M1774 Combination Therapy for Solid Tumors

Recruiting at 27 trial locations

Overseen By US Medical Information

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: EMD Serono Research & Development Institute, Inc.

Disqualifiers: Uncontrolled disease, Additional malignancy, Carcinomatous meningitis, Serious gastrointestinal issues, Organ transplantation, others

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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: Unknown

Duration: 4 weeks

120 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of medications to treat various solid tumors, aiming to find safe and effective doses. It focuses on prostate and endometrial cancers with specific genetic mutations affecting cell repair. People with advanced forms of these cancers who have not responded to standard treatments might be suitable candidates. Participants should have a decent overall health condition, specifically with certain blood and organ health markers.

As a Phase 1 trial, the research aims to understand how the treatment works in people, offering participants the opportunity to be among the first to receive this new treatment.

Do I have to stop taking my current medications for the trial?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial team or your doctor.

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

A previous study found tuvusertib to be generally safe and well-tolerated when used alone, meaning participants did not experience severe, unmanageable side effects. Similarly, research has shown that avelumab is well-tolerated, with most experiencing only mild side effects and serious ones being rare. This trial now tests both treatments together to assess their safety in combination. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about this combination therapy for solid tumors because it involves innovative treatments like M1774, M4076, and Avelumab. These treatments are unique as they offer a novel approach to targeting specific genetic mutations, such as ATM in prostate cancer and ARID1A in endometrial cancer, which are not the primary focus of current standard treatments like chemotherapy or radiation. Additionally, M1774 and M4076 are being evaluated for their bioavailability in different formulations, which could enhance their effectiveness and patient convenience. This combination therapy represents a significant step forward in personalized medicine, potentially offering more targeted and effective treatment options for patients with these specific tumor types.

What evidence suggests that this trial's treatments could be effective for solid tumors?

Research has shown that tuvusertib, an ATR inhibitor, may help treat advanced solid tumors. It blocks proteins that assist cancer cells in repairing their DNA, potentially stopping their growth. Early studies found that tuvusertib is generally safe and works well with other DNA-targeting drugs. In this trial, some participants will receive tuvusertib with lartesertib, while others will receive tuvusertib with avelumab. Specifically, research has shown that avelumab can be effective against some solid tumors, with some patients benefiting for several months. This suggests that combining these treatments could effectively combat various solid tumors. ^{4 6 7 8 9}

Who Is on the Research Team?

Medical Responsible

Principal Investigator

Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany

Are You a Good Fit for This Trial?

This trial is for adults with advanced solid tumors that standard treatments haven't helped or aren't suitable. They should be in fairly good physical shape (ECOG 0-1), expected to live at least 3 more months, and have their major organs working well. People can't join if they have other serious health issues, brain cancer spread, recent severe GI bleeding, trouble absorbing food, or had an organ transplant.

Inclusion Criteria

Participants with eastern Cooperative Oncology Group (ECOG) performance status 0 or 1, with estimated life expectancy of at least 3 months

Adequate hematological, hepatic, and renal function as defined in the protocol

There may be additional requirements that need to be met as stated in the study guidelines.

Exclusion Criteria

Participants with any condition, including any uncontrolled disease state other than with metastatic or locally advanced unresectable solid tumors, that in the Investigator's opinion constitutes an inappropriate risk or a contraindication for participation in the study or that could interfere with the study objectives, conduct, or evaluation

Participants with carcinomatous meningitis are excluded regardless of clinical stability

You have recently had severe bleeding in your stomach or intestines, persistent nausea and vomiting, uncontrollable diarrhea, or difficulties absorbing medications through your digestive system.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive tuvusertib in combination with lartesertib or avelumab to assess safety, tolerability, and pharmacokinetic/pharmacodynamic profile

4 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Open-label extension (optional)

Participants may opt into continuation of treatment long-term to further assess safety and efficacy

What Are the Treatments Tested in This Trial?

Interventions

• Avelumab
• Drug A
• Drug B
• M1774
• M4076

Trial Overview The study tests M1774 combined with either M4076 or avelumab to find safe doses and see early effects on certain types of prostate and endometrial cancers with specific genetic changes. It's open-label so everyone knows what treatment they're getting; it includes dose finding and testing how the body absorbs the drug.

How Is the Trial Designed?

