M6620 + Irinotecan for Cancer

Not currently recruiting at 28 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: National Cancer Institute (NCI)

Must not be taking: CYP3A4 inducers, Valproic acid

Disqualifiers: Unstable brain metastases, Severe infection, others

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

Compensation: Varies

Number of Visits: 28

Duration: 48 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the safety and optimal dose of two drugs, Berzosertib (M6620) and irinotecan, for treating solid tumors that have spread or cannot be surgically removed. These drugs aim to halt tumor growth by blocking enzymes that aid cancer cell growth. The trial targets individuals with cancers such as pancreatic, colorectal, or small cell lung cancer that have not responded to standard treatments or lack available standard treatments. Participants should have a type of cancer that has spread or cannot be surgically removed and must be able to measure their tumors using imaging techniques like CT scans. As a Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new treatment.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications, but it advises avoiding certain drugs that interact with the trial medications. You should discuss your current medications with the study team to ensure there are no interactions.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research has shown that the combination of berzosertib (also known as M6620) and irinotecan has been studied for safety and effectiveness. One study found that this combination generally causes manageable side effects for most patients. The study also identified the safest dose levels for these drugs when used together, reducing the risk of serious side effects.

This trial is in an early phase, focusing on finding the best dose and understanding any side effects. Early-phase trials typically involve small groups of patients to ensure safety. Although the treatment is experimental, previous studies suggest this combination might be safe for many people. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about the combination of Berzosertib and Irinotecan Hydrochloride because it offers a novel approach to treating cancer. Unlike traditional chemotherapy that targets dividing cells indiscriminately, Berzosertib is a targeted therapy that inhibits ATR, a protein involved in DNA repair. This mechanism makes cancer cells more susceptible to damage from Irinotecan, which interferes with DNA replication. By combining these treatments, there's potential for enhanced effectiveness, particularly in tumors resistant to standard therapies.

What evidence suggests that M6620 and irinotecan could be effective for metastatic or unresectable solid tumors?

Research has shown that using berzosertib and irinotecan together may stop tumors from growing by blocking essential enzymes. One study reported a 26% reduction in tumor size in a patient with a specific type of colorectal cancer, lasting 7.5 months. In this trial, participants will receive the combination of irinotecan and berzosertib. These drugs complement each other, as irinotecan targets the tumor's DNA, and berzosertib enhances this effect. Early trials have shown promising results, particularly for cancers like pancreatic cancer. This combination aims to fight cancer cells more effectively by disrupting their growth and multiplication. ^{1 2 3 4 6}

Who Is on the Research Team?

Liza C. Villaruz

Principal Investigator

University of Pittsburgh Cancer Institute LAO

Are You a Good Fit for This Trial?

Adults with metastatic or inoperable solid tumors, including pancreatic, colorectal, and small cell lung cancer. Participants must have certain organ functions within normal limits and a life expectancy over 12 weeks. They should be willing to use contraception and undergo mandatory biopsies if in the expansion cohort.

Inclusion Criteria

You need to have a certain level of a type of white blood cell called neutrophils.

I have a known DNA repair issue or specific cancer types like pancreatic, colorectal, or small cell lung cancer.

Your white blood cell count is 3,000 or higher.

Exclusion Criteria

I am not taking strong medication that affects liver enzyme activity.

I don't have any severe illnesses that would stop me from following the study's requirements.

My HIV is not well-managed.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Patients receive irinotecan hydrochloride IV over 90 minutes and M6620 IV over 60 minutes on days 1 and 15. Treatment repeats every 28 days for 12 cycles.

48 weeks

24 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 months

3 visits (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Berzosertib
• Irinotecan Hydrochloride

Trial Overview The trial is testing M6620 (berzosertib) combined with irinotecan hydrochloride to determine safe dosages and side effects. It targets patients whose tumors may not respond to standard treatments or for whom no standard treatment exists.

How Is the Trial Designed?

Group I: Treatment (irinotecan, M6620) Experimental Treatment 5 Interventions

Patients receive irinotecan hydrochloride IV over 90 minutes and M6620 IV over 60 minutes on days 1 and 15. Treatment repeats every 28 days for 12 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo biopsy and collection of blood samples throughout the study and undergo CT at screening, throughout the study, and during follow up.

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

The maximum tolerated dose (MTD) of irinotecan for patients with the UGT1A1 *1/*1 genotype is 310 mg/m2, while for those with the *1/*28 genotype, it is 260 mg/m2, indicating that genetic differences can influence drug tolerance in metastatic colorectal cancer treatment.

