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

PRIMARY OBJECTIVE:

I. 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:

I. 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:

I. 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.

• Berzosertib (Drug), 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: Given IV
• Computed Tomography Assisted Biopsy (Procedure), also known as Computed Tomography Biopsy, Computed Tomography-Guided Needle Biopsy, CT Assisted Biopsy, CT Guided Biopsy: Undergo CT assisted biopsy
• Endoscopic Biopsy (Procedure), also known as Endoscopy and Biopsy: Undergo endoscopic biopsy
• Irinotecan (Drug): Given IV
• Magnetic Resonance Imaging (Procedure), 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: Undergo MRI

Primary outcomes

• Objective Response Rate (ORR) According to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Response Criteria [Up to 1 year]: 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.

Secondary outcomes

• 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]: As 0 participants achieved a response (either complete response or partial response), data for this outcome measure can not be calculated.
• Time to Progression (TTP) [From start of treatment to time of progression or death from progression, assessed up to 1 year]: 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.
• Progression-free Survival (PFS) [From enrollment to disease progression or death for any reason, assessed up to 1 year]: 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.
• Overall Survival (OS) [From study enrollment to death for any reason, assessed up to 1 year]: Overall survival was calculated for all participants. Will be estimated using the method of Kaplan and Meier and presented with 95% confidence intervals.

Other outcomes

• ORR in Sub-cohorts Based on First-line Platinum Sensitivity [Up to 1 year]: Number of participants that had a partial response or complete response to treatment per RECIST v1.1 categorized by platinum sensitivity. Platinum sensitivity was defined as receiving a prior platinum-based therapy for more than 3 months. 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.
• DOR in Sub-cohorts Based on First-line Platinum Sensitivity [Up to 1 year]: As 0 participants achieved a response (either complete response or partial response), data for this outcome measure can not be calculated.
• TTP in Sub-cohorts Based on First-line Platinum Sensitivity [Up to 1 year]: Time to progression was calculated for sub cohorts of participants based on sensitivity to prior platinum-based treatment. 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.
• PFS in Sub-cohorts Based on First-line Platinum Sensitivity [Up to 1 year]: Progression-free survival was calculated for sub cohorts of participants based on sensitivity to prior platinum-based treatment. 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.
• OS in Sub-cohorts Based on First-line Platinum Sensitivity [Up to 1 year]: Overall survival was calculated for sub cohorts of participants based on sensitivity to prior platinum-based treatment
• Presence of Other Deoxyribonucleic Acid (DNA) Damage Response Defects (DDRD) [Up to 1 year]: Mutations present will be summarized as frequency counts and percent of study group.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* 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.
* 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.

Exclusion Criteria:

* 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.

Participant flow

Outcome results

• Objective Response Rate (ORR) According to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Response Criteria (Primary), Count of participants, Participants: Treatment (Irinotecan and M6620) 0
• Duration of Responses (DOR) (Secondary), Median, months: Treatment (Irinotecan and M6620) NA (NA to NA)
• Time to Progression (TTP) (Secondary), Median, months: Treatment (Irinotecan and M6620) 3.5 (1.8 to 4.8)
• Progression-free Survival (PFS) (Secondary), Median, months: Treatment (Irinotecan and M6620) 4.01 (2.07 to NA)
• Overall Survival (OS) (Secondary), Median, months: Treatment (Irinotecan and M6620) 6.21 (4.83 to 8.61)
• ORR in Sub-cohorts Based on First-line Platinum Sensitivity (Other pre specified), Count of participants, Participants: Platinum Sensitive 0; Platinum Not Sensitive 0
• DOR in Sub-cohorts Based on First-line Platinum Sensitivity (Other pre specified), Median, months: Platinum Sensitive NA (NA to NA); Platinum Not Sensitive NA (NA to NA)
• TTP in Sub-cohorts Based on First-line Platinum Sensitivity (Other pre specified), Median, months: Platinum Sensitive 4.3 (1.7 to NA); Platinum Not Sensitive 1.9 (1.8 to NA)
• PFS in Sub-cohorts Based on First-line Platinum Sensitivity (Other pre specified), Median, months: Platinum Sensitive 4.0 (1.7 to 4.8); Platinum Not Sensitive 1.9 (1.8 to NA)
• OS in Sub-cohorts Based on First-line Platinum Sensitivity (Other pre specified), Median, months: Platinum Sensitive 6.2 (3.7 to 7.2); Platinum Not Sensitive 4.4 (2.1 to NA)
• Presence of Other Deoxyribonucleic Acid (DNA) Damage Response Defects (DDRD) (Other pre specified), Count of participants, Participants: ATRX Mutation 1; MDM2 Mutation 1

Adverse events

Time frame: Adverse events that emerge (or worsen) after the first dose of study drug and within 30 days after the last dose.

Serious adverse events by term

Other adverse events by term

27 more terms not shown.

• Results publication: 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

• Study Protocol and Statistical Analysis Plan (PDF, 2022-12-02)
• Informed Consent Form (PDF, 2022-12-02)

• Jordan D Berlin, Principal investigator, Yale University Cancer Center LAO

NIH grants: UM1CA186689