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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the safety and optimal dosage of two drugs, ALRN-6924 (an experimental treatment) and paclitaxel, for individuals with advanced solid tumors that cannot be surgically removed or have metastasized. The drugs aim to halt tumor growth by either killing cancer cells or preventing their division and spread. This trial may suit individuals with advanced cancers lacking effective standard treatments, particularly those diagnosed with breast cancer that is estrogen receptor positive and HER2 negative or with tumors exhibiting specific genetic profiles. Participants should have tumors unmanageable with existing treatments or find those treatments ineffective or intolerable.

As a Phase 1 trial, the research focuses on understanding how the treatment 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 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.

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

Research shows that ALRN-6924 is a new drug tested alongside paclitaxel, a common chemotherapy medication. Studies suggest that using these two drugs together might enhance the effectiveness of cancer treatments for certain tumor types.

Early tests have focused on understanding the side effects and determining the right dose of ALRN-6924 when combined with paclitaxel. These studies have not reported any major safety concerns. However, since this treatment is still in the early stages of testing, researchers are learning how well people tolerate this combination and are closely monitoring for any unexpected reactions.

As ALRN-6924 is still under investigation and not yet approved for any condition, joining a trial helps researchers gather more information on its safety and effectiveness. Participants should feel comfortable asking questions and discussing any concerns with their doctors. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about ALRN-6924 combined with Paclitaxel for advanced cancers because it offers a novel approach to treatment. Unlike traditional chemotherapy, which generally targets rapidly dividing cells indiscriminately, ALRN-6924 specifically inhibits MDM2 and MDMX proteins. This mechanism can potentially reactivate the tumor-suppressing abilities of the p53 protein, which is often disabled in cancer cells. By doing so, it may enhance the effectiveness of Paclitaxel and reduce the chances of cancer progression, offering hope for improved outcomes in patients with advanced cancers.

What evidence suggests that ALRN-6924 + Paclitaxel might be an effective treatment for advanced cancers?

Research has shown that combining ALRN-6924 with paclitaxel may help treat certain cancers. ALRN-6924 blocks proteins called MDM2 and MDMX, which can stop cancer cells from growing. Early findings suggest that using ALRN-6924 with paclitaxel enhances chemotherapy effectiveness, particularly in some breast cancer cases. This trial will evaluate the effectiveness of this drug combination for patients with advanced cancers. These initial results support further research to determine how well this combination works for such patients. ^{1 2 4 6 7}

Who Is on the Research Team?

Ecaterina E Dumbrava

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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 (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]

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]

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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7934277/

First in class dual MDM2/MDMX inhibitor ALRN-6924 ... We sought to determine the antitumor efficacy of the combination of ALRN-6924, a dual inhibitor of MDM2/MDMX, with chemotherapy in ER+ breast cancer models.

2. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2018-02192

ALRN-6924 and Paclitaxel in Treating Patients with ... 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 ...

3. researchgate.net researchgate.net/publication/333029145_The_stapled_peptide_ALRN-6924_a_dual_inhibitor_of_MDMX_and_MDM2_enhances_antitumor_efficacy_of_paclitaxel_and_Nab-paclitaxel_in_TP53_wild-type_MCF-7_breast_cancer_models

The stapled peptide ALRN-6924, a dual inhibitor of MDMX ... Conclusion: The significant increase in efficacy observed with ALRN-6924 in combination with paclitaxel supports further evaluation in patients ...

4. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/33663585/

First in class dual MDM2/MDMX inhibitor ALRN-6924 ... We sought to determine the antitumor efficacy of the combination of ALRN-6924, a dual inhibitor of MDM2/MDMX, with chemotherapy in ER+ breast cancer models.

5. clinicaltrials.gov clinicaltrials.gov/study/NCT02264613

ALRN-6924 in Patients With Advanced Solid Tumors or ... The Phase 1 portion of the study will enroll adults with histologically or cytologically confirmed malignancies that are metastatic or unresectable and for ...

6. gatewaycr.org gatewaycr.org/for-researchers/clinical-trials/alrn-6924-and-paclitaxel-in-treating-patients-with-advanced-metastatic-or-unresectable-solid-tumors/

ALRN-6924 and Paclitaxel in Treating Patients With ... This phase I study will establish the safety of ALRN-6924 in combination with paclitaxel in patients with advanced or metastatic solid tumors without a ...

7. mdanderson.org mdanderson.org/patients-family/diagnosis-treatment/clinical-trials/clinical-trials-index/clinical-trials-detail.ID2018-0561.html

A Phase 1b Study of ALRN-6924 in Combination with ... 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 ...