Berzosertib and Irinotecan in Treating Patients With Progressive, Metastatic, or Unresectable TP53 Mutant Gastric or Gastroesophageal Junction Cancer

NCT03641313 | Active Not Recruiting Phase 2 Results FDA Drug

• 4 other identifiers: NCI-2018-01739VICC LOI#1801210211UM1CA186689
• Study Type: interventional
• Target: 17
• Locations: 1 country
• Sites: 31

Brief Summary

This phase II trial studies the how well berzosertib and irinotecan work in treating patients with gastric or gastroesophageal junction cancer that is growing, spreading or getting worse (progressive), has spread to other places in the body (metastatic), or cannot be removed by surgery (unresectable). Berzosertib may stop the growth of tumor cells by blocking some of the enzymes needed for growth. Chemotherapy drugs, such as irinotecan, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving berzosertib and irinotecan may work better than irinotecan alone in treating patients with gastric and gastroesophageal junction cancer.

Conditions

Clinical Stage IV Gastric Cancer AJCC v8; Metastatic Gastric Adenocarcinoma; Unresectable Gastric Adenocarcinoma; Metastatic Gastroesophageal Junction Adenocarcinoma; Unresectable Gastroesophageal Junction Adenocarcinoma; Clinical Stage III Gastroesophageal Junction Adenocarcinoma AJCC v8; Clinical Stage IV Gastroesophageal Junction Adenocarcinoma AJCC v8; Clinical Stage III Gastric Cancer AJCC v8

Outcome Measures

Primary Outcomes (1)

• Objective Response Rate (ORR) According to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Response Criteria

  Number of patients that achieved either a partial response or complete response as measured by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 response criteria. Per RECIST v.1.1 assessed by CT or MRI: complete response (CR) is disappearance of all target lesions; partial response (PR) is \>=30% decrease in the sum of the longest diameter of target lesions; Overall response (OR) = CR + PR.

  Up to 1 year

Secondary Outcomes (4)

• Duration of Responses (DOR)

  From when patients achieve their best response (complete response [CR] or partial response [PR]) to when they progress or die for any reason, assessed up to 1 year

• Time to Progression (TTP)

  From start of treatment to time of progression or death from progression, assessed up to 1 year

• Progression-free Survival (PFS)

  From enrollment to disease progression or death for any reason, assessed up to 1 year

• Overall Survival (OS)

  From study enrollment to death for any reason, assessed up to 1 year

Other Outcomes (6)

• ORR in Sub-cohorts Based on First-line Platinum Sensitivity

  Up to 1 year

• DOR in Sub-cohorts Based on First-line Platinum Sensitivity

  Up to 1 year

• TTP in Sub-cohorts Based on First-line Platinum Sensitivity

  Up to 1 year

Study Arms (1)

Treatment (irinotecan and M6620)

EXPERIMENTAL

Patients receive irinotecan IV over 90 minutes and berzosertib IV over 60 minutes on days 1 and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo endoscopic or CT assisted biopsy and MRI on study.

Drug: Berzosertib; Procedure: Computed Tomography Assisted Biopsy; Procedure: Endoscopic Biopsy; Drug: Irinotecan; Procedure: Magnetic Resonance Imaging

Interventions

Magnetic Resonance Imaging PROCEDURE

Undergo MRI

Also known as: Magnetic Resonance, Magnetic Resonance Imaging (MRI), Magnetic resonance imaging (procedure), Magnetic Resonance Imaging Scan, Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance, MR, MR Imaging, MRI, MRI Scan, MRIs, NMR Imaging, NMRI, Nuclear Magnetic Resonance Imaging, sMRI, Structural MRI

Treatment (irinotecan and M6620)

Berzosertib DRUG

Given IV

Also known as: 2-Pyrazinamine, 3-(3-(4-((Methylamino)methyl)phenyl)-5-isoxazolyl)-5-(4-((1-methylethyl)sulfonyl)phenyl)-, M 6620, M6620, VX 970, VX-970, VX970

Treatment (irinotecan and M6620)

Computed Tomography Assisted Biopsy PROCEDURE

Undergo CT assisted biopsy

Also known as: Computed Tomography Biopsy, Computed Tomography-Guided Needle Biopsy, CT Assisted Biopsy, CT Guided Biopsy

Treatment (irinotecan and M6620)

Endoscopic Biopsy PROCEDURE

Undergo endoscopic biopsy

Also known as: Endoscopy and Biopsy

Treatment (irinotecan and M6620)

Irinotecan DRUG

Given IV

Treatment (irinotecan and M6620)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients must have histologically or cytologically confirmed progressive metastatic or unresectable gastric or GEJ adenocarcinoma.
• Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as \>= 20 mm (\>= 2 cm) by chest x-ray or as \>= 10 mm (\>= 1 cm) with computed tomography (CT) scan, magnetic resonance imaging (MRI), or calipers by clinical exam.
• Patients must have progressed after or been intolerant of at least two lines of systemic therapy. Patients with HER2 positive gastric and GEJ adenocarcinoma must have progressed on trastuzumab plus chemotherapy in the first line setting. Patients with microsatellite unstable (MSI-H) tumors must have received prior immunotherapy with pembrolizumab.
• Age \>= 18 years. Because no dosing or adverse event data are currently available on the use of M6620 in combination with irinotecan in patients \< 18 years of age, children are excluded from this study, but will be eligible for future pediatric trials.
• Both men and women of all races and ethnic groups are eligible for this trial.
• Eastern Cooperative Oncology Group (ECOG) performance status =\< 1 (Karnofsky \>= 60%).
• Leukocytes \>= 3,000/mcL.
• Absolute neutrophil count \>= 1,500/mcL.
• Platelets \>= 100,000/mcL.
• Hemoglobin \>= 9 g/dL.
• Total bilirubin within normal institutional limits.
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (serum glutamic pyruvic transaminase \[SGPT\]) =\< 2.5 x institutional upper limit of normal (ULN); if liver involvement =\< 5 x ULN.
• Creatinine clearance \>= 45 mL/min/1.73 m\^2 for patients with creatinine levels above institutional normal.
• Patients must have a TP53 mutation (only those known hot-spot mutations that fall within exon 2 or exons 4-11 will be accepted) determined from available archived tumor tissue that has been subjected to next generation sequencing (NGS) through FoundationOne/FoundationOneCDx or a similar assay performed in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory. Investigators from other sites, who have potential patients who meet study eligibility, will send copies of NGS reports from these patients via Medidata Rave case reports to the responsible study coordinator. Our research team will review each report to ensure each patient possesses the mutations of interest. Similar review will happen for each patient we enroll on the study at our institution. Case reports from all screened patients will be centrally available on the Rave study database.
• Nine patients must be willing to undergo endoscopic or CT guided tumor biopsies for mandatory correlative studies. If the biopsy is deemed not safe by the treating physician, the patient may still enroll given that the other eligibility criteria are met.

You may not qualify if:

• Patients with early stage untreated or resectable gastric adenocarcinoma.
• Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study.
• Patients who have previously received irinotecan.
• Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities \> grade 1, except alopecia) that was administered more than four weeks prior to starting study therapy.
• Patients who are receiving any other investigational agents.
• Patients with untreated or symptomatic brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to M6620 or irinotecan.
• M6620 is primarily metabolized by CYP3A4, and irinotecan and its active metabolite, SN-38, are metabolized by CYP3A4 and UGT1A1, respectively; therefore, concomitant administration with strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, clarithromycin, ritonavir, indinavir, nelfinavir and saquinavir) or inducers of CYP3A4 (e.g. rifampin, phenytoin, carbamazepine, phenobarbital, St. John's Wort) should be avoided. Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated medical reference for a list of drugs to avoid or minimize use of. As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product.
• 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 women are excluded from this study because M6620 as a DNA-damage response (DDR) inhibitor may 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 M6620, breastfeeding should be discontinued if the mother is treated with M6620. These potential risks also apply to irinotecan.
• Human immunodeficiency virus (HIV)-positive patients are excluded unless they have an undetectable viral load and are able to use anti-viral agents that do not interact with CYP3A4 (or regimens with agents that are not major inhibitors of cytochrome P450 enzymes).
• History of other malignancy within 36 months prior to enrollment. Patients with local cancers of any type, provided no recurrence over this timeframe, are eligible.

