Clinical Trials /

Testing the Addition of an Anti-cancer Drug, BAY 1895344, to the Usual Chemotherapy Treatment (Cisplatin, or Cisplatin and Gemcitabine) for Advanced Solid Tumors With Emphasis on Urothelial Cancer

NCT04491942

Description:

This phase I trial investigates the best dose and side effects of BAY 1895344 when given together with chemotherapy in treating patients with solid tumors or urothelial cancer that has spread to other places in the body (advanced). BAY 1895344 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Chemotherapy drugs, such as cisplatin and gemcitabine, 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. The purpose of this trial is to test the safety of a drug called BAY 1895344 in combination with the usual chemotherapy treatment (cisplatin, or cisplatin and gemcitabine) for the treatment of advanced solid tumors, including urothelial cancer.

Related Conditions:
  • Biliary Tract Carcinoma
  • Breast Carcinoma
  • Cervical Carcinoma
  • Endometrial Carcinoma
  • Esophageal Carcinoma
  • Gastric Carcinoma
  • Head and Neck Carcinoma
  • Malignant Pleural Mesothelioma
  • Non-Small Cell Lung Carcinoma
  • Ovarian Carcinoma
  • Penile Carcinoma
  • Small Cell Lung Carcinoma
  • Urothelial Carcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Testing the Addition of an Anti-cancer Drug, BAY 1895344, to the Usual Chemotherapy Treatment (Cisplatin, or Cisplatin and Gemcitabine) for Advanced Solid Tumors With Emphasis on Urothelial Cancer
  • Official Title: A Phase I Trial of the ATR Inhibitor BAY 1895344 in Combination With Cisplatin and With Cisplatin Plus Gemcitabine in Advanced Solid Tumors With an Emphasis on Urothelial Carcinoma

Clinical Trial IDs

  • ORG STUDY ID: NCI-2020-05428
  • SECONDARY ID: NCI-2020-05428
  • SECONDARY ID: PHI-117
  • SECONDARY ID: 10404
  • SECONDARY ID: 10404
  • SECONDARY ID: UM1CA186717
  • NCT ID: NCT04491942

