Metarrestin for Advanced Cancer

Recruiting at 1 trial location

Overseen By Udo Rudloff, M.D.

Age: Any Age

Sex: Any

Trial Phase: Phase 1

Sponsor: National Cancer Institute (NCI)

Must not be taking: CYP3A4 inhibitors/inducers, Antivirals

Disqualifiers: Cardiomyopathy, CNS metastases, Seizures, others

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

Compensation: Varies

Number of Visits: 2

Duration: 28 days per cycle

116 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new drug called metarrestin, which aims to stop cancer from spreading and shrink tumors. The main goal is to determine a safe dose and assess its effectiveness against advanced cancers, such as pancreatic and breast cancer, especially when standard treatments have failed. It suits adults with certain solid tumors and children aged 12-17 with solid tumors who have no other treatment options. Participants will take the medication orally and attend regular check-ups to monitor their health and the drug's effects. As a Phase 1 trial, this research focuses on understanding how metarrestin 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 participants to stop taking medications that are moderate or strong inhibitors or inducers of CYP3A4 enzymes before starting the treatment. If you are on such medications, you will need to stop them within a specific time frame based on their half-lives. However, dihydropyridine calcium-channel blockers are allowed.

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

Research shows that metarrestin is a new drug tested for safety in people with advanced cancer. As this is its first human trial, limited information exists on human reactions. The main goal is to find a dose that people can take safely without serious side effects.

Metarrestin aims to prevent cancer cells from spreading. Earlier lab studies showed promise in achieving this, but its effects in humans remain under investigation. Participants will continue taking the drug until they either cannot tolerate it well or it ceases to be helpful.

Since metarrestin is in the early stages of human testing, the focus remains on finding a safe dose. As more people try it, researchers will gain further insights into its safety. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for advanced cancer, which often include chemotherapy, radiation, and immunotherapy, Metarrestin is unique because it targets a specific cellular structure called the perinucleolar compartment (PNC). This compartment is associated with cancer metastasis, and by targeting it, Metarrestin aims to inhibit the spread of cancer cells. Researchers are excited about Metarrestin because it offers a novel mechanism of action that could potentially reduce metastasis, paving the way for more effective management of advanced cancers.

What evidence suggests that metarrestin might be an effective treatment for advanced cancer?

Research has shown that metarrestin targets a specific part of cancer cells called the perinucleolar compartment (PNC), which is linked to cancer spreading. In studies with mice, metarrestin stopped cancer from spreading and even shrank tumors. This suggests it could help fight metastatic cancer, which is cancer that has spread to other parts of the body, in humans. Scientists believe that by blocking the PNC, metarrestin prevents cancer cells from growing and moving to other organs. These promising results in animal studies have led researchers to test its effects in humans in this trial, where participants will receive either escalating/de-escalating doses of metarrestin or the maximum tolerated dose (MTD) of metarrestin. ^{1 2 3 6 7}

Who Is on the Research Team?

Udo Rudloff, M.D.

Principal Investigator

National Cancer Institute (NCI)

Are You a Good Fit for This Trial?

Adults and children (12-17) with metastatic solid tumors like pancreatic, breast, or colorectal cancer that standard treatments haven't cured. Participants must be over 35 kg in weight, have a certain level of physical ability, and their major organs need to function well. Women who can become pregnant and men must use birth control during the trial.

Inclusion Criteria

I am mostly able to care for myself and carry on normal activities.

I have been diagnosed with pancreatic, colorectal, or breast cancer.

Adequate hematological function defined by ANC >=1.0 (SqrRoot) 10(9)/L, transfusion-independent platelet count >=100 (SqrRoot) 10(9)/L, Hgb >=9 g/dL

Exclusion Criteria

I have had cancer other than the one currently being treated.

I haven't had cancer treatment recently.

I was diagnosed with cardiomyopathy less than 6 months ago.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive metarrestin orally in cycles of 28 days until progression or unacceptable toxicity

28 days per cycle

Weekly or every other week visits during the first month, then regular visits

Follow-up

Participants have a follow-up visit 30 days after treatment ends, then follow-up phone calls or emails every 6 months

30 days after treatment, then every 6 months

1 visit (in-person), then remote follow-ups

Dose Escalation

Phase IA to determine the maximum tolerated dose (MTD) of metarrestin

28 days

Dose Expansion

Phase IB to determine the Objective Response Rate (ORR) at the MTD

Every 2 months

What Are the Treatments Tested in This Trial?

Interventions

• Metarrestin

Trial Overview The trial is testing Metarrestin's safety and effectiveness at shrinking tumors in patients with metastatic cancers. Patients will take Metarrestin orally for as long as they can tolerate it while undergoing regular health checks including blood tests, heart exams, brain activity assessments, imaging scans like CT or MRI, and possibly tumor biopsies.

How Is the Trial Designed?

Group I: 2/Arm 2 Experimental Treatment 1 Intervention

MTD of metarrestin

Group II: 1/Arm 1 Experimental Treatment 1 Intervention

Escalating/de-escalation doses of metarrestin

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

In a study of 60 advanced breast cancer patients who had previously been treated with anthracyclines, the combination of vinorelbine and mitomycin C resulted in a 40% overall response rate, with 3 complete and 21 partial responses.

