Combination Chemotherapy for Advanced Cancer

Age: Any Age

Sex: Any

Trial Phase: Phase 1

Sponsor: M.D. Anderson Cancer Center

Must not be taking: P450 3A4 inducers/inhibitors

Disqualifiers: Uncontrolled 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: 1

Duration: 56 days

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to find the highest safe dose of a combination of cancer drugs, including bevacizumab (Avastin), temsirolimus (Torisel), and one of three other drugs: carboplatin (Paraplatin), paclitaxel (Taxol), or sorafenib (Nexavar). The main goal is to assess how well these drugs work together and their safety for people with advanced cancer that hasn't responded to standard treatments. The trial seeks participants whose cancer has either returned or hasn't improved significantly with other treatments. Those with advanced cancer that hasn't improved with other treatments might be a good fit. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering a chance to be among the first to receive this combination therapy.

Will I have to stop taking my current medications?

The trial requires that you stop taking previous chemotherapy or radiotherapy for three weeks before joining, and six weeks if the therapy has delayed toxicity. Additionally, medications that strongly affect the enzyme P450 3A4 should be avoided within five half-lives of temsirolimus.

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

Various studies have shown that bevacizumab (Avastin) is generally well-tolerated for treating certain cancers, such as colorectal and lung cancer. Temsirolimus (Torisel), approved for kidney cancer, also has a known safety profile. Reports indicate that combining these drugs can be effective, though side effects may occur.

Carboplatin, often used with paclitaxel, is a common chemotherapy treatment with usually manageable side effects. Combining carboplatin with bevacizumab and paclitaxel has improved survival in lung cancer, demonstrating that these drugs can work together safely.

Sorafenib, used for kidney and liver cancer, has been tested with temsirolimus and bevacizumab. The side effects of sorafenib align with typical cancer treatments and are considered acceptable.

This study is in its early phase, focusing on identifying the safest and most effective dose combinations. Safety remains a primary concern, and researchers will closely monitor any serious side effects. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for advanced cancer because they combine multiple drugs that target cancer in unique ways. Bevacizumab, a part of each treatment group, inhibits blood vessel growth in tumors, starving them of nutrients. Sorafenib and Temsirolimus add layers of action by blocking specific proteins and pathways that cancer cells use to grow and multiply. This multi-pronged attack is different from most standard treatments, which typically focus on a single approach. These combinations hold promise for more effective control of cancer progression.

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

This trial will evaluate different combinations of treatments for advanced cancer. One group will receive a combination of bevacizumab, temsirolimus, and carboplatin. Research has shown that this combination can extend the lives of patients with advanced cancers. Bevacizumab, often used for colorectal and lung cancers, works by cutting off the blood supply to tumors. Temsirolimus, used for kidney cancer, stops cancer cells from growing. Another group will receive paclitaxel instead of carboplatin, as studies have found that both carboplatin and paclitaxel are effective for some cancers, such as lung cancer. A third group will receive sorafenib, which targets proteins that help cancer cells grow, in combination with bevacizumab and temsirolimus. Overall, these drug combinations have shown promise in treating various advanced cancers. ^{1 2 3 6 7}

Who Is on the Research Team?

Shannon Westin, MD

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults with advanced or metastatic cancer that's resistant to standard treatments, relapsed, or without beneficial standard options. Participants must have stable vital signs and organ function, not be on other experimental drugs, and agree to use contraception. Excluded are pregnant women, those with recent surgery or significant cardiovascular issues, uncontrolled hypertension, certain allergies to the study drugs or their components.

Inclusion Criteria

I can take care of myself but might not be able to do active work.

My organs are functioning normally.

Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria

I have a serious heart condition.

History of hypersensitivity to specific medications or components

I am not taking strong drugs that affect liver enzyme P450 3A4 within a certain period before starting temsirolimus.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a combination of bevacizumab and temsirolimus with either carboplatin, paclitaxel, or sorafenib. The treatment cycles are 21 or 28 days long, depending on the drug combination.

56 days

Visits on Days 1, 8, and 15 of each cycle

Dose Escalation

Participants are assigned to dose levels to determine the maximum tolerated dose. Dose escalation continues until the highest tolerable dose is found.

Variable

Follow-up

Participants are monitored for safety and effectiveness after treatment. CT or MRI scans are performed every 2-3 cycles, and after 6 months, every 4 cycles if deemed necessary.

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Bevacizumab
• Carboplatin
• Paclitaxel
• Sorafenib
• Temsirolimus

Trial Overview Researchers are testing the highest dose of Bevacizumab (Avastin) and Temsirolimus (Torisel) that can be safely given with one of three other drugs: Carboplatin (Paraplatin), Paclitaxel (Taxol), or Sorafenib (Nexavar). The aim is to determine safety and tolerability of these combinations in treating advanced cancers.

How Is the Trial Designed?

Group I: Sorafenib Group Experimental Treatment 3 Interventions

Sorafenib: Starting dose 200 mg by mouth daily for a 21 day cycle. Temsirolimus: Starting dose 12.5 mg by vein given on day 1, 8, and 15 of a 21 day cycle. Bevacizumab: Starting dose 5 mg/kg given by vein on day 1 of a 21 day cycle.

