Tuvusertib for Refractory Prostate Cancer

Not currently recruiting at 31 trial locations

Overseen By Janaki N. Sharma

Age: 18+

Sex: Male

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

Must be taking: Androgen deprivation therapy

Must not be taking: Proton pump inhibitors

Disqualifiers: Uncontrolled illness, QT interval > 470, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: Up to 2 years

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to evaluate the effectiveness of a new treatment, M1774 (also known as Tuvusertib), for prostate cancer that has not responded to other treatments. Researchers believe M1774 helps stop tumor growth by blocking certain enzymes. The trial seeks men whose prostate cancer has a specific genetic mutation known as SPOP and who have already tried certain cancer therapies without success. Participants will take M1774 in cycles and undergo regular scans and tests to monitor their progress. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial requires you to stop taking proton pump inhibitors (medications that reduce stomach acid) and certain other drugs that affect liver enzymes (CYP3A4 or CYP1A2) and transport proteins (hMATE1 or hMATE2-K).

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

Research has shown that tuvusertib, also known as M1774, is generally well-tolerated when used alone. In a study where researchers first tested it in humans, patients took the drug and managed its effects well, with no unexpected safety issues. This suggests that tuvusertib is safe enough for further testing, although some side effects might still occur. It's important to remember that this drug remains under study, so doctors closely monitor safety as more people participate in trials. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about tuvusertib for refractory prostate cancer because it introduces a novel mechanism of action that differs from existing treatments like hormone therapy and chemotherapy. Unlike these therapies, which typically focus on altering hormone levels or killing rapidly dividing cells, tuvusertib targets specific pathways within cancer cells, potentially offering a more precise attack on the cancer. Additionally, its oral administration makes it more convenient compared to treatments that require intravenous delivery. This innovative approach could lead to better outcomes with fewer side effects for patients.

What evidence suggests that M1774 might be an effective treatment for refractory prostate cancer?

Research has shown that tuvusertib, also known as M1774, blocks certain enzymes essential for cancer cell growth. In studies, it effectively halted cancer cell growth, even in small amounts. Tuvusertib demonstrated more activity compared to other treatments like ceralasertib and berzosertib, which are also used in cancer therapy. Additionally, patients have tolerated it well, experiencing few unwanted side effects. Overall, these findings suggest that tuvusertib could be promising for treating prostate cancer that resists other treatments. ^{1 2 3 4 6}

Who Is on the Research Team?

Jacob Orme

Principal Investigator

Dana-Farber - Harvard Cancer Center LAO

Are You a Good Fit for This Trial?

This trial is for adults with hard-to-treat prostate cancer that has a specific SPOP gene mutation. Participants must have measurable disease, be on hormone therapy or surgically castrated, and have adequate organ function. People with controlled HIV or hepatitis are eligible; those with certain heart conditions may join after assessment. Women of childbearing potential and men must agree to use contraception.

Inclusion Criteria

I have chronic hepatitis B but it's under control with treatment.

Ability to understand and willingness to sign a written informed consent document

Creatinine clearance >= 60 mL/min

Exclusion Criteria

I have recovered from side effects of previous cancer treatments, except for hair loss.

Patients receiving any other investigational agents

Patients with uncontrolled intercurrent illness

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive tuvusertib orally every day on days 1-14 of each 21-day cycle. Biopsy, imaging, and blood sample collection are conducted throughout the trial.

Up to 2 years

Follow-up

Participants are monitored for safety and effectiveness after treatment completion, with follow-up every 6 months for 2 years.

2 years

What Are the Treatments Tested in This Trial?

Interventions

• M1774

Trial Overview The trial tests M1774's effectiveness in shrinking or stabilizing refractory SPOP-mutant prostate cancer by inhibiting enzymes needed for tumor cell growth. It involves various assessments like biospecimen collection, imaging (ultrasound, CT, MRI, PET), and biopsy to monitor the treatment's impact.

How Is the Trial Designed?

Group I: Treatment (tuvusertib) Experimental Treatment 7 Interventions

Patients receive tuvusertib PO QD on days 1-14 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients also undergo biopsy, MRI, CT, PET/MRI, PET/CT or U/S and collection of blood samples throughout the trial.

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

Docetaxel remains the standard treatment for metastatic castration-resistant prostate cancer, but there is a critical need for new therapies due to its limited survival benefits.

Recent advancements have led to the development of various targeted therapies, including mTOR inhibitors and EGFR inhibitors, which are currently being tested in clinical trials to improve treatment outcomes for this aggressive form of cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Novel targeted therapeutics for metastatic castration-resistant prostate cancer. Antonarakis, ES., Carducci, MA., Eisenberger, MA.[2021]

Dovitinib demonstrated modest antitumor activity in men with metastatic castration-resistant prostate cancer (mCRPC), with a median progression-free survival (PFS) of 3.67 months and an overall survival (OS) of 13.70 months in a study involving 44 participants.