Conditions

  • Advanced Bile Duct Carcinoma
  • Advanced Breast Carcinoma
  • Advanced Cervical Carcinoma
  • Advanced Endometrial Carcinoma
  • Advanced Esophageal Carcinoma
  • Advanced Gastric Carcinoma
  • Advanced Head and Neck Carcinoma
  • Advanced Lung Non-Small Cell Carcinoma
  • Advanced Lung Small Cell Carcinoma
  • Advanced Malignant Solid Neoplasm
  • Advanced Ovarian Carcinoma
  • Advanced Penile Carcinoma
  • Advanced Pleural Malignant Mesothelioma
  • Advanced Urothelial Carcinoma
  • Anatomic Stage III Breast Cancer AJCC v8
  • Anatomic Stage IIIA Breast Cancer AJCC v8
  • Anatomic Stage IIIB Breast Cancer AJCC v8
  • Anatomic Stage IIIC Breast Cancer AJCC v8
  • Anatomic Stage IV Breast Cancer AJCC v8
  • Clinical Stage III Gastric Cancer AJCC v8
  • Clinical Stage IV Gastric Cancer AJCC v8
  • Clinical Stage IVA Gastric Cancer AJCC v8
  • Clinical Stage IVB Gastric Cancer AJCC v8
  • Pathologic Stage III Gastric Cancer AJCC v8
  • Pathologic Stage IIIA Gastric Cancer AJCC v8
  • Pathologic Stage IIIB Gastric Cancer AJCC v8
  • Pathologic Stage IIIC Gastric Cancer AJCC v8
  • Pathologic Stage IV Gastric Cancer AJCC v8
  • Prognostic Stage III Breast Cancer AJCC v8
  • Prognostic Stage IIIA Breast Cancer AJCC v8
  • Prognostic Stage IIIB Breast Cancer AJCC v8
  • Prognostic Stage IIIC Breast Cancer AJCC v8
  • Prognostic Stage IV Breast Cancer AJCC v8
  • Stage III Cervical Cancer AJCC v8
  • Stage III Distal Bile Duct Cancer AJCC v8
  • Stage III Intrahepatic Bile Duct Cancer AJCC v8
  • Stage III Lung Cancer AJCC v8
  • Stage III Ovarian Cancer AJCC v8
  • Stage III Penile Cancer AJCC v8
  • Stage III Pleural Malignant Mesothelioma AJCC v8
  • Stage IIIA Cervical Cancer AJCC v8
  • Stage IIIA Distal Bile Duct Cancer AJCC v8
  • Stage IIIA Intrahepatic Bile Duct Cancer AJCC v8
  • Stage IIIA Lung Cancer AJCC v8
  • Stage IIIA Ovarian Cancer AJCC v8
  • Stage IIIA Penile Cancer AJCC v8
  • Stage IIIA Pleural Malignant Mesothelioma AJCC v8
  • Stage IIIA1 Ovarian Cancer AJCC v8
  • Stage IIIA2 Ovarian Cancer AJCC v8
  • Stage IIIB Cervical Cancer AJCC v8
  • Stage IIIB Distal Bile Duct Cancer AJCC v8
  • Stage IIIB Intrahepatic Bile Duct Cancer AJCC v8
  • Stage IIIB Lung Cancer AJCC v8
  • Stage IIIB Ovarian Cancer AJCC v8
  • Stage IIIB Penile Cancer AJCC v8
  • Stage IIIB Pleural Malignant Mesothelioma AJCC v8
  • Stage IIIC Lung Cancer AJCC v8
  • Stage IIIC Ovarian Cancer AJCC v8
  • Stage IV Cervical Cancer AJCC v8
  • Stage IV Distal Bile Duct Cancer AJCC v8
  • Stage IV Intrahepatic Bile Duct Cancer AJCC v8
  • Stage IV Lung Cancer AJCC v8
  • Stage IV Ovarian Cancer AJCC v8
  • Stage IV Penile Cancer AJCC v8
  • Stage IV Pleural Malignant Mesothelioma AJCC v8
  • Stage IVA Cervical Cancer AJCC v8
  • Stage IVA Lung Cancer AJCC v8
  • Stage IVA Ovarian Cancer AJCC v8
  • Stage IVB Cervical Cancer AJCC v8
  • Stage IVB Lung Cancer AJCC v8
  • Stage IVB Ovarian Cancer AJCC v8
  • Triple-Negative Breast Carcinoma
  • Unresectable Urothelial Carcinoma

Interventions

DrugSynonymsArms
ATR Kinase Inhibitor BAY1895344ATR Inhibitor BAY1895344, BAY 1895344, BAY-1895344, BAY1895344Arm I (cisplatin, BAY 1895344)
CisplatinAbiplatin, Blastolem, Briplatin, CDDP, Cis-diammine-dichloroplatinum, Cis-diamminedichloridoplatinum, Cis-diamminedichloro Platinum (II), Cis-diamminedichloroplatinum, Cis-dichloroammine Platinum (II), Cis-platinous Diamine Dichloride, Cis-platinum, Cis-platinum II, Cis-platinum II Diamine Dichloride, Cismaplat, Cisplatina, Cisplatinum, Cisplatyl, Citoplatino, Citosin, Cysplatyna, DDP, Lederplatin, Metaplatin, Neoplatin, Peyrone''s Chloride, Peyrone''s Salt, Placis, Plastistil, Platamine, Platiblastin, Platiblastin-S, Platinex, Platinol, Platinol- AQ, Platinol-AQ, Platinol-AQ VHA Plus, Platinoxan, Platinum, Platinum Diamminodichloride, Platiran, Platistin, PlatosinArm I (cisplatin, BAY 1895344)
Gemcitabine HydrochloridedFdCyd, Difluorodeoxycytidine Hydrochloride, FF 10832, FF-10832, FF10832, Gemcitabine HCI, Gemzar, LY-188011, LY188011Arm II (cisplatin, gemcitabine, BAY 1895344)

Purpose

This phase I trial investigates the best dose and side effects of BAY 1895344 when given together with chemotherapy in treating patients with solid tumors or urothelial cancer that has spread to other places in the body (advanced). BAY 1895344 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Chemotherapy drugs, such as cisplatin and gemcitabine, 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. The purpose of this trial is to test the safety of a drug called BAY 1895344 in combination with the usual chemotherapy treatment (cisplatin, or cisplatin and gemcitabine) for the treatment of advanced solid tumors, including urothelial cancer.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To establish the safety and tolerability of the combination of cisplatin + ATR kinase
      inhibitor BAY1895344 (BAY 1895344) in patients with advanced solid tumors.

