ALRN-6924 + Paclitaxel for Advanced Cancers

Overseen By Ecaterina E Dumbrava

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Antiretrovirals, CYP3A4 substrates

Disqualifiers: Cardiovascular risk, Active infections, others

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

Compensation: Varies

Number of Visits: 3

Duration: 28 days per cycle

35 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase Ib trial studies the side effects and best dose of ALRN-6924 when given together with paclitaxel in treating patients with solid tumors that have spread to other places in the body or cannot be removed by surgery. Drugs used in chemotherapy, such as ALRN-6924 and paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot take any investigational drugs or anticancer treatments within 21 days before starting the trial, and certain medications that are cleared by specific liver transporters are not allowed around the time of ALRN-6924 infusion.

What data supports the effectiveness of the drug ALRN-6924 + Paclitaxel for advanced cancers?

Research shows that nab-paclitaxel (a form of paclitaxel) is effective in treating metastatic breast cancer, with studies indicating it has a better therapeutic index (balance of effectiveness and side effects) compared to traditional paclitaxel. This suggests that nab-paclitaxel, a component of the treatment, may be effective in other advanced cancers as well. ^{1 2 3 4 5}

Is the combination of ALRN-6924 and Paclitaxel safe for humans?

Paclitaxel, including its nanoparticle albumin-bound form (Abraxane), has been studied in various cancers and is generally well-tolerated, though it can cause side effects like sensory neuropathy (nerve damage causing tingling or numbness) and other toxicities. In studies, most patients tolerated the treatment, but some needed dose reductions or discontinued due to side effects. ^{1 4 6 7 8}

What makes the drug ALRN-6924 + Paclitaxel unique for treating advanced cancers?

The combination of ALRN-6924 with Paclitaxel is unique because ALRN-6924 is designed to reactivate the p53 protein, which can help stop cancer cells from growing, while Paclitaxel is a chemotherapy drug that prevents cancer cells from dividing. This dual approach may offer a novel way to target cancer cells more effectively than using Paclitaxel alone. ^{2 4 9 10 11}

Research Team

Ecaterina E Dumbrava

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

This trial is for adults with advanced or inoperable solid tumors, including a specific type of breast cancer (ER positive, HER2 negative) with WT TP53. Participants must not have had another cancer within the last 2 years and should have no major health issues that could affect study participation. They need to use effective contraception and cannot be pregnant or nursing.

Inclusion Criteria

I haven't taken any experimental drugs or cancer treatments recently.

I haven't had major surgery in the last month and have fully recovered.

My breast cancer is ER positive, HER2 negative, and cannot be removed by surgery.

Exclusion Criteria

My cancer is HPV-positive.

I am not pregnant or nursing.

I have not had serious stomach or intestine bleeding in the last 6 months.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive paclitaxel and ALRN-6924 intravenously on days 1, 8, and 15 of each 28-day cycle

28 days per cycle

3 visits per cycle (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment completion

1 year with visits every 2 months, then every 3 months thereafter

Treatment Details

Interventions

• ALRN-6924
• Paclitaxel

Trial Overview The trial is testing the combination of ALRN-6924, an experimental drug, with paclitaxel, a chemotherapy medication. It aims to find the safest dose and observe how well this combo works against metastatic or unresectable solid tumors by stopping their growth or spread.

Participant Groups

Group I: Treatment (paclitaxel, ALRN-6924) Experimental Treatment 2 Interventions

Patients receive paclitaxel IV over 1 hour and MDM2/MDMX inhibitor ALRN-6924 IV over 1 hour on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

Nab-paclitaxel (Abraxane(®)) has been approved by the FDA for treating breast cancer after chemotherapy failure, showing superior efficacy compared to traditional paclitaxel (Taxol(®)).

This new formulation not only demonstrates better effectiveness but also has less toxicity, which enhances its safety profile and therapeutic index, making it a promising option for combination therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nab-paclitaxel in the treatment of metastatic breast cancer: a comprehensive review. Montero, AJ., Adams, B., Diaz-Montero, CM., et al.[2021]

Nab-paclitaxel (Abraxane) is an effective treatment for metastatic breast cancer, showing a superior therapeutic index compared to conventional paclitaxel in a Phase III study with a standard dose of 260 mg/m² every three weeks.

In patients with poor prognostic factors, nab-paclitaxel demonstrated rapid and significant tumor responses, indicating it may be particularly beneficial for those with more severe disease, and lower doses (100 and 150 mg/m² weekly) also showed promising efficacy, suggesting potential for dose tailoring in treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluating the role of nab-paclitaxel (Abraxane) in women with aggressive metastatic breast cancer. Ciruelos, E., Jackisch, C.[2015]

In a study of 30 women with advanced breast cancer, the combination of doxorubicin and paclitaxel resulted in a high overall response rate of 83%, with 24% achieving complete remission, indicating strong efficacy for this treatment regimen.