Group II: Paclitaxel Group Experimental Treatment 3 Interventions

Paclitaxel: Starting dose 30 mg/m2 given by vein on day 1 of a 21 day cycle. Temsirolimus: Starting dose 12.5 mg by vein given on day 1, 8, and 15 of a 21 day cycle. Bevacizumab: Starting dose 5 mg/kg given by vein on day 1 of a 21 day cycle.

Group III: Carboplatin Group Experimental Treatment 3 Interventions

Carboplatin: Starting dose AUC 2 by vein on day 1 of a 21 day cycle. Temsirolimus: Starting dose 12.5 mg by vein given on day 1, 8, and 15 of a 21 day cycle. Bevacizumab: Starting dose 5 mg/kg given by vein on day 1 of a 21 day cycle.

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+

Published Research Related to This Trial

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]

Patients with metastatic colorectal cancer (mCRC) receiving antiangiogenic agents like aflibercept and bevacizumab alongside chemotherapy may face a range of toxicities from both treatments, including hypertension and nausea.

Effective management of these toxicities through evidence-based interventions and patient education can enhance treatment outcomes and improve the quality of life for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Managing toxicities associated with antiangiogenic biologic agents in combination with chemotherapy for metastatic colorectal cancer. Grenon, NN.[2013]

In a phase III trial involving 1,043 patients with advanced nonsquamous non-small-cell lung cancer, the combination of bevacizumab with cisplatin and gemcitabine significantly improved progression-free survival (PFS) compared to placebo, with hazard ratios of 0.75 for low-dose and 0.82 for high-dose bevacizumab.

The treatment also resulted in higher objective response rates (34.1% for low-dose and 30.4% for high-dose bevacizumab) compared to placebo (20.1%), while maintaining a similar incidence of serious adverse events across all treatment groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer: AVAil. Reck, M., von Pawel, J., Zatloukal, P., et al.[2022]

Cytoreductive surgery followed by platinum-based chemotherapy, particularly with carboplatin, remains the standard treatment for advanced epithelial ovarian cancer, but most patients are not cured, highlighting the need for improved therapies.

Paclitaxel, a novel agent effective in platinum-resistant ovarian cancer, is being tested in combination with platinum compounds in clinical trials for previously untreated patients, aiming to enhance treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of ovarian cancer: current status. Ozols, RF.[2015]

In a study involving 247 patients with advanced ovarian cancer, both treatment regimens (standard carboplatin plus paclitaxel and alternating carboplatin/cisplatin plus paclitaxel) showed similar efficacy, with no significant differences in progression-free survival (PFS) or overall survival.

Both regimens were well tolerated, indicating that while the alternating regimen does not provide additional benefits, it is a safe option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Paclitaxel plus carboplatin versus paclitaxel plus alternating carboplatin and cisplatin for initial treatment of advanced ovarian cancer: long-term efficacy results: a Hellenic Cooperative Oncology Group (HeCOG) study. Aravantinos, G., Fountzilas, G., Kosmidis, P., et al.[2022]

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 study of 59 elderly patients (aged 70 and above) with metastatic colorectal cancer, the combination of capecitabine and bevacizumab resulted in a 34% overall response rate and 71% disease control, indicating its efficacy as a treatment option.

While the treatment was generally effective, 54% of patients experienced grade 3/4 adverse events, with some serious complications, highlighting the need for careful monitoring, especially in patients with lower kidney function.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Capecitabine and bevacizumab as first-line treatment in elderly patients with metastatic colorectal cancer. Feliu, J., Safont, MJ., Salud, A., et al.[2022]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT01187199

Phase I Trial of Bevacizumab and Temsirolimus in ... Bevacizumab is FDA approved for the treatment of colorectal cancer and a type of lung cancer. Temsirolimus is FDA approved for the treatment of kidney cancer ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/29804638/

A phase II study of frontline paclitaxel/carboplatin ... - PubMed Paclitaxel and carboplatin (PC) is a standard initial therapy for advanced endometrial cancer. We evaluated the efficacy and tolerability of incorporating ...

3. withpower.com withpower.com/trial/phase-1-neoplasms-7-2010-195f6

Combination Chemotherapy for Advanced Cancer The combination of Bevacizumab, Carboplatin, and Paclitaxel has been shown to improve overall survival in patients with advanced non-small cell lung cancer, as ...

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

Phase II trial of combination bevacizumab and ... This two-stage phase II study was designed to assess the activity of the combination of temsirolimus and bevacizumab in patients with recurrent or ...

5. ascopubs.org ascopubs.org/doi/10.1200/jco.2015.33.15_suppl.5500

A randomized phase II study of paclitaxel/carboplatin ... We evaluated efficacy and tolerability of incorporating three novel agents into initial therapy. Methods: Patients (pts) had received no prior ...

6. sciencedirect.com sciencedirect.com/science/article/pii/S1040842824002981

First-line treatments for advanced or recurrent endometrial ... A systematic literature review was conducted to evaluate the efficacy and safety of first-line treatments for advanced/recurrent EC.

7. frontiersin.org frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2023.1163805/full

Efficacy and safety of bevacizumab in patients with ... This study showed that bevacizumab combined with chemotherapy might be effective and well-tolerated in patients with stage III or IV unresectable malignant ...