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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine the safest dose and examine the side effects of two drugs, peposertib and tuvusertib, for treating advanced cancers. These medications stop enzyme activity that aids cancer cell growth. The trial seeks participants with solid tumors that have spread and who have tried at least one other treatment without success. Participants should have specific genetic changes in their cancer, such as MYC amplification or certain mutations, and must be able to swallow pills. As a Phase 1 trial, the 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 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.

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

Research shows that the safety of combining peposertib and tuvusertib remains under investigation. This early-phase trial aims to assess how well participants tolerate the treatment and identify potential side effects.

Currently, detailed safety information from studies on this specific combination is limited. Early-phase trials like this one indicate that the complete safety profile is not yet known. This does not imply the treatment is unsafe; rather, researchers are still learning about its effects on people.

If peposertib or tuvusertib has been tested with other treatments, those studies might provide insights into possible side effects or tolerance levels. Always consult the trial team or your doctor to understand what to expect. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about peposertib and tuvusertib for advanced cancer because these treatments offer a new approach by targeting specific molecular pathways involved in cancer progression. Most current treatments focus on broad approaches like chemotherapy or radiation, but peposertib and tuvusertib work by inhibiting key proteins that cancer cells need to survive and grow. This targeted action could potentially lead to more effective results with fewer side effects compared to traditional options. Moreover, the use of these drugs in combination may enhance their effectiveness, offering hope for improved outcomes in patients with advanced stages of cancer.

What evidence suggests that this trial's treatments could be effective for advanced cancer?

Research shows that peposertib and tuvusertib block certain proteins essential for cancer cell growth. In this trial, participants will receive a combination of these drugs. Early findings suggest that peposertib is safe for patients with advanced solid tumors and may slow tumor growth. Tuvusertib may enhance this effect by further disrupting cancer cell functions. Although detailed results from human studies remain limited, these drugs aim to target tumors more precisely, potentially preventing their spread. These are promising early steps in treating advanced cancers. ^{1 3 6 7 8}

Who Is on the Research Team?

Gregory Cote, MD

Principal Investigator

Dana-Farber - Harvard Cancer Center LAO

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05687136?term=AREA%5BInterventionSearch%5D(MSC2490484A)%20AND%20AREA%5BStudyType%5D(INTERVENTIONAL)&rank=9

Study Details | NCT05687136 | Testing the Combination of ... 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 ...

2. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2022-10210

Testing the Combination of two Anti-cancer Drugs ... 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 ...

3. trialx.com trialx.com/clinical-trials/listings/222418/testing-the-combination-of-two-anti-cancer-drugs-peposertib-m3814-and-m1774-for-advanced-solid-tumors/

Testing the Combination of Two Anti-cancer Drugs ... This phase I trial tests the safety, side effects and best dose of peposertib (M3814) in combination with tuvusertib (M1774) in treating ...

4. clinicaltrials.med.nyu.edu clinicaltrials.med.nyu.edu/cancer/clinicaltrial/2764/molecularly-driven-phase-1b/?qd=47723632

Perlmutter Cancer Center - Clinical Trials This study tests the effectiveness of two drugs, peposertib (M3814) and M1774, in patients with advanced solid tumors who have certain genetic changes or signs ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11565114/

DNA-dependent protein kinase inhibitor as a sensitizer of ... In the initial investigation involving humans, peposertib was well tolerated in patients with advanced solid tumors. Currently, numerous ongoing ...

6. cancer.gov cancer.gov/clinicaltrials/NCI-2022-10210

Testing the Combination of two Anti-cancer Drugs ... 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 ...

7. centerwatch.com centerwatch.com/clinical-trials/listings/NCT05687136/testing-the-combination-of-two-anti-cancer-drugs-peposertib-m3814-and-m1774-for-advanced-solid-tumors

Testing the Combination of Two Anti-cancer Drugs ... This phase I trial tests the safety, side effects and best dose of peposertib (M3814) in combination with tuvusertib (M1774) in treating ...

8. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38051750/

A Phase Ib Study of the DNA-PK Inhibitor Peposertib ... Peposertib plus capecitabine-based chemoradiotherapy (CRT) and assessed its safety and efficacy in locally advanced rectal cancer.