What is the mechanism of action of this treatment?

Berzosertib, an enzyme inhibitor, blocks enzymes essential for tumor cell growth, potentially stopping cancer progression. Irinotecan, a chemotherapy drug, disrupts DNA replication in cancer cells, leading to their death. These mechanisms are significant for Gastroesophageal Junction Adenocarcinoma patients as they offer a targeted approach to hinder cancer cell growth and division, potentially improving treatment outcomes.

What side effects are associated with this type of intervention?

Common side effects of enzyme inhibitors like Berzosertib include fatigue, nausea, and potential hematologic toxicities such as neutropenia and thrombocytopenia. Irinotecan, a chemotherapy agent, often causes diarrhea, nausea, vomiting, and myelosuppression, which can lead to neutropenia and increased risk of infection. Both treatments may also cause general side effects such as hair loss, loss of appetite, and weakness.

What prior FDA approvals exist?

FDA-approved treatments for Gastroesophageal Junction Adenocarcinoma include various chemotherapy agents and targeted therapies. Irinotecan, a chemotherapy drug, has been used in combination with other agents like cisplatin and paclitaxel. Targeted therapies such as trastuzumab, a monoclonal antibody targeting HER2, and ramucirumab, a VEGFR2 antagonist, have also been approved. While berzosertib, an enzyme inhibitor, is still under investigation, other enzyme inhibitors like pembrolizumab, targeting PD-1, have shown efficacy in this cancer type.

What other types of research exist?

Promising novel alternatives for Gastroesophageal Junction Adenocarcinoma include Pembrolizumab, an anti-PD-1 monoclonal antibody approved for patients with high PD-L1 expression, and Nivolumab, another anti-PD-1 monoclonal antibody showing activity in esophageal squamous cell carcinoma. Additionally, Anlotinib, a tyrosine kinase inhibitor, has shown efficacy in esophageal squamous cell carcinoma and may be considered.

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PARP Inhibitor

Berzosertib + Irinotecan for Gastric Cancer

Phase 2

Waitlist Available

Led By Jordan D Berlin

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

Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as >= 20 mm (>= 2 cm) by chest x-ray or as >= 10 mm (>= 1 cm) with computed tomography (CT) scan, magnetic resonance imaging (MRI), or calipers by clinical exam.

Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 60%).

Must not have

Patients with untreated or symptomatic brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events.

Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > grade 1, except alopecia) that was administered more than four weeks prior to starting study therapy.

Timeline

Screening 3 weeks

Treatment Varies

Follow Up up to 1 year

Awards & highlights

No Placebo-Only Group

Summary

This trial tests a combination of berzosertib and irinotecan in patients with advanced gastric or gastroesophageal junction cancer. Berzosertib blocks enzymes needed for cancer growth, and irinotecan kills or stops the spread of cancer cells. Irinotecan has been used in various combinations for treating advanced gastric and gastroesophageal cancers, showing some efficacy but not proving superior to other treatments. The goal is to find a more effective treatment for these difficult-to-treat cancers.

Who is the study for?

This trial is for adults over 18 with progressive, metastatic, or unresectable gastric or gastroesophageal junction cancer that has a TP53 mutation. Participants must have tried at least two systemic therapies and meet certain health criteria (like blood cell counts). Women of childbearing age and men with partners of childbearing age must use contraception.

What is being tested?

The trial is testing the effectiveness of combining berzosertib, which blocks enzymes needed for tumor growth, with irinotecan, a chemotherapy drug that kills or stops the spread of cancer cells. The goal is to see if this combination works better than irinotecan alone in treating these cancers.

What are the potential side effects?

Potential side effects may include typical chemotherapy-related issues such as nausea, fatigue, hair loss (alopecia), low blood cell counts leading to increased infection risk or bleeding problems. Berzosertib's side effects are not fully known but could involve similar reactions due to its role in blocking cell growth.

Eligibility Criteria

Inclusion Criteria

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

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I have a tumor that can be measured with imaging or physical exam.

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I am mostly self-sufficient and can carry out daily activities.

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I agree to use effective birth control during and 6 months after the study if I can have children.

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I am 18 years old or older.

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My kidney function is good enough for the trial.

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My cancer is a type that started in the stomach or where the stomach meets the esophagus, and it cannot be removed by surgery.

Exclusion Criteria

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

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I do not have untreated or symptomatic brain metastases.

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I still have side effects from cancer treatment that are not hair loss.

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I do not have any serious illnesses that would stop me from following the study's requirements.

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I have been treated with irinotecan before.

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I have early stage stomach cancer that has not been treated or can be surgically removed.

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I am not pregnant or breastfeeding.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ up to 1 year

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~up to 1 year

This trial's timeline: 3 weeks for screening, Varies for treatment, and up to 1 year for reporting.