However, the treatment was associated with significant toxicities, including neutropenia and cardiotoxicity, with 50% of patients experiencing reduced heart function and 20% developing congestive heart failure, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined doxorubicin and paclitaxel in advanced breast cancer: effective and cardiotoxic. Gehl, J., Boesgaard, M., Paaske, T., et al.[2020]

In a study involving 74 patients with metastatic melanoma, nab-Paclitaxel showed a response rate of 21.6% in chemotherapy-naive patients and 2.7% in previously treated patients, indicating better efficacy in those who had not undergone prior treatment.

The treatment was well tolerated, with 78% of previously treated patients and 49% of chemotherapy-naive patients able to complete therapy without dose reductions, suggesting a favorable safety profile compared to standard therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase 2 clinical trial of nab-paclitaxel in previously treated and chemotherapy-naive patients with metastatic melanoma. Hersh, EM., O'Day, SJ., Ribas, A., et al.[2020]

Combination therapies using paclitaxel with non-anthracycline agents have shown promising response rates between 40% to 80% and median time to progression exceeding 6 months in phase II and III studies.

Further research through prospective, randomized phase III trials is needed to confirm the benefits of these combinations over older treatments, particularly regarding quality of life, response rates, and survival in metastatic breast cancer patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Paclitaxel plus nonanthracycline combinations in metastatic breast cancer. Perez, EA.[2015]

Nab-PTX (Abraxane®) was administered to 31 breast cancer patients without any allergic reactions, indicating it is well tolerated, even in those with alcohol intolerance.

Among patients with locally advanced operable breast cancer, higher doses (260 mg/m²) resulted in a better response rate, with 10 out of 13 showing a partial response, suggesting its efficacy in treating advanced stages of the disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Clinical experience of nab-Paclitaxel treatment in 31 patients with breast cancer]. Tauchi, Y., Kashiwagi, S., Ishihara, S., et al.[2015]

Nab-paclitaxel was well tolerated in pediatric solid tumor models, with a maximum weight loss of about 10% that returned to baseline after treatment, indicating a favorable safety profile.

The treatment showed significant efficacy, improving event-free survival in 19 out of 20 solid tumor xenograft models, particularly demonstrating high activity against Ewing sarcoma and rhabdomyosarcoma, making it a promising candidate for further pediatric evaluation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Initial testing (stage 1) of the tubulin binding agent nanoparticle albumin-bound (nab) paclitaxel (Abraxane(®)) by the Pediatric Preclinical Testing Program (PPTP). Houghton, PJ., Kurmasheva, RT., Kolb, EA., et al.[2022]

Combining paclitaxel with doxorubicin has shown impressive remission rates for metastatic breast cancer, with overall rates exceeding 90% and nearly 50% achieving complete remission, especially when administered in a specific sequence.

While other combinations of paclitaxel with drugs like cisplatin and vinorelbine have shown variable results, the doxorubicin/paclitaxel combination remains the most effective and tolerable treatment option currently available.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Paclitaxel-containing combination chemotherapy for metastatic breast cancer. Hortobagyi, GN., Ibrahim, N.[2018]

References

1. England pubmed.ncbi.nlm.nih.gov

Nab-paclitaxel in the treatment of metastatic breast cancer: a comprehensive review. [2021]

2. England pubmed.ncbi.nlm.nih.gov

Evaluating the role of nab-paclitaxel (Abraxane) in women with aggressive metastatic breast cancer. [2015]

3. England pubmed.ncbi.nlm.nih.gov

Combined doxorubicin and paclitaxel in advanced breast cancer: effective and cardiotoxic. [2020]

4. United States pubmed.ncbi.nlm.nih.gov

A phase 2 clinical trial of nab-paclitaxel in previously treated and chemotherapy-naive patients with metastatic melanoma. [2020]

5. United States pubmed.ncbi.nlm.nih.gov

Paclitaxel plus nonanthracycline combinations in metastatic breast cancer. [2015]

6. Japan pubmed.ncbi.nlm.nih.gov

[Clinical experience of nab-Paclitaxel treatment in 31 patients with breast cancer]. [2015]

7. China pubmed.ncbi.nlm.nih.gov

[Study of bioequiavailability of paclitaxel for Injection (Albumin Bound) and abraxane and the efficacy of extension treatments in patients with metastatic breast cancer]. [2018]

8. United States pubmed.ncbi.nlm.nih.gov

Initial testing (stage 1) of the tubulin binding agent nanoparticle albumin-bound (nab) paclitaxel (Abraxane(®)) by the Pediatric Preclinical Testing Program (PPTP). [2022]

9. Netherlands pubmed.ncbi.nlm.nih.gov

Quantitative determination of total and unbound paclitaxel in human plasma following Abraxane treatment. [2019]

10. United States pubmed.ncbi.nlm.nih.gov

Paclitaxel-containing combination chemotherapy for metastatic breast cancer. [2018]

11. England pubmed.ncbi.nlm.nih.gov

Phase II multicenter study of larotaxel (XRP9881), a novel taxoid, in patients with metastatic breast cancer who previously received taxane-based therapy. [2020]