IACS-6274 +/− Bevacizumab/Paclitaxel for Cancer

Overseen By Timothy Yap

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: M.D. Anderson Cancer Center

Must not be taking: CYP3A4 inducers/inhibitors

Disqualifiers: Prior malignancy, CNS metastasis, others

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

Compensation: Varies

Number of Visits: Unknown

54 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine the highest safe dose of a new drug, IACS-6274, which could be used alone or with other drugs like bevacizumab (Avastin), paclitaxel, and capivasertib, to treat people with solid tumors. Researchers are assessing the safety of these treatments and their tolerability in patients. Suitable candidates for this trial include those with advanced solid tumors, particularly if previous treatments were ineffective and they have specific genetic mutations or tumor types, such as certain ovarian or lung cancers. 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 drug.

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications before starting the study. Specifically, you must stop taking strong CYP3A4 inducers and inhibitors, as well as strong CYP2D6 inhibitors, within a specified period before the first dose of the study drug. Additionally, you must stop taking St. John's Wort 3 weeks prior and enzalutamide 4 weeks prior to the start of treatment.

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

Research has shown that IACS-6274 is generally safe and well-tolerated by patients. Studies found no major harmful effects when combined with other drugs like bevacizumab and paclitaxel. Patients handled the treatments well, and early signs indicated that the treatment might help fight tumors.

When combined with bevacizumab and paclitaxel, IACS-6274 showed no major safety problems, suggesting the combination is safe and could help manage tumors. Early data also shows that IACS-6274 combined with capivasertib is well-tolerated. Capivasertib has been tested for safety, showing acceptable side effects at the doses used in trials.

As this is a Phase 1 trial, the main goal is to find the safest dose, so safety remains under close observation. However, the current data provides some reassurance about the treatment's safety for those considering participation. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about IACS-6274 because it offers a fresh approach to cancer treatment. Unlike current standard therapies that often target cancer cells broadly, IACS-6274 works by inhibiting oxidative phosphorylation, a key energy-producing process in cancer cells, potentially leading to more effective targeting and disruption of cancer growth. Additionally, when combined with bevacizumab and paclitaxel or capivasertib, the treatment may enhance its potency by attacking the cancer from multiple angles. This multi-pronged strategy could provide a more robust response compared to traditional methods.

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

Research shows that IACS-6274, which participants in this trial may receive, may help stop tumor growth in patients with advanced cancer. One study found that 17 out of 20 patients had stable disease, meaning their cancer did not worsen. In this trial, one treatment arm will explore adding bevacizumab and paclitaxel to IACS-6274, as this combination has effectively treated some lung and breast cancers. Another arm will study IACS-6274 with capivasertib, which has successfully slowed cancer growth, especially in certain types of breast cancer. Overall, the trial aims to determine if these combinations can better control cancer growth. ^{1 2 4 6 7}

Who Is on the Research Team?

Timothy Yap

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

Adults with advanced solid tumors, including specific types of ovarian, uterine, head and neck cancers, melanoma, and chondrosarcoma. Participants must have adequate organ function and no severe recent illnesses or treatments that could interfere with the study. They should not be at high risk for bleeding or infection and must use effective contraception if applicable.

Inclusion Criteria

My ovarian cancer is ARID1A mutant clear cell type.

I have had immunotherapy for melanoma for at least 12 weeks.

Provision of written informed consent prior to any study related procedures and compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol

Exclusion Criteria

You have had serious allergic reactions to monoclonal antibodies, a history of anaphylaxis, or uncontrolled asthma.

I have received radiotherapy within the required timeframe before starting the study drug.

I am legally unable to make my own decisions.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose-Escalation

Patients receive IACS-6274 orally, with or without additional drugs, to determine the maximum tolerated dose

Up to 90 days

Regular visits for dose escalation monitoring

Dose-Expansion

Patients continue to receive IACS-6274, with or without additional drugs, to further assess safety and efficacy

Ongoing

Regular visits for safety and efficacy assessment

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Bevacizumab
• IACS-6274
• Paclitaxel

Trial Overview

The trial is testing IACS-6274 alone or in combination with other drugs like bevacizumab (which inhibits blood vessel growth in tumors), paclitaxel (a chemotherapy drug), or capivasertib (targets cancer cell growth). The goal is to find the highest dose patients can tolerate without significant side effects.

How Is the Trial Designed?

Group I: Part B (IACS-6274, bevacizumab, paclitaxel) Experimental Treatment 3 Interventions

Patients receive IACS-6274 PO, paclitaxel IV, and bevacizumab IV throughout the study.

Group II: Part A (IACS-6274) Experimental Treatment 1 Intervention

Patients receive IACS-6274 PO throughout the study.

Group III: PART C: (IACS-6274) with capivasertib Experimental Treatment 2 Interventions

Patients receive IACS-627 PO, with capivasertib PO throughout the study.

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

Published Research Related to This Trial

In a study of Chinese patients with advanced non-squamous non-small cell lung cancer (NSCLC), bevacizumab combined with chemotherapy showed a manageable safety profile, with only one case of grade 3 epistaxis and one case of grade 4 thrombosis reported.

