M1774 + Niraparib for Solid Tumors

Not currently recruiting at 19 trial locations

Overseen By US Medical Information

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: EMD Serono Research & Development Institute, Inc.

Must not be taking: Live vaccines

Disqualifiers: Major surgery, Uncontrolled infection, Hypertension, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: Variable, based on dose escalation and confirmation phases

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment approach for individuals with solid tumors, using a combination of two drugs: M1774 (Tuvusertib) and Niraparib (Zejula). The main goal is to assess the safety and tolerability of these drugs both together and separately, as well as to understand their processing in the body. Individuals with advanced or metastatic cancer unresponsive to standard treatments might be suitable candidates. Participants must have controlled cancer, particularly in the brain, and meet specific health criteria. As a Phase 1 trial, this 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 need to stop my current medications to join the trial?

The trial protocol mentions 'prohibited concomitant medication,' but it does not specify which medications are prohibited. It's best to discuss your current medications with the trial team to see if any need to be stopped.

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

Research has shown that Tuvusertib (M1774) is generally safe when used alone, with most participants experiencing no serious side effects. This makes it a promising candidate for further studies.

For Niraparib, studies involving 830 patients found that common side effects included nausea and tiredness, affecting more than 10% of users. These side effects can usually be managed by adjusting the dose.

When combined, Tuvusertib and Niraparib still present manageable side effects, indicating that their combined use is not too severe and suitable for further research. Overall, both treatments have demonstrated safety for humans in controlled settings. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

M1774, also known as Tuvusertib, is unique because it targets specific mutations in tumors that other treatments might not address. Researchers are excited about Tuvusertib because it works by inhibiting certain proteins that are crucial for tumor growth, offering a new avenue for treating solid tumors. Unlike standard chemotherapy, which attacks all rapidly dividing cells, Tuvusertib's targeted approach could lead to fewer side effects and more effective treatment outcomes for patients with specific genetic profiles. Additionally, its combination with Niraparib, a PARP inhibitor, is promising as it could enhance the overall effectiveness in combating resistant cancer cells.

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

Research has shown that Tuvusertib (M1774) effectively targets cancer cells in lab tests. It halts cancer cell growth even at very low doses and outperforms similar treatments. In this trial, some participants will receive Tuvusertib (M1774) alone, while others will receive it with Niraparib, a drug that prevents cancer cells from repairing themselves. The researchers are studying this combination to determine if it can enhance cancer treatment. Early results suggest that this combination is safe and could be promising for treating solid tumors. These findings offer hope that M1774, alone or with Niraparib, could effectively combat certain cancers. ^{6 7 8 9 10}

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 haven't responded to standard treatments or have no suitable standard options. They should be relatively healthy (ECOG <=1), possibly with treated, symptom-free brain metastases. Specific genetic mutations are required for some parts of the study, and participants must not be pregnant or breastfeeding.

Inclusion Criteria

My blood, liver, and kidney functions meet the required levels.

My cancer has specific genetic mutations in ARID1A, ATRX, DAXX, or ATM.

I am not pregnant or breastfeeding.

Exclusion Criteria

Participants with active and/or uncontrolled infection with exceptions

I haven't had a heart attack, severe chest pain, heart failure, or heart surgery in the last 6 months.

Uncontrolled arterial hypertension (systolic blood pressure >140 mmHg; Diastolic blood pressure >90mmHg)

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Tuvusertib (M1774) as monotherapy or in combination with Niraparib, with dose escalation and confirmation phases

Variable, based on dose escalation and confirmation phases

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 30 days after the last dose, assessed up to approximately 2.2 years

What Are the Treatments Tested in This Trial?

Interventions

• M1774
• Niraparib

Trial Overview The trial tests M1774 alone and combined with Niraparib, a PARP inhibitor, in people with certain solid tumors. It's an early-phase study to determine safety, tolerability, how the body processes the drugs (with/without food), and any preliminary signs of effectiveness.

How Is the Trial Designed?

