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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine the optimal dose and understand any side effects of a drug combination, including bevacizumab (Avastin), temsirolimus, valproic acid, and cetuximab, for treating cancers that have spread or other serious diseases. These treatments target cancer cells directly or enhance the body's immune response. The trial is suitable for individuals with advanced cancer or serious non-cancerous diseases unresponsive to standard treatments. Participants should not have recent unexplained bleeding or certain heart issues and must be off other investigational drugs. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants a chance to be among the first to receive potentially groundbreaking therapies.

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.

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

Research shows that using temsirolimus and bevacizumab together is generally feasible for patients. However, some studies have found this combination can have a poor safety profile, with common side effects like digestive problems and infections. When temsirolimus, bevacizumab, and valproic acid are combined, early findings suggest feasibility, but several side effects require careful monitoring.

Studies have tested the combination of temsirolimus, bevacizumab, and cetuximab on patients with advanced solid tumors. While no major safety issues emerged, it still requires close monitoring.

Since the trial is in its early stages, the main goal is to determine the best dosage and check for side effects. While some evidence exists on how each combination might be tolerated, the safety information remains incomplete. Participants should be aware of potential risks and discuss them in detail with their healthcare provider. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because they combine bevacizumab, temsirolimus, cetuximab, and valproic acid, each with unique effects against cancer. Bevacizumab, a monoclonal antibody, inhibits blood vessel growth in tumors, cutting off their nutrient supply. Temsirolimus, an mTOR inhibitor, disrupts cell growth and proliferation. Cetuximab targets and blocks the epidermal growth factor receptor (EGFR), which is overexpressed in many cancers, hindering cancer cell survival. Valproic acid, typically a mood stabilizer, is believed to enhance the effects of other cancer treatments by altering gene expression. This multi-pronged approach targets cancer cells in several ways, potentially offering a more comprehensive treatment strategy than current standards.

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

Research has shown that using bevacizumab and temsirolimus together can help treat advanced cancers. In this trial, participants in Group III will receive this combination. One study found that 24.5% of patients experienced a positive response, with their cancer either shrinking or stopping its growth. Nearly half of the patients did not see their cancer worsen for a significant period.

Participants in Group II will receive bevacizumab, temsirolimus, and valproic acid. Adding valproic acid has shown some effectiveness, but it requires careful handling due to possible side effects.

Meanwhile, Group I will receive the combination of bevacizumab, temsirolimus, and cetuximab, which has been active in treating some cancers, such as head and neck cancer, though side effects need close monitoring. Overall, these drugs work by stopping cancer cells from growing and may help prevent tumors from spreading. ^{6 7 8 9 10}

Who Is on the Research Team?

Sarina Piha-Paul, MD

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

Citations

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A Phase I Trial of Bevacizumab and Temsirolimus in ... - PubMed Combination therapy with bevacizumab, temsirolimus, and valproic acid was feasible, but there were numerous toxicities, which will require careful management.

2. clinicaltrials.gov clinicaltrials.gov/study/NCT01187199

Phase I Trial of Bevacizumab and Temsirolimus in ... Temsirolimus is designed to block the growth of cancer cells, which may eventually cause the cancer cells to die.

3. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/24297945/

Randomized phase III trial of temsirolimus and ... Patients receiving temsirolimus/bevacizumab reported significantly higher overall mean scores in the Functional Assessment of Cancer Therapy- ...

4. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0090825812009705

Phase II trial of combination bevacizumab and ... Twelve patients (24.5%) experienced clinical responses (one complete and 11 partial responses), and 23 patients (46.9%) survived progression free for at least ...

5. aacrjournals.org aacrjournals.org/clincancerres/article/19/13/3611/208507/Clinical-Activity-and-Safety-of-Combination

Clinical Activity and Safety of Combination Therapy with ... This study provides evidence for clinical activity of combination temsirolimus and bevacizumab in patients with advanced metastatic melanoma, particularly in ...

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A PHASE 2 CONSORTIUM STUDY - PMC Conclusions. Temsirolimus and Bevacizumab is a feasible combination in patients with advanced RCC previously exposed to oral anti-VEGF agents. The safety and ...

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Combination of Temsirolimus and Bevacizumab in Patient ... This is a phase II, open label, randomized, parallel group, multicenter study evaluating first-line treatment of patients with metastatic renal cancer using a ...

8. ascopubs.org ascopubs.org/doi/10.1200/jco.2011.29.15_suppl.4548

Final phase II safety and efficacy results of study MC0452 We previously reported the phase I safety and initial efficacy results of temsirolimus (T) +bevacizumab (B) in RTKI naïve stage IV RCC patients (pts) (J Clin ...

9. pfizer.com pfizer.com/news/press-release/press-release-detail/pfizer_reports_results_from_phase_3_study_of_torisel_temsirolimus_in_combination_with_bevacizumab_in_advanced_renal_cell_carcinoma_rcc

Pfizer Reports Results From Phase 3 Study Of Torisel ... The study outcome, involving combination therapy, does not change the safety and efficacy relationship of single-agent TORISEL for advanced RCC ...

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Combination bevacizumab plus temsirolimus for second- ... The safety profile of the combination was poor, and the most frequently reported adverse events were metabolic, gastrointestinal, and infections, leading to a ...