Most patients experienced mild adverse effects, such as hemoptysis, hypertension, and proteinuria, which were well tolerated, indicating that bevacizumab can be safely used in this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Acceptable safety of bevacizumab therapy in combination with chemotherapy in patients with advanced lung cancer.]. Wu, W., Xu, L., Liu, Z., et al.[2010]

A case study of a 39-year-old woman with recurrent breast cancer treated with bevacizumab and paclitaxel revealed a serious side effect: diverticular bleeding after the third treatment cycle.

The report suggests that bevacizumab may contribute to diverticular bleeding, highlighting the importance of assessing patient history for risk factors like diverticulitis and prior abdominal surgeries before starting this combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Diverticular Bleeding of the Colon during Combination Chemotherapy with Bevacizumab and Paclitaxel for Recurrent Breast Cancer. Nakayama, Y., Ito, Y., Tanabe, M., et al.[2021]

In a phase II trial involving 50 patients with resectable nonsquamous NSCLC, the addition of bevacizumab to neoadjuvant chemotherapy did not improve the rate of pathological downstaging, which was 38%.

The study found that new intratumoral cavitation occurred in 18% of patients treated with single-agent bevacizumab, suggesting it may serve as a potential biomarker for treatment response, particularly since no patients with KRAS-mutant tumors showed a pathologic response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II trial of neoadjuvant bevacizumab plus chemotherapy and adjuvant bevacizumab in patients with resectable nonsquamous non-small-cell lung cancers. Chaft, JE., Rusch, V., Ginsberg, MS., et al.[2022]

A study analyzing 12,010 adverse event reports for bevacizumab from the FDA's database identified 63 novel adverse events that were both unlabelled and clinically significant, highlighting the need for ongoing monitoring of this drug post-approval.

The most frequently reported adverse events included electrolyte abnormalities, cardiovascular issues, and gastrointestinal disorders, indicating that while bevacizumab is effective, it may carry risks that require careful management in clinical settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Novel adverse events of bevacizumab in the US FDA adverse event reporting system database: a disproportionality analysis. Shamloo, BK., Chhabra, P., Freedman, AN., et al.[2022]

Bevacizumab (Avastin) effectively targets VEGF to inhibit tumor angiogenesis, showing a safety profile that includes mostly mild to moderate side effects such as hypertension and proteinuria, which are manageable in clinical settings.

The side effects associated with bevacizumab, including rare but serious events like gastrointestinal perforation and arterial thrombosis, do not typically exacerbate the toxicity of standard chemotherapy, making it a suitable adjunct treatment for metastatic colorectal cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Managing patients treated with bevacizumab combination therapy. Gordon, MS., Cunningham, D.[2015]

The combination of paclitaxel, carboplatin, and bevacizumab showed a high objective response rate of 88% in 34 patients with advanced or recurrent cervical cancer, indicating strong efficacy in this difficult-to-treat population.

While the treatment was effective, it was associated with significant hematologic toxicities, including neutropenia and leukopenia in 41.2% of patients, highlighting the need for careful monitoring during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II trial of paclitaxel, carboplatin, and bevacizumab for advanced or recurrent cervical cancer. Suzuki, K., Nagao, S., Shibutani, T., et al.[2019]

In a case series of 15 patients with metastatic non-squamous cell lung carcinoma, the combination of paclitaxel and bevacizumab showed a partial response rate of 44% based on CT scans and 65% based on PET scans, indicating potential efficacy in this patient population.

No major toxicity was observed in the treatment, and the median progression-free survival was 4.6 months, suggesting that this regimen is safe and may improve patient outcomes, warranting further investigation in a randomized clinical trial.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination of paclitaxel and bevacizumab in heavily pre-treated non-small-cell lung cancer (NSCLC) patients: a case series study on 15 patients. Le Moulec, S., Hadoux, J., Gontier, E., et al.[2015]

A study of 27 cancer patients with inflammatory bowel disease (IBD) showed that combining bevacizumab with chemotherapy is safe, with no observed clinical flares of IBD during treatment.

Despite some patients experiencing grade 2 or higher complications like proteinuria and hypertension, the overall safety profile suggests that bevacizumab can be effectively used in patients with either quiescent or moderately active IBD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and Efficacy of Bevacizumab in Cancer Patients with Inflammatory Bowel Disease. Herrera-Gómez, RG., Grecea, M., Gallois, C., et al.[2022]

Bevacizumab (Avastin) combined with carboplatin and paclitaxel significantly improves overall survival in patients with advanced nonsquamous non-small cell lung cancer, with a median survival of 12.3 months compared to 10.3 months for those receiving chemotherapy alone.

While bevacizumab shows efficacy, it is associated with a higher incidence of severe adverse events, including neutropenia and hypertension, and carries risks of serious complications like gastrointestinal perforation and pulmonary hemorrhage, highlighting the need for careful patient monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA drug approval summary: bevacizumab (Avastin) plus Carboplatin and Paclitaxel as first-line treatment of advanced/metastatic recurrent nonsquamous non-small cell lung cancer. Cohen, MH., Gootenberg, J., Keegan, P., et al.[2022]

In a phase II trial involving 99 patients with advanced or recurrent non-small-cell lung cancer, the combination of bevacizumab with carboplatin and paclitaxel significantly improved response rates (31.5% vs. 18.8%) and extended median time to disease progression (7.4 months vs. 4.2 months) compared to carboplatin and paclitaxel alone.

