Clinical Trials /

ATR Kinase Inhibitor M6620 and Irinotecan in Treating Patients With Progressive, Metastatic, or Unresectable TP53 Mutant Gastric or Gastroesophageal Junction Cancer

NCT03641313

Description:

This phase II trial studies the how well ATR kinase inhibitor M6620 and irinotecan work in treating participants with gastric or gastroesophageal junction cancer that is growing, spreading or getting worse, has spread to other places in the body, or cannot be removed by surgery. ATR kinase inhibitor M6620 may stop the growth of tumor cells by blocking some of the enzymes needed for growth. Drugs used in chemotherapy, 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 ATR kinase inhibitor M6620 and irinotecan may work better in treating participants with gastric and gastroesophageal junction cancer.

Related Conditions:
  • Adenocarcinoma of the Gastroesophageal Junction
  • Gastric Adenocarcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: ATR Kinase Inhibitor M6620 and Irinotecan in Treating Patients With Progressive, Metastatic, or Unresectable TP53 Mutant Gastric or Gastroesophageal Junction Cancer
  • 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 IDs

  • ORG STUDY ID: NCI-2018-01739
  • SECONDARY ID: NCI-2018-01739
  • SECONDARY ID: VICC LOI#18012
  • SECONDARY ID: 10211
  • SECONDARY ID: 10211
  • SECONDARY ID: UM1CA186689
  • NCT ID: NCT03641313

Conditions

  • 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
  • Clinical Stage IVA Gastric Cancer AJCC v8
  • Clinical Stage IVA Gastroesophageal Junction Adenocarcinoma AJCC v8
  • Clinical Stage IVB Gastric Cancer AJCC v8
  • Clinical Stage IVB Gastroesophageal Junction Adenocarcinoma AJCC v8
  • Metastatic Gastric Adenocarcinoma
  • Metastatic Gastroesophageal Junction Adenocarcinoma
  • Pathologic Stage III Gastric Cancer AJCC v8
  • Pathologic Stage III Gastroesophageal Junction Adenocarcinoma AJCC v8
  • Pathologic Stage IIIA Gastric Cancer AJCC v8
  • Pathologic Stage IIIA Gastroesophageal Junction Adenocarcinoma AJCC v8
  • Pathologic Stage IIIB Gastric Cancer AJCC v8
  • Pathologic Stage IIIB Gastroesophageal Junction Adenocarcinoma AJCC v8
  • Pathologic Stage IIIC Gastric Cancer AJCC v8
  • Pathologic Stage IV Gastric Cancer AJCC v8
  • Pathologic Stage IV Gastroesophageal Junction Adenocarcinoma AJCC v8
  • Pathologic Stage IVA Gastroesophageal Junction Adenocarcinoma AJCC v8
  • Pathologic Stage IVB Gastroesophageal Junction Adenocarcinoma AJCC v8
  • Postneoadjuvant Therapy Stage III Gastric Cancer AJCC v8
  • Postneoadjuvant Therapy Stage III Gastroesophageal Junction Adenocarcinoma AJCC v8
  • Postneoadjuvant Therapy Stage IIIA Gastroesophageal Junction Adenocarcinoma AJCC v8
  • Postneoadjuvant Therapy Stage IIIB Gastroesophageal Junction Adenocarcinoma AJCC v8
  • Postneoadjuvant Therapy Stage IV Gastric Cancer AJCC v8
  • Postneoadjuvant Therapy Stage IV Gastroesophageal Junction Adenocarcinoma AJCC v8
  • Postneoadjuvant Therapy Stage IVA Gastroesophageal Junction Adenocarcinoma AJCC v8
  • Postneoadjuvant Therapy Stage IVB Gastroesophageal Junction Adenocarcinoma AJCC v8
  • TP53 Gene Mutation
  • Unresectable Gastroesophageal Junction Adenocarcinoma

Interventions

DrugSynonymsArms
ATR Kinase Inhibitor M6620M 6620, M6620, VX-970Treatment (irinotecan and M6620)
IrinotecanTreatment (irinotecan and M6620)

Purpose

This phase II trial studies the how well ATR kinase inhibitor M6620 and irinotecan work in treating participants with gastric or gastroesophageal junction cancer that is growing, spreading or getting worse, has spread to other places in the body, or cannot be removed by surgery. ATR kinase inhibitor M6620 may stop the growth of tumor cells by blocking some of the enzymes needed for growth. Drugs used in chemotherapy, 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 ATR kinase inhibitor M6620 and irinotecan may work better in treating participants with gastric and gastroesophageal junction cancer.

Detailed Description

      PRIMARY OBJECTIVES:

      I. Determine objective response rate (ORR) superiority (target 35%) in TP53 mutant patients
      with progressive metastatic or unresectable gastric/gastroesophageal junction (GEJ) cancer
      who receive ATR kinase inhibitor M6620 (M6620) and irinotecan compared to ORR (15%) 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 the first 9 patients: gamma-H2AX, KAP1
      phosphorylated (p)-Ser 824 and p-ATR analysis from cycle 1 day 1 (C1D1) post-irinotecan
      biopsy and cycle 2 day 2 (C2D2) within 24 hours post-M6620 biopsy.

      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:

      Participants receive irinotecan intravenously (IV) over 90 minutes and ATR kinase inhibitor
      M6620 IV over 60 minutes on days 1 and 15. Courses repeat every 28 days in the absence of
      disease progression or unacceptable toxicity.

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

Trial Arms

NameTypeDescriptionInterventions
Treatment (irinotecan and M6620)ExperimentalParticipants receive irinotecan IV over 90 minutes and ATR kinase inhibitor M6620 IV over 60 minutes on days 1 and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • ATR Kinase Inhibitor M6620
  • Irinotecan

Eligibility Criteria

        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 one prior
             chemotherapy regimen. 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 within normal institutional limits or 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 our study coordinator
             Brenda Merriweather. 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.

          -  The first 9 patients must be willing to undergo endoscopic tumor biopsies for
             mandatory correlative studies.

          -  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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 response criteria
Time Frame:Up to 1 year
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Duration of responses (DOR)
Time Frame:From when patients achieve their best response (complete response [CR] or partial response [PR]) to when they progress, assessed up to 1 year
Safety Issue:
Description:Will be estimated using the method of Kaplan and Meier. 95% confidence intervals for all point estimates of variables overall and for effect sizes (odd ratios, hazard ratios, differential pre-post biomarker expression) among subgroups will be estimated.
Measure:Time to progression (TTP)
Time Frame:From enrollment to disease progression or death due to progression, assessed up to 1 year
Safety Issue:
Description:Will be estimated using the method of Kaplan and Meier. 95% confidence intervals for all point estimates of variables overall and for effect sizes (odd ratios, hazard ratios, differential pre-post biomarker expression) among subgroups will be estimated.
Measure:Progression-free survival (PFS)
Time Frame:From enrollment to disease progression or death for any reason, assessed up to 1 year
Safety Issue:
Description:
Measure:Overall survival (OS)
Time Frame:From study enrollment to death for any reason, assessed up to 1 year
Safety Issue:
Description:Will be estimated using the method of Kaplan and Meier. 95% confidence intervals for all point estimates of variables overall and for effect sizes (odd ratios, hazard ratios, differential pre-post biomarker expression) among subgroups will be estimated.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:National Cancer Institute (NCI)

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