M6620 + Topotecan for Small Cell Lung Cancer

Recruiting at 39 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: CYP3A4 inhibitors, CYP3A4 inducers

Disqualifiers: Symptomatic brain metastasis, prior topotecan, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 13

Duration: 21-day cycles, up to 2 years

104 Participants Needed

Trial Summary

What is the purpose of this trial?

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.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications, but you should avoid medications that strongly affect the enzyme CYP3A4, like certain antibiotics and herbal supplements. It's important to discuss your current medications with the trial team to ensure there are no interactions.

What data supports the effectiveness of the drug combination M6620 (Berzosertib) and Topotecan for treating small cell lung cancer?

Research shows that some small cell lung cancers, which become resistant to standard treatments, may benefit from a combination of topotecan and berzosertib. This combination targets cancer cells that have become resistant to platinum-based chemotherapy, offering a potential new option for patients. ^{1 2 3 4 5}

What is known about the safety of the combination of M6620 (Berzosertib) and Topotecan in humans?

The combination of M6620 (Berzosertib) and Topotecan has been tested in humans and is generally well tolerated, with the most common serious side effects being low blood cell counts, such as anemia (low red blood cells), leukopenia (low white blood cells), and neutropenia (low neutrophils, a type of white blood cell). One patient experienced severe thrombocytopenia (low platelets) requiring a transfusion, which was a dose-limiting side effect. ^{1 3 6 7 8}

What makes the drug combination of M6620 (Berzosertib) and Topotecan unique for treating small cell lung cancer?

This drug combination is unique because it includes Berzosertib, a first-in-class inhibitor that targets a specific protein (ATR) involved in DNA repair, potentially enhancing the effectiveness of Topotecan, especially in cases where the cancer has become resistant to standard treatments. ^{3 4 7 9 10}

Research Team

Anish Thomas

Principal Investigator

National Cancer Institute LAO

Eligibility Criteria

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.

Inclusion Criteria

Platelets >= 100,000/mcL

I am HIV-positive, on effective treatment with no detectable virus, and my medication does not interact with M6220.

My hepatitis B virus is under control with treatment.

Exclusion Criteria

I do not have Li-Fraumeni syndrome.

Patients with uncontrolled intercurrent illness

I am not pregnant or breastfeeding.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive topotecan hydrochloride IV over 30 minutes on days 1-5, with or without 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.

21-day cycles, up to 2 years

Multiple visits per cycle (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment completion, with follow-up at 4 weeks and then every 12 weeks thereafter.

Up to 31.5 months

Regular visits every 12 weeks (in-person)

Treatment Details

Interventions

• Berzosertib
• Topotecan Hydrochloride

Trial Overview 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.

Participant Groups

Group I: Cohort II (exploratory cohort: topotecan, berzosertib (M6620)) Experimental Treatment 5 Interventions

Cohort II: Participants receive topotecan hydrochloride 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 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 I Arm II (topotecan hydrochloride, berzosertib (M6620)) Experimental Treatment 5 Interventions

Participants receive topotecan hydrochloride 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 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 Control 4 Interventions

Participants receive topotecan hydrochloride 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 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.

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Findings from Research

Berzosertib, an ATR inhibitor, combined with cisplatin was well tolerated in a study of 31 patients with advanced solid tumors, with the recommended dose established at 140 mg/m2 for berzosertib and 75 mg/m2 for cisplatin.

Despite prior treatment failures with platinum-based chemotherapy, 4 out of 31 patients showed a partial response to the combination therapy, indicating preliminary efficacy that supports further investigation in Phase 2 trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1 study of the ATR inhibitor berzosertib in combination with cisplatin in patients with advanced solid tumours. Shapiro, GI., Wesolowski, R., Devoe, C., et al.[2023]

In a review of 77 patients with relapsed small cell lung cancer, 23 had pre-existing interstitial lung disease (ILD), and intravenous topotecan treatment was associated with a significant risk of acute exacerbation of ILD (AE-ILD), occurring in 21.7% of these patients.

