Neoplasms

Urinary Tract, Sexual Organs, and Pregnancy Conditions

All Conditions

Digestive System Diseases

Respiratory Tract (Lung and Bronchial) Diseases

Skin and Connective Tissue Diseases

Gland and Hormone Related Diseases

Rare Diseases

Uterine Cervical Neoplasms

Esophageal Neoplasms

Carcinoma

Small Cell Lung Carcinoma

Cholangiocarcinoma

Breast Neoplasms

Carcinoma, Non-Small-Cell Lung

Carcinoma, Transitional Cell

Stomach Neoplasms

Carcinoma, Small Cell

Lung Neoplasms

Ovarian Neoplasms

Carcinoma, Ovarian Epithelial

Carcinoma, Ductal

Mesothelioma

Mesothelioma, Malignant

Endometrial Neoplasms

Bile Duct Neoplasms

Penile Neoplasms

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Breast Diseases

Skin Diseases

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

Endocrine Gland Neoplasms

Ovarian Diseases

Adnexal Diseases

Genital Diseases, Female

Genital Diseases

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Genital Neoplasms, Female

Urogenital Neoplasms

Endocrine System Diseases

Gonadal Disorders

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Stomach Diseases

Uterine Neoplasms

Uterine Cervical Diseases

Uterine Diseases

Adenoma

Neoplasms, Mesothelial

Pleural Neoplasms

Biliary Tract Neoplasms

Bile Duct Diseases

Biliary Tract Diseases

Adenocarcinoma

Head and Neck Neoplasms

Esophageal Diseases

Carcinoma, Bronchogenic

Bronchial Neoplasms

Genital Neoplasms, Male

Genital Diseases, Male

Penile Diseases

Male Urogenital Diseases

Esophageal Cancer

Small Cell Lung Cancer

Ovarian Cancer

Transitional Cell Carcinoma

Bile Duct Cancer

Stomach Cancer

Ovarian Epithelial Cancer

Malignant Mesothelioma

Penile Cancer

Antineoplastic Agents

All Drugs and Chemicals

Gemcitabine

Cisplatin

Antimetabolites

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.

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.

Elimusertib

Gemcitabine Hydrochloride

Mamta Parikh

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.

PRIMARY OBJECTIVES:

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.

SECONDARY OBJECTIVES:

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.

EXPLORATORY OBJECTIVES:

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.

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 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

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.

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.

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).

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.

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.

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.

The percent of responders will be calculated and associated exact 95% confidence intervals will be constructed.

Kaplan-Meier plots will be used to summarize PFS.

National Cancer Institute (NCI)

Symptoms and General Pathology

Recurrence

Disease Attributes

Micronutrients

Hematinics

Amino Acids

Vitamins

Carboplatin

Pemetrexed

Enzyme Inhibitors

Folic Acid

Vitamin B Complex

Folic Acid Antagonists

Glutamic Acid

Folinic Acid

Folate

Vitamin B9

Patients receive methoxyamine PO QD on days 1-4, pemetrexed disodium IV over 10 minutes, and cisplatin IV over 30-60 minutes on day 1. Treatment repeats every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients may continue methoxyamine and pemetrexed disodium beyond cycle 6 if the patient continues to benefit from treatment at the discretion of the treating physician.

Patients receive methoxyamine PO QD on days 1-4 and pemetrexed disodium IV over 10 minutes on day 1. Treatment repeats every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients may continue methoxyamine and pemetrexed disodium beyond cycle 6 if the patient continues to benefit from treatment at the discretion of the treating physician.

Methoxyamine

Pemetrexed Disodium

Marianna Koczywas

This phase I/II trial studies the side effects and the best dose of methoxyamine when given together with cisplatin and pemetrexed disodium and to see how well it works in treating patients with solid tumors or mesothelioma that have spread to other places in the body and usually cannot be cured or controlled with standard treatment (advanced), or mesothelioma that does not respond to pemetrexed disodium and cisplatin or carboplatin (refractory). Methoxyamine may shrink the tumor and may also help cisplatin and pemetrexed disodium work better by making tumor cells more sensitive to the drugs. Drugs used in chemotherapy, such as cisplatin and pemetrexed disodium, 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 methoxyamine together with cisplatin and pemetrexed disodium may be a better treatment for solid tumors or mesothelioma than methoxyamine and pemetrexed disodium.

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) and the recommended phase 2 dose (RP2D) for the combination of methoxyamine (TRC102) with pemetrexed (pemetrexed disodium) and cisplatin in patients with advanced solid tumors. (Arm A) II. To describe the toxicities of TRC102 combined with pemetrexed and cisplatin at each dose studied. (Arm A) III. To describe responses to the drug combination at each dose level. (Arm A) IV. To detect activity of the combination of TRC102 and pemetrexed, as evidenced by tumor response in patients with advanced malignant mesothelioma previously treated with pemetrexed and cisplatin. (Arm B)

SECONDARY OBJECTIVES:

I. To describe pharmacokinetic parameters of TRC102 given concurrent with pemetrexed and cisplatin.

II. To evaluate the pharmacodynamic parameters of TRC102 given concurrently with pemetrexed and cisplatin.

III. To explore the feasibility of establishing pleural and peritoneal effluent-derived cell lines and to evaluate the response of cultured pleural and peritoneal mesothelioma cells to cisplatin, pemetrexed, and TRC102.