Bevacizumab does not significantly affect the pharmacokinetics of irinotecan, suggesting that the dosing adjustments based on genotype can be made without concern for altered drug metabolism due to this additional treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Genotype-Guided Dosing Study of FOLFIRI plus Bevacizumab in Patients with Metastatic Colorectal Cancer. Toffoli, G., Sharma, MR., Marangon, E., et al.[2022]

Irinotecan (CPT-11) has demonstrated a broad range of antitumor activity across various cancer types, including lymphoma, leukemia, and several solid tumors, although most studies have focused on colorectal and gastrointestinal cancers.

Preliminary results indicate that irinotecan shows modest but reproducible activity in multiple cancers, suggesting the need for further well-designed clinical trials to better understand its efficacy and optimal use in combination therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Irinotecan in lymphoma, leukemia, and breast, pancreatic, ovarian, and small-cell lung cancers. Rosen, LS.[2018]

In a phase II trial involving 36 patients with irinotecan-refractory metastatic colorectal cancer, the combination of cetuximab, bevacizumab, and irinotecan (CBI) showed a statistically significant improvement in overall survival (OS) compared to cetuximab and irinotecan alone (CI), with median OS of 19.7 months versus 10.2 months.

Although there was no significant difference in progression-free survival (PFS) between the two treatment groups, the study suggests that further investigation into the CBI combination is warranted due to the observed benefits in overall survival.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cetuximab and Irinotecan With or Without Bevacizumab in Refractory Metastatic Colorectal Cancer: BOND-3, an ACCRU Network Randomized Clinical Trial. Lipsyc-Sharf, M., Ou, FS., Yurgelun, MB., et al.[2022]

The addition of bevacizumab to the VOIT regimen (vincristine, oral irinotecan, and temozolomide) in a pediatric trial showed some antitumor activity, particularly in patients with Ewing sarcoma, but the overall benefit of adding bevacizumab is still uncertain.

Reducing the dose of temozolomide from 150 mg/m² to 100 mg/m² improved the tolerability of the treatment, allowing more patients to complete the therapy without significant dose reductions due to side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pilot study of vincristine, oral irinotecan, and temozolomide (VOIT regimen) combined with bevacizumab in pediatric patients with recurrent solid tumors or brain tumors. Wagner, L., Turpin, B., Nagarajan, R., et al.[2020]

In a phase II study involving 77 previously untreated patients with metastatic colorectal cancer, the combination of capecitabine, irinotecan, and bevacizumab showed a promising progression-free survival rate of 61% at 9 months, with median overall survival of 24.8 months.

While 62% of patients experienced at least one severe adverse event, the regimen was generally well-tolerated, and quality of life remained stable throughout the treatment cycles.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Capecitabine and irinotecan with bevacizumab 2-weekly for metastatic colorectal cancer: the phase II AVAXIRI study. Garcia-Alfonso, P., Chaves, M., Muñoz, A., et al.[2018]

Citations

1. ascopubs.org ascopubs.org/doi/10.1200/JCO.2022.40.16_suppl.3012

NCI 9938: Phase I clinical trial of ATR inhibitor berzosertib ... An additional pt with ATM S214fs*40 mutant colorectal cancer (CRC) experienced a 26% decrease lasting 7.5 months. Conclusions: Berzosertib 270 ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT03641313

Study Details | Berzosertib and Irinotecan in Treating ... Berzosertib may stop the growth of tumor cells by blocking some of the enzymes needed for growth. Chemotherapy drugs, such as irinotecan, work in different ways ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5978471/

Phase I Study of ATR Inhibitor M6620 in Combination With ... The results are consistent with preclinical data that support a synergistic interaction of TOP1 inhibition with ATR inhibition. The study also ...

4. youtube.com youtube.com/watch?v=lHocGUfHaM4

Promising efficacy of berzosertib and irinotecan in pancreatic ... Liza Villaruz, MD, University of Pittsburgh, Pittsburgh, PA, discusses results from the phase I trial (NCT02595931) of berzosertib, ...

5. mycancergenome.org mycancergenome.org/content/clinical_trials/NCT02595931/

Clinical Trial: NCT02595931 M6620 and irinotecan hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Related Conditions ...

6. umiamihealth.org umiamihealth.org/ht/sylvester-comprehensive-cancer-center/ese-klinik/trials/berzosertib-and-irinotecan-in-treating-patients-with-progressive-metastatic-or-unresectable-tp53-mut

Berzosertib and Irinotecan in Treating Patients With ... Berzosertib and Irinotecan in Treating Patients With Progressive, Metastatic, or Unresectable TP53 Mutant Gastric or Gastroesophageal Junction Cancer. Principal ...