      II. To establish the safety and tolerability of the combination of cisplatin + gemcitabine +
      BAY 1895344 in patients with advanced solid tumors with an emphasis on urothelial carcinoma
      (UC).

      III. To establish the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of
      cisplatin + BAY 1895344 and cisplatin + gemcitabine + BAY 1895344.

      SECONDARY OBJECTIVES:

      I. To observe and record anti-tumor activity. II. To evaluate the pharmacokinetic profile of
      BAY 1895344 (in the doublet and triplet combinations) and gemcitabine (in the triplet) in
      combination with cisplatin.

      III. To further evaluate the toxicity of the combination of cisplatin + gemcitabine + BAY
      1895344 in patients with UC.

      IV. To evaluate preliminary efficacy observed with cisplatin + BAY 1895344 and cisplatin +
      gemcitabine + BAY 1895344 in patients with advanced solid tumors, including UC.

      V. To evaluate the association between ATM expression by immunohistochemical staining and
      responses to therapy.

      EXPLORATORY OBJECTIVES:

      I. To evaluate the responses to therapy using whole exome sequencing (WES) and messenger
      ribonucleic acid (RNA) sequencing (RNA Seq) analysis of archival formalin fixed paraffin
      embedded (FFPE) tissue.

      II. To correlate drug exposure with response and/or toxicity.

      OUTLINE: This is a dose-escalation study of BAY 1895344. Patients are assigned to 1 of 2
      arms.

      ARM I (DOUBLET COMBINATION): Patients receive cisplatin intravenously (IV) over 1-2 hours on
      day 1, and BAY 1895344 orally (PO) twice daily (BID) on days 2 and 9. Treatment repeats every
      21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.

      ARM II (TRIPLET COMBINATION): Patients receive cisplatin IV over 1-2 hours on day 1,
      gemcitabine IV over 30 minutes on days 1 and 8, and BAY 1895344 PO BID on days 2 and 9.
      Treatment repeats every 21 days for up to 6 cycles in the absence of disease progression or
      unacceptable toxicity.

      After completion of study treatment, patients are followed up at 30 days, then every 3 months
      thereafter.
    

Trial Arms

NameTypeDescriptionInterventions
Arm I (cisplatin, BAY 1895344)ExperimentalPatients receive cisplatin IV over 1-2 hours on day 1, and BAY 1895344 PO BID on days 2 and 9. Treatment repeats every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.
  • ATR Kinase Inhibitor BAY1895344
  • Cisplatin
Arm II (cisplatin, gemcitabine, BAY 1895344)ExperimentalPatients receive cisplatin IV over 1-2 hours on day 1, gemcitabine IV over 30 minutes on days 1 and 8, and BAY 1895344 PO BID on days 2 and 9. Treatment repeats every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.
  • ATR Kinase Inhibitor BAY1895344
  • Cisplatin
  • Gemcitabine Hydrochloride

Eligibility Criteria

        Inclusion Criteria:

          -  Histologically-confirmed advanced solid tumor with measurable disease by Response
             Evaluation Criteria in Solid Tumors (RECIST) version (v)2.0 criteria, for which
             cisplatin-based therapy would be considered appropriate, including:

               -  Non-small cell lung cancer (NSCLC)

               -  UC

               -  Penile cancer

               -  Malignant pleural mesothelioma

               -  Small cell lung cancer

               -  Biliary tract cancer

               -  Esophageal and gastric cancers

               -  Ovarian cancer

               -  Endometrial cancer

               -  Cervical cancer

               -  Head and neck cancer

               -  Triple-negative breast cancer (Her2/neu-negative, estrogen receptor
                  [ER]/progesterone receptor [PR]-negative breast cancer)

          -  For the expansion cohort of the triplet combination at MTD/RP2D only:

               -  Patients with histologically confirmed advanced or unresectable urothelial
                  carcinoma are eligible

               -  The histology should be predominantly urothelial (>= 50% of sample evaluated
                  contains urothelial histology)

          -  Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)

          -  Availability of archival FFPE tissue

          -  Prior cisplatin exposure of < 300 mg/m^2, with last cisplatin treatment > 6 months
             prior to enrollment is permitted