IV. To document all objective clinical responses to TRC102 in combination with pemetrexed and cisplatin.

OUTLINE: This is a phase I, dose-escalation study of methoxyamine, followed by a phase II study. Patients are assigned to 1 of 2 treatment arms.

ARM A: Patients receive methoxyamine orally (PO) once daily (QD) on days 1-4, pemetrexed disodium intravenously (IV) over 10 minutes, and cisplatin IV over 30-60 minutes on day 1. Treatment repeats every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients may continue methoxyamine and pemetrexed disodium beyond cycle 6 if the patient continues to benefit from treatment at the discretion of the treating physician.

ARM B: Patients receive methoxyamine PO QD on days 1-4 and pemetrexed disodium IV over 10 minutes on day 1. Treatment repeats every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients may continue methoxyamine and pemetrexed disodium beyond cycle 6 if the patient continues to benefit from treatment at the discretion of the treating physician.

After completion of study treatment, patients are followed up for 8 weeks.

Methoxyamine, Cisplatin, and Pemetrexed Disodium in Treating Patients With Advanced Solid Tumors or Mesothelioma That Cannot Be Removed by Surgery or Mesothelioma That Is Refractory to Pemetrexed Disodium and Cisplatin or Carboplatin

Phase I Study of TRC102 in Combination With Cisplatin and Pemetrexed in Patients With Advanced Solid Tumors / Phase II Study of TRC102 With Pemetrexed in Patients Refractory to Pemetrexed and Cisplatin or Carboplatin

Dose-limiting toxicity will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. Pre-specified DLT criteria included the following adverse events (AE), judged to be at least possibly related to study therapy: grade 3 or greater non-hematologic toxicity, grade 3 thrombocytopenia with bleeding, any grade 4 thrombocytopenia, grade 4 febrile neutropenia lasting \> 7 day, any grade febrile neutropenia, any grade 5 toxicity. Treatment delay of cycle 2 by more than 2 weeks and inability to administer 3 of the 4 doses due to toxicity in the first treatment course were also considered DLTs. Controllable nausea, vomiting and diarrhea, electrolyte toxicities correctable (to baseline or grade 1) with repletion and grade 3 creatinine elevation correctable (to grade 1 or less) with IV hydration were not considered DLT's.

The maximum tolerated dose of TRC102 in combination with 500mg/m\^2 IV of Pemetrex and 60 or 75 mg/m\^2 IV of Cisplatin is based on toxicities observed during the first cycle and is defined as the highest dose tested in which fewer than 33% of patients experience an attributable DLT to the study drug, when at least 6 patients are treated at that dose and are evaluable for toxicity. Dose escalations proceeded according to a standard 3+3 design.

Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm; Partial Response (PR), at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters; Overall Response (OR) = CR + PR

Progression-free survival will be summarized as time from first protocol treatment until progression or death from any cause, using the product-limit Kaplan-Meier estimator. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECISTv1.1), as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression).

Overall survival will be summarized as time from first protocol treatment until death from any cause, using the product-limit Kaplan-Meier estimator.

"Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.

TRC102 50 mg PO days 1-4; Pemetrex 500 mg/m\^2 IV over 10 min day1; Cisplatin 60 mg/m\^2 IV over 30-60 min day1

Arm A, Dose Level 1 - 50mg TRC102, 60mg/m^2 Cisplatin (Phase I)

TRC102 75 mg PO days 1-4; Pemetrex 500 mg/m\^2 IV over 10 min day1; Cisplatin 60 mg/m\^2 IV over 30-60 min day1

Arm A, Dose Level 2 - 75mg TRC102, 60mg/m^2 Cisplatin (Phase I)

TRC102 100 mg PO days 1-4; Pemetrex 500 mg/m\^2 IV over 10 min day1; Cisplatin 60 mg/m\^2 IV over 30-60 min day1

Arm A, Dose Level 3 - 100mg TRC102, 60mg/m^2 Cisplatin (Phase I)

TRC102 100 mg PO days 1-4; Pemetrex 500 mg/m\^2 IV over 10 min day1; Cisplatin 75 mg/m\^2 IV over 30-60 min day1

Arm A, Dose Level 4 - 100mg TRC102, 75mg/m^2 Cisplatin (Phase I)

TRC102 50mg PO on days 1-4; Pemetrex 500mg/m\^2 IV over 10 min day 1

Arm B, Dose Level 1 - 50mg TRC102 (Phase II)

TRC102 50 mg/day PO days 1-4; Pemetrex 500 mg/m\^2 IV over 10 min day1; Cisplatin 60 mg/m\^2 IV over 30-60 min day1

