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Clinical Stage III Gastric Cancer AJCC v8Phase 2NCT03641313

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

A Phase 2 study testing Berzosertib, Computed Tomography Assisted Biopsy and Endoscopic Biopsy in people with Clinical Stage III Gastric Cancer AJCC v8 and Clinical Stage III Gastroesophageal Junction Adenocarcinoma AJCC v8, run by National Cancer Institute (NCI) at 31 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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Trial 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). Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Berzosertib, Computed Tomography Assisted Biopsy and Endoscopic Biopsy
Could I receive a placebo?
No, everyone receives an active treatment
How many people
17 participants
Where
31 sitesUnited States
Study dates
16 Nov 2020to 14 Sep 2026
Phase
Phase 2

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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%).
Show all 17Show fewer
  • 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.
  • The effects of M6620 on the developing human fetus are unknown. For this reason and because deoxyribonucleic acid (DNA)-damage response (DDR) inhibitors, as well as irinotecan, are known to be teratogenic, women of child-bearing potential and men able to father children who have female partners of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 6 months after trial participant's final dose of M6620 or irinotecan (whichever agent is completed last). Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.
  • Ability to understand and the willingness to sign a written informed consent document.

Who cannot join

  • 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.
Show all 12Show fewer
  • 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.

Trial locations and contacts

31 sites in 1 country.

31 sites in 1 country

United States31 sites

  • Northwestern University

    Chicago, Illinois, 60611

  • Wake Forest University at Clemmons

    Clemmons, North Carolina, 27012

  • Ohio State University Comprehensive Cancer Center

    Columbus, Ohio, 43210

  • UM Sylvester Comprehensive Cancer Center at Coral Gables

    Coral Gables, Florida, 33146

  • UM Sylvester Comprehensive Cancer Center at Deerfield Beach

    Deerfield Beach, Florida, 33442

  • City of Hope Comprehensive Cancer Center

    Duarte, California, 91010

  • University of Kansas Clinical Research Center

    Fairway, Kansas, 66205

  • HaysMed

    Hays, Kansas, 67601

  • University Health Truman Medical Center

    Kansas City, Missouri, 64108

  • University of Kansas Cancer Center - North

    Kansas City, Missouri, 64154

  • Lawrence Memorial Hospital

    Lawrence, Kansas, 66044

  • University of Kansas Cancer Center - Lee's Summit

    Lee's Summit, Missouri, 64064

  • Los Angeles General Medical Center

    Los Angeles, California, 90033

  • USC / Norris Comprehensive Cancer Center

    Los Angeles, California, 90033

  • University of Miami Miller School of Medicine-Sylvester Cancer Center

    Miami, Florida, 33136

  • UM Sylvester Comprehensive Cancer Center at Kendall

    Miami, Florida, 33176

  • Vanderbilt University/Ingram Cancer Center

    Nashville, Tennessee, 37232

  • University of Kansas Cancer Center at North Kansas City Hospital

    North Kansas City, Missouri, 64116

  • University of Oklahoma Health Sciences Center

    Oklahoma City, Oklahoma, 73104

  • The University of Kansas Cancer Center - Olathe

    Olathe, Kansas, 66061

  • UC Irvine Health/Chao Family Comprehensive Cancer Center

    Orange, California, 92868

  • University of Kansas Cancer Center-Overland Park

    Overland Park, Kansas, 66210

  • Mercy Hospital Pittsburg

    Pittsburg, Kansas, 66762

  • UM Sylvester Comprehensive Cancer Center at Plantation

    Plantation, Florida, 33324

  • University of California Davis Comprehensive Cancer Center

    Sacramento, California, 95817

  • Salina Regional Health Center

    Salina, Kansas, 67401

  • Huntsman Cancer Institute/University of Utah

    Salt Lake City, Utah, 84112

  • University of Kansas Health System Saint Francis Campus

    Topeka, Kansas, 66606

  • University of Kansas Hospital-Westwood Cancer Center

    Westwood, Kansas, 66205

  • Wake Forest Baptist Health - Wilkes Medical Center

    Wilkesboro, North Carolina, 28659

  • Wake Forest University Health Sciences

    Winston-Salem, North Carolina, 27157

Other trials in United States

About this study

Official title: A Phase 2 Single-Arm Study of M6620 in Combination With Irinotecan in Patients With Progressive TP53 Mutant Gastric and Gastro-Esophageal Junction Cancer

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.

Read the detailed description

PRIMARY OBJECTIVE:

  1. Determine objective response rate (ORR) superiority (target 25%) in TP53 mutant patients with progressive metastatic or unresectable gastric/gastroesophageal junction (GEJ) cancer who receive berzosertib (M6620) and irinotecan compared to ORR (5%) in historical control patients treated with single agent irinotecan alone.

