Neoplasms

Skin and Connective Tissue Diseases

All Conditions

Breast Neoplasms

Breast Diseases

Skin Diseases

Antineoplastic Agents

All Drugs and Chemicals

Niraparib

Mitogens

Poly(ADP-ribose) Polymerase Inhibitors

Enzyme Inhibitors

Participants with baseline body weight \< 77 kilograms (kg) or baseline platelet count \< 150, 000 per cubic millimeter will be included in this Part. Dose escalation of M4344 administered along with niraparib.

Participants with baseline body weight \> =77 kilograms (kg) and baseline platelet count \>=150, 000 per cubic millimeter will be included in this Part. M4344 will be administered at a dose and schedule that was determined as the recommended dose for expansion (RDE) in Part 1A. Dose of niraparib will be escalated to the next higher dose level.

Participants with Poly(ADP-ribose) polymerase inhibitor (PARPi) resistant, germline breast cancer 1/2 mutated (gBRCA1/2m) human epidermal growth factor receptor 2 (HER2) negative advanced Breast Cancer (aBC) will receive the combination of niraparib and M4344 at the RDE which was determined in Part 1.

Participants with PARPi-naive germline BRCA1/2 wild type (gBRCAwt) homologous recombination repair gene mutated (HRRm) advanced breast cancer (aBC) will be randomized to receive niraparib as a single agent.

Participants with PARPi-naive germline BRCA1/2 wild type (gBRCAwt) homologous recombination repair gene mutated (HRRm) advanced breast cancer (aBC) will be randomized to receive the combination of niraparib and M4344 at the RDE as determined in Part 1 of this study.

Niraparib will be administered orally, once daily.

M4344 will be administered once daily or on an intermittent schedule in combination with niraparib.

M4344

Niraparib will be administered orally once daily at the RDE as determined in Part 1 of this study.

M4344 will be administered at a dose and schedule that was determined as RDE in Part 1A in combination with niraparib.

Niraparib will be administered orally, once daily. Dose of niraparib will be escalated beyond the dose in Part 1A.

Niraparib will be administered as single agent at the approved dose.

Medical Responsible

Study will include 3 parts. Aim of Part 1 of this study is to establish the maximum tolerated dose (MTD) and recommended dose for expansion (RDE) for M4344 (is an Ataxia Telangiectasia Mutated and Rad3-related \[ATR\] inhibitors) in combination with niraparib in participants with advanced solid tumors. Aim of Parts 2 and 3 of the study is to provide clinical proof-of-concept for the preclinically predicted synergistic efficacy of ATR and poly(ADP-Ribose) polymerase (PARP) inhibitors (PARPi) in defined populations of participants with advanced breast cancer (aBC) with DDR mutations with an unmet medical need.

Study of M4344 in Combination With Niraparib

A Phase I Dose Escalation Study of ATR Inhibitor M4344 in Combination With Niraparib in Participants With Advanced Solid Tumors Followed by Phase II Cohort Expansion in Participants With Breast Cancer With DNA Damage Response (DDR) Mutations

Per company policy, following approval of a new product or a new indication for an approved product in both the EU and the US, EMD Serono will share study protocols, anonymized patient level and study level data and redacted clinical study reports from clinical trials in patients with qualified scientific and medical researchers, upon request, as necessary for conducting legitimate research. Further information on how to request data can be found on our website https://www.emdgroup.com/en/research/our-approach-to-research-and-development/healthcare/clinical-trials/commitment-responsible-data-sharing.html

Number of participants with clinically significant changes from baseline in vital signs, 12-Lead Electrocardiogram (ECG) assessments findings and laboratory parameters will be reported.

Merck KGaA, Darmstadt, Germany

EMD Serono Research & Development Institute, Inc.

