Clincosm LogoSign in Get a demo

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

Sponsor
National Cancer Institute (NCI) (NIH)
Overall Status
Recruiting
CT.gov ID
NCT03641313
Collaborator
(none)
18
Enrollment
31
Locations
1
Arm
36
Anticipated Duration (Months)
0.6
Patients Per Site
0
Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease Intervention/Treatment Phase
Phase 2

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.

  2. 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.

  2. 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.

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

Study Design

Study Type:
Interventional
Anticipated Enrollment :
18 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
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
Actual Study Start Date :
Jun 30, 2020
Anticipated Primary Completion Date :
Jul 1, 2023
Anticipated Study Completion Date :
Jul 1, 2023

Arms and Interventions

Arm Intervention/Treatment
Experimental: Treatment (irinotecan and M6620)

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.

Drug: Berzosertib
Given IV
Other Names:
  • 2-Pyrazinamine, 3-(3-(4-((Methylamino)methyl)phenyl)-5-isoxazolyl)-5-(4-((1-methylethyl)sulfonyl)phenyl)-
  • M 6620
  • M6620
  • VX 970
  • VX-970
  • VX970

    • Drug: Irinotecan
    Given IV

    Outcome Measures

    Primary Outcome Measures

    1. Objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 response criteria [Up to 1 year]

    Secondary Outcome Measures

    1. 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]

      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.

    2. Time to progression (TTP) [From start of treatment to time of progression or death from progression, assessed up to 1 year]

      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.

    3. Progression-free survival (PFS) [From enrollment to disease progression or death for any reason, assessed up to 1 year]

    4. Overall survival (OS) [From study enrollment to death for any reason, assessed up to 1 year]

      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.

    Other Outcome Measures

    1. ORR in sub-cohorts based on first-line platinum sensitivity [Up to 1 year]

    2. DOR in sub-cohorts based on first-line platinum sensitivity [Up to 1 year]

    3. TTP in sub-cohorts based on first-line platinum sensitivity [Up to 1 year]

    4. PFS in sub-cohorts based on first-line platinum sensitivity [Up to 1 year]

    5. OS in sub-cohorts based on first-line platinum sensitivity [Up to 1 year]

    6. Presence of other deoxyribonucleic acid (DNA) damage response defects (DDRD) [Up to 1 year]

      Will be summarized as frequency counts and percent of study group.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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.

    • 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.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 City of Hope Comprehensive Cancer Center Duarte California United States 91010
    2 Los Angeles County-USC Medical Center Los Angeles California United States 90033
    3 USC / Norris Comprehensive Cancer Center Los Angeles California United States 90033
    4 UC Irvine Health/Chao Family Comprehensive Cancer Center Orange California United States 92868
    5 University of California Davis Comprehensive Cancer Center Sacramento California United States 95817
    6 UM Sylvester Comprehensive Cancer Center at Coral Gables Coral Gables Florida United States 33146
    7 UM Sylvester Comprehensive Cancer Center at Deerfield Beach Deerfield Beach Florida United States 33442
    8 University of Miami Miller School of Medicine-Sylvester Cancer Center Miami Florida United States 33136
    9 UM Sylvester Comprehensive Cancer Center at Kendall Miami Florida United States 33176
    10 UM Sylvester Comprehensive Cancer Center at Plantation Plantation Florida United States 33324
    11 Northwestern University Chicago Illinois United States 60611
    12 University of Kansas Clinical Research Center Fairway Kansas United States 66205
    13 HaysMed University of Kansas Health System Hays Kansas United States 67601
    14 Lawrence Memorial Hospital Lawrence Kansas United States 66044
    15 Olathe Health Cancer Center Olathe Kansas United States 66061
    16 University of Kansas Cancer Center-Overland Park Overland Park Kansas United States 66210
    17 Ascension Via Christi - Pittsburg Pittsburg Kansas United States 66762
    18 Salina Regional Health Center Salina Kansas United States 67401
    19 University of Kansas Health System Saint Francis Campus Topeka Kansas United States 66606
    20 University of Kansas Hospital-Westwood Cancer Center Westwood Kansas United States 66205
    21 Truman Medical Centers Kansas City Missouri United States 64108
    22 University of Kansas Cancer Center - North Kansas City Missouri United States 64154
    23 University of Kansas Cancer Center - Lee's Summit Lee's Summit Missouri United States 64064
    24 University of Kansas Cancer Center at North Kansas City Hospital North Kansas City Missouri United States 64116
    25 Wake Forest University at Clemmons Clemmons North Carolina United States 27012
    26 Wake Forest Baptist Health - Wilkes Medical Center Wilkesboro North Carolina United States 28659
    27 Wake Forest University Health Sciences Winston-Salem North Carolina United States 27157
    28 Ohio State University Comprehensive Cancer Center Columbus Ohio United States 43210
    29 University of Oklahoma Health Sciences Center Oklahoma City Oklahoma United States 73104
    30 Vanderbilt University/Ingram Cancer Center Nashville Tennessee United States 37232
    31 Huntsman Cancer Institute/University of Utah Salt Lake City Utah United States 84112

    Sponsors and Collaborators

    • National Cancer Institute (NCI)

    Investigators

    • Principal Investigator: Satya Das, Yale University Cancer Center LAO

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    National Cancer Institute (NCI)
    ClinicalTrials.gov Identifier:
    NCT03641313
    Other Study ID Numbers:
    • NCI-2018-01739
    • NCI-2018-01739
    • VICC LOI#18012
    • 10211
    • 10211
    • UM1CA186689
    First Posted:
    Aug 22, 2018
    Last Update Posted:
    Aug 23, 2022
    Last Verified:
    Jul 1, 2022
    Individual Participant Data (IPD) Sharing Statement:
    Yes
    Plan to Share IPD:
    Yes
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Additional relevant MeSH terms:
    Adenocarcinoma
    Stomach Neoplasms
    Esophageal Neoplasms
    Irinotecan

    Study Results

    No Results Posted as of Aug 23, 2022