Peposertib + Tuvusertib for Advanced Cancer

Recruiting at 6 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: National Cancer Institute (NCI)

Must not be taking: Immunotherapy, Radiation, PPIs, others

Disqualifiers: Active brain metastases, Allergic reactions, others

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

Compensation: Varies

Number of Visits: 8

66 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase I trial tests the safety, side effects and best dose of peposertib (M3814) in combination with tuvusertib (M1774) in treating patients with solid tumors that have spread to other places in the body (advanced). Peposertib and tuvusertib stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications, especially those that strongly affect specific liver enzymes (CYP3A4/5, CYP2C19, CYP2C9) and some other specific drug transporters. You may need to stop these medications for at least 1 to 3 weeks before starting the trial, depending on the type of medication. It's best to discuss with the study doctor to see if alternative medications can be used.

What data supports the effectiveness of the drug combination Peposertib and Tuvusertib for advanced cancer?

Research on similar drug combinations, like the use of dual inhibitors in cancer treatment, shows that combining different types of inhibitors can improve treatment effectiveness. For example, combining VEGF and EGFR inhibitors has been shown to improve outcomes in certain cancers, suggesting that a similar approach with Peposertib and Tuvusertib might also be beneficial. ^{1 2 3 4 5}

Research Team

Gregory Cote, MD

Principal Investigator

Dana-Farber - Harvard Cancer Center LAO

Eligibility Criteria

Adults with advanced solid tumors and specific genetic mutations (ATM, MYC, FBXW7, etc.) can join this trial. They must have a life expectancy over 3 months, good organ function, no major surgery or immunotherapy within the last 21 days, and not be on certain drugs that affect enzymes. HIV-positive patients on effective therapy are eligible.

Inclusion Criteria

Absolute neutrophil count >= 1,500/mcL

Total bilirubin =< 1.5 x institutional upper limit of normal (ULN)

Ability to understand and sign a written informed consent document

Exclusion Criteria

Pregnant women and breastfeeding women are excluded

History of allergic reactions to compounds similar to study drugs

QTcF > 470 msec

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Patients receive peposertib and tuvusertib to determine the maximum tolerated dose and recommended phase 2 dose

28 days per cycle

Weekly visits for blood sample collection and tumor biopsy

Dose Expansion

Patients continue to receive the combination treatment to further assess safety and efficacy

28 days per cycle

Bi-weekly imaging and regular blood sample collection

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 2 years

Imaging every 8 weeks for 24 weeks, then every 12 weeks

Treatment Details

Interventions

• Peposertib
• Tuvusertib

Trial Overview The safety and optimal dosing of two anti-cancer drugs—Peposertib (M3814) and Tuvusertib (M1774)—are being tested in adults with advanced solid tumors. These drugs aim to stop tumor growth by blocking key enzymes needed for cell growth.

Participant Groups

Group I: Treatment (peposertib, tuvusertib) Experimental Treatment 7 Interventions

Patients receive peposertib PO in combination with tuvusertib PO QD or BID daily on days 1-14 of each cycle. Cycles repeat every 28 days in the absence of disease progression, pregnancy, non-compliance, unacceptable toxicity, termination of the study or the study drug is no longer available. Patients also undergo tumor biopsy before C1D1, C1D10 and at progression and blood sample collection during prestudy and weeks 1, 2, 3, 4, 5, 6, and at progression. Patients additionally undergo PET, CT, and MRI at baseline and are repeated every 8 weeks for 24 weeks then every 12 weeks unless clinically indicated.

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Findings from Research

In the Phase III RELAY trial, the combination of ramucirumab and erlotinib (RAM + ERL) significantly improved progression-free survival (PFS) in European and US patients with EGFR mutation-positive non-small cell lung cancer (NSCLC), with a median PFS of 20.6 months compared to 10.9 months for the placebo group.

The safety profile of RAM + ERL was consistent with the overall population, with hypertension being the most common severe side effect, indicating that ramucirumab is a safe and effective addition to standard EGFR-TKI therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

RELAY, ramucirumab plus erlotinib versus placebo plus erlotinib in patients with untreated, EGFR-mutated, metastatic non-small cell lung cancer: Europe/United States subset analysis. Ponce Aix, S., Novello, S., Garon, EB., et al.[2023]

In a phase I/II study, patients with BRAF-mutant metastatic colorectal cancer showed a higher response rate when treated with an EGFR inhibitor combined with dual MAPK blockade (trametinib and dabrafenib) compared to single-level blockade.

Although the combination therapy modestly increased median progression-free survival, the presence of RAS mutations and a temporary decrease in the BRAF V600E mutant allele fraction may have limited the overall effectiveness of the treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Triple Therapy Improves Colorectal Cancer Response. [2018]

In a phase I trial involving 45 patients with advanced solid tumors, the combination of lapatinib and capecitabine was found to be well tolerated, with the optimal regimen established as lapatinib 1,250 mg daily and capecitabine 2,000 mg/m² daily.

The treatment resulted in clinical activity, including one complete response and three partial responses, while common side effects were mostly mild (grade 1 to 2), such as diarrhea and nausea, indicating a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I and pharmacokinetic study of lapatinib in combination with capecitabine in patients with advanced solid malignancies. Chu, QS., Schwartz, G., de Bono, J., et al.[2022]

Neratinib combined with paclitaxel showed a high overall response rate of 73% in patients with HER2-positive breast cancer, indicating its efficacy as a treatment option.

The combination therapy had manageable side effects, with common adverse events including diarrhea and peripheral sensory neuropathy, but no dose-limiting toxicities were observed during the study.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination neratinib (HKI-272) and paclitaxel therapy in patients with HER2-positive metastatic breast cancer. Chow, LW., Xu, B., Gupta, S., et al.[2023]

The ARTEMIS study shows that combining the VEGF inhibitor bevacizumab with the EGFR inhibitor erlotinib significantly improves progression-free survival in patients with EGFR mutant non-small-cell lung cancer by over 6 months.

Patients with brain metastases and the EGFR L858R mutation experienced even greater benefits, highlighting the importance of personalized treatment strategies in cancer therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

ARTEMIS highlights VEGF inhibitors as effective partners for EGFR TKIs in EGFR mutant NSCLC. Le, X., Nilsson, MB., Robichaux, JP., et al.[2021]

References

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

RELAY, ramucirumab plus erlotinib versus placebo plus erlotinib in patients with untreated, EGFR-mutated, metastatic non-small cell lung cancer: Europe/United States subset analysis. [2023]

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

Triple Therapy Improves Colorectal Cancer Response. [2018]

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

Phase I and pharmacokinetic study of lapatinib in combination with capecitabine in patients with advanced solid malignancies. [2022]

4. England pubmed.ncbi.nlm.nih.gov

Combination neratinib (HKI-272) and paclitaxel therapy in patients with HER2-positive metastatic breast cancer. [2023]

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

ARTEMIS highlights VEGF inhibitors as effective partners for EGFR TKIs in EGFR mutant NSCLC. [2021]