Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03641313
Recruitment Status : Not yet recruiting
First Posted : August 22, 2018
Last Update Posted : September 13, 2019
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
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 Drug: ATR Kinase Inhibitor M6620 Drug: Irinotecan Phase 2

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.


Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 28 participants
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
Estimated Study Start Date : January 2, 2020
Estimated Primary Completion Date : May 31, 2020
Estimated Study Completion Date : May 31, 2020


Arm Intervention/treatment
Experimental: Treatment (irinotecan and M6620)
Participants 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.
Drug: ATR Kinase Inhibitor M6620
Given IV
Other Names:
  • M 6620
  • M6620
  • VX-970

Drug: Irinotecan
Given IV




Primary Outcome Measures :
  1. Objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 response criteria [ Time Frame: Up to 1 year ]

Secondary Outcome Measures :
  1. 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 ]
    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.

  2. Time to progression (TTP) [ Time Frame: From enrollment to disease progression or death due to progression, assessed up to 1 year ]
    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.

  3. Progression-free survival (PFS) [ Time Frame: From enrollment to disease progression or death for any reason, assessed up to 1 year ]
  4. Overall survival (OS) [ Time Frame: 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 variables overall and for 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 [ Time Frame: Up to 1 year ]
  2. DOR in sub-cohorts based on first-line platinum sensitivity [ Time Frame: Up to 1 year ]
  3. TTP in sub-cohorts based on first-line platinum sensitivity [ Time Frame: Up to 1 year ]
  4. PFS in sub-cohorts based on first-line platinum sensitivity [ Time Frame: Up to 1 year ]
  5. OS in sub-cohorts based on first-line platinum sensitivity [ Time Frame: Up to 1 year ]
  6. Presence of other deoxyribonucleic acid (DNA) damage response defects (DDRD) [ Time Frame: Up to 1 year ]
    Will be summarized as frequency counts and percent of study group.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03641313


Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
Layout table for investigator information
Principal Investigator: Jordan D Berlin Yale University Cancer Center LAO

Layout table for additonal information
Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT03641313     History of Changes
Other Study ID Numbers: NCI-2018-01739
NCI-2018-01739 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
VICC LOI#18012
10211 ( Other Identifier: Yale University Cancer Center LAO )
10211 ( Other Identifier: CTEP )
UM1CA186689 ( U.S. NIH Grant/Contract )
First Posted: August 22, 2018    Key Record Dates
Last Update Posted: September 13, 2019
Last Verified: September 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page
URL: https://grants.nih.gov/policy/sharing.htm

Layout table for additional information
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
Layout table for MeSH terms
Adenocarcinoma
Stomach Neoplasms
Esophageal Neoplasms
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Gastrointestinal Diseases
Stomach Diseases
Head and Neck Neoplasms
Esophageal Diseases
Irinotecan
Topoisomerase I Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents