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
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|ClinicalTrials.gov Identifier: NCT04491942|
Recruitment Status : Recruiting
First Posted : July 30, 2020
Last Update Posted : February 15, 2023
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|Condition or disease||Intervention/treatment||Phase|
|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 IV Breast Cancer AJCC v8 Clinical Stage III Gastric Cancer AJCC v8 Clinical Stage IV Gastric 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 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 Triple-Negative Breast Carcinoma Unresectable Urothelial Carcinoma||Drug: Cisplatin Drug: Elimusertib Drug: Gemcitabine Hydrochloride||Phase 1|
I. To establish the safety and tolerability of the combination of cisplatin + elimusertib (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.
I. To evaluate the pharmacokinetic profile of BAY 1895344 (in the doublet and triplet combinations) and gemcitabine (in the triplet) in combination with cisplatin.
II. To further evaluate the toxicity of the combination of cisplatin + gemcitabine + BAY 1895344 in patients with UC.
III. To evaluate preliminary efficacy observed with cisplatin + BAY 1895344 and cisplatin + gemcitabine + BAY 1895344 in patients with advanced solid tumors, including UC.
IV. To monitor for tumor response and symptom relief in addition to safety and tolerability.
V. To evaluate the association between ATM expression by immunohistochemical staining and responses to therapy.
I. To evaluate the correlation of biomarkers, including deleterious deoxyribonucleic acid (DNA) damage response (DDR) gene alterations and circulating tumor (ct)DNA with responses to therapy using whole exome sequencing (WES) and messenger ribonucleic acid sequencing (RNA seq) analysis of archival formalin fixed paraffin embedded (FFPE) tissue, as well as blood.
II. To correlate drug exposure with response and/or toxicity.
OUTLINE: This is a dose-escalation study of elimusertib. 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 8, and elimusertib orally (PO) once daily (QD) 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 and 8, gemcitabine IV over 30 minutes on days 1 and 8, and elimusertib PO QD 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.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||74 participants|
|Intervention Model:||Parallel Assignment|
|Masking:||None (Open Label)|
|Official Title:||A Phase 1 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|
|Actual Study Start Date :||February 1, 2021|
|Estimated Primary Completion Date :||December 31, 2023|
|Estimated Study Completion Date :||December 31, 2023|
Experimental: Arm I (cisplatin, elimusertib)
Patients receive cisplatin IV over 1-2 hours on day 1 and 8, and elimusertib PO QD on days 2 and 9. Treatment repeats every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.
Experimental: Arm II (cisplatin, gemcitabine, elimusertib)
Patients receive cisplatin IV over 1-2 hours on day 1 and 8, gemcitabine IV over 30 minutes on days 1 and 8, and elimusertib PO QD on days 2 and 9. Treatment repeats every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.
Drug: Gemcitabine Hydrochloride
- Incidence of adverse events [ Time Frame: Up to 28 days after completion of study treatment ]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.
- Recommended phase 2 dose (RP2D) of BAY 1895344 [ Time Frame: Up to 21 days from treatment start date ]
- Pharmacokinetic (PK) parameter - maximum concentration (Cmax) [ Time Frame: Day 2 and day 9 after treatment start date ]Estimated 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).
- PK parameter - area under the concentration-time curve (AUC) [ Time Frame: Day 2 and day 9 after treatment start date ]Estimated 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.
- Deoxyribonucleic acid (DNA) damage repair (DDR) mutations [ Time Frame: Up to 2 years ]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.
- ATM expression [ Time Frame: Up to 2 years ]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.
- Response rate [ Time Frame: Up to 2 years ]The percent of responders will be calculated and associated exact 95% confidence intervals will be constructed.
- Progression-free survival (PFS) [ Time Frame: Up to 2 years ]Kaplan-Meier plots will be used to summarize PFS.
