Bevacizumab + Temsirolimus for Cancer

Overseen By Sarina Piha-Paul

Age: Any Age

Sex: Any

Trial Phase: Phase 1

Sponsor: M.D. Anderson Cancer Center

Must not be taking: CYP3A4 inducers/inhibitors

Disqualifiers: Unexplained bleeding, Hypertension, Cardiovascular disease, others

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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: Unknown

Duration: 4 weeks per course

155 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase I trial studies the side effects and best dose of bevacizumab and temsirolimus alone or in combination with valproic acid or cetuximab in treating patients with a malignancy that has spread to other places in the body or other disease that is not cancerous. Immunotherapy with bevacizumab and cetuximab, may induce changes in body's immune system and may interfere with the ability of tumor cells to grow and spread. Temsirolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as valproic acid, 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. It is not yet known whether bevacizumab and temsirolimus work better when given alone or with valproic acid or cetuximab in treating patients with a malignancy or other disease that is not cancerous.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications, but it does require that you are not taking any other investigational or anticancer agents. If you are taking drugs that affect CYP3A4 enzymes, you may need to stop and wait for a certain period before starting the trial.

What data supports the effectiveness of the drug combination Bevacizumab, Cetuximab, and Temsirolimus for cancer?

Research shows that Bevacizumab and Temsirolimus are active in treating advanced solid tumors, and Temsirolimus may help overcome resistance to Cetuximab and Bevacizumab. Additionally, Bevacizumab and Cetuximab are approved for treating metastatic colorectal cancer, improving survival and response rates. ^{1 2 3 4 5}

Is the combination of Bevacizumab and Temsirolimus safe for humans?

Bevacizumab, when used in combination with other treatments, has been generally well-tolerated in studies, with common side effects including high blood pressure, bleeding, and gastrointestinal issues. Cetuximab, another drug often used with Bevacizumab, can cause mild skin rashes and fatigue. While specific data on the combination of Bevacizumab and Temsirolimus is not provided, Bevacizumab's safety profile is well-documented in various cancer treatments. ^{5 6 7 8 9}

What makes the drug combination of Bevacizumab, Cetuximab, Temsirolimus, and Valproic Acid unique for cancer treatment?

This drug combination is unique because it combines multiple agents that target different pathways in cancer cells, potentially enhancing treatment effectiveness. Bevacizumab and Cetuximab target blood vessel growth and cell growth signals, while Temsirolimus and Valproic Acid may enhance these effects by inhibiting cancer cell metabolism and growth. ^{10 11 12 13 14}

Research Team

Sarina Piha-Paul, MD

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

This trial is for adults and children with advanced or metastatic cancer, or progressive benign diseases like LAM, NF type 2, Erdheim Chester disease. Participants must be in a certain health condition (Karnofsky >=60%, Lansky status >=60% for under 16s), not pregnant, using contraception, and have specific blood counts and organ function levels. They should not be on other cancer treatments or have had major surgery recently.

Inclusion Criteria

I can take care of myself and perform daily activities.

I have not had certain cancer treatments for a specific time before joining this trial.

Your platelet count is at least 50,000 per microliter.

Exclusion Criteria

You have had a bad reaction to temsirolimus or its ingredients in the past.

My colorectal cancer has a KRAS mutation.

I have not had major surgery in the last 6 weeks.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients receive temsirolimus, bevacizumab, and either valproic acid or cetuximab in a dose-escalation study to determine maximum tolerated doses and dose-limiting toxicities

4 weeks per course

Weekly visits for IV administration

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Long-term follow-up

Preliminary assessment of anti-tumor efficacy and pharmacokinetic markers

Up to 6 years

Treatment Details

Interventions

• Bevacizumab
• Cetuximab
• Temsirolimus
• Valproic Acid

Trial Overview The study tests the effects of Bevacizumab and Temsirolimus alone or combined with Valproic Acid or Cetuximab on various cancers and benign diseases. It aims to find the safest doses while assessing how these drugs affect tumor growth by altering immune responses or blocking enzymes needed for cell growth.

Participant Groups

Group I: Group III (temsirolimus, bevacizumab) Experimental Treatment 4 Interventions

Patients receive temsirolimus and bevacizumab as in Group I. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Group II: Group II (temsirolimus, bevacizumab, valproic acid) Experimental Treatment 5 Interventions

Patients receive temsirolimus and bevacizumab as in Group I and valproic acid PO on days 1-7 and 15-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Group III: Group I (temsirolimus, bevacizumab, cetuximab) Experimental Treatment 5 Interventions

Patients receive temsirolimus IV over 30-60 minutes on days 1, 8, 15, and 22; bevacizumab IV over 30-90 minutes on days 1 and 15; and cetuximab IV over 60-120 minutes on days 1, 8, 15, and 22. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Bevacizumab is already approved in European Union, United States, Japan, Canada for the following indications:

Approved in European Union as Avastin for:

• Colorectal cancer
• Breast cancer
• Non-small cell lung cancer
• Renal cell carcinoma
• Ovarian cancer

Approved in United States as Avastin for:

• Colorectal cancer
• Non-small cell lung cancer
• Glioblastoma
• Renal cell carcinoma
• Cervical cancer
• Ovarian cancer

Approved in Japan as Avastin for:

• Colorectal cancer
• Non-small cell lung cancer
• Breast cancer
• Renal cell carcinoma
• Ovarian cancer

Approved in Canada as Avastin for:

• Colorectal cancer
• Non-small cell lung cancer
• Breast cancer
• Renal cell carcinoma
• Ovarian cancer

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

Cetuximab, a monoclonal antibody targeting the EGFR, has been approved for first-line treatment of KRAS mutation-negative metastatic colorectal cancer (mCRC) in combination with FOLFIRI, showing significant improvements in progression-free survival and overall survival.

