months ago

Overview Investigators Eligibility Criteria Arms & Interventions Outcomes Sites Similar Trials

Overview

Brief Summary

The main purpose of this clinical trial is to learn about the good and the bad effects of all trans retinoic acid (ATRA), atezolizumab and bevacizumab as a possible treatment for advanced colorectal patients.

Participants will be treated with the following combination of these drugs:

ATRA will be given in a pill form to be taken twice a day at home for 7 days starting on day 1 of a cycle.
Atezolizumab will be given through a vein in arm or through mediport over 60-90 minutes every 2 weeks in the outpatient chemotherapy infusion centers at UTSW.
Bevacizumab will be given through a vein in arm or through mediport over 20-40 minutes every 2 weeks in the outpatient chemotherapy infusion centers at UTSW.

Registry

clinicaltrials.gov

Start Date

December 19, 2023

End Date

October 1, 2028

Last Updated

11 months ago

Study Type

Interventional

Study Design

Single Group

Sex

All

Investigators

Sponsor

University of Texas Southwestern Medical Center

Responsible Party

Principal Investigator

Syed Kazmi

Assistant Professor, Internal Medicine

University of Texas Southwestern Medical Center

Eligibility Criteria

Inclusion Criteria

•Histologically proven stage IV colon adenocarcinoma (any T \[Tx, T1, T2, T3, or T4\], N1- 2, M1). Tumors must be deemed to originate in the colon including tumors that extend into/involve the small bowel (e.g. those at the ileocecal valve).
•Known DNA mismatch repair or microsatellite instability status. Only one of these tests is required for enrollment as there is 95% concordance rate of these tests.
•The eligible patient's tumors be classified as proficient in DNA mismatch repair (pMMR) by immunohistochemistry (IHC) for MMR protein expression (MLH1, MutS homolog 2 (MSH2), MutS homolog 6 (MSH6), PMS
•Tumors with intact expression of all MMR proteins will be considered pMMR.
•The eligible patient's tumor be classified by Pathologic Complete Response (pCR) as stable microsatellite stability status (MSS) for panel of microsatellite markers, OR
•MSS by commercially available next generation sequencing testing. OR
•If tumor-based test are not feasible, then commercially available circulating tumor DNA tests showing MSS status will also be acceptable.
•The patients should have received at least two lines of systemic chemotherapies in metastatic setting. They should have received fluoropyrimidine, irinotecan, and oxaliplatin unless medically contraindicated. Prior anti-VEGF (vascular endothelial growth factor) therapy is accepted for enrollment since anti-VEGF therapy maintains its benefit across several lines of therapy. If clinically appropriate, the patients should have received anti-EGFR (epidermal growth factor receptor) therapy for all Rat sarcoma (RAS) wild type colorectal cancers and v-raf murine sarcoma viral oncogene homolog B1 (BRAF) V600E mutation-directed therapy for BRAF V600E mutant colorectal cancers and HER2 targeted therapy for HER2 amplified colorectal cancers.
•Age 18 and above
•Performance status Eastern Cooperative Oncology Group (ECOG) 0-2

Exclusion Criteria

•Microsatellite unstable colorectal (MSI-H) cancers identified by PCR testing OR by commercially available Next-generation sequencing (NGS) and Circulating tumor DNA (ctDNA) testing OR by loss of expression of one or more of the MMR enzymes (MLH1, MSH2, MSH6, PMS2) on immunohistochemistry. Only one such test is required to confirm eligibility.
•Current active known or suspected autoimmune disease such as including colitis, inflammatory bowel disease (i.e. ulcerative colitis or Crohn's disease), rheumatoid arthritis, pan-hypopituitarism, History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan, adrenal insufficiency treated with immunosuppressive steroids and biologics treatment. Patients with controlled disease with no active treatment or prednisone \< 10 mg daily may be eligible based on treating physician assessment.
•Participants with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, history of radiation pneumonitis in the radiation field (fibrosis) is permitted or conditions not expected to recur in the absence of an external trigger are permitted to enroll.
•Any condition requiring systemic treatment with either corticosteroids (\> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days prior to the first dose of study drug. Inhaled steroids and adrenal replacement steroid doses up to 10 mg daily prednisone equivalent are permitted (although not encouraged) in the absence of active autoimmune disease.
•Prior use of atezolizumab or ATRA is not eligible. Prior use of any other immunotherapy such anti programmed death-ligand 1 (PD-L1), anti- programmed cell death protein 1 (PD-1), Anti-CTLA4 will also be excluded.
•Chemotherapy, radiotherapy, or other cancer therapy within 3 weeks prior to starting study treatment.
•Subjects must have recovered from prior treatment-related to toxicities to grade 1 or baseline (excluding alopecia and clinically stable toxicities requiring ongoing medical management, such as hypothyroidism from prior immune checkpoint inhibitor treatment).
•Subjects may not be receiving any other investigational agents for the treatment of the cancer under study within 28 days prior to initiation of study treatment
•Untreated brain metastases are not allowed. If prior treatment of brain metastases with surgery and/or radiation therapy has been provided, those patients will be clinically stable and not requiring escalating doses of steroids.
•History of allergic reactions attributed to compounds of similar chemical or biologic composition to ATRA, atezolizumab, and bevacizumab or other agents used in study.

Arms & Interventions

Treatment Arm

* ATRA orally 45 mg/m2 daily in 2 divided doses days 1-7, repeat every 14 days * Atezolizumab IV D1, 840 mg every 14 days * Bevacizumab IV D1, 10 mg/kg every 14 days

Intervention: all trans Retinoic Acid

Treatment Arm

* ATRA orally 45 mg/m2 daily in 2 divided doses days 1-7, repeat every 14 days * Atezolizumab IV D1, 840 mg every 14 days * Bevacizumab IV D1, 10 mg/kg every 14 days

Intervention: Atezolizumab

Treatment Arm

* ATRA orally 45 mg/m2 daily in 2 divided doses days 1-7, repeat every 14 days * Atezolizumab IV D1, 840 mg every 14 days * Bevacizumab IV D1, 10 mg/kg every 14 days

Intervention: Bevacizumab

Outcomes

Primary Outcomes

Objective Response Rate of of ATRA, bevacizumab and atezolizumab combination

Time Frame: From time of enrollment/treatment until disease progression, unacceptable toxicity, death, or discontinuation from the study treatment for any other reason up to 24 months

To determine the objective response rate of ATRA, bevacizumab and atezolizumab combination. Complete response+ partial response measured by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 in refractory microsatellite stable (proficient mismatch repair) colorectal cancers

Secondary Outcomes

Disease Control Rate of of ATRA, bevacizumab and atezolizumab combination(From time of enrollment/treatment until disease progression, unacceptable toxicity, death, or discontinuation from the study treatment for any other reason up to 24 months)
Frequency of adverse events(From time of enrollment/treatment until disease progression, unacceptable toxicity, death, or discontinuation from the study treatment for any other reason up to 24 months)