Treatment Details

Study Objectives

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

Secondary study objectives

Duration of responses (DOR)

Overall survival (OS)

Time to progression (TTP)

Other study objectives

Presence of other deoxyribonucleic acid (DNA) damage response defects (DDRD)

Side effects data

From 2023 Phase 2 trial • 76 Patients • NCT04768296

66%

Anaemia

36%

Thrombocytopenia

32%

Neutropenia

30%

Platelet count decreased

27%

Nausea

25%

Decreased appetite

25%

Asthenia

18%

White blood cell count decreased

18%

Constipation

16%

Neutrophil count decreased

15%

Dyspnoea

15%

Diarrhoea

14%

Vomiting

14%

Fatigue

12%

Lymphocyte count decreased

11%

Hypokalaemia

11%

Pneumonia

10%

Hypoalbuminaemia

10%

Headache

10%

Alanine aminotransferase increased

10%

Aspartate aminotransferase increased

10%

Cough

Weight decreased

Epistaxis

Blood alkaline phosphatase increased

Lipase increased

Hypocalcaemia

Hyponatraemia

Pyrexia

Insomnia

Dizziness

Haemoptysis

Malaise

Mucosal inflammation

Hypomagnesaemia

Gamma-glutamyltransferase increased

Hyperglycaemia

Febrile neutropenia

COVID-19

Hypertension

Gastrooesophageal reflux disease

Liver injury

Oedema peripheral

Dyspnoea exertional

Alopecia

COVID-19 pneumonia

Tachycardia

Abdominal pain

Blood creatinine increased

Hypophosphataemia

Dysgeusia

Haemoglobin decreased

Productive cough

Blood bilirubin increased

Pleural effusion

Localised oedema

Night sweats

Blood magnesium decreased

Neuropathy peripheral

Pruritus

Chest discomfort

Paraesthesia

Pain

Anxiety

Sepsis

Leukopenia

Atrial fibrillation

Abdominal pain upper

Chills

Upper respiratory tract infection

Activated partial thromboplastin time prolonged

Amylase increased

Blood albumin decreased

Blood lactate dehydrogenase increased

Arthralgia

Back pain

Muscle spasms

Dysphonia

Hypotension

Pallor

Metastases to central nervous system

Photosensitivity reaction

Creatinine renal clearance decreased

Acute kidney injury

Electrolyte imbalance

Hepatic pain

Decubitus ulcer

Memory impairment

Pleuritic pain

Blood sodium decreased

Tremor

Gout

Presyncope

Seizure

Pneumonia bacterial

Blood urea increased

Hemiparesis

Device malfunction

Skin lesion

Hypoglycaemia

Lip dry

Herpes zoster reactivation

Cholestasis

Wound infection

Influenza like illness

Conjunctival pallor

Diplopia

Haemorrhoids

Generalised oedema

Injection site pruritus

Electrocardiogram QT prolonged

Rash

Blood phosphorus decreased

C-reactive protein increased

CD4/CD8 ratio decreased

Hypochloraemia

Depression

Dyspnoea paroxysmal nocturnal

Rash pruritic

Secretion discharge

Hyperthermia

Choluria

Swelling face

Hyperbilirubinaemia

Respiratory tract infection

Nail disorder

Haemorrhoids thrombosed

Hyperkalaemia

Transient aphasia

Sinusitis

Confusional state

Pneumonia pneumococcal

Eye discharge

Gingival pain

Sputum discoloured

Oral disorder

Wheezing

Hypoxia

Pneumothorax

Lower gastrointestinal haemorrhage

Pulmonary embolism

Petechiae

Tooth loss

Spinal compression fracture

Cancer pain

Hemianopia homonymous

Nasal congestion

Myelosuppression

Acute coronary syndrome

Vestibular disorder

Disease progression

General physical health deterioration

Multiple organ dysfunction syndrome

Enterococcal sepsis

Lung abscess

Septic shock

Serratia sepsis

Staphylococcal sepsis

Urinary tract infection

Urosepsis

Acute respiratory distress syndrome

Respiratory failure

Coagulopathy

Thrombocytosis

Arrhythmia

Cardiac failure

Sinus tachycardia

Hypothyroidism

Immune-mediated hypothyroidism

Macular oedema

Abdominal discomfort

Abdominal distension

Dry mouth

Dyspepsia

Dysphagia

Flatulence

Chest pain

Face oedema

Gait disturbance

Hypersensitivity

Bronchiolitis

Bronchitis

Candida infection

Diverticulitis

Gastroenteritis

Compression fracture

Fall

Radiation oesophagitis

Radiation pneumonitis

Spinal fracture

Aspartate aminotransferase decreased

Blood cholesterol increased

Blood glucose increased

Blood lactic acid increased

Platelet count increased

Urine output decreased

Malnutrition

Muscular weakness

Pain in extremity

Tumour pain

Disturbance in attention

Nephrolithiasis

Renal impairment

Aphonia

Deep vein thrombosis

Orthostatic hypotension

Phlebitis

100%

80%

60%

40%

20%

Study treatment Arm

Safety run-in Part (DL2) + Main Part: Berzosertib 210 mg/m^2 + Topotecan 1.25 mg/m^2

Safety run-in Part (Dose Level 1 [DL 1]): Berzosertib 105 mg/m^2 + Topotecan 1.25 mg/m^2

Awards & Highlights

No Placebo-Only Group

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

Trial Design

1Treatment groups

Experimental Treatment

Group I: Treatment (irinotecan and M6620)Experimental Treatment5 Interventions

Patients receive irinotecan IV over 90 minutes and berzosertib IV over 60 minutes on days 1 and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo endoscopic or CT assisted biopsy and MRI on study.

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

Magnetic Resonance Imaging

2017

Completed Phase 3

~1180

Irinotecan

2017

Completed Phase 3

~2590

Berzosertib

2021

Completed Phase 2

~90

0 / 12Eligibility 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

Berzosertib, an enzyme inhibitor, blocks enzymes essential for tumor cell growth, potentially stopping cancer progression. Irinotecan, a chemotherapy drug, disrupts DNA replication in cancer cells, leading to their death. These mechanisms are significant for Gastroesophageal Junction Adenocarcinoma patients as they offer a targeted approach to hinder cancer cell growth and division, potentially improving treatment outcomes.