IACS-6274 +/− Bevacizumab/Paclitaxel for Cancer

Recruiting in Palo Alto (17 mi)

Overseen by Timothy Yap

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: M.D. Anderson Cancer Center

Must not be taking: CYP3A4 inducers/inhibitors

Disqualifiers: Prior malignancy, CNS metastasis, others

No Placebo Group

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

To find the highest tolerable dose of IACS-6274 that can be given alone, in combination with bevacizumab and paclitaxel, or in combination with capivasertib to patients who have solid tumors. The safety and tolerability of the study drug(s) will also be studied.

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.

What data supports the effectiveness of the drug combination of IACS-6274, Bevacizumab, and Paclitaxel for cancer?

Research shows that combining paclitaxel and bevacizumab is effective in treating advanced breast cancer and non-small-cell lung cancer, suggesting a potential benefit when used together in other cancers. ^{1 2 3 4 5}

What is the safety profile of the cancer treatment involving IACS-6274, Bevacizumab, and Paclitaxel?

Bevacizumab, used in combination with chemotherapy, can cause side effects like high blood pressure, protein in urine, and bleeding, which are usually mild to moderate and manageable. However, serious side effects like gastrointestinal perforation, wound healing issues, and severe bleeding can occur, though they are less common. Paclitaxel, another component, is known to cause side effects such as low blood cell counts, hair loss, and nerve damage. ^{6 7 8 9 10}

What makes the drug IACS-6274 unique compared to other cancer treatments?

IACS-6274 is unique because it is being studied in combination with bevacizumab and paclitaxel, which are known to have a synergistic effect (work better together) in targeting cancer by inhibiting blood vessel growth and directly attacking cancer cells. This combination is being explored for its potential to enhance treatment effectiveness in cancers where standard options may be limited. ^{2 3 11 12 13}

Research Team

Timothy Yap

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

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

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

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

I am legally unable to make my own decisions.

Trial Timeline

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

Treatment Details

Interventions

• Bevacizumab (Anti-angiogenic Agent)
• IACS-6274 (Glutaminase Inhibitor)
• Paclitaxel (Antimicrotubule Agent)

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.

Participant Groups

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+

Dr. Peter WT Pisters

M.D. Anderson Cancer Center

Chief Executive Officer since 2017

MD from University of Western Ontario

Dr. Jeffrey E. Lee

M.D. Anderson Cancer Center

Chief Medical Officer

MD from Stanford University School of Medicine

Findings from Research

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 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]

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]

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) 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]

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 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]

References

1. Italy 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. [2022]

2. France 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. [2015]

3. United States 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. [2022]

4. United States 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. [2023]

5. United States 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. [2023]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Managing patients treated with bevacizumab combination therapy. [2015]

7. New Zealand pubmed.ncbi.nlm.nih.gov

Novel adverse events of bevacizumab in the US FDA adverse event reporting system database: a disproportionality analysis. [2022]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Safety and Efficacy of Bevacizumab in Cancer Patients with Inflammatory Bowel Disease. [2022]

9. England pubmed.ncbi.nlm.nih.gov

A pharmacovigilance study of adverse event profiles and haemorrhagic safety of bevacizumab based on the FAERS database. [2023]

10. England 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. [2022]

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

Phase II trial of paclitaxel, carboplatin, and bevacizumab for advanced or recurrent cervical cancer. [2019]

12. China pubmed.ncbi.nlm.nih.gov

[Acceptable safety of bevacizumab therapy in combination with chemotherapy in patients with advanced lung cancer.]. [2010]

13. Switzerland pubmed.ncbi.nlm.nih.gov

Diverticular Bleeding of the Colon during Combination Chemotherapy with Bevacizumab and Paclitaxel for Recurrent Breast Cancer. [2021]