What side effects are associated with this type of intervention?

Common treatments for bladder carcinoma, particularly those involving DNA repair inhibition and chemotherapy, often result in side effects such as anemia, neutropenia, and thrombocytopenia. Non-hematologic side effects include nausea, fatigue, and gastrointestinal disturbances. Severe side effects may include increased risk of infections and potential organ-specific toxicities.

What prior FDA approvals exist?

FDA-approved treatments for bladder carcinoma that target DNA repair mechanisms include immune checkpoint inhibitors such as pembrolizumab and nivolumab. These drugs enhance the immune system's ability to fight cancer by blocking proteins that prevent immune cells from attacking cancer cells. While not directly targeting DNA repair, they are part of the broader category of treatments that modulate cellular repair and survival pathways. Specific ATR kinase inhibitors like Berzosertib (M6620) are still under investigation and have not yet received FDA approval for bladder carcinoma.

What other types of research exist?

Promising novel alternatives to Berzosertib for bladder carcinoma patients include Atezolizumab, an immune checkpoint inhibitor, and Enfortumab Vedotin, an antibody-drug conjugate targeting Nectin-4. Both have shown efficacy in clinical trials for advanced urothelial carcinoma.

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ATR Kinase Inhibitor

M6620 + Topotecan for Small Cell Lung Cancer

Phase 2

Waitlist Available

Led By Anish Thomas

Research Sponsored by National Cancer Institute (NCI)

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated

Patients enrolled to the primary cohort must have limited- or extensive-disease SCLC at diagnosis, with relapse at study entry with measurable disease at random assignment per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Both platinum-sensitive and platinum-resistant patients will be included

Must not have

Patients with Li-Fraumeni syndrome will not be eligible

Pregnant women are excluded from this study because M6620 as a DDR inhibitor 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 M6620, breastfeeding should be discontinued if the mother is treated with M6620. These potential risks may also apply to topotecan used in this study

Timeline

Screening 3 weeks

Treatment Varies

Follow Up up to 2 years for pulmonary cohort and up 31.5 for exploratory cohort

Awards & highlights

No Placebo-Only Group

Summary

This trial is testing if combining two drugs, berzosertib and topotecan, works better than using topotecan alone for patients with relapsed small cell lung cancer or small cell cancer from other areas. Topotecan damages cancer cell DNA, and berzosertib stops the cells from fixing this damage, making the treatment more effective.

Who is the study for?

Adults with relapsed small cell lung cancer or small cell cancers from other body parts, who have measurable disease and are in good physical condition. They must not be pregnant, agree to contraception, and can't have untreated brain metastases or severe illnesses that could interfere with the trial.

What is being tested?

The trial is testing if adding berzosertib (M6620) to topotecan chemotherapy is more effective for patients whose small cell lung cancer has returned compared to topotecan alone. Berzosertib may block enzymes that help cancer cells repair damaged DNA.

What are the potential side effects?

Potential side effects include typical chemotherapy-related issues like fatigue, nausea, low blood counts leading to increased infection risk, hair loss, and possible organ damage due to the new drug's effect on DNA repair.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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My hepatitis B virus is under control with treatment.

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My small cell lung cancer has returned and can be measured.

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I had hepatitis C but am cured, or I'm being treated with no detectable virus.

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I can take care of myself but might not be able to do heavy physical work.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

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I do not have Li-Fraumeni syndrome.

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I am not pregnant or breastfeeding.

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I am not taking any strong medication that affects liver enzymes.

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I have recovered from side effects of cancer treatment, except for hair loss or nerve issues.

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I have previously been treated with topotecan.

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I have allergies to medications similar to M6620 or topotecan.

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My cancer is high grade neuroendocrine without small cell features.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ up to 2 years for pulmonary cohort and up 31.5 for exploratory cohort

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~up to 2 years for pulmonary cohort and up 31.5 for exploratory cohort

This trial's timeline: 3 weeks for screening, Varies for treatment, and up to 2 years for pulmonary cohort and up 31.5 for exploratory cohort for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

Progression-free Survival (PFS) Reported With 80% Confidence Interval

Progression-free Survival (PFS) Reported With 95% Confidence Interval

Secondary study objectives

Objective Response Rate (ORR)

Overall Survival (OS) Reported With 80% Confidence Interval

Overall Survival (OS) Reported With 95% Confidence Interval

Other study objectives

Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0).