Group I: Part B1: Tuvusertib and Avelumab Experimental Treatment 2 Interventions

Group II: Part A3: Tuvusertib and Lartesertib Experimental Treatment 2 Interventions

ARID1A in endometrial cancer

Group III: Part A2: Tuvusertib and Lartesertib Experimental Treatment 2 Interventions

ATM in prostate cancer (Part A2)

Group IV: Part A2/A3: Tuvusertib and Lartesertib Experimental Treatment 2 Interventions

Tablet formulation (TF1, test) compared to a capsule formulation (reference)

Group V: Part A1: Tuvusertib and Lartesertib Experimental Treatment 2 Interventions

Group VI: Part A1.2: Tuvusertib and Lartesertib Experimental Treatment 2 Interventions

Relative Bioavailability Assessment of Tuvusertib Tablet (TF1) vs Capsule Followed by Treatment with Tuvusertib in Combination with Lartesertib

Group VII: Part A1.1: Tuvusertib and Lartesertib Experimental Treatment 2 Interventions

Assessment of the Effect of Food (Low-fat Meal) on the PK of M4076 Monotherapy Followed by Treatment with M1774 in Combination with M4076

Avelumab is already approved in European Union, United States, Japan for the following indications:

Approved in European Union as Bavencio for:

• Merkel cell carcinoma
• Renal cell carcinoma
• Urothelial carcinoma

Approved in United States as Bavencio for:

• Merkel cell carcinoma
• Renal cell carcinoma
• Urothelial carcinoma

Approved in Japan as Bavencio for:

• Merkel cell carcinoma
• Renal cell carcinoma
• Urothelial carcinoma

Who Is Running the Clinical Trial?

EMD Serono Research & Development Institute, Inc.

Lead Sponsor

Trials

86

Recruited

22,700+

Miguel Fernández Alcalde

EMD Serono Research & Development Institute, Inc.

Chief Executive Officer

Bachelor’s Degree in Pharmacy from the University Complutense in Madrid, MBA from the University of Alcalá de Henares, Master’s Degree in Management from IESE Business School

Danny Bar-Zohar

EMD Serono Research & Development Institute, Inc.

Chief Medical Officer since 2022

MD

Merck KGaA, Darmstadt, Germany

Industry Sponsor

Trials

449

Recruited

122,000+

Danny Bar-Zohar

Merck KGaA, Darmstadt, Germany

Chief Medical Officer since 2022

MD

Belén Garijo

Merck KGaA, Darmstadt, Germany

Chief Executive Officer since 2021

MD

Published Research Related to This Trial

Avelumab, an immune checkpoint inhibitor, demonstrated a 14.18% objective response rate in 3935 cancer patients across 21 trials, showing more tumor responses compared to conventional treatments.

The treatment was associated with a lower incidence of adverse events, with only 14.44% experiencing high-grade treatment-related adverse events, indicating that avelumab has an active anti-tumor effect with manageable safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety profile of avelumab monotherapy. Zhao, B., Gao, M., Zhao, H., et al.[2021]

Avelumab, an anti-PD-L1 monoclonal antibody, and cetuximab, an anti-EGFR monoclonal antibody, have complementary mechanisms of action that may enhance treatment efficacy when used together, particularly in cancer therapies.

Both drugs not only target tumor growth but also activate the immune system, potentially leading to improved patient outcomes through increased immune response, as seen in ongoing clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Avelumab and cetuximab as a therapeutic combination: An overview of scientific rationale and current clinical trials in cancer. Bourhis, J., Stein, A., Paul de Boer, J., et al.[2021]

In a long-term study of 123 patients with advanced nonsquamous NSCLC, the combination of pembrolizumab with pemetrexed-carboplatin significantly improved the objective response rate (58% vs. 33%) and progression-free survival (24.5 months vs. 9.9 months) compared to chemotherapy alone.

Patients who completed 2 years of pembrolizumab treatment had a remarkable 92% survival rate at the data cutoff, indicating a durable clinical benefit, while the safety profile remained manageable with no new safety concerns identified.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-Term Overall Survival From KEYNOTE-021 Cohort G: Pemetrexed and Carboplatin With or Without Pembrolizumab as First-Line Therapy for Advanced Nonsquamous NSCLC. Awad, MM., Gadgeel, SM., Borghaei, H., et al.[2021]

In the JAVELIN Lung 100 trial involving 1214 patients with advanced NSCLC, avelumab showed longer median progression-free survival (PFS) compared to platinum-based chemotherapy (8.4 months vs. 5.6 months), indicating its potential efficacy as a first-line treatment.