Respiratory Tract (Lung and Bronchial) Diseases

Carcinoma

Carcinoma, Non-Small-Cell Lung

Lung Neoplasms

Lung Diseases

Respiratory Tract Diseases

Thoracic Neoplasms

Respiratory Tract Neoplasms

Bronchial Neoplasms

Carcinoma, Bronchogenic

Immunomodulating Agents

Durvalumab

Antineoplastic Agents, Immunological

Ceralasertib plus durvalumab combination therapy Participants will be administered orally ceralasertib followed by IV durvalumab each 28 days cycle.

Participants will receive ceralasertib oral tablets.

Ceralasertib

Participants will receive durvalumab as an intravenous infusion

A study to investigate efficacy and safety of ceralasertib plus durvalumab in participants aged ≥ 18 years with advanced or metastatic non-small cell lung cancer whose disease progressed on or after prior anti-PD-(L)1 therapy and platinum-based chemotherapy.

This is a single-arm study, all participants will be assigned to one treatment group - ceralasertib plus durvalumab combination therapy. Each 28-day cycle will begin with ceralasertib administered orally followed by durvalumab administered intravenously.

The objectives of the current single-arm local study are to estimate the efficacy and safety of ceralasertib and durvalumab combination in local population to obtain relevant information for routine clinical practice. The results of this additional study will provide clinical data on efficacy and safety of an innovation drug in the new region - Russian Federation.

A Study to Investigate Efficacy and Safety of Ceralasertib Plus Durvalumab in Participants Aged ≥ 18 Years With Advanced or Metastatic Non-small Cell Lung Cancer Whose Disease Progressed on or After Prior Anti-PD-(L)1 Therapy and Platinum-based Chemotherapy

A Phase II, Open-label, Multicentre, Non-comparative, Single-arm Local Study of Ceralasertib Plus Durvalumab in Patients With Advanced or Metastatic Non-Small Cell Lung Cancer Without Actionable Genomic Alterations, and Whose Disease Has Progressed On or After Prior Anti-PD-(L)1 Therapy and Platinum-based Chemotherapy

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.Yes,indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.

Objective response rate (ORR) is defined as the proportion of participants who have a complete response (CR) or partial response (PR) per RECIST 1.1.

DoR is defined as the time from the date of first documented response until date of documented progression per RECIST 1.1.

Time to response (TTR) is defined as the time from the start of treatment until the date of first documented objective response per RECIST 1.1.

DCR at 18 weeks is defined as the percentage of participants who have a CR or PR or who have stable disease (SD) for at least 17 weeks per RECIST 1.1.

PFS is defined as time from the start of treatment until progression per Response Evaluation Criteria in Solid Tumours, Version 1.1 (RECIST 1.1).

OS is defined as time from the start of treatment until the date of death due to any cause.

The safety and tolerability profile of Ceralasertib and Durvalumab combination will be evaluated using vital signs, laboratory data, electrocardiograms (ECGs), and adverse event data

AstraZeneca

Symptoms and General Pathology

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Gland and Hormone Related Diseases

Rare Diseases

Recurrence

Ovarian Neoplasms

Carcinoma, Ovarian Epithelial

Disease Attributes

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

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Ovarian Cancer

Ovarian Epithelial Cancer

all PARP resistant, recurrent ovarian cancer

The first phase will be a 3+3 design of fixed dose Niraparib by mouth (PO) every day (QD) and M4344 will be escalated from 100-200 mg PO QD (28-day cycle). There will be a 4-week lead in with niraparib only.

M4344+Niraparib

In the second phase eligible patients will receive combination Niraparib + the determined dose of M4344 from the first phase.

Rebecca C Arend, MD, MSPH

The purpose of this study is to find out if a new drug, M4344, is safe and has beneficial effects when given in combination with the PARP inhibitor, Niraparib, in women with recurrent ovarian cancer that has progressed while on a PARP inhibitor.

