Principal Investigator
Enrollment Status
Clinical Trial ID
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.
Phase
Phase 2
Funding Agency/Sponsor
National Cooperative Group
Disease
Stomach and Esophageal Cancer
Enrollment 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.