Cyclophosphamide + Sirolimus for Advanced Thyroid Cancer

Overseen by Paul Swiecicki

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: University of Michigan Rogel Cancer Center

Must not be taking: CYP3A4 inhibitors, P-glycoprotein inducers

Disqualifiers: GI impairment, Uncontrolled disorders, others

No Placebo Group

Prior Safety Data

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

This trial uses two drugs, Cyclophosphamide and Sirolimus, to treat patients with thyroid cancer that has spread. Cyclophosphamide kills cancer cells by breaking their DNA, while Sirolimus stops them from growing. Sirolimus has been used in various treatments and has shown effectiveness against different cancers. Patients are monitored for side effects and effectiveness.

Will I have to stop taking my current medications?

The trial requires that you stop taking any strong inhibitors or inducers of CYP3A4 or P-glycoprotein at least one week before starting the study medications. If you are on these types of medications, you will need to discontinue them.

What data supports the effectiveness of the drug combination Cyclophosphamide and Sirolimus for advanced thyroid cancer?

A retrospective study suggests that combining sirolimus, an mTOR inhibitor, with cyclophosphamide, a cytotoxic agent, may offer a promising alternative treatment for advanced differentiated thyroid cancers, indicating potential effectiveness. ^{1 2 3 4 5}

What safety data exists for Cyclophosphamide and Sirolimus in humans?

Cyclophosphamide has been associated with risks of long-term side effects such as heart problems, hormone issues, secondary cancers, and bone damage, especially when used in high doses or over long periods. Sirolimus, while not specifically mentioned in the provided studies, is generally known to have side effects like increased risk of infection and potential kidney issues. ^{6 7 8 9 10}

How is the drug combination of Cyclophosphamide and Sirolimus unique for advanced thyroid cancer?

This drug combination is unique because it pairs sirolimus, an mTOR inhibitor that blocks a pathway cancer cells use to grow, with cyclophosphamide, a well-known chemotherapy drug, offering a potentially well-tolerated and promising alternative for advanced thyroid cancer compared to traditional chemotherapy options. ^{2 3 11 12 13}

Research Team

Paul Swiecicki

Principal Investigator

University of Michigan Rogel Cancer Center

Eligibility Criteria

This trial is for adults over 18 with advanced thyroid cancer that's spread and doesn't respond to radioactive iodine treatment. They should be able to perform daily activities (ECOG 0-2), not have had certain treatments recently, and must agree to follow the study plan. Pregnant or breastfeeding women, those unable to use contraception, and individuals with specific health issues or sensitivities to the drugs tested are excluded.

Inclusion Criteria

My thyroid cancer cannot be cured by surgery or I have chosen not to undergo curative treatment.

My cancer has grown despite treatment, and I have a tumor larger than 10 mm.

My organs and bone marrow are working well.

Exclusion Criteria

People who are in jail or prison.

Prior experimental therapy within 4 weeks of planned start of this trial

I do not have any serious health issues or infections that would stop me from receiving the study treatment.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Sirolimus 4 mg, PO, days 1-28 and Cyclophosphamide 100 mg, PO, days 1-5 and 15-19 in 28-day cycles

Up to 2 years

Imaging every 2 cycles

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 2 years

Toxicity Monitoring

Participants are monitored for toxicity up to 30 days after the last dose of study drug

30 days

Treatment Details

Interventions

• Cyclophosphamide (Alkylating agents)
• Sirolimus (mTOR inhibitor)

Trial Overview The trial tests Cyclophosphamide and Sirolimus in patients with metastatic differentiated thyroid cancer. It's a non-randomized pilot study where participants take Sirolimus daily for 28 days and Cyclophosphamide on specified days within this cycle. The effectiveness is checked every two cycles through imaging.

Participant Groups

Group I: Cyclophosphamide and Sirolimus Experimental Treatment 2 Interventions

Sirolimus 4 mg, PO, days 1-28 as well as Cyclophosphamide 100 mg, PO, days 1-5 and 15-19

Cyclophosphamide is already approved in Canada, Japan for the following indications:

Approved in Canada as Neosar for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in Japan as Endoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma

Who Is Running the Clinical Trial?

University of Michigan Rogel Cancer Center

Lead Sponsor

Trials

303

Recruited

20,700+

Marschall S. Runge

University of Michigan Rogel Cancer Center

Chief Executive Officer since 2015

MD, PhD

Eric R. Fearon

University of Michigan Rogel Cancer Center

Chief Medical Officer since 2016

MD, PhD

Findings from Research

Well-differentiated thyroid carcinoma can be effectively treated with surgery and thyroid hormone therapy, often combined with radioiodine therapy, while some patients with more aggressive forms may benefit from chemotherapy.