The primary, secondary, and exploratory objective are to assess the safety of the combination of M4344 and Niraparib in a phase 1 trial of patients with PARP resistant recurrent ovarian cancer; to determine the response rate and percentage of participants who remain progression free survival (PFS) at 6 months (%PFS) among ovarian cancer participants that have become resistant to poly (adenosine diphosphate \[ADP\]) ribose polymerase inhibitors (PARPi) who are treated with ataxia telangiectasia and Rad3-related protein inhibitors (ATRi) + Niraparib in the dose expansion cohort; and to identify potential biological predictors of response and progression of disease with the combination of M4344 and Niraparib.

Trial of M4344 and Niraparib in Patients With Poly (ADP-ribose) Polymerase (PARP) Resistant Recurrent Ovarian Cancer

Trial of M4344 and Niraparib in Patients With PARP Resistant Recurrent Ovarian Cancer

Number and percentage of patients with treatment emergent adverse events and toxicity based upon CTCAE v.4.03 scoring.

To determine the MTD of M4344 and Niraparib during the dose escalation as defined by CTCAE v.4.03

To determine response rate among ovarian cancer patients that have become resistant to PARPi who are treated with ATRi + Niraparib as defined by RECIST v.1.1.

To determine percentage of patients who remain progression free at 6 months (%PFS) among ovarian cancer patients that have become resistant to PARPi who are treated with ATRi + Niraparib as defined by RECIST v.1.1.

University of Alabama at Birmingham

Primary Investigator

Nervous System Diseases

Heart and Blood Diseases

Diseases and Abnormalities at or Before Birth

Nutritional and Metabolic Diseases

Immune System Diseases

Ataxia

Cerebellar Ataxia

Telangiectasis

Ataxia Telangiectasia

Topotecan

Topoisomerase I Inhibitors

Participants will receive single intravenous infusion of \[14C\]M6620 on Day 1 in Period 1 and stay in clinical research unit (CRU) is required until the discharge criteria are met with a maximum confinement period of 15 days.

[14C]M6620

Participants will receive intravenous infusion of M6620 on Day 2 and Day 5 of each 21-day cycle in period 2 until disease progression or other criteria for study intervention discontinuation are met.

M6620

Participants will receive intravenous infusion of topotecan on Day 1 through Day 5 of each 21-day cycle in period 2 until disease progression or other criteria for study intervention discontinuation are met.

The study will be conducted in two periods, Period 1 (mass balance) and Period 2 (extension). The purpose of Period 1 of this study is to provide a quantitative characterization of the mass balance, rates and routes of elimination, and metabolic pathways after a single intravenous administration of \[14C\]berzosertib. The purpose of Period 2 is to assess safety and efficacy of berzosertib in combination with topotecan.

Berzosertib Human Mass Balance Study (DDRiver Solid Tumors 208)

Phase I Study to Evaluate the Mass Balance, PK, Metabolism and Excretion of Berzosertib (Intravenous) Containing Microtracer [14C]Berzosertib in Participants With Advanced Solid Tumors (DDRiver Solid Tumors 208)

Per company policy, following approval of a new product or a new indication for an approved product in both the EU and the US, Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany, will share study protocols, anonymized patient level and study level data and redacted clinical study reports from clinical trials in patients with qualified scientific and medical researchers, upon request, as necessary for conducting legitimate research. Further information on how to request data can be found on our website https://www.merckgroup.com/en/research/our-approach-to-research-and-development/healthcare/clinical-trials/commitment-responsible-data-sharing.html

Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany

Participants will initially receive Tuvusertib (M1774) once daily under fasting conditions. Additional schedules may be evaluated if needed.

Participants in the food effect assessment will receive Tuvusertib (M1774) at the dose and schedule determined as recommended dose for expansion (RDE) in Part A1. A single dose of Tuvusertib (M1774) will be administered on Day -7 under a fed (low-fat meal) or fasted condition, followed by a 1-week washout period. After completion of the scheduled food effect assessments, participants will follow the same schedule as participants in Part A1.

Part A3 is an expansion of Part A1 where Tuvusertib (M1774) will be administered as a single agent at the RDE established in Part A1. Participants with defined loss-of-function mutation in ARID1A, ATRX and/or DAXX, and ATM will be enrolled.