          -  Prior treatment with PARP inhibitors is permitted

          -  Prior immune checkpoint inhibitor therapy is permitted

          -  Leukocytes >= 3,000/mcL

          -  Hemoglobin >= 9 g/dL

          -  Neutrophil count >= 1.5 K/mm^3

          -  Platelets >= 100 K/mm^3

          -  Total bilirubin =< 2 mg/dL

          -  Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
             [SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =<
             3 x institutional upper limit of normal (ULN)

          -  Creatinine clearance >= 40 mL/min OR glomerular filtration rate (GFR) >= 60
             mL/min/1.73 m^2 unless data exists supporting safe use at lower kidney function
             values, no lower than 30 mL/min/1.73 m^2

          -  Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral
             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, 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.

          -  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 new or progressive brain metastases (active brain metastases) or
             leptomeningeal disease are eligible if the treating physician determines that
             immediate CNS specific treatment is not required and is unlikely to be required during
             the first cycle of therapy

          -  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, cisplatin, and gemcitabine on the developing human fetus
             are unknown. For this reason and because deoxyribonucleic acid (DNA)-damage response
             inhibitors agents as well as other therapeutic agents used in this trial 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 BAY 1895344 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:

          -  Life expectancy < 6 weeks by investigator assessment

          -  History of prior malignancy requiring intervention in the past 3 years, except for
             cutaneous malignancies that require resection, such as squamous cell carcinoma, basal
             cell carcinoma, or cutaneous melanomas

          -  Significant peripheral neuropathy or sensorineural hearing loss (< grade 1 by Common
             Terminology Criteria for Adverse Events [CTCAE])

          -  Must NOT have had prior treatment with ATR inhibitor (prior BAY1895344 or other
             investigational ATR inhibitors), or current treatment with any other investigational
             agents

          -  Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for
             nitrosoureas or mitomycin C) prior to entering the study

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to BAY 1895344 or other agents used in study

          -  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

          -  Pregnant women are excluded from this study because BAY 1895344 as a DNA-damage
             response inhibitor, cisplatin, and gemcitabine 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:Incidence of adverse events
Time Frame:Up to 28 days after completion of study treatment
Safety Issue:
Description:Toxicities will be tabulated and reported according to dose level, grade, type, cycle, and attribution. Tables will be created to summarize these toxicities and side effects, overall and by cohort. Proportions and associated 95% confidence intervals will be calculated for each cohort separately. Cumulative incidence curves will be used to estimate the proportion of patients who will discontinue therapy for reasons of toxicity or general inability to tolerate the regimen.

Secondary Outcome Measures

Measure:Pharmacokinetic (PK) parameters - maximum concentration (Cmax)
Time Frame:Day 2 and day 9
Safety Issue:
Description:Estimated using using non-compartmental methods. The PK variables will be tabulated and descriptive statistics (e.g., geometric means and coefficients of variation) calculated for each dose level. PK parameters will be reported descriptively for exploratory comparison with historical data (gemcitabine).
Measure:PK parameters - area under the concentration-time curve (AUC)
Time Frame:Day 2 and day 9
Safety Issue:
Description:Estimated using using non-compartmental methods. The PK variables will be tabulated and descriptive statistics (e.g., geometric means and coefficients of variation) calculated for each dose level. PK parameters will be reported descriptively for exploratory comparison with historical data (gemcitabine). The impact of cisplatin on BAY 1895344 exposure will be evaluated by calculation of the AUC ratio of (day 9 / day 2) and testing non-parametrically with a null hypothesis of a ratio = 1.
Measure:Deoxyribonucleic acid (DNA) damage repair (DDR) mutations
Time Frame:Up to 2 years
Safety Issue:
Description:The association between DDR mutations and responses will be described, with a table outlining patients who achieved by progressive disease, stable disease, partial or complete responses and DDR mutation status.
Measure:ATM expression
Time Frame:Up to 2 years
Safety Issue:
Description: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 immunohistochemistry (IHC) or not.
Measure:Response rate
Time Frame:Up to 2 years
Safety Issue:
Description:The percent of responders will be calculated and associated exact 95% confidence intervals will be constructed.
Measure:Progression-free survival (PFS)
Time Frame:Up to 2 years
Safety Issue:
Description:Kaplan-Meier plots will be used to summarize PFS.

Details

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

Last Updated

August 6, 2020