The treatment was generally well tolerated, with myelosuppression being the main side effect, but it was mostly mild to moderate, indicating that this combination could be a viable option for patients with limited treatment alternatives.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vinorelbine and mitomycin C in anthracycline-pretreated patients with advanced breast cancer. Vici, P., Di Lauro, L., Carpano, S., et al.[2018]

In a randomized phase II study involving 101 patients with locally advanced and locally recurrent breast carcinoma, three new cisplatin-containing chemotherapy combinations showed high rates of complete response (CR) and partial response (PR), with CR rates of 7% for locally advanced and 43% for locally recurrent disease.

The study demonstrated a pathologic complete response (pCR) rate of 12% in locally advanced disease, indicating that these innovative regimens are effective and warrant further testing in phase III trials, despite some severe but generally tolerable toxicities.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Three new active cisplatin-containing combinations in the neoadjuvant treatment of locally advanced and locally recurrent breast carcinoma: a randomized phase II trial. Cocconi, G., Bisagni, G., Ceci, G., et al.[2019]

Recent advancements in the treatment of disseminated non-small-cell lung cancer have introduced newer agents like vinorelbine and paclitaxel, which, when combined with cisplatin, can modestly improve patient survival.

Patients receiving these newer regimens experience a median survival increase of 10 to 15 weeks and a 10% to 15% improvement in 1-year survival rates compared to older treatment combinations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recent advances with chemotherapy for NSCLC: the ECOG experience. Eastern Cooperative Oncology Group. Johnson, DH., Chang, AY., Ettinger, DS., et al.[2015]

In a phase II study involving 72 patients with metastatic breast cancer who had previously received anthracycline treatment, the combination of vinorelbine and mitoxantrone showed a 49% objective response rate, indicating significant efficacy in this patient population.

The treatment was associated with manageable side effects, including a 46% incidence of grade 3-4 granulocytopenia and 10% experiencing severe cardiotoxicity, suggesting that with careful dose management, this regimen can be a viable option for patients with prior anthracycline exposure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First-line vinorelbine-mitoxantrone combination in metastatic breast cancer patients relapsing after an adjuvant anthracycline regimen: results of a phase II study. Llombart-Cussac, A., Pivot, X., Rhor-Alvarado, A., et al.[2018]

In a study of 55 patients with advanced endometrial cancer, the combination of doxorubicin, cisplatin, and vinblastine resulted in a low overall response rate, with only 7% achieving complete responses and 24% achieving partial responses.

The treatment led to significant toxicity, particularly leukopenia, affecting two-thirds of patients, and did not improve survival outcomes, with a median survival of only 10 months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Doxorubicin-cisplatin-vinblastine combination chemotherapy of advanced endometrial carcinoma: a Southwest Oncology Group Study. Alberts, DS., Mason, NL., O'Toole, RV., et al.[2019]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39768145/

Metarrestin Targets the Perinucleolar Compartment in Cancer ... Metarrestin (ML246) is a first-in-class pyrrole-pyrimidine-derived small molecule that selectively targets the perinucleolar compartment (PNC).

2. clinicaltrials.gov clinicaltrials.gov/study/NCT04222413

Metarrestin (ML-246) in Subjects With Metastatic Solid ... This is first-in-human Phase I trial to investigate the safety and clinical activity of metarrestin in subjects with metastatic solid tumors.

3. pubchem.ncbi.nlm.nih.gov pubchem.ncbi.nlm.nih.gov/compound/Metarrestin

Ml-246 - PubChem - NIH Metarrestin is an orally available small molecule inhibitor of perinucleolar compartment (PNC), with potential antineoplastic activities.

4. mdpi.com mdpi.com/2073-4409/13/24/2053

Small Molecule with Big Impact: Metarrestin Targets the ... Metarrestin (ML246) is a first-in-class pyrrole–pyrimidine-derived small molecule that selectively targets the perinucleolar compartment (PNC).

5. news.feinberg.northwestern.edu news.feinberg.northwestern.edu/2019/10/30/experimental-drug-may-reduce-cancer-growth-and-progression/

Experimental Drug May Reduce Cancer Growth and ... Using pancreatic cancer mouse models, the scientists found that metarrestin prevented further metastasis by inhibiting cancer cells' ability to ...

6. aobious.com aobious.com/aobious/pathway-inhibitors/2092-ml246-metarrestin.html

ML246 and Metarrestin Supplier | CAS 1443414-10-5 Data sheet ; Purity, 98% by HPLC ; IUPAC/Chemical Name, trans-4-(7-benzyl-4-imino-5,6-diphenylpyrrolo[2,3-d]pyrimidin-3-yl)cyclohexan-1-ol ; SMILES Code, O[C@H]1CC ...

7. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCT04222413

Metarrestin (ML-246) in Subjects With Metastatic Solid ... It causes 90% of cancer deaths. No treatment specifically prevents or reduces metastasis. Researchers hope a new drug can help. It stops cancer cells from ...