Patients who had not previously undergone chemotherapy experienced significantly longer PFS (17.90 months) compared to those who had been treated with docetaxel (2.07 months), indicating that dovitinib may be more effective in earlier treatment stages.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II Study of Dovitinib in Patients with Castration-Resistant Prostate Cancer (KCSG-GU11-05). Choi, YJ., Kim, HS., Park, SH., et al.[2022]

In a phase II study involving 30 patients with advanced prostate cancer, erlotinib showed moderate toxicity but resulted in clinical benefit for 40% of participants, indicating some effectiveness in improving patient outcomes.

While no patients experienced a decrease in prostate-specific antigen (PSA) levels, 14% had stabilization of PSA, and 10 patients showed a significant increase in PSA-doubling time, suggesting potential for further investigation in earlier stages of prostate cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Results from a monocentric phase II trial of erlotinib in patients with metastatic prostate cancer. Gravis, G., Bladou, F., Salem, N., et al.[2020]

In a phase 2 trial involving 39 patients with castration-resistant prostate cancer, the combination of sorafenib and bicalutamide resulted in a 47% rate of PSA response or stable disease for at least 6 months, indicating potential efficacy of this treatment approach.

The treatment was associated with some significant side effects, including fatigue and skin rash, but showed promise even in patients who had previously progressed on bicalutamide, suggesting that further research into combining these therapies is warranted.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase II study of sorafenib in combination with bicalutamide in patients with chemotherapy-naive castration resistant prostate cancer. Beardsley, EK., Hotte, SJ., North, S., et al.[2021]

In a phase 2 study involving 51 men with castration-resistant prostate cancer (CRPC), gefitinib showed minimal clinical efficacy, with only 2% of patients achieving a significant reduction in prostate-specific antigen (PSA) levels.

The treatment was associated with notable side effects, leading to dose reductions in 13 patients and withdrawal in 9 due to adverse events, indicating that while some patients maintained stable performance status, the overall response to gefitinib was limited.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An open-label, single-arm phase two trial of gefitinib in patients with advanced or metastatic castration-resistant prostate cancer. Pezaro, C., Rosenthal, MA., Gurney, H., et al.[2018]

Erlotinib, an EGFR inhibitor, showed reduced effectiveness in treating castration-resistant prostate cancer, particularly when the EGFR/Her2 ratio was low, which was influenced by chronic treatment with bicalutamide.

The study suggests that erlotinib may be more effective in hormone-naive prostate cancer patients rather than those who have undergone hormonal treatment, as low levels of Her2 and a higher EGFR/Her2 ratio were associated with better drug efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of EGFR tyrosine kinase inhibitor erlotinib in prostate cancer cells in vitro. Festuccia, C., Gravina, GL., Biordi, L., et al.[2018]

The combination of vandetanib and bicalutamide in patients with metastatic castration-resistant prostate cancer did not show superior efficacy compared to bicalutamide alone, with similar PSA response rates of 18% for the combination and 19% for bicalutamide alone.

Patients receiving the combination therapy experienced significantly higher rates of treatment discontinuation due to adverse events (42% vs. 5%), indicating that the combination is associated with considerable toxicity and is not recommended for further evaluation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A randomized phase II efficacy and safety study of vandetanib (ZD6474) in combination with bicalutamide versus bicalutamide alone in patients with chemotherapy naïve castration-resistant prostate cancer. Azad, AA., Beardsley, EK., Hotte, SJ., et al.[2022]

In a phase II trial involving 30 men with metastatic castration-resistant prostate cancer (mCRPC), buparlisib showed a low 6-month progression-free survival rate of only 10%, indicating limited efficacy in this patient population.

Concurrent use of enzalutamide significantly reduced buparlisib concentrations and was associated with severe adverse events in some patients, highlighting the need for careful consideration of treatment combinations and dosing strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II trial of the PI3 kinase inhibitor buparlisib (BKM-120) with or without enzalutamide in men with metastatic castration resistant prostate cancer. Armstrong, AJ., Halabi, S., Healy, P., et al.[2022]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05828082

Testing the Effect of M1774 on Hard-to-Treat Refractory ... This phase II trial tests how well M1774 works in treating patients with prostate cancer that does not respond to treatment (refractory) and that has a ...

2. withpower.com withpower.com/trial/phase-2-prostatic-neoplasms-7-2023-977b3

Tuvusertib for Refractory Prostate Cancer Dovitinib demonstrated modest antitumor activity in men with metastatic castration-resistant prostate cancer (mCRPC), with a median progression-free survival ( ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11094421/

First-in-Human Study of the Ataxia Telangiectasia and Rad3 ... This first-in-human study demonstrates that ataxia telangiectasia and Rad3-related inhibitor tuvusertib as monotherapy is well tolerated, has a manageable ...

4. aacrjournals.org aacrjournals.org/mct/article/23/7/911/746064/The-Novel-ATR-Inhibitor-Tuvusertib-M1774-Induces

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 ...

5. clinicaltrials.gov clinicaltrials.gov/study/NCT05396833

NCT05396833 | Study of Tuvusertib (M1774) in ... This is an open-label, multicenter, clinical study conducted in multiple parts to establish the safety, tolerability, Pharmacokinetic/Pharmacodynamic ...

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

Pharmacokinetic (PK) and pharmacodynamic (PD) findings ... Conclusions: Tuvusertib and avelumab were combined at established monotherapy doses with no new safety findings. Tuvusertib PD and exposure data ...