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Testing the Addition of an Anticancer Drug, BAY 1895344, to the Usual Chemotherapy With FOLFIRI in Advanced or Metastatic Cancers of the Stomach and Intestines

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ClinicalTrials.gov Identifier: NCT04535401
Recruitment Status : Recruiting
First Posted : September 2, 2020
Last Update Posted : August 4, 2021
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Brief Summary:
This phase I trial investigates the best dose, possible benefits and/or side effects of BAY 1895344 in combination with FOLFIRI in treating patients with stomach or intestinal cancer that is unlikely to be cured or controlled with treatment or has spread to other places in the body (advanced or metastatic). BAY 1895344 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Chemotherapy drugs, such as irinotecan, fluorouracil, and leucovorin, (called FOLFIRI in short) 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 BAY 1895344 in combination with FOLFIRI may help shrink advanced or metastatic stomach and/or intestinal cancer.

Condition or disease Intervention/treatment Phase
Advanced Colorectal Carcinoma Advanced Digestive System Carcinoma Advanced Gastric Carcinoma Advanced Gastroesophageal Junction 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 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 Colorectal Carcinoma Metastatic Digestive System Carcinoma Metastatic Gastric Carcinoma 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 Stage III Colorectal Cancer AJCC v8 Stage IIIA Colorectal Cancer AJCC v8 Stage IIIB Colorectal Cancer AJCC v8 Stage IIIC Colorectal Cancer AJCC v8 Stage IV Colorectal Cancer AJCC v8 Stage IVA Colorectal Cancer AJCC v8 Stage IVB Colorectal Cancer AJCC v8 Stage IVC Colorectal Cancer AJCC v8 Drug: Elimusertib Drug: Fluorouracil Drug: Irinotecan Hydrochloride Drug: Leucovorin Calcium Phase 1

Detailed Description:

PRIMARY OBJECTIVE:

I. Determine the safety and maximum tolerated dose (MTD) of elimusertib (BAY 1895344) with leucovorin calcium, fluorouracil, and irinotecan hydrochloride (FOLFIRI).

SECONDARY OBJECTIVES:

I. To observe and record anti-tumor activity by overall response rate (ORR), progression-free survival (PFS), and overall survival (OS).

II. Determine the response and clinical benefit rate (complete response + partial response + stable disease) of BAY 1895344 with FOLFIRI in colorectal and gastric/gastroesophageal cancers.

III. Evaluate tumor and peripheral blood mononuclear cell (PBMC) deoxyribonucleic acid (DNA) damage signaling in the context of the chemotherapy backbone alone and when combined with BAY 1895344.

IV. Evaluate the pharmacokinetics (PK) profile of fluorouracil (5-FU) and irinotecan.

V. Evaluate the PK profile of BAY 1895344. VI. Evaluate the relationship between ATM status by immunohistochemistry (IHC) and clinical efficacy of the BAY 1895344/FOLFIRI combination.

EXPLORATORY OBJECTIVES:

I. Evaluate the exposure-response relationship between drug exposures and toxicity and response, and UGT1A1 genotype.

II. Evaluate the relationship between tumor mutations and clinical efficacy of the BAY 1895344/FOLFIRI combination.

OUTLINE: This is a dose-escalation study of elimusertib, irinotecan, and fluorouracil with fixed-dose leucovorin followed by a dose-expansion study.

Patients receive elimusertib orally (PO) twice daily (BID) on days 1, 2, 15, and 16 and irinotecan hydrochloride intravenously (IV) over 90 minutes, fluorouracil IV over 46 hours, and leucovorin calcium IV on days 1 and 15. Cycles repeat every 28 day in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days and then every 3 months for up to 1 year or until their disease gets worse or they begin a new treatment for their cancer.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 90 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I/Ib Trial of ATR Inhibitor BAY 1895344 in Combination With FOLFIRI in GI Malignancies With a Focus on Metastatic Colorectal and Gastric/Gastroesophageal Cancers
Actual Study Start Date : March 15, 2021
Estimated Primary Completion Date : December 31, 2022
Estimated Study Completion Date : December 31, 2022

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Treatment (elimusertib, FOLFIRI)
Patients receive elimusertib PO BID on days 1, 2, 15, and 16 and irinotecan hydrochloride IV over 90 minutes, fluorouracil IV over 46 hours, and leucovorin calcium IV on days 1 and 15. Cycles repeat every 28 day in the absence of disease progression or unacceptable toxicity.
Drug: Elimusertib
Given PO
Other Names:
  • ATR Inhibitor BAY1895344
  • ATR Kinase Inhibitor BAY1895344
  • BAY 1895344
  • BAY-1895344
  • BAY1895344

Drug: Fluorouracil
Given IV
Other Names:
  • 5 Fluorouracil
  • 5 Fluorouracilum
  • 5 FU
  • 5-Fluoro-2,4(1H, 3H)-pyrimidinedione
  • 5-Fluorouracil
  • 5-Fluracil
  • 5-Fu
  • 5FU
  • AccuSite
  • Carac
  • Fluoro Uracil
  • Fluouracil
  • Flurablastin
  • Fluracedyl
  • Fluracil
  • Fluril
  • Fluroblastin
  • Ribofluor
  • Ro 2-9757
  • Ro-2-9757