SECONDARY OBJECTIVES:

  1. Determine duration of response (DOR), time to progression (TTP), progression-free survival (PFS), and overall survival (OS) superiority in TP53 mutant gastric/GEJ cancer patients who receive M6620 and irinotecan compared to these measures in historical control patients treated with irinotecan alone.

II. Perform the following correlative studies in 9 patients: gamma-H2AX, KAP1 phosphorylated (p)-Ser 824 and p-ATR analysis from biopsies collected at 24 hours (+/- 1 hour) post-irinotecan infusion on cycle 1 day 2 (C1D2) and at 24 hours (+/- 1 hour) post-M6620 on cycle 2 day 2 (C2D2).

EXPLORATORY OBJECTIVES:

  1. Determine ORR, DOR, TTP, PFS, and OS in patients with other concomitant damage response defects (DDRD), such as mutations in BRCA1, BRCA2, MRE11, RAD50, RAD51, RAD52, RAD54L, NBN, ATM, H2AX, PALB2, RPA, BRIP1, BARD1, ATR, ATRX, CHK1, CHK2, MDM2, MDM4, FANCA, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCL, treated with the experimental combination.

II. Determine whether patients with first line platinum sensitivity (PFS > 3 months) demonstrate improved ORR, DOR, TTP, PFS, and OS compared to patients who were platinum insensitive (PFS < 3 months).

OUTLINE:

Patients receive irinotecan intravenously (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 computed tomography (CT) assisted biopsy and magnetic resonance imaging (MRI) on study.

After completion of study treatment, patients are followed up for 30 days and then every 2 months for up to 1 year.

Being tested
Berzosertib, Computed Tomography Assisted Biopsy, Endoscopic Biopsy, Irinotecan, Magnetic Resonance Imaging

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • BerzosertibDrug

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

    Given IV

  • Computed Tomography Assisted BiopsyProcedure or surgery

    Also called Computed Tomography Biopsy, Computed Tomography-Guided Needle Biopsy, CT Assisted Biopsy, CT Guided Biopsy

    Undergo CT assisted biopsy

  • Endoscopic BiopsyProcedure or surgery

    Also called Endoscopy and Biopsy

    Undergo endoscopic biopsy

  • IrinotecanDrug

    Given IV

  • Magnetic Resonance ImagingProcedure or surgery

    Also called Magnetic Resonance, Magnetic Resonance Imaging (MRI), Magnetic resonance imaging (procedure), Magnetic Resonance Imaging Scan

    Undergo MRI

Study groups in NCT03641313
Study groupRoleWhat they receive
Treatment (irinotecan and M6620)ExperimentalPatients 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.
Receives: Drug: Berzosertib; Procedure: Computed Tomography Assisted Biopsy; Procedure: Endoscopic Biopsy; Drug: Irinotecan; Procedure: Magnetic Resonance Imaging

What is being measured

The primary outcome is the main question the study is designed to answer.

  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.

    Measured: Up to 1 year

Secondary outcomes (4)

  1. Duration of Responses (DOR)

    As 0 participants achieved a response (either complete response or partial response), data for this outcome measure can not be calculated.

    Measured: 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

  2. Time to Progression (TTP)

    Time to progression was calculated for all participants. Progression was defined as: 1) using the Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, a measurable increase in a non-target lesion, or the appearance of new lesions; and 2) clinical progression as defined by participant's treating physician. This measure was estimated using the method of Kaplan and Meier and presented with 95% confidence intervals.

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

  3. Progression-free Survival (PFS)

    Progression-free survival was calculated for all participants. Progression was defined as: 1) using the Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, a measurable increase in a non-target lesion, or the appearance of new lesions; and 2) clinical progression as defined by participant's treating physician. This measure was estimated using the method of Kaplan and Meier and presented with 95% confidence intervals.

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

  4. Overall Survival (OS)

    Overall survival was calculated for all participants. Will be estimated using the method of Kaplan and Meier and presented with 95% confidence intervals.

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

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted22 Aug 2018
  2. Study start16 Nov 2020
  3. Primary completion1 Jul 2024
  4. Study completion14 Sep 2026

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
17 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03641313
Sponsor's protocol ID
NCI-2018-01739
Other IDs
NCI-2018-01739, VICC LOI#18012, 10211, 10211, UM1CA186689
Status last verified
Sep 2026
First submitted
21 Aug 2018
Last updated
20 Oct 2026
Data monitoring committee
No
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
Yes: NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page

Publications

  • 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.

    PubMed 41335461

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