TRC102 75 mg/day PO days 1-4; Pemetrex 500 mg/m\^2 IV over 10 min day1; Cisplatin 60 mg/m\^2 IV over 30-60 min day1

TRC102 100 mg/dayPO days 1-4; Pemetrex 500 mg/m\^2 IV over 10 min day1; Cisplatin 60 mg/m\^2 IV over 30-60 min day1

TRC102 100 mg/day PO days 1-4; Pemetrex 500 mg/m\^2 IV over 10 min day1; Cisplatin 75 mg/m\^2 IV over 30-60 min day1

TRC102 50mg/day PO on days 1-4; Pemetrex 500mg/m\^2 IV over 10 min day 1

Total

Age, Continuous

Sex: Female, Male

Caucasian

Hispanic

Unknown

Asian

Race/Ethnicity, Customized

United States

Region of Enrollment

0=Asymptomatic and fully active

1=Symptomatic; fully ambulatory; restricted in physically strenuous activity

ECOG performance status

Paul Frankel, Ph.D.

TRC102 100/day mg PO days 1-4; Pemetrex 500 mg/m\^2 IV over 10 min day1; Cisplatin 60 mg/m\^2 IV over 30-60 min day1

TRC102 100/day mg PO days 1-4; Pemetrex 500 mg/m\^2 IV over 10 min day1; Cisplatin 75 mg/m\^2 IV over 30-60 min day1

Number of Participants With at Least One Dose Limiting Toxicity (DLT) - Phase I

Patients receive starting dose of TRC102 50 mg/day PO on days 1-4, 500 mg/m\^2 pemetrexed disodium IV over 10 minutes, and 60 or 75 mg/m\^2 of cisplatin IV over 30-60 minutes on day 1. Treatment repeats every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients may continue TRC102 and pemetrexed disodium beyond cycle 6 if the patient continues to benefit from treatment at the discretion of the treating physician.

Cisplatin: Given IV

TRC102: Given PO

Pemetrexed Disodium: Given IV

Treatment (TRC102, Pemetrexed Disodium, Cisplatin)

Maximum Tolerated Dose (MTD)

TRC102 100 mg/day PO days 1-4; Pemetrex 500 mg/m\^2 IV over 10 min day1; Cisplatin 60 mg/m\^2 IV over 30-60 min day1

TRC102 50 mg/day PO on days 1-4; Pemetrex 500mg/m\^2 IV over 10 min day 1

Number of Subject With Overall Response

Patients receive 50, 75 or 100 mg/day of TRC102 PO QD on days 1-4, 500 mg/m\^2 of pemetrexed disodium IV over 10 minutes, and 60 or 75 mg/m\^2 of cisplatin IV over 30-60 minutes on day 1. Treatment repeats every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients may continue TRC102 and pemetrexed disodium beyond cycle 6 if the patient continues to benefit from treatment at the discretion of the treating physician.

Arm A (TRC102, Pemetrexed Disodium, Cisplatin) - Phase I

Patients receive 50 mg/day of TRC102 PO QD on days 1-4 and 500 mg/m\^2 of pemetrexed disodium IV over 10 minutes on day 1. Treatment repeats every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients may continue TRC102 and pemetrexed disodium beyond cycle 6 if the patient continues to benefit from treatment at the discretion of the treating physician.

Arm B (TRC102, Pemetrexed Disodium) - Phase II

Pre-specified in the Study Protocol to collect, analyze, and report data for this Outcome Measure by Phase and not by dose-level.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
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	Advanced Bile D... Advanced Breast... Advanced Cervic... Advanced Endome... Advanced Esopha... Advanced Gastri... Advanced Head a... Advanced Lung N... Advanced Lung S... Advanced Malign... Advanced Ovaria... Advanced Penile... Advanced Pleura... Advanced Urothe... Anatomic Stage ... Anatomic Stage ... Clinical Stage ... Clinical Stage ... Stage III Cervi... Stage III Dista... Stage III Intra... Stage III Lung ... Stage III Ovari... Stage III Penil... Stage III Pleur... Stage IV Cervic... Stage IV Distal... Stage IV Intrah... Stage IV Lung C... Stage IV Ovaria... Stage IV Penile... Stage IV Pleura... Triple-Negative... Unresectable Ur...	Cisplatin Elimusertib Gemcitabine Hyd...	18 Years -	National Cancer Institute (NCI)
Methoxyamine, Cisplatin, and Pemetrexed Disodium in Treating Patients With Advanced Solid Tumors or Mesothelioma That Cannot Be Removed by Surgery or Mesothelioma That Is Refractory to Pemetrexed Disodium and Cisplatin or Carboplatin	NCT02535312	Advanced Malign... Advanced Perito... Advanced Pleura... Recurrent Perit... Recurrent Pleur... Refractory Mali... Unresectable So...	Cisplatin Methoxyamine Pemetrexed Diso...	18 Years -	National Cancer Institute (NCI)

Spots Global Cancer Trial Database for advanced pleural malignant mesothelioma