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

Metastatic Gastroesophageal Junction Adenocarcinoma Clinical Trial

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03641313
• Other study ID #: NCI-2018-01739
• Secondary ID: NCI-2018-01739VI
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: November 16, 2020
• Est. completion date: July 1, 2024

Study information

• Verified date: March 2024
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical 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). 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.

Description:

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 18
• Est. completion date: July 1, 2024
• Est. primary completion date: July 1, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Adenocarcinoma
• Clinical Stage III Gastric Cancer AJCC v8
• Clinical Stage III Gastroesophageal Junction Adenocarcinoma AJCC v8
• Clinical Stage IV Gastric Cancer AJCC v8
• Clinical Stage IV Gastroesophageal Junction Adenocarcinoma AJCC v8
• Esophageal Neoplasms
• Metastatic Gastric Adenocarcinoma
• Metastatic Gastroesophageal Junction Adenocarcinoma
• Stomach Neoplasms
• Unresectable Gastric Adenocarcinoma
• Unresectable Gastroesophageal Junction Adenocarcinoma

Intervention

Drug:
• Berzosertib
Given IV

Procedure:
• Computed Tomography Assisted Biopsy
Undergo CT assisted biopsy
• Endoscopic Biopsy
Undergo endoscopic biopsy

Drug:
• Irinotecan
Given IV

Procedure:
• Magnetic Resonance Imaging
Undergo MRI

Locations

Country	Name	City	State
United States	Northwestern University	Chicago	Illinois
United States	Wake Forest University at Clemmons	Clemmons	North Carolina
United States	Ohio State University Comprehensive Cancer Center	Columbus	Ohio
United States	UM Sylvester Comprehensive Cancer Center at Coral Gables	Coral Gables	Florida
United States	UM Sylvester Comprehensive Cancer Center at Deerfield Beach	Deerfield Beach	Florida
United States	City of Hope Comprehensive Cancer Center	Duarte	California
United States	University of Kansas Clinical Research Center	Fairway	Kansas
United States	HaysMed	Hays	Kansas
United States	University Health Truman Medical Center	Kansas City	Missouri
United States	University of Kansas Cancer Center - North	Kansas City	Missouri
United States	Lawrence Memorial Hospital	Lawrence	Kansas
United States	University of Kansas Cancer Center - Lee's Summit	Lee's Summit	Missouri
United States	Los Angeles General Medical Center	Los Angeles	California
United States	USC / Norris Comprehensive Cancer Center	Los Angeles	California
United States	UM Sylvester Comprehensive Cancer Center at Kendall	Miami	Florida
United States	University of Miami Miller School of Medicine-Sylvester Cancer Center	Miami	Florida
United States	Vanderbilt University/Ingram Cancer Center	Nashville	Tennessee
United States	University of Kansas Cancer Center at North Kansas City Hospital	North Kansas City	Missouri
United States	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma
United States	Olathe Health Cancer Center	Olathe	Kansas
United States	UC Irvine Health/Chao Family Comprehensive Cancer Center	Orange	California
United States	University of Kansas Cancer Center-Overland Park	Overland Park	Kansas
United States	Ascension Via Christi - Pittsburg	Pittsburg	Kansas
United States	UM Sylvester Comprehensive Cancer Center at Plantation	Plantation	Florida
United States	University of California Davis Comprehensive Cancer Center	Sacramento	California
United States	Salina Regional Health Center	Salina	Kansas
United States	Huntsman Cancer Institute/University of Utah	Salt Lake City	Utah
United States	University of Kansas Health System Saint Francis Campus	Topeka	Kansas
United States	University of Kansas Hospital-Westwood Cancer Center	Westwood	Kansas
United States	Wake Forest Baptist Health - Wilkes Medical Center	Wilkesboro	North Carolina
United States	Wake Forest University Health Sciences	Winston-Salem	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	ORR in sub-cohorts based on first-line platinum sensitivity		Up to 1 year
Other	DOR in sub-cohorts based on first-line platinum sensitivity		Up to 1 year
Other	TTP in sub-cohorts based on first-line platinum sensitivity		Up to 1 year
Other	PFS in sub-cohorts based on first-line platinum sensitivity		Up to 1 year
Other	OS in sub-cohorts based on first-line platinum sensitivity		Up to 1 year
Other	Presence of other deoxyribonucleic acid (DNA) damage response defects (DDRD)	Will be summarized as frequency counts and percent of study group.	Up to 1 year
Primary	Objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 response criteria		Up to 1 year
Secondary	Duration of responses (DOR)	Will be estimated using the method of Kaplan and Meier. 95% confidence intervals for all point estimates of effect sizes (odd ratios, hazard ratios, differential pre-post biomarker expression) among subgroups will be estimated.	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
Secondary	Time to progression (TTP)	Will be estimated using the method of Kaplan and Meier. 95% confidence intervals for all point estimates of effect sizes (odd ratios, hazard ratios, differential pre-post biomarker expression) among subgroups will be estimated.	From start of treatment to time of progression or death from progression, assessed up to 1 year
Secondary	Progression-free survival (PFS)		From enrollment to disease progression or death for any reason, assessed up to 1 year
Secondary	Overall survival (OS)	Will be estimated using the method of Kaplan and Meier. 95% confidence intervals for all point estimates of effect sizes (odd ratios, hazard ratios, differential pre-post biomarker expression) among subgroups will be estimated.	From study enrollment to death for any reason, assessed up to 1 year