Clinical Trials /

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

NCT04535401

Description:

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.

Related Conditions:
  • Colorectal Carcinoma
  • Esophagogastric Carcinoma
  • Small Intestinal Carcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Testing the Addition of an Anticancer Drug, BAY 1895344, to the Usual Chemotherapy in Advanced or Metastatic Cancers of the Stomach and Intestines
  • 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

Clinical Trial IDs

  • ORG STUDY ID: NCI-2020-06482
  • SECONDARY ID: NCI-2020-06482
  • SECONDARY ID: 10406
  • SECONDARY ID: 10406
  • SECONDARY ID: UM1CA186690
  • NCT ID: NCT04535401

Conditions

  • 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

Interventions

DrugSynonymsArms
ATR Kinase Inhibitor BAY1895344ATR Inhibitor BAY1895344, BAY 1895344, BAY-1895344, BAY1895344Treatment (BAY 1895344, usual chemotherapy)
Fluorouracil5 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-2-9757Treatment (BAY 1895344, usual chemotherapy)
Irinotecan HydrochlorideCampto, Camptosar, Camptothecin 11, Camptothecin-11, CPT 11, CPT-11, Irinomedac, Irinotecan Hydrochloride Trihydrate, Irinotecan Monohydrochloride Trihydrate, U-101440ETreatment (BAY 1895344, usual chemotherapy)
Leucovorin CalciumAdinepar, 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, WellcovorinTreatment (BAY 1895344, usual chemotherapy)

Purpose

This phase I trial investigates the side effects and best dose of BAY 1895344 when giving together with usual chemotherapy in treating patients with stomach or intestinal cancer that 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, 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 with usual chemotherapy may help shrink cancer.

Detailed Description

      PRIMARY OBJECTIVE:

      I. Determine the safety and maximum tolerated dose (MTD) of ATR kinase inhibitor BAY1895344
      (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 BAY 1895344, irinotecan, and fluorouracil.

      Patients receive BAY 1895344 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 30
      days for up to 1 year.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (BAY 1895344, usual chemotherapy)ExperimentalPatients receive BAY 1895344 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.
  • ATR Kinase Inhibitor BAY1895344
  • Fluorouracil
  • Irinotecan Hydrochloride
  • Leucovorin Calcium

Eligibility 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

          -  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 RP2D OR

               -  Gastroesophageal cancer who have progressed on at least one first-line therapy
                  for metastatic disease

          -  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

          -  Patients must be >= 3 weeks since completion of the previous chemotherapy regimen

          -  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 4 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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum tolerated dose (MTD) of ATR kinase inhibitor BAY1895344 (BAY 1895344)
Time Frame:Up to 28 days
Safety Issue:
Description:A BOIN - Bayesian Optimal intervals trial design will be used to determine the MTD.

Secondary Outcome Measures

Measure:Overall response rate
Time Frame:Up to 1 year post treatment
Safety Issue:
Description: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.
Measure:Progression-free survival (PFS)
Time Frame:From start of treatment to time of progression or death, whichever occurs first, assessed up to 1 year
Safety Issue:
Description:Progression-free survival will be estimated within disease cohorts by the product-limit (Kaplan-Meier) estimator, along with 95% confidence regions.
Measure:Overall survival
Time Frame:Up to 1 year post treatment
Safety Issue:
Description:Overall survival will be estimated within disease cohorts by the product-limit (Kaplan-Meier) estimator, along with 95% confidence regions.
Measure:Peripheral blood mononuclear cell (PBMC) gammaH2AX and p-ATM signaling
Time Frame:Up to 1 year post treatment
Safety Issue:
Description: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.
Measure:Tumor multiplex incomplete Freund's adjuvant (IFA) signaling
Time Frame:Up to 1 year post treatment
Safety Issue:
Description: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.
Measure:Area under curve (AUC) and concentration maximum (Cmax) of irinotecan and 5-FU
Time Frame:Up to 1 year post treatment
Safety Issue:
Description: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.
Measure:AUC and Cmax of BAY 1895344
Time Frame:Up to 1 year post treatment
Safety Issue:
Description:PK of BAY 1895344 in combination with irinotecan and 5-FU will be compared with historical controls in an exploratory fashion.
Measure:ATM status
Time Frame:Up to 1 year post treatment
Safety Issue:
Description: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.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:National Cancer Institute (NCI)

Last Updated

September 8, 2020