Although avelumab demonstrated longer median overall survival (OS) compared to chemotherapy (20.1 months vs. 14.9 months), the differences were not statistically significant, suggesting that while avelumab may be beneficial, it did not meet the primary objective of the trial.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Avelumab Versus Platinum-Based Doublet Chemotherapy as First-Line Treatment for Patients With High-Expression Programmed Death-Ligand 1-Positive Metastatic NSCLC: Primary Analysis From the Phase 3 JAVELIN Lung 100 Trial. Reck, M., Barlesi, F., Yang, JC., et al.[2023]

The combination of vibostolimab and pembrolizumab is well tolerated by patients, indicating a favorable safety profile for this treatment regimen.

This combination therapy demonstrates antitumor activity, suggesting it may be an effective option for cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An Anti-TIGIT Antibody with a PD-1 Inhibitor Shows Promise in Solid Tumors. [2022]

M7824, a novel bifunctional fusion protein, effectively targets both PD-L1 and TGFβ in urothelial carcinoma, enhancing the immune response against tumor cells by increasing T-cell trafficking and susceptibility to immune-mediated lysis.

In comparison to traditional anti-PD-L1 treatments, M7824 shows improved immunogenic modulation of urothelial carcinoma cell lines, suggesting it may be a promising candidate for future clinical trials in treating urothelial cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-PD-L1/TGFβR2 (M7824) fusion protein induces immunogenic modulation of human urothelial carcinoma cell lines, rendering them more susceptible to immune-mediated recognition and lysis. Grenga, I., Donahue, RN., Gargulak, ML., et al.[2021]

Avelumab is an antibody that blocks programmed cell death ligand-1 (PD-L1) and has received accelerated approval in the USA for treating metastatic Merkel cell carcinoma (mMCC) in both adults and children aged 12 and older.

The drug is also undergoing regulatory reviews for other cancer treatments, including urothelial carcinoma, indicating its potential as a versatile cancer therapy in various stages of development worldwide.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Avelumab: First Global Approval. Kim, ES.[2022]

Axitinib shows significant long-term benefits for patients with metastatic renal cell carcinoma (mRCC), with long responders (LR) experiencing a median progression-free survival (PFS) of 18.1 months and overall survival (OS) of 36.0 months, based on a study of 157 patients.

Older age at treatment initiation and higher hemoglobin levels were identified as independent predictors for better outcomes with axitinib, suggesting that these factors can help clinicians identify patients who may benefit most from this therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical Factors Associated With Long-Term Benefit in Patients With Metastatic Renal Cell Carcinoma Treated With Axitinib: Real-World AXILONG Study. Pinto, Á., Reig, O., Iglesias, C., et al.[2022]

Avelumab, a monoclonal antibody targeting PD-L1, demonstrated an acceptable safety profile in a phase 1a trial with 53 patients, with only one dose-limiting toxicity observed at the highest dose of 20 mg/kg, indicating that the maximum tolerated dose was not reached.

The pharmacokinetic analysis showed a dose-proportional exposure and a half-life of approximately 4 days at higher doses, leading to the selection of 10 mg/kg every 2 weeks for further development, as it achieved over 90% target occupancy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Avelumab for metastatic or locally advanced previously treated solid tumours (JAVELIN Solid Tumor): a phase 1a, multicohort, dose-escalation trial. Heery, CR., O'Sullivan-Coyne, G., Madan, RA., et al.[2022]

The phase I trial of MEDI5752, a bispecific antibody that targets both PD-1 and CTLA4, shows that the drug is well tolerated by patients.

Preliminary results indicate that MEDI5752 is active in treating various tumor types, with durable responses observed, suggesting potential effectiveness in cancer therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

MEDI5752 Suppresses Two Immune Checkpoints. [2022]

Avelumab, an anti-PD-L1 antibody, was evaluated for safety and antitumor activity in pediatric patients with refractory/relapsed solid tumors, with dosing determined through pharmacokinetic modeling in a study involving 21 patients.

