M6620 + Topotecan for Small Cell Lung Cancer

Not currently 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether combining berzosertib with topotecan can be more effective than using topotecan alone for individuals with relapsed small cell lung cancer or small cell cancers originating outside the lung. Topotecan, a chemotherapy drug, damages the DNA in cancer cells to kill them, but some cancer cells can repair this damage. Berzosertib (also known as M6620) may block this repair, enhancing the chemotherapy's effectiveness. Individuals diagnosed with small cell lung cancer or similar small cell cancers that have returned after initial treatment might be suitable candidates. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group, offering a chance for potentially more effective therapy.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that the combination of berzosertib (M6620) and topotecan has been tested for safety in patients with small cell lung cancer. In earlier studies, this combination helped shrink tumors in some patients whose cancer had returned, indicating potential effectiveness against the cancer.

However, the combination did not significantly increase the time patients lived without their cancer worsening compared to using topotecan alone. This means it didn't greatly extend the period during which the cancer was controlled.

Regarding safety, the combination is generally considered tolerable. It is important to remember that all chemotherapy treatments, including topotecan, can cause side effects. Adding berzosertib aims to enhance topotecan's effectiveness, but patients might still experience common chemotherapy side effects such as tiredness, nausea, and low blood cell counts.

Overall, while the combination has been studied and shows some promise, potential participants should consider possible side effects and discuss them with their healthcare provider. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about berzosertib combined with topotecan hydrochloride for small cell lung cancer because it introduces a new mechanism of action. Most treatments for this condition, like chemotherapy, broadly attack rapidly dividing cells. However, berzosertib is an ATR inhibitor, which means it specifically targets and interferes with the DNA damage repair process in cancer cells, potentially making them more susceptible to topotecan. This combination could lead to more effective treatment by enhancing the cancer-killing effects while potentially sparing more healthy cells.

What evidence suggests that this trial's treatments could be effective for small cell lung cancer?

This trial will compare the effects of topotecan hydrochloride alone with the combination of topotecan hydrochloride and berzosertib (M6620) for treating small cell lung cancer. Research has shown that combining berzosertib with topotecan might help treat small cell lung cancer, especially if the cancer returns after initial treatment. Topotecan damages the DNA in cancer cells, aiding in tumor shrinkage. However, some cancer cells can repair this damage and survive. Berzosertib aims to block the enzymes these cells use to repair their DNA, potentially enhancing topotecan's effectiveness. Although studies have not shown a significant improvement in the time patients live without disease progression compared to using topotecan alone, the combination might still benefit some patients by better targeting cancer cells. ^{1 2 3 4 5}

Who Is on the Research Team?

Anish Thomas

Principal Investigator

National Cancer Institute LAO

Are You a Good Fit for This Trial?

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 for a Trial Participant

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)

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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 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]

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 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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT03896503

NCT03896503 | Randomized Trial of Topotecan With ... This phase II trial studies how well berzosertib (M6620) works when given in combination with topotecan hydrochloride (topotecan) compared with topotecan ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/37824137/

Berzosertib Plus Topotecan vs Topotecan Alone in Patients ... In this randomized clinical trial, treatment with berzosertib plus topotecan did not improve PFS compared with topotecan therapy alone among patients with ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT03896503?term=Topotecan&rank=8&tab=results

Randomized Trial of Topotecan With M6620, an ATR ... Berzosertib Plus Topotecan vs Topotecan Alone in Patients With Relapsed Small Cell Lung Cancer: A Randomized Clinical Trial. JAMA Oncol. 2023 Dec 1;9(12): ...

4. withpower.com withpower.com/trial/m6620-topotecan-for-small-cell-lung-cancer-f781a

M6620 + Topotecan for Small Cell Lung Cancer This trial is testing if combining two drugs, berzosertib and topotecan, works better than using topotecan alone for patients with relapsed small cell lung ...

5. cancer.gov cancer.gov/news-events/cancer-currents-blog/2021/topotecan-berzosertib-small-cell-lung-cancer

Topotecan–Berzosertib Combination for Small Cell Lung ... Researchers have identified a combination of two drugs that can shrink the tumors of some patients with small cell lung cancer (SCLC), the most aggressive form ...