Drug: Irinotecan Hydrochloride
Given IV
Other Names:
  • Campto
  • Camptosar
  • Camptothecin 11
  • Camptothecin-11
  • CPT 11
  • CPT-11
  • Irinomedac
  • Irinotecan Hydrochloride Trihydrate
  • Irinotecan Monohydrochloride Trihydrate
  • U-101440E

Drug: Leucovorin Calcium
Given IV
Other Names:
  • Adinepar
  • Calcifolin
  • Calcium (6S)-Folinate
  • Calcium Folinate
  • Calcium Leucovorin
  • Calfolex
  • Calinat
  • Cehafolin
  • Citofolin
  • Citrec
  • Citrovorum Factor
  • Cromatonbic Folinico
  • Dalisol
  • Disintox
  • Divical
  • Ecofol
  • Emovis
  • Factor, Citrovorum
  • Flynoken A
  • Folaren
  • Folaxin
  • FOLI-cell
  • Foliben
  • Folidan
  • Folidar
  • Folinac
  • Folinate Calcium
  • folinic acid
  • Folinic Acid Calcium Salt Pentahydrate
  • Folinoral
  • Folinvit
  • Foliplus
  • Folix
  • Imo
  • Lederfolat
  • Lederfolin
  • Leucosar
  • leucovorin
  • Rescufolin
  • Rescuvolin
  • Tonofolin
  • Wellcovorin




Primary Outcome Measures :
  1. Maximum tolerated dose (MTD) of elimusertib (BAY 1895344) in combination with irinotecan, fluorouracil, and leucovorin (FOLFIRI) [ Time Frame: Up to 28 days ]
    A BOIN - Bayesian Optimal intervals trial design will be used to determine the MTD.


Secondary Outcome Measures :
  1. Overall response rate [ Time Frame: Up to 1 year post treatment ]
    Assessed per Response Evaluation Criteria in Solid Tumors. The probability of clinical response (complete response [CR]+partial response [PR]) and disease control (CR+PR+stable disease) will be estimated within the disease cohorts, with consideration of previous irinotecan exposure, with exact 95% binomial confidence intervals.

  2. Progression-free survival (PFS) [ Time Frame: From start of treatment to time of progression or death, whichever occurs first, assessed up to 1 year ]
    Progression-free survival will be estimated within disease cohorts by the product-limit (Kaplan-Meier) estimator, along with 95% confidence regions.

  3. Overall survival [ Time Frame: Up to 1 year post treatment ]
    Overall survival will be estimated within disease cohorts by the product-limit (Kaplan-Meier) estimator, along with 95% confidence regions.

  4. Peripheral blood mononuclear cell (PBMC) gammaH2AX and p-ATM signaling [ Time Frame: Up to 1 year post treatment ]
    Signaling during the PK lead-in and in combination with BAY 1895344 will be compared with a non-parametric paired test (e.g. Wilcoxon rank test), at a significance level at p < 0.05. For tumors, this will be performed only for patients in the dose expansion cohorts.

  5. Tumor multiplex incomplete Freund's adjuvant (IFA) signaling [ Time Frame: Up to 1 year post treatment ]
    Signaling during the PK lead-in and in combination with BAY 1895344 will be compared with a non-parametric paired test (e.g. Wilcoxon rank test), at a significance level at p < 0.05. For tumors, this will be performed only for patients in the dose expansion cohorts.

  6. Area under curve (AUC) and concentration maximum (Cmax) of irinotecan and 5-FU [ Time Frame: Up to 1 year post treatment ]
    PK during the PK lead-in and in combination with BAY 1895344 will be compared with a non-parametric paired test, at a significance level at p < 0.05.

  7. AUC and Cmax of BAY 1895344 [ Time Frame: Up to 1 year post treatment ]
    PK of BAY 1895344 in combination with irinotecan and 5-FU will be compared with historical controls in an exploratory fashion.

  8. ATM status [ Time Frame: Up to 1 year post treatment ]
    Will be assessed by immunohistochemistry (IHC) and PFS. The association between ATM and responses will be described, with a table outlining patients who achieved progressive disease, stable disease, partial or complete responses and whether they exhibited ATM expression by IHC or not.


Other Outcome Measures:
  1. Incidence of adverse events [ Time Frame: Up to 1 year post treatment ]
    Logistic regression and proportional hazards (Cox) regression will be used to assess the relationships between exposure and response and toxicity; exposure-response will be assessed within disease cohorts of sufficient size, while exposure-toxicity will pool all patients. All patients will be used for the E-R analyses. Advanced population PK methods may be employed at a later stage to assess the link between drug exposure and biological effects and efficacy.

  2. Status of deoxyribonucleic acid damage repair genes [ Time Frame: Up to 1 year post treatment ]
    Assessed by whole exome sequencing and ribonucleic acid sequencing. The efficacy analyses will be repeated by DDR tumor mutation status, but these analyses will have limited sample sizes and will not be adequately powered for statistical comparisons.