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (31)

City of Hope Comprehensive Cancer Center

Duarte, California, 91010, United States

Location

Los Angeles General Medical Center

Los Angeles, California, 90033, United States

Location

USC / Norris Comprehensive Cancer Center

Los Angeles, California, 90033, United States

Location

UC Irvine Health/Chao Family Comprehensive Cancer Center

Orange, California, 92868, United States

Location

University of California Davis Comprehensive Cancer Center

Sacramento, California, 95817, United States

Location

UM Sylvester Comprehensive Cancer Center at Coral Gables

Coral Gables, Florida, 33146, United States

Location

UM Sylvester Comprehensive Cancer Center at Deerfield Beach

Deerfield Beach, Florida, 33442, United States

Location

University of Miami Miller School of Medicine-Sylvester Cancer Center

Miami, Florida, 33136, United States

Location

UM Sylvester Comprehensive Cancer Center at Kendall

Miami, Florida, 33176, United States

Location

UM Sylvester Comprehensive Cancer Center at Plantation

Plantation, Florida, 33324, United States

Location

Northwestern University

Chicago, Illinois, 60611, United States

Location

University of Kansas Clinical Research Center

Fairway, Kansas, 66205, United States

Location

HaysMed

Hays, Kansas, 67601, United States

Location

Lawrence Memorial Hospital

Lawrence, Kansas, 66044, United States

Location

The University of Kansas Cancer Center - Olathe

Olathe, Kansas, 66061, United States

Location

University of Kansas Cancer Center-Overland Park

Overland Park, Kansas, 66210, United States

Location

Mercy Hospital Pittsburg

Pittsburg, Kansas, 66762, United States

Location

Salina Regional Health Center

Salina, Kansas, 67401, United States

Location

University of Kansas Health System Saint Francis Campus

Topeka, Kansas, 66606, United States

Location

University of Kansas Hospital-Westwood Cancer Center

Westwood, Kansas, 66205, United States

Location

University Health Truman Medical Center

Kansas City, Missouri, 64108, United States

Location

University of Kansas Cancer Center - North

Kansas City, Missouri, 64154, United States

Location

University of Kansas Cancer Center - Lee's Summit

Lee's Summit, Missouri, 64064, United States

Location

University of Kansas Cancer Center at North Kansas City Hospital

North Kansas City, Missouri, 64116, United States

Location

Wake Forest University at Clemmons

Clemmons, North Carolina, 27012, United States

Location

Wake Forest Baptist Health - Wilkes Medical Center

Wilkesboro, North Carolina, 28659, United States

Location

Wake Forest University Health Sciences

Winston-Salem, North Carolina, 27157, United States

Location

Ohio State University Comprehensive Cancer Center

Columbus, Ohio, 43210, United States

Location

University of Oklahoma Health Sciences Center

Oklahoma City, Oklahoma, 73104, United States

Location

Vanderbilt University/Ingram Cancer Center

Nashville, Tennessee, 37232, United States

Location

Huntsman Cancer Institute/University of Utah

Salt Lake City, Utah, 84112, United States

Location

Related Publications (1)

• Wheless MC, Stockton S, Soares HP, Dayyani F, Saeed A, Kim E, Jin N, Yacoub G, Florou V, Ayers GD, Guerrouahen BS, Contreras A, Li L, Ferry-Galow KV, Gore S, Das S, Berlin J. NCI 10211: a phase II, single-arm study of berzosertib in combination with irinotecan in patients with advanced TP53 mutant gastroesophageal cancer. Oncologist. 2025 Dec 1;30(12):oyaf400. doi: 10.1093/oncolo/oyaf400.

  PMID: 41335461 DERIVED

MeSH Terms

Interventions

berzosertib; Endoscopic Mucosal Resection; Endoscopy; Biopsy; Irinotecan; Magnetic Resonance Spectroscopy

Intervention Hierarchy (Ancestors)

Endoscopy, Gastrointestinal; Endoscopy, Digestive System; Diagnostic Techniques, Digestive System; Diagnostic Techniques and Procedures; Diagnosis; Diagnostic Techniques, Surgical; Digestive System Surgical Procedures; Surgical Procedures, Operative; Minimally Invasive Surgical Procedures; Cytodiagnosis; Cytological Techniques; Clinical Laboratory Techniques; Specimen Handling; Investigative Techniques; Camptothecin; Alkaloids; Heterocyclic Compounds; Spectrum Analysis; Chemistry Techniques, Analytical

Results Point of Contact

• Title: Jordan Berlin
• Organization: Vanderbilt-Ingram Cancer Center

jordan.berlin@vumc.org

6153434128

Study Officials

• Jordan D Berlin

  Yale University Cancer Center LAO

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 21, 2018
• First Posted: August 22, 2018
• Study Start: November 16, 2020
• Primary Completion: July 1, 2024
• Study Completion (Estimated): January 28, 2027
• Last Updated: April 13, 2026
• Results First Posted: July 8, 2025

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will share

Locations

US (31)