Group I: Part B1: Combination Therapy Dose Finding Experimental Treatment 2 Interventions

B1a: Participants with baseline body weight less than (\<) 77 kilogram (kg) or platelets \<150,000 cubic per millimeter (mm\^3) will receive Niraparib once daily combined with different doses of Tuvusertib (M1774). B1b: Participants with baseline body weight greater than or equal to (\>=) 77 kg and or platelets \>= 150,000 mm\^3 will receive Niraparib once daily combined with different doses of Tuvusertib (M1774) and schedule determined as recommended dose for expansion (RDE) in Part B1a.

Group II: Part A5: China Dose Confirmation Monotherapy Experimental Treatment 1 Intervention

Starting at global RDE from Part A1, in China. Participants will initially receive Tuvusertib (M1774) once daily under fasting conditions. Additional schedules may be evaluated if needed.

Group III: Part A4: Japan Dose Confirmation Monotherapy Experimental Treatment 1 Intervention

Starting at global RDE from Part A1, in Japan. Participants will initially receive Tuvusertib (M1774) once daily under fasting conditions. Additional schedules may be evaluated if needed.

Group IV: Part A3 - Monotherapy Expansion Experimental Treatment 1 Intervention

Part A3 is an expansion of Part A1 where Tuvusertib (M1774) will be administered as a single agent at the RDE established in Part A1. Participants with defined loss-of-function mutation in ARID1A, ATRX and/or DAXX, and ATM will be enrolled.

Group V: Part A2 - Preliminary Food Effect Assessment Experimental Treatment 1 Intervention

Participants in the food effect assessment will receive Tuvusertib (M1774) at the dose and schedule determined as recommended dose for expansion (RDE) in Part A1. A single dose of Tuvusertib (M1774) will be administered on Day -7 under a fed (low-fat meal) or fasted condition, followed by a 1-week washout period. After completion of the scheduled food effect assessments, participants will follow the same schedule as participants in Part A1.

Group VI: Part A1: Monotherapy Dose Escalation Experimental Treatment 1 Intervention

Participants will initially receive Tuvusertib (M1774) once daily under fasting conditions. Additional schedules may be evaluated if needed.

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

Niraparib at a dose of 200 mg/day was determined to be the recommended phase 2 dose when combined with abiraterone acetate plus prednisone (AAP) for patients with metastatic castration-resistant prostate cancer (mCRPC), as it showed a tolerable safety profile with no new safety signals.

The combination of niraparib with apalutamide resulted in a higher incidence of dose-limiting toxicities, leading to the decision not to further evaluate this combination, highlighting the importance of monitoring drug interactions in treatment regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Niraparib with androgen receptor-axis-targeted therapy in patients with metastatic castration-resistant prostate cancer: safety and pharmacokinetic results from a phase 1b study (BEDIVERE). Saad, F., Chi, KN., Shore, ND., et al.[2021]

Niraparib significantly extends progression-free survival in patients with newly diagnosed advanced ovarian cancer, showing efficacy in both homologous-recombination deficiency positive (HRd) and negative (HRp) populations, based on a phase III trial.

The treatment has a manageable safety profile, with myelosuppression as the main concern, which can be effectively managed through monitoring and individualized dosing based on weight and platelet count.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Niraparib: A Review in First-Line Maintenance Therapy in Advanced Ovarian Cancer. Lee, A.[2022]

Niraparib, a recently approved treatment for recurrent platinum-sensitive ovarian cancer, has demonstrated a high oral bioavailability of 72.7% in humans, indicating effective absorption when taken orally.

The study involved six patients who received a therapeutic dose of 300 mg of niraparib, followed by a small intravenous dose to measure its levels in the bloodstream, confirming its potential as a convenient oral treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Determination of the absolute oral bioavailability of niraparib by simultaneous administration of a 14C-microtracer and therapeutic dose in cancer patients. van Andel, L., Rosing, H., Zhang, Z., et al.[2019]

Niraparib has been approved by the FDA for patients with complete or partial response to first-line platinum-based chemotherapy, regardless of their BRCAm or HRD status, expanding treatment options for more patients.