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.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • For Dose Escalation: Patients must have histologically or cytologically confirmed advanced or metastatic gastrointestinal (GI) cancers with Response Evaluation Criteria in Solid Tumors 1.1 (RECIST1.1) measurable disease who have progressed on at least one prior treatment for metastatic disease and for whom FOLFIRI is considered a reasonable treatment option. Patients with mismatch repair deficiency should have progressed on immunotherapy
  • For Dose Expansion: Patients must have either:

    • Colorectal cancer who have previously progressed on irinotecan and tolerated an irinotecan dose equal to or greater than the recommended phase 2 dose (RP2D). If they have mismatch repair deficiency they should have progressed on immunotherapy OR
    • Gastroesophageal cancer who have progressed on at least one first-line therapy for metastatic disease. If they have mismatch repair deficiency they should have progressed on immunotherapy
  • For Dose Expansion: Patients be willing to undergo biopsies for research purposes only. The accessible tumor can be the primary or metastatic tumor site. Both research biopsies should be taken from the same tumor site
  • Patients must have progressive disease on at least first-line therapy for metastatic disease. Previous treatment with irinotecan is allowed
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 1
  • Leukocytes >= 3,000/mcL
  • Absolute neutrophil count >= 1,500/mcL
  • Platelets >= 100,000/mcL
  • Total bilirubin =< 1.5 x institutional upper limit of normal (ULN)
  • Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x institutional ULN
  • Glomerular filtration rate (GFR) >= 60 mL/min/1.73 m^2 using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation
  • Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy, that does not interact with study therapy, with undetectable viral load within 6 months are eligible for this trial
  • For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy that does not interact with study therapy, if indicated
  • Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load and HCV therapy does not interact with study therapy
  • Patients with treated brain metastases are eligible if follow-up brain imaging after central nervous system (CNS)-directed therapy shows no evidence of progression
  • Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
  • Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better
  • The effects of BAY 1895344 on the developing human fetus are unknown. For this reason and because DNA-damage response inhibitors agents as well as other therapeutic agents used in this trial, 5-FU and irinotecan, are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation and for 6 months after completion of BAY 1895344 administration

    • 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. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 6 months after completion of study treatment administration
  • Ability to understand and the willingness to sign a written informed consent document. Participants with impaired decision-making capacity (IDMC) who have a legally-authorized representative (LAR) and/or family member available will also be eligible

Exclusion Criteria:

  • Patients with a history of prior treatment with an ATR inhibitor
  • Patients with a history of other malignancy that could affect compliance with the protocol or interpretation of the results
  • Patients who have had chemotherapy or radiotherapy within 3 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study
  • Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > grade 1) with the exception of alopecia
  • Patients who are receiving any other investigational agents
  • History of hypersensitivity or allergic reactions attributed to compounds of similar chemical or biologic composition to BAY 1895344, 5-FU, leucovorin, or irinotecan
  • Patients receiving any medications that are substrates of CYP3A4 with a narrow therapeutic window or strong inhibitors/inducers of CYP3A4 are ineligible, if they cannot be transferred to alternative medication. Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated medical reference. 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
  • Patients with uncontrolled intercurrent illness
  • Patients with psychiatric illness/social situations that would limit compliance with study requirements
  • Gastrointestinal pathology or history that adversely impact the ability to take or absorb oral medication
  • Pregnant women are excluded from this study because BAY 1895344 as a DNA-damage response 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 BAY 1895344 breastfeeding should be discontinued if the mother is treated with BAY 1895344 and for 4 months after end of treatment. These potential risks may also apply to other agents used in this study
  • Patients who were unable to tolerate prior irinotecan treatment are excluded from this study
  • Patients with a corrected QT (QTc) interval >= 470 msec are excluded from this study

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): NCT04535401


Locations
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United States, Pennsylvania
University of Pittsburgh Cancer Institute (UPCI) Recruiting
Pittsburgh, Pennsylvania, United States, 15232
Contact: Site Public Contact    412-647-8073      
Principal Investigator: Anuradha Krishnamurthy         
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Anuradha Krishnamurthy University of Pittsburgh Cancer Institute LAO
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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT04535401    
Other Study ID Numbers: NCI-2020-06482
NCI-2020-06482 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
10406 ( Other Identifier: University of Pittsburgh Cancer Institute LAO )
10406 ( Other Identifier: CTEP )
UM1CA186690 ( U.S. NIH Grant/Contract )
First Posted: September 2, 2020    Key Record Dates
Last Update Posted: August 4, 2021
Last Verified: July 2021
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

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Carcinoma
Colorectal Neoplasms
Adenocarcinoma
Stomach Neoplasms
Esophageal Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Stomach Diseases
Head and Neck Neoplasms
Esophageal Diseases
Calcium, Dietary
Leucovorin
Folic Acid
Fluorouracil
Irinotecan
Camptothecin
Calcium
Levoleucovorin
Calcium-Regulating Hormones and Agents
Physiological Effects of Drugs