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|Ages Eligible for Study:||18 Years and older (Adult, Older Adult)|
|Sexes Eligible for Study:||All|
|Accepts Healthy Volunteers:||No|
Histologically-confirmed advanced solid tumor with measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1 criteria, for which cisplatin-based therapy would be considered appropriate, including:
- Non-small cell lung cancer (NSCLC)
- 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)
- Age >= 18 years. Because no dosing or adverse event data are currently available on the use of BAY 1895344 in combination with gemcitabine and cisplatin in patients < 18 years of age, children are excluded from this study
- Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
- Availability of archival FFPE tissue
- Prior cisplatin exposure of < 300 mg/m^2. Patients with prior cisplatin treatment must have received last cisplatin treatment > 6 months prior to enrollment
- Prior treatment with PARP inhibitors is permitted (such as olaparib, rucaparib, or other experimental inhibitors of PARP administered in a clinical trial)
- Prior immune checkpoint inhibitor therapy is permitted (including anti-programmed cell death protein 1 [PD-1], anti-PD-ligand [L]1 therapy, such as pembrolizumab, nivolumab, avelumab, durvalumab, atezolizumab, or anti-cytotoxic t-lymphocyte protein 4 [CTLA4] therapy such as ipilimumab, or other experimental immune checkpoint pathway inhibitors administered in a clinical trial)
- Leukocytes >= 3,000/mcL
- Hemoglobin >= 9 g/dL
- Neutrophil count >= 1,500/mcL
- Platelets >= 100,000/mcL
- 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) >= 40 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 stable brain metastases that are asymptomatic and on a stable dose of steroids are also considered eligible
- 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
- Life expectancy < 6 weeks by investigator assessment
- Other active malignancy requiring treatment, except for cutaneous malignancies that require resection such as squamous cell carcinoma, basal cell carcinoma, or cutaneous melanoma, and except for prostate cancer if only on androgen deprivation therapy
- Significant peripheral neuropathy (grade 2 or higher by Common Terminology Criteria for Adverse Events [CTCAE])
- Sensorineural hearing loss (grade 2 or higher by 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. Patients who have targeted therapies (such as PARP inhibitors) within 2 weeks 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
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): NCT04491942
|United States, California|
|University of California Davis Comprehensive Cancer Center||Recruiting|
|Sacramento, California, United States, 95817|
|Contact: Site Public Contact 916-734-3089|
|Principal Investigator: Mamta Parikh|
|United States, Maryland|
|National Cancer Institute Developmental Therapeutics Clinic||Recruiting|
|Bethesda, Maryland, United States, 20892|
|Contact: Site Public Contact 800-411-1222|
|Principal Investigator: Naoko Takebe|
|National Institutes of Health Clinical Center||Recruiting|
|Bethesda, Maryland, United States, 20892|
|Contact: Site Public Contact 800-411-1222|
|Principal Investigator: Naoko Takebe|
|United States, New York|
|NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center||Suspended|
|New York, New York, United States, 10032|
|United States, Ohio|
|Ohio State University Comprehensive Cancer Center||Recruiting|
|Columbus, Ohio, United States, 43210|
|Contact: Site Public Contact 800-293-5066 Jamesline@osumc.edu|
|Principal Investigator: Ming Yin|
|United States, Pennsylvania|
|University of Pittsburgh Cancer Institute (UPCI)||Recruiting|
|Pittsburgh, Pennsylvania, United States, 15232|
|Contact: Site Public Contact 412-647-8073|
|Principal Investigator: Leonard J. Appleman|
|United States, Wisconsin|
|University of Wisconsin Carbone Cancer Center||Recruiting|
|Madison, Wisconsin, United States, 53792|
|Contact: Site Public Contact 800-622-8922|
|Principal Investigator: Hamid Emamekhoo|
|University Health Network-Princess Margaret Hospital||Recruiting|
|Toronto, Ontario, Canada, M5G 2M9|
|Contact: Site Public Contact 416-946-4501 firstname.lastname@example.org|
|Principal Investigator: Philippe L. Bedard|
|Principal Investigator:||Mamta Parikh||City of Hope Comprehensive Cancer Center LAO|
|Responsible Party:||National Cancer Institute (NCI)|
|Other Study ID Numbers:||
NCI-2020-05428 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
10404 ( Other Identifier: City of Hope Comprehensive Cancer Center LAO )
10404 ( Other Identifier: CTEP )
UM1CA186717 ( U.S. NIH Grant/Contract )
|First Posted:||July 30, 2020 Key Record Dates|
|Last Update Posted:||February 15, 2023|
|Last Verified:||January 2023|
|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.|
|Studies a U.S. FDA-regulated Drug Product:||Yes|
|Studies a U.S. FDA-regulated Device Product:||No|
Carcinoma, Ovarian Epithelial
Uterine Cervical Neoplasms
Carcinoma, Transitional Cell
Bile Duct Neoplasms
Carcinoma, Non-Small-Cell Lung
Carcinoma, Small Cell
Small Cell Lung Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms by Site
Respiratory Tract Neoplasms
Respiratory Tract Diseases
Endocrine Gland Neoplasms