Side effects data

From 2013 Phase 3 trial • 4312 Patients • NCT00011986

95%

Neutropenia

87%

Leukopenia

59%

Anemia

49%

Gastrointestinal

42%

Constitutional

37%

Thrombocytopenia

37%

Pain

24%

Peripheral neurologic

19%

Other Hemotologic

16%

Infection/Fever

14%

Neurologic

14%

Metabolic

12%

Pulmonary

2nd Primary

Allergy

Dermatologic

Musculoskeletal

Cardiovascular

Ocular/Visual

Hepatic

Genitourinary/Renal

Endocrine

Auditory

Hemorrhage

Coagulation

Thrombosis/Embolism

Constipation

Syncope

Vomiting

Abdominal Pain Or Cramping

Infection Documented W Grd 3/4 Neutropn.

Ileus

Febrile Neutropenia-Fuo Infect Not Docum

Allergy-Other

Allergic Reaction/Hypersensitivity

Infection Without Neutropenia

100%

80%

60%

40%

20%

Study treatment Arm

Carbo/Taxol

Carbo/Taxol/Gemcitabine

Carbo/Taxol/Doxil

Carbo/Topotecan - Carbo/Taxol

Carbo/Gemcitabine - Carbo/Taxol

Awards & Highlights

No Placebo-Only Group

All patients enrolled in this study will receive some form of active treatment.

Trial Design

3Treatment groups

Experimental Treatment

Active Control

Group I: Cohort I Arm II (topotecan hydrochloride & Berzosertib (M6620)Experimental Treatment5 Interventions

Participants receive topotecan hydrochloride intravenously (IV) over 30 minutes on days 1-5 and Berzosertib (M6620) IV over 60 minutes on days 2 and 5. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Participants undergo a computed tomography (CT) scan during screening and on study as well as a tumor biopsy during screening. Participants may also undergo blood sample collection during screening and on study.

Group II: Cohort 2: Exploratory Cohort: Topotecan & Berzosertib (M6620) Combination TherapyExperimental Treatment5 Interventions

Arm II (topotecan hydrochloride \& Berzosertib (M6620) Participants receive topotecan hydrochloride intravenously (IV) over 30 minutes on days 1-5 and Berzosertib (M6620) IV over 60 minutes on days 2 and 5. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Participants undergo a computed tomography (CT) scan during screening and on study as well as a tumor biopsy during screening. Participants may also undergo blood sample collection during screening and on study.

Group III: Cohort I Arm I (topotecan hydrochloride)Active Control4 Interventions

Participants receive topotecan hydrochloride intravenously (IV) over 30 minutes on days 1-5. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Participants may crossover to Arm II at disease progression. Participants undergo a computed tomography (CT) scan during screening and on study as well as a tumor biopsy during screening. Participants may also undergo blood sample collection during screening and on study.

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

Topotecan Hydrochloride

2013

Completed Phase 3

~6270

Biopsy

2014

Completed Phase 4

~1150

Berzosertib

2021

Completed Phase 2

~90

Computed Tomography

2017

Completed Phase 2

~2790

Biospecimen Collection

2004

Completed Phase 3

~2030

0 / 11Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

Bladder carcinoma treatments often include chemotherapy, targeted therapy, and immunotherapy. Chemotherapy drugs, such as cisplatin and gemcitabine, work by damaging the DNA of cancer cells, leading to cell death. Targeted therapies, like FGFR inhibitors, specifically target genetic mutations or proteins that drive cancer growth. Immunotherapy, including checkpoint inhibitors like pembrolizumab, enhances the immune system's ability to recognize and destroy cancer cells. Treatments like Berzosertib (M6620), an ATR kinase inhibitor, block DNA repair mechanisms, making cancer cells more susceptible to DNA-damaging agents. These mechanisms are crucial for bladder carcinoma patients as they offer multiple avenues to disrupt cancer cell survival and proliferation, potentially improving treatment outcomes.