The study recommends avelumab dosing of 15 mg/kg every 2 weeks for children under 12 years or weighing less than 40 kg, and an adult flat dose of 800 mg every 2 weeks for those aged 12 years and older or weighing 40 kg or more, ensuring effective exposure similar to adults.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Avelumab Dose Selection for Clinical Studies in Pediatric Patients with Solid Tumors. Vugmeyster, Y., Grisic, AM., Brockhaus, B., et al.[2022]

Ipilimumab has shown a positive impact on overall survival in patients with stage IV melanoma, with long-term follow-up indicating its effectiveness compared to conventional treatments.

While 84.8% of patients experience drug-related adverse events, most are mild to moderate; however, severe reactions can occur, necessitating careful monitoring and management, especially when combined with other therapies like vemurafenib.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CTLA-4 blockade with ipilimumab: biology, safety, efficacy, and future considerations. Camacho, LH.[2022]

In a phase 2a trial involving 43 patients with advanced squamous non-small cell lung cancer (NSCLC), the combination of avelumab and cetuximab with chemotherapy resulted in a 34.9% objective response rate, indicating notable antitumor activity.

While the treatment showed tolerable safety, with 88.4% of patients experiencing treatment-related adverse events, the overall response rate was not significantly better than existing standard treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Avelumab in Combination With Cetuximab and Chemotherapy as First-Line Treatment for Patients With Advanced Squamous NSCLC. Andric, Z., Gálffy, G., Cobo Dols, M., et al.[2023]

Combining nivolumab and ipilimumab shows improved effectiveness in treating metastatic melanoma compared to using either drug alone, based on a retrospective analysis of approximately 7700 patients.

The combination therapy presents a safety profile that includes immune-related adverse events from both drugs, indicating that while the combination is effective, it also carries a heightened risk of toxicity that needs further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Retrospective Side Effect Profiling of the Metastatic Melanoma Combination Therapy Ipilimumab-Nivolumab Using Adverse Event Data. Soldatos, TG., Dimitrakopoulou-Strauss, A., Larribere, L., et al.[2022]

Citations

1. nejm.org nejm.org/doi/full/10.1056/NEJMoa2002788

Avelumab Maintenance Therapy for Advanced or ... Among patients with PD-L1–negative tumors, the median overall survival was 18.8 months (95% CI, 13.3 to 22.5) in the avelumab group and 13.7 ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6387686/

Avelumab for metastatic or locally advanced previously ... We aimed to establish the safety and pharmacokinetics of avelumab in patients with solid tumours while assessing biological correlatives for future development.

3. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/33037118/

Avelumab as second-line therapy for metastatic, platinum ... Conclusions: After ≥2 years of follow-up, avelumab showed prolonged efficacy and acceptable safety in patients with platinum-treated advanced/metastatic ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT01772004

Avelumab in Metastatic or Locally Advanced Solid Tumors ... Participants with metastatic or locally advanced solid tumors received intravenous infusion of Avelumab at a dose of 10.0 mg/kg once every 2 weeks in dose ...

5. pfizer.com pfizer.com/news/press-release/press-release-detail/european_commission_approves_bavencio_avelumab_for_metastatic_merkel_cell_carcinoma

European Commission Approves Bavencio (avelumab) for ... At the time of analysis, tumor responses were durable, with 93% of responses lasting at least 6 months (n=25) and 71% of responses lasting at ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5947549/

Safety profile of avelumab in patients with advanced solid ... Avelumab generally was found to be well tolerated and to have a manageable safety profile. A minority of patients experienced grade ≥3 TRAEs or irAEs, and ...

7. ascopubs.org ascopubs.org/doi/10.1200/JCO.2016.34.15_suppl.3055

Avelumab (MSB0010718C; anti-PD-L1) in patients with ... We report updated safety data of single-agent avelumab in patients (pts) with locally advanced or metastatic (LA/M) solid tumors from a phase 1b ...

8. annalsofoncology.org annalsofoncology.org/article/S0923-7534(19)64278-X/fulltext

Phase I JAVELIN solid tumor trial of avelumab ... Conclusions: Avelumab showed an acceptable safety profile, a predictable PK profile, and full TO over the dosing period. Clinical activity and PD-L1 expression ...

9. fda.gov fda.gov/drugs/resources-information-approved-drugs/avelumab-bavencio

Avelumab (BAVENCIO) Among the 29 responding patients, the response duration ranged from 2.8 to 23.3+ months with 86% of responses durable for 6 months or longer.