Doxorubicin has shown effectiveness in treating thyroid carcinoma, but multiple-agent chemotherapy has only slightly better response rates than doxorubicin alone, highlighting the need for a collaborative approach in evaluating treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adjunctive management of thyroid cancer: chemotherapy. Shimaoka, K.[2019]

The combination of sirolimus and cyclophosphamide showed a one-year progression-free survival rate of 45% in patients with advanced differentiated thyroid cancers, which is higher than the 30% rate in the standard care comparison group, suggesting it may be a promising treatment option.

Patients receiving the sirolimus and cyclophosphamide combination experienced fewer average toxicities (0.87) compared to those on standard care (1.71), indicating that this treatment may be better tolerated.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Retrospective Study of Sirolimus and Cyclophosphamide in Patients with Advanced Differentiated Thyroid Cancers. Manohar, PM., Beesley, LJ., Taylor, JM., et al.[2020]

In a study of 29 patients with advanced thyroid cancer, etoposide, carboplatin, and cis-platinum were found to be active treatments, with etoposide showing the highest response rate and one complete response observed.

Patients under 65 years and those with medullary carcinoma had better response rates, and overall mean survival was 11.9 months, with responders living significantly longer (19 months) compared to non-responders (5.4 months).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chemotherapy for thyroid cancer. Hoskin, PJ., Harmer, C.[2019]

Doxorubicin is currently the most effective chemotherapy for metastatic differentiated thyroid carcinoma, but it has limited effectiveness with rare complete responses and significant toxicity.

Newer agents like pemetrexed may offer better tolerance and potential benefits, highlighting the need for improved trial designs and patient recruitment to enhance treatment options for thyroid cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cytotoxic chemotherapy for differentiated thyroid carcinoma. Sherman, SI.[2022]

In a phase 2 study involving 36 patients with radioactive iodine-refractory thyroid carcinoma, the combination of sorafenib and temsirolimus resulted in a partial response rate of 22%, indicating improved efficacy compared to sorafenib alone, which had a response rate of only 12.2%.

The combination treatment showed a progression-free survival rate of 30.5% at one year, particularly benefiting patients who had not received prior systemic treatments, suggesting that this regimen could be a promising option for this challenging patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 2 study evaluating the combination of sorafenib and temsirolimus in the treatment of radioactive iodine-refractory thyroid cancer. Sherman, EJ., Dunn, LA., Ho, AL., et al.[2018]

In a phase II study involving 15 patients with non-Hodgkin's lymphoma (NHL) who had previously failed chemotherapy, the DHAOx regimen (dexamethasone, high-dose ara-C, and oxaliplatin) resulted in a 53% complete response rate, indicating its potential efficacy as a salvage treatment.

DHAOx demonstrated a favorable safety profile, with no increase in serum creatinine levels, suggesting low renal toxicity, and manageable side effects like myelosuppression and transient sensory peripheral neuropathy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dexamethasone, high-dose cytarabine, and oxaliplatin (DHAOx) as salvage treatment for patients with initially refractory or relapsed non-Hodgkin's lymphoma. Machover, D., Delmas-Marsalet, B., Misra, SC., et al.[2020]

In the Euro-EWING99-R1 trial, cyclophosphamide was found to be as effective as ifosfamide for treating standard-risk Ewing sarcoma, with similar 10-year event-free survival rates of 93% for VAC and 95% for VAI.

However, patients treated with ifosfamide (VAI) experienced significantly higher kidney toxicity (43.0% vs 25.7% for VAC), highlighting the need to manage cumulative doses of alkylating agents to reduce long-term side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Late toxicity comparison of alkylating-based maintenance regimen with cyclophosphamide (VAC) vs ifosfamide (VAI) in Ewing sarcoma survivors treated in the randomized clinical trial Euro-EWING99-R1 in France. Corvest, V., Marec-Bérard, P., Lervat, C., et al.[2023]

The hyper-CVAD regimen, which includes cyclophosphamide, vincristine, doxorubicin, and dexamethasone, has shown significant effectiveness in treating adult lymphocytic leukemia and other blood cancers, such as Burkitt's disease and multiple myeloma.