B1a: Participants with baseline body weight less than (\<) 77 kilogram (kg) or platelets \<150,000 cubic per millimeter (mm\^3) will receive Niraparib once daily combined with different doses of Tuvusertib (M1774).

B1b: Participants with baseline body weight greater than or equal to (\>=) 77 kg and or platelets \>= 150,000 mm\^3 will receive Niraparib once daily combined with different doses of Tuvusertib (M1774) and schedule determined as recommended dose for expansion (RDE) in Part B1a.

Starting at global RDE from Part A1, in Japan. Participants will initially receive Tuvusertib (M1774) once daily under fasting conditions. Additional schedules may be evaluated if needed.

Starting at global RDE from Part A1, in China. Participants will initially receive Tuvusertib (M1774) once daily under fasting conditions. Additional schedules may be evaluated if needed.

M1774 will be administered orally throughout the study.

M1774

Niraparib will be administered orally throughout the study.

This is an open-label, Phase I, first-in-human (FIH) multicenter, clinical study conducted in multiple parts to establish the safety, tolerability and pharmacokinetic/pharmacodynamic (PK/PD) profile (with and without food) and early signs of efficacy of Tuvuseritib (M1774) as monotherapy and in combination with the poly (ADP-ribose) polymerase (PARP) inhibitor niraparib.

Tuvusertib (M1774) in Participants With Metastatic or Locally Advanced Unresectable Solid Tumors (DDRiver Solid Tumors 301)

An Open-label, Multicenter Trial of the Safety, Tolerability, and Pharmacokinetic/Pharmacodynamic Profile of Tuvusertib (M1774) in Participants With Metastatic or Locally Advanced Unresectable Solid Tumors (DDRiver Solid Tumors 301)

We are committed to enhancing public health through responsible sharing of clinical trial data. Following approval of a new product or a new indication for an approved product in both the US and the European Union, the study sponsor and/or its affiliated companies will share study protocols, anonymized patient data and study level data, and redacted clinical study reports with qualified scientific and medical researchers, upon request, as necessary for conducting legitimate research. Further information on how to request data can be found on our website bit.ly/IPD21

Participants with a clinical benefit, defined as an objective response or stable disease for at least 6 months, as determined by the Investigator through the use of RECIST version 1.1.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Study of M4344 in Combination With Niraparib	NCT04655183	Advanced Solid ... Breast Cancer	Niraparib M4344 Niraparib M4344 Niraparib Niraparib	18 Years -	EMD Serono
A Study to Investigate Efficacy and Safety of Ceralasertib Plus Durvalumab in Participants Aged ≥ 18 Years With Advanced or Metastatic Non-small Cell Lung Cancer Whose Disease Progressed on or After Prior Anti-PD-(L)1 Therapy and Platinum-based Chemotherapy	NCT05941897	Advanced or Met...	Ceralasertib Durvalumab	18 Years -	AstraZeneca
Trial of M4344 and Niraparib in Patients With Poly (ADP-ribose) Polymerase (PARP) Resistant Recurrent Ovarian Cancer	NCT04149145	Ovarian Cancer ...	M4344+Niraparib M4344+Niraparib	18 Years -	University of Alabama at Birmingham
Berzosertib Human Mass Balance Study (DDRiver Solid Tumors 208)	NCT05246111	Advanced Solid ...	[14C]M6620 M6620 Topotecan	18 Years -	Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany
Tuvusertib (M1774) in Participants With Metastatic or Locally Advanced Unresectable Solid Tumors (DDRiver Solid Tumors 301)	NCT04170153	Metastatic or L...	M1774 Niraparib	18 Years -	EMD Serono
Trial of M4344 and Niraparib in Patients With Poly (ADP-ribose) Polymerase (PARP) Resistant Recurrent Ovarian Cancer	NCT04149145	Ovarian Cancer ...	M4344+Niraparib M4344+Niraparib	18 Years -	University of Alabama at Birmingham

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