The combination of cetuximab with FOLFIRI also resulted in higher objective response rates compared to FOLFIRI alone, making it a valuable treatment option for patients with EGFR-expressing, KRAS wild-type mCRC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cetuximab: a guide to its use in combination with FOLFIRI in the first-line treatment of metastatic colorectal cancer in the USA. Lyseng-Williamson, KA.[2021]

In a phase I study involving 41 heavily pretreated patients with metastatic colorectal cancer, the combination of erlotinib, cetuximab, and bevacizumab was well tolerated, with 88% of patients able to handle the full FDA-approved doses without severe side effects.

The treatment showed promising antitumor activity, with 34% of patients achieving stable disease for at least 6 months or a partial response, indicating potential effectiveness in this challenging patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dual EGFR inhibition in combination with anti-VEGF treatment in colorectal cancer. Falchook, GS., Naing, A., Wheler, JJ., et al.[2022]

Bevacizumab, when combined with chemotherapy (like irinotecan/5-FU/leucovorin), significantly improves survival rates in patients with metastatic colorectal cancer, leading to its approval for first-line treatment.

While generally well-tolerated, bevacizumab can cause manageable side effects such as hypertension (3-16%) and other serious but less common toxicities, highlighting the need for guidelines on managing these risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Incidence and management of bevacizumab-related toxicities in colorectal cancer. Saif, MW., Mehra, R.[2022]

In a study of 6803 colorectal cancer patients aged 65 and older, bevacizumab (BEV) was found to significantly increase the risk of arterial thromboembolic events (ATEs) by 82%, indicating a notable cardiovascular risk associated with its use.

However, there was no observed increase in the risk of cardiac death or cardiomyopathy/congestive heart failure, suggesting that while BEV does pose some cardiovascular risks, these may be lower than previously reported in clinical trials, possibly due to careful patient selection.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bevacizumab use and risk of cardiovascular adverse events among elderly patients with colorectal cancer receiving chemotherapy: a population-based study. Tsai, HT., Marshall, JL., Weiss, SR., et al.[2022]

Temsirolimus enhances the effectiveness of cetuximab in treating colon cancer by reducing the levels of CIP2A, which helps cancer cells resist treatment, thus making them more susceptible to cetuximab.

The study found that temsirolimus not only inhibits CIP2A transcription but also promotes its degradation, and this mechanism is particularly effective in colon cancer cells without the K-ras codon 12 mutation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temsirolimus enhances the efficacy of cetuximab in colon cancer through a CIP2A-dependent mechanism. Wang, HW., Yang, SH., Huang, GD., et al.[2021]

References

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

Cetuximab: a guide to its use in combination with FOLFIRI in the first-line treatment of metastatic colorectal cancer in the USA. [2021]

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

Healthcare costs associated with bevacizumab and cetuximab in second-line treatment of metastatic colorectal cancer. [2015]

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

Symptom burden & quality of life among patients receiving second-line treatment of metastatic colorectal cancer. [2021]

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

Advanced malignancies treated with a combination of the VEGF inhibitor bevacizumab, anti-EGFR antibody cetuximab, and the mTOR inhibitor temsirolimus. [2018]

5. England pubmed.ncbi.nlm.nih.gov

Bevacizumab and cetuximab for colorectal cancer. [2015]

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

Dual EGFR inhibition in combination with anti-VEGF treatment in colorectal cancer. [2022]

7. England pubmed.ncbi.nlm.nih.gov

Incidence and management of bevacizumab-related toxicities in colorectal cancer. [2022]

8. France pubmed.ncbi.nlm.nih.gov

[Inhibitors of epidermal growth factor receptor and colorectal cancer]. [2018]

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

Bevacizumab use and risk of cardiovascular adverse events among elderly patients with colorectal cancer receiving chemotherapy: a population-based study. [2022]

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

Plasma Protein Biomarkers in Advanced or Metastatic Colorectal Cancer Patients Receiving Chemotherapy With Bevacizumab or Cetuximab: Results from CALGB 80405 (Alliance). [2023]

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

Clinical activity and safety of combination therapy with temsirolimus and bevacizumab for advanced melanoma: a phase II trial (CTEP 7190/Mel47). [2022]

12. England pubmed.ncbi.nlm.nih.gov

Design paper: a phase II study of bevacizumab and erlotinib in patients with non-squamous non-small cell lung cancer that is refractory or relapsed after 1-2 previous treatment (BEST). [2021]

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

Phase 1 and pharmacodynamic trial of everolimus in combination with cetuximab in patients with advanced cancer. [2021]

14. Germany pubmed.ncbi.nlm.nih.gov

Temsirolimus enhances the efficacy of cetuximab in colon cancer through a CIP2A-dependent mechanism. [2021]