Clinical trials conducted at the University of Texas M. D. Anderson Cancer Center have provided strong evidence for the efficacy of hyper-CVAD, leading to ongoing discussions about strategies to enhance treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The hyper-CVAD regimen in adult acute lymphocytic leukemia. Garcia-Manero, G., Kantarjian, HM.[2019]

The CHOP chemotherapy regimen used for treating post-transplant lymphoproliferative disease (PTLD) is associated with significant long-term health risks, including cardiac toxicity, hormone deficiencies, secondary leukemia, and osteonecrosis, affecting a high percentage of pediatric patients.

There is a dose-dependent increase in the risk of these long-term consequences, highlighting the urgent need for safer and more effective treatment options for PTLD that minimize these adverse effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A review of the risks of long-term consequences associated with components of the CHOP chemotherapy regimen. Watson, C., Gadikota, H., Barlev, A., et al.[2022]

A study involving 108 patients with refractory or relapsing multiple myeloma found that a single high dose of cyclophosphamide (2400 mg/m2) was more toxic and did not improve treatment response compared to standard dosing over four days.

Adding vincristine (1.4 mg/m2) at a specific time after cyclophosphamide did not enhance the treatment's effectiveness, showing no significant differences in response rates or survival between the treatment groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Timed-sequential high-dose cyclophosphamide and vincristine in the treatment of multiple myeloma. Lenhard, RE., Kalish, LA., Oken, MM., et al.[2019]

Adriamycin and bleomycin have shown definite activity against advanced thyroid carcinoma, making them the most studied agents for this condition.

Many other single agents and drug combinations were reviewed, but due to low patient enrollment in studies, meaningful statistical analysis was not possible; ongoing cooperative group protocols aim to improve patient accrual for better insights.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Current status of chemotherapy in the treatment of advanced carcinoma of the thyroid gland. Poster, DS., Bruno, S., Penta, J., et al.[2004]

In a study of 11 patients with metastatic thyroid cancer treated with a combination of chemotherapy drugs, 6 patients showed a response, including one complete response that has lasted over 60 months.

While most responses were short-lived (2-3 months), the treatment was associated with moderate toxicity, primarily affecting blood cell counts, indicating that while chemotherapy can be effective, careful monitoring for side effects is necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination chemotherapy of metastatic thyroid cancer. Phase II study. Bukowski, RM., Brown, L., Weick, JK., et al.[2022]

In a study of 49 patients with metastatic nonanaplastic thyroid carcinoma treated over 10 years, only 3% showed any objective response to five different chemotherapy protocols, indicating very low efficacy of these treatments.

The disappointing results suggest a need for further research, specifically Phase II trials with new chemotherapeutic agents for this type of cancer, to explore potentially more effective treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chemotherapy in metastatic nonanaplastic thyroid cancer: experience at the Institut Gustave-Roussy. Droz, JP., Schlumberger, M., Rougier, P., et al.[2022]

References

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

Adjunctive management of thyroid cancer: chemotherapy. [2019]

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

Retrospective Study of Sirolimus and Cyclophosphamide in Patients with Advanced Differentiated Thyroid Cancers. [2020]

3. Ireland pubmed.ncbi.nlm.nih.gov

Chemotherapy for thyroid cancer. [2019]

4. England pubmed.ncbi.nlm.nih.gov

Cytotoxic chemotherapy for differentiated thyroid carcinoma. [2022]

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

Phase 2 study evaluating the combination of sorafenib and temsirolimus in the treatment of radioactive iodine-refractory thyroid cancer. [2018]

6. England pubmed.ncbi.nlm.nih.gov

Dexamethasone, high-dose cytarabine, and oxaliplatin (DHAOx) as salvage treatment for patients with initially refractory or relapsed non-Hodgkin's lymphoma. [2020]

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

Late toxicity comparison of alkylating-based maintenance regimen with cyclophosphamide (VAC) vs ifosfamide (VAI) in Ewing sarcoma survivors treated in the randomized clinical trial Euro-EWING99-R1 in France. [2023]

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

The hyper-CVAD regimen in adult acute lymphocytic leukemia. [2019]

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

A review of the risks of long-term consequences associated with components of the CHOP chemotherapy regimen. [2022]

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

Timed-sequential high-dose cyclophosphamide and vincristine in the treatment of multiple myeloma. [2019]

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

Current status of chemotherapy in the treatment of advanced carcinoma of the thyroid gland. [2004]

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

Combination chemotherapy of metastatic thyroid cancer. Phase II study. [2022]

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

Chemotherapy in metastatic nonanaplastic thyroid cancer: experience at the Institut Gustave-Roussy. [2022]