Olaparib, in combination with bevacizumab, has also received FDA approval for patients with epithelial ovarian cancer, indicating that PARP inhibitors are now beneficial not only for BRCAm and HRD-deficient patients but also for those with HRD-proficient tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

PARP inhibitors in the treatment of ovarian cancer: a review. Washington, CR., Moore, KN.[2023]

Niraparib, administered at doses of 200 mg and 300 mg daily, was found to be tolerable in Japanese patients with advanced solid tumors, with only one case of dose-limiting toxicity observed.

The study demonstrated a favorable pharmacokinetic profile for niraparib, with dose-proportional increases in drug levels and some patients showing a partial response to treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The safety, tolerability and pharmacokinetics of niraparib in Japanese patients with solid tumours: results of a phase I dose-escalation study. Yonemori, K., Shimizu, T., Kondo, S., et al.[2021]

Niraparib (NIRA) is an effective treatment for patients with metastatic castration-resistant prostate cancer who have specific genetic alterations, showing promising results in a Phase II study.

When combined with abiraterone acetate and prednisone, NIRA demonstrated a manageable safety profile while effectively disrupting cancer cell signaling pathways.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Niraparib with Abiraterone Acetate and Prednisone for Metastatic Castration-Resistant Prostate Cancer: Phase II QUEST Study Results. Chi, KN., Fleshner, N., Chiuri, VE., et al.[2023]

Citations

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First-in-Human Study of the Ataxia Telangiectasia and Rad3 ... Tuvusertib (M1774) is a potent, selective, orally administered ATR inhibitor with antitumor activity as monotherapy in preclinical models with DDR pathway gene ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT04170153

Study Details | NCT04170153 | Tuvusertib (M1774) in ... This is an open-label, Phase I, first-in-human (FIH) multicenter, clinical study conducted in multiple parts to establish the safety, tolerability and ...

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The Novel ATR Inhibitor Tuvusertib (M1774) Induces ... As single agent, M1774 suppressed cancer cell viability at nanomolar concentrations, showing greater activity than ceralasertib and berzosertib, but less ...

4. ascopubs.org ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.2614

Pharmacokinetic (PK) and pharmacodynamic (PD) findings ... A first-in-human phase I study of ATR inhibitor M1774 in patients with solid tumors. Timothy A. Yap et al. +0 authors. Developmental ...

5. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38407317/

First-in-Human Study of the Ataxia Telangiectasia and Rad3 ... Tuvusertib (M1774) is a potent, selective, orally administered ataxia telangiectasia and Rad3-related (ATR) protein kinase inhibitor.

6. zejulahcp.com zejulahcp.com/

Ovarian Cancer Treatment | ZEJULA (niraparib) for HCPs Individualized starting dose gives your patients a tailored dose. · View the Efficacy Data · Safety Profile · Dosing · INDICATION & IMPORTANT SAFETY INFORMATION.

7. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2019/208447s014lbl.pdf

ZEJULA® (niraparib) - accessdata.fda.gov The most common adverse reactions in >10% of 830 patients who received ZEJULA in the NOVA and QUADRA trials (n = 830) were nausea (70%), fatigue (58%), ...

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10313963/

Safety and management of niraparib monotherapy in ... Long-term safety data from the NOVA trial confirmed that, with appropriate and early dose modifications, niraparib is well tolerated. Keywords: ...

9. academic.oup.com academic.oup.com/jjco/article/51/5/693/6148807

The safety, tolerability and pharmacokinetics of niraparib in ... This study investigated the safety of niraparib in Japanese patients with metastatic or locally advanced solid tumours.

10. ascopubs.org ascopubs.org/doi/10.1200/JCO.2020.38.15_suppl.6054

Pharmacokinetics and safety following a single oral dose of ... Safety data during the PK phase of the study is consistent with the known profile for niraparib. Conclusions: Pts with moderate hepatic ...