Topotecan treatment led to severe adverse events, including neutropenia and thrombocytopenia, with AE-ILD being fatal in 3 out of 5 cases, highlighting the need for caution when administering this drug to patients with ILD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of topotecan monotherapy for relapsed small cell lung cancer patients with pre-existing interstitial lung disease. Enomoto, Y., Inui, N., Imokawa, S., et al.[2015]

In a study involving 60 patients with advanced solid tumors, the combination of berzosertib and gemcitabine was found to be well tolerated, with a recommended Phase 2 dose established for this combination.

The treatment showed preliminary signs of efficacy, with many patients achieving either a partial response or stable disease, indicating potential benefits for those with resistant or refractory tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1 study of the ATR inhibitor berzosertib (formerly M6620, VX-970) combined with gemcitabine ± cisplatin in patients with advanced solid tumours. Middleton, MR., Dean, E., Evans, TRJ., et al.[2023]

The combination of the ATR inhibitor M6620 and the TOP1 inhibitor topotecan was well tolerated in a phase I study involving 21 patients, allowing for dose escalation to the maximum planned dose, despite some instances of dose-limiting toxicities like thrombocytopenia.

This treatment showed promising efficacy, particularly in patients with platinum-refractory small-cell lung cancer, with two partial responses and several cases of stable disease lasting over three months, indicating potential for further investigation in phase II studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I Study of ATR Inhibitor M6620 in Combination With Topotecan in Patients With Advanced Solid Tumors. Thomas, A., Redon, CE., Sciuto, L., et al.[2022]

In a study of 23 patients with relapsed or refractory small-cell lung cancer, the combination of topotecan and etoposide showed a modest overall response rate of 17.4%, with a median progression-free survival of 4.7 months and median overall survival of 9.5 months.

The treatment was associated with significant toxicities, including severe myelosuppression, with 78.3% of patients experiencing grade 3/4 neutropenia, indicating that while the regimen has some efficacy, it also carries considerable risks that need to be managed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination of topotecan and etoposide as a salvage treatment for patients with recurrent small cell lung cancer following irinotecan and platinum first-line chemotherapy. Choi, HJ., Cho, BC., Shin, SJ., et al.[2018]

References

1. England pubmed.ncbi.nlm.nih.gov

Phase 1 study of the ATR inhibitor berzosertib in combination with cisplatin in patients with advanced solid tumours. [2023]

2. Germany pubmed.ncbi.nlm.nih.gov

Safety of topotecan monotherapy for relapsed small cell lung cancer patients with pre-existing interstitial lung disease. [2015]

3. England pubmed.ncbi.nlm.nih.gov

Phase 1 study of the ATR inhibitor berzosertib (formerly M6620, VX-970) combined with gemcitabine ± cisplatin in patients with advanced solid tumours. [2023]

4. United States pubmed.ncbi.nlm.nih.gov

A rational targeted therapy for platinum-resistant small-cell lung cancer. [2021]

5. Germany pubmed.ncbi.nlm.nih.gov

Population pharmacokinetics of ATR inhibitor berzosertib in phase I studies for different cancer types. [2021]

6. United States pubmed.ncbi.nlm.nih.gov

Phase I Study of ATR Inhibitor M6620 in Combination With Topotecan in Patients With Advanced Solid Tumors. [2022]

7. United States pubmed.ncbi.nlm.nih.gov

Berzosertib Plus Topotecan vs Topotecan Alone in Patients With Relapsed Small Cell Lung Cancer: A Randomized Clinical Trial. [2023]

8. New Zealand pubmed.ncbi.nlm.nih.gov

Topotecan: An evolving option in the treatment of relapsed small cell lung cancer. [2021]

9. Germany pubmed.ncbi.nlm.nih.gov

Combination of topotecan and etoposide as a salvage treatment for patients with recurrent small cell lung cancer following irinotecan and platinum first-line chemotherapy. [2018]

10. United States pubmed.ncbi.nlm.nih.gov

Efficacy and safety of oral topotecan and bevacizumab combination as second-line treatment for relapsed small-cell lung cancer: an open-label multicenter single-arm phase II study. [2015]