While the treatment showed efficacy, the most common adverse event was bleeding, particularly major hemoptysis, which was linked to specific tumor characteristics, indicating that careful patient selection may enhance safety and outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small-cell lung cancer. Johnson, DH., Fehrenbacher, L., Novotny, WF., et al.[2023]

A comprehensive analysis of 96,477 adverse event reports related to bevacizumab revealed 2,847 cases of hemorrhage, highlighting significant safety concerns associated with its use in treating advanced malignant tumors.

The study identified 37 specific hemorrhagic signals linked to bevacizumab, particularly affecting the vascular, gastrointestinal, and nervous systems, with colorectal, lung, and breast cancers being the most commonly associated malignancies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A pharmacovigilance study of adverse event profiles and haemorrhagic safety of bevacizumab based on the FAERS database. Tang, L., Ding, C., Li, H., et al.[2023]

The AVALUZ trial demonstrated that the combination of bevacizumab, gemcitabine, and paclitaxel resulted in a median progression-free survival of 12.3 months and a median overall survival of 27.4 months in previously untreated HER-2 negative breast cancer patients.

The treatment was generally well tolerated, with manageable adverse events, and showed that baseline circulating tumor cells and angiotensin type 1 receptor expression could predict patient responses and progression-free survival.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Final results of a phase II study of paclitaxel, bevacizumab, and gemcitabine as first-line therapy for patients with HER2-negative metastatic breast cancer. Salvador, J., Manso, L., de la Haba, J., et al.[2022]

In a phase II trial involving 99 patients with advanced or recurrent non-small-cell lung cancer, the combination of bevacizumab (15 mg/kg) with carboplatin and paclitaxel significantly improved response rates (31.5% vs. 18.8%) and extended median time to disease progression (7.4 months vs. 4.2 months) compared to carboplatin and paclitaxel alone.

While the treatment showed improved efficacy, the most common adverse event was bleeding, particularly major hemoptysis, which was linked to specific tumor characteristics, indicating that patients with nonsquamous cell histology may benefit more with manageable safety risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized Phase II Trial Comparing Bevacizumab Plus Carboplatin and Paclitaxel With Carboplatin and Paclitaxel Alone in Previously Untreated Locally Advanced or Metastatic Non-Small-Cell Lung Cancer. Johnson, DH., Fehrenbacher, L., Novotny, WF., et al.[2023]

Citations

1.

mdanderson.org

mdanderson.org/newsroom/metabolic-inhibitor-iacs-6274-shows-early-antitumor-effects-underserved-patients-advanced-cancer.h00-159460845.html

Metabolic inhibitor IACS-6274 shows early antitumor ...

On the trial, 17 of 20 evaluable patients achieved a best response of stable disease, with a disease control rate of 60% at 12 weeks. Six ...

2.

ascopubs.org

ascopubs.org/doi/10.1200/JCO.2021.39.15_suppl.3001

First-in-human biomarker-driven phase I trial of the potent ...

Conclusions: IACS-6274 was well tolerated at biologically active doses with good human PK, significant PD target modulation and preliminary ...

3.

clinicaltrials.gov

clinicaltrials.gov/study/NCT05039801

IACS-6274 With or Without Bevacizumab and Paclitaxel for ...

To assess the preliminary antitumor activity of IACS-6274 in the combination with bevacizumab and weekly paclitaxel (Part B) in patients with recurrent platinum ...

4.

conferences.medicom-publishers.com

conferences.medicom-publishers.com/content/conference-reports/iacs-6274-is-well-tolerated-and-biologically-active-in-selected-advanced-tumours/

IACS-6274 is well tolerated and biologically active in selected ...

Results from a biomarker-driven phase 1 trial showed treatment with IACS-6274, a potent oral glutaminase-1 (GLS1) inhibitor, to be safe and ...

5.

sciencedirect.com

sciencedirect.com/science/article/abs/pii/S0006295225005404

Review Glutaminase 1 inhibitors: Therapeutic potential, ...

Glutaminase 1 (GLS1) is a critical enzyme in glutamine metabolism, supporting both energy production and biosynthesis in tumor cells.

6.

nursingcenter.com

nursingcenter.com/wkhlrp/Handlers/articleContent.pdf?key=pdf_00130989-202106200-00021

metabolic inhibitor iaCs-6274 shows antitumor Effects

The study was designed to evalu ate the safety and tolerability of IACS6274, identify the maximum tolerated dose, and establish a recommended Phase II dose.

7.

asco.org

asco.org/abstracts-presentations/ABSTRACT329737

First-in-human biomarker-driven phase I trial of the potent ...

IACS-6274 is a potent oral GLS1 inhibitor discovered at MD Anderson Cancer Center with excellent pharmacokinetics (PK) and antitumor activity in biomarker ...