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BRIEF TITLE: ATR Inhibitor BAY 1895344 in Combination With Cisplatin and With Cisplatin Plus Gemcitabine in Advanced Solid Tumors With an Emphasis on Urothelial Carcinoma

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


  • Org Study ID: NCI-2020-05428
  • Secondary ID: NCI-2020-05428,PHI-117,10404,10404,UM1CA186717
  • NCT ID: NCT04491942
  • NCT Alias:
  • Sponsor: National Cancer Institute (NCI) - NIH
  • Source: National Cancer Institute (NCI)

Brief Summary

This phase I trial identifies the best dose, possible benefits and/or side effects of BAY 1895344 in combination 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. Cisplatin and gemcitabine are chemotherapy drugs that stop the growth of tumor cells by killing the cells. Combining BAY 1895344 with chemotherapy treatment (cisplatin, or cisplatin and gemcitabine) may be effective 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.

Overal Status Start Date Phase Study Type
Recruiting February 1, 2021 Phase 1 Interventional

Primary Outcomes:

Primary Outcome 1 - Measure: Incidence of adverse events

Primary Outcome 1 - Time Frame: Up to 28 days after completion of study treatment

Primary Outcome 2 - Measure: Recommended phase 2 dose (RP2D) of BAY 1895344

Primary Outcome 2 - Time Frame: Up to 21 days from treatment start date

Condition:

  • 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

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
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Gender: All

Minimum Age: 18 Years

Maximum Age: N/A

Healthy Volunteers: No

Official Information

Name: Mamta Parikh

Role: Principal Investigator

Affiliation: City of Hope Comprehensive Cancer Center LAO

Location

Facility Status Contact
University of California Davis Comprehensive Cancer Center
Sacramento, California 95817
United States
Recruiting Site Public Contact
916-734-3089