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

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

Sponsors

Lead Sponsor: National Cancer Institute (NCI)

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.

Overall Status Recruiting
Start Date 2021-02-01
Completion Date 2022-12-31
Primary Completion Date 2022-12-31
Phase Phase 1
Study Type Interventional
Primary Outcome
Measure Time Frame
Incidence of adverse events Up to 28 days after completion of study treatment
Recommended phase 2 dose (RP2D) of BAY 1895344 Up to 21 days from treatment start date
Secondary Outcome
Measure Time Frame
Pharmacokinetic (PK) parameter - maximum concentration (Cmax) Day 2 and day 9 after treatment start date
PK parameter - area under the concentration-time curve (AUC) Day 2 and day 9 after treatment start date
Deoxyribonucleic acid (DNA) damage repair (DDR) mutations Up to 2 years
ATM expression Up to 2 years
Response rate Up to 2 years
Progression-free survival (PFS) Up to 2 years
Enrollment 68
Condition
Intervention

Intervention Type: Drug

Intervention Name: Cisplatin

Description: Given IV

Intervention Type: Drug

Intervention Name: Elimusertib

Description: Given PO

Intervention Type: Drug

Intervention Name: Gemcitabine Hydrochloride

Description: Given IV

Arm Group Label: Arm II (cisplatin, gemcitabine, BAY 1895344)

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

Gender:

All

Minimum Age:

18 Years

Maximum Age:

N/A

Healthy Volunteers:

No

Overall Official
Last Name Role Affiliation
Mamta Parikh Principal Investigator City of Hope Comprehensive Cancer Center LAO
Location
Facility: Status: Contact: Investigator:
University of California Davis Comprehensive Cancer Center | Sacramento, California, 95817, United States Recruiting Site Public Contact 916-734-3089 Mamta Parikh Principal Investigator
National Cancer Institute Developmental Therapeutics Clinic | Bethesda, Maryland, 20892, United States Recruiting Site Public Contact 800-411-1222 Naoko Takebe Principal Investigator
National Institutes of Health Clinical Center | Bethesda, Maryland, 20892, United States Recruiting Site Public Contact 800-411-1222 Naoko Takebe Principal Investigator
Ohio State University Comprehensive Cancer Center | Columbus, Ohio, 43210, United States Recruiting Site Public Contact 800-293-5066 [email protected] Ming Yin Principal Investigator
University of Pittsburgh Cancer Institute (UPCI) | Pittsburgh, Pennsylvania, 15232, United States Recruiting Site Public Contact 412-647-8073 Leonard J. Appleman Principal Investigator
University of Wisconsin Hospital and Clinics | Madison, Wisconsin, 53792, United States Recruiting Site Public Contact 800-622-8922 Hamid Emamekhoo Principal Investigator
Location Countries

United States

Verification Date

2021-04-01

Responsible Party

Type: Sponsor

Condition Browse
Number Of Arms 2
Arm Group

Label: Arm I (cisplatin, BAY 1895344)

Type: Experimental

Description: Patients 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.

Label: Arm II (cisplatin, gemcitabine, BAY 1895344)

Type: Experimental

Description: 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.

Patient Data Yes
Study Design Info

Allocation: Non-Randomized

Intervention Model: Parallel Assignment

Primary Purpose: